Category: The Pipeline Blog

Author: Colin McArdle
Editor: Michaela Price, PhD

Although typically mischaracterized as just a ‘strong headache’, migraines are a chronic neurological disorder that affect approximately 15% of people worldwide.¹ While symptoms are heterogeneous between individuals, migraine attacks typically present with extreme head throbbing, dizziness, fatigue, nausea, and confusion.² These symptoms are often preceded by an aura, where patients experience visual and/or sensory distortions.²  The onset of a migraine is extremely sensitive to environmental triggers that include changes in air pressure, light, air quality, as well as odors.³ In addition, lifestyle choices can also exacerbate the frequency of migraine attacks including inadequate sleep, diet, and physical activity.⁴ Although risk factors for migraines are identifiable and modifiable, there is still unfortunately no cure. Despite this, scientists and clinicians are still actively investigating the biological mechanisms of migraines to further improve treatment efficacy.

Migraine Pathophysiology: An Interplay Between the Trigeminal Nerve & Calcitonin Gene-Related Peptide (CGRP)

The onset of migraine-related symptoms stem from heightened trigeminal nerve activity, which can be triggered by the lifestyle and environmental factors noted before.⁵ Originating from the brainstem, the trigeminal nerve sends neural projections to facial regions that specifically detect touch, pain, and temperature sensations.⁵ During a migraine, the trigeminal nerve releases neuropeptides – or chemical signals – that initiate downstream effects that result in pain-related symptoms.⁶ One neuropeptide in particular, calcitonin gene-related peptide (CGRP), has been highly characterized in the involvement of migraine pathophysiology.⁵ How exactly does CGRP cause migraine-related symptoms? The answer can be outlined through three different mechanisms: cerebral vasodilation, neurogenic inflammation, and central pain sensitization (Figure 1).⁷

The first mechanism, cerebral vasodilation, or the increase in diameter of blood vessels that cover the brain, is thought to cause the intense throbbing sensations during a migraine.⁸ The expansion and constriction of blood vessels is regulated by a specific CGRP receptor that resides on the surrounding smooth muscle. When CGRP binds to its receptors, a series of downstream effects elevate levels of small molecules such as cyclic AMP (cAMP) and nitric oxide (NO), which further relaxes the smooth muscle, increasing vessel diameter and blood flow.⁹

The second mechanism, neurogenic inflammation, or inflammatory responses triggered by neuronal activity, results in the circulation of inflammatory regulators that exacerbate migraine-related pathology.¹⁰ This negative cascade of events can be traced back to a specific immune cell-type called a mast cell, which resides in the meningeal layer surrounding the brain.¹¹ Similar to the smooth muscles on the cerebral blood vessels, mast cells also express receptors that are specific towards CGRP. Once CGRP is bound to its receptor, mast cells release their intracellular components into the extracellular space through a process known as degranulation.¹¹ Some of these intracellular components include inflammatory regulators, such as histamines and prostaglandins, which can induce an immune response. Both histamines and prostaglandins can bind to their respective receptors on cerebral blood vessels and nerve endings to either increase vasodilation or the sensitization of pain pathways during a migraine.¹¹

The third mechanism, central pain sensitization, arises from heightened activity of the pain pathways in the central nervous system (CNS).¹² This process is regulated by specific pain-sensing neurons, or nociceptors, that are triggered by both CGRP release and neuroinflammatory regulators, such as histamines and prostaglandins. All three of these neurochemicals can directly activate and potentiate nociceptor signaling, resulting in the localization and perception of pain throughout the facial regions.¹²

Understanding the Current Acute & Preventative Treatments for Migraines

The current list of migraine treatments approved by the Food and Drug Administration (FDA) can be classified into two categories: acute and preventative.¹³ Acute treatments are designed to alleviate and abort symptoms during the onset of a migraine. This includes specific drug classes such as ergots, triptans, ditans, gepants, non-steroidal anti-inflammatory drugs (NSAIDS), and steroids (Figure 2).

Triptans, ergots, and ditans all work by binding and activating 5-hydroxytryptamine (5-HT) serotonin receptors. What makes them different? Triptans, which include Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, Almotriptan, Frovatriptan, and Eletriptan, are highly selective towards 5-HT_1B and 5-HT_1D receptor subtypes that reside predominantly along the pain signaling pathways.¹⁴ Localized presynaptically along the axon terminal, 5-HT_1B/1D receptor activation diminishes the release of CGRP from the trigeminal nerve, preventing downstream vasodilation, pain sensitization, and neurogenic inflammation. Additionally, triptans can bind to 5-HT_1B/1D receptors on the smooth muscle surrounding cerebral blood vessels, causing vasoconstriction, or the decrease in vessel diameter.¹⁴ Ergots, which include dihydroergotamine and ergotamine, work similarly to triptans but are non-selective and bind to all 5-HT receptors in the body. Unfortunately, due to its non-specificity, ergots typically result in more side effects that include nausea and vomiting.¹⁵ Ditans, which include lasmiditan, are highly selective towards activating 5-HT_1F receptors localized only on trigeminal nerve terminals, not blood vessels. Furthermore, ditans prevent the release of CGRP without causing vasoconstriction.¹⁶

Gepants, which include Rimegepant, Ubrogepant, Vazegepant, Zavegepant, work by blocking CGRP signaling in the brain. Acting as CGRP receptor antagonists, gepants selectively bind to their receptors to further mitigate vasodilation, inflammation, and pain signaling.¹⁷ Both NSAIDS and steroids are designed to combat neurogenic inflammation. NSAIDS, including ibuprofen, aspirin, and celecoxib, all selectively antagonize the immune response by inhibiting the enzymes responsible for converting arachidonic acid into prostaglandins, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2).¹⁸  Decreasing neurogenic inflammation by inhibiting the production of prostaglandin further alleviates migraine-related pathophysiology via two mechanisms: 1) diminishing prostaglandin receptor activation on blood vessels to prevent vasodilation and 2) mitigating the sensitization of nociceptors to downregulate pain signaling.¹⁸ Steroids, which include dexamethasone, also combat the downstream effects of inflammation alongside NSAIDS.¹⁹

The other form of treatment, preventative, is designed to decrease the onset of future migraines.¹³ This includes specific drug classes such as beta blockers, anticonvulsants, monoclonal antibodies, botulinum toxin, and antidepressants (Figure 3). Beta blockers, which include propranolol, timolol, and metoprolol, are designed to block β-adrenoceptors that reside on cerebral blood vessels. β-adrenoceptor activation normally results in vasodilation, so utilizing beta blockers as antagonists would cause vasoconstriction to counter the migraine-related pain.²⁰ Anticonvulsants, such as topiramate and valproate, selectively block voltage-gated sodium channels, which are responsible for initiating action potential firing and neuronal activity. These therapeutics also notably block sodium channels across the entire central nervous system (CNS). While the target of anticonvulsants is not specific to pain pathways, blocking ion channels on the trigeminal nerve, in theory, would therefore decrease its electrical activity and diminish CGRP release.²¹ Erenumab, galcanezumab, fremanezumab, and eptinezumab are all monoclonal antibodies that are uniquely engineered to block CGRP signaling. Galcanezumab, fremanezumab, and eptinezumab all bind specifically to the CGRP ligand, while erenumab binds to the CGRP receptor. Utilizing monoclonal antibodies to interfere with ligand-receptor binding decreases CGRP-mediated downstream signaling that induces the migraine.²² While antibodies are typically used in preventative migraine treatment to reduce CGRP signaling, gepants are also prescribed in preventative care to antagonize CGRP signaling.¹³

Botulinum toxin type A, or botox, is another form of preventative migraine treatment that is typically injected into the muscle tissue surrounding the pain-related area of interest. Once administered, botox is taken up into the axon terminal where it blocks synaptic vesicle motility and the release of neurotransmitters involved in the pain pathways.²³ The final form of preventative treatment are antidepressants, specifically tricyclic antidepressants (TCAs). TCAs, which include amitriptyline, work by blocking the reuptake of serotonin back into the axon terminal. By increasing its availability in the extracellular space, serotonin can bind to 5-HT receptors on cerebral blood vessels, causing vasoconstriction.¹³

Two is Better Than One: The Mechanism of Symbravo

Approved by the FDA in January 2025,²⁴ Symbravo (AXS-07) offers a novel acute approach to treating migraines. It targets not one but two pathways involved in the pathophysiology. How does it work exactly? Symbravo uses the combined effects of two FDA-approved medications: meloxicam and rizatriptan (Figure 4). 

Meloxicam is an NSAID that selectively inhibits COX enzymes that are responsible for synthesizing prostaglandins. Although it targets both COX enzyme subtypes, meloxicam is preferential towards the COX-2 subtype that is highly involved in inflammation.²⁵ By decreasing prostaglandin production in mast cells, meloxicam effectively reduces neurogenic inflammation during migraines. As discussed, rizatriptan is a type of triptan that selectively activates 5-HT_1B/1D receptors. After binding to its target, rizatriptan decreases both CGRP release from the trigeminal nerve and the vasodilation of cerebral blood vessels, mitigating the onset of migraine-related pain.¹⁴

Evaluating the Clinical Significance of Symbravo in Treating Migraines

The FDA approval of Symbravo for migraine treatment was supported by two double-blind, randomized, phase 3 clinical trials: INTERCEPT and MOMENTUM.^26,27 While both trials evaluated the therapeutic efficacy, they differed based on when Symbravo was administered during a migraine attack. 

During the INTERCEPT trial (ClinicalTrials.gov Identifier: NCT04163185),²⁶ which was completed in 2020, approximately 280 participants were randomly assigned to receive either Symbravo (20 mg Meloxicam + 10 mg Rizatriptan) or placebo. Participants were further instructed to take either Symbravo or placebo starting at the earliest sign of a migraine attack. The two primary endpoints were determined as the percentage of participants with pain freedom and a resolution of their most bothersome symptom (MBS) 2 hours after dosage. Secondary endpoints included the duration of sustained pain freedom, freedom from migraine pain progression, changes in functional disability, and the use of a rescue medication to abort the migraine. At the conclusion of the trial, INTERCEPT met both primary endpoints. 32.6% of participants receiving Symbravo reported pain freedom after 2 hours while 43.9% reported a resolution of the MBS. Compared to the placebo, where only 16.3% reported pain freedom and 26.7% reported resolution of the MBS, Symbravo statistically and clinically alleviated pain-related symptoms during a migraine.²⁶

Secondary endpoints were also met during INTERCEPT.²⁶ 22.7% of participants that received Symbravo reported pain freedom after 24 hours compared to the 12.6% that received placebo. 47.4% of participants that received the placebo experienced no functional disabilities during the migraine and reported that the pain did not progress past mild severity. In contrast, 73.5% of participants that received Symbravo experienced no functional disabilities and reported that the pain did not progress past mild severity. Finally, 42.2% of participants that received the placebo reported later use of a rescue medication to abort the migraine, while 15.3% of participants receiving Symbravo reported use of a rescue medication.²⁶

The MOMENTUM clinical trial (ClinicalTrials.gov Identifier: NCT03896009), which was completed in 2019, also evaluated the therapeutic efficacy of Symbravo.²⁷ Similar to INTERCEPT, MOMENTUM determined if Symbravo effectively mitigated migraine-related pain in patients. However, there are two differences in the study design of MOMENTUM that made it different. First, patients were instructed to administer Symbravo when migraine pains were already moderate or severe. Second, the treatment effects of Symbravo were not only compared to placebo but also to meloxicam and rizatriptan alone. This study design determines if there is a synergistic effect when combining meloxicam and rizatriptan. In other words, the study determined if Symbravo was superior in alleviating migraines compared to meloxicam or rizatriptan alone.

Approximately 1,500 participants were enrolled to receive either Symbravo (20 mg meloxicam + 10 mg rizatriptan), 20 mg meloxicam, 10 mg rizatriptan, or placebo. As noted, participants administered their respective dose at the onset of a qualifying migraine when the pain was considered moderate to severe. The two primary endpoints were determined as the percentage of participants with pain freedom and a resolution of the MBS after dosage. 19.9% and 36.9% of participants that received Symbravo achieved pain and MBS freedom within 2 hours, respectively, while only 6.7% and 24.4% of participants reported pain and MBS freedom after receiving the placebo.²⁷

The key secondary endpoint was to assess not only the change in sustained pain freedom between Symbravo and placebo but also between Symbravo, meloxicam, and rizatriptan.²⁷ All secondary endpoints were met as Symbravo outperformed in alleviating pain in participants when compared to the placebo, meloxicam, and rizatriptan. This effect was also consistent across various time points after dosage since Symbravo was superior in achieving pain freedom at all timepoints between 15 minutes and 48 hours after administration. Symbravo also alleviated pain more rapidly when compared to the other groups. The estimated time to pain relief was approximately 1.5 hours after taking Symbravo, while it was approximately 4 hours after taking meloxicam or rizatriptan. In addition to these secondary outcomes, Symbravo outperformed meloxicam and rizatriptan in preventing pain relapse, requiring the use of a rescue medication, and improving daily function and quality of life.²⁷ The results of the MOMENTUM trial highlight the synergistic advantage of Symbravo’s mechanism of action in enhancing sustained migraine-related pain relief in patients.

No serious adverse effects in the INTERCEPT and MOMENTUM trial were reported after the use of Symbravo.^26,27 The only prominent treatment-emergent adverse effects reported were somnolence (sleepiness), dizziness, and nausea. In the INTERCEPT trial, 4.3% and 2.9% of participants that received Symbravo experienced somnolence and dizziness, respectively.²⁶ In the MOMENTUM trial, 1.4% of participants reported somnolence after receiving Symbravo, while 2.1%, 2.3%, and 1.4% of participants reported this after receiving rizatriptan, meloxicam, and placebo, respectively.  4.8%, 3.2%, and 3.7% of participants also reported nausea after receiving rizatriptan, meloxicam, and placebo, respectively, while this was only reported in 2.7% of participants who received Symbravo.²⁷

What’s Next For Symbravo?

The conclusion of the INTERCEPT and MOMENTUM trials provide key results highlighting that Symbravo effectively induces rapid and sustained migraine-related pain relief. Both studies also show that regardless of when Symbravo is taken, either when the migraine is mild, moderate, or severe, pain relief is still achieved rapidly. Two follow-up clinical trials also supported the use of Symbravo in treating migraines: MOVEMENT and EMERGE.^28,29 The MOVEMENT trial (ClinicalTrials.gov Identifier: NCT04068051) assessed the long-term safety of Symbravo over a 12-month period.²⁸ Less than 2% of participants receiving Symbravo experienced any serious treatment-emergent adverse effects (TEAEs) after the 12-month period, indicating that Symbravo is safe for long-term use. The EMERGE trial (ClinicalTrials.gov Identifier: NCT05550207), which was recently completed in 2024, compared the treatment efficacy of Symbravo to current CGRP inhibitors.²⁹ Symbravo outperformed in alleviating migraine-related symptoms, as 47.9% of participants receiving Symbravo reported pain freedom after 24 hours, while pain freedom was only reported in 16.7% of participants who received CGRP inhibitors. Furthermore, Symbravo offers a novel method for migraine treatment, allowing for rapid and sustainable pain relief that is superior to other FDA-approved therapeutics.

References:

1.      Steiner TJ, Stovner LJ. Global epidemiology of migraine and its implications for public health and health policy. Nat Rev Neurol. 2023;19(2):109-117.

2.      Eigenbrodt AK, Ashina H, Khan S, et al. Diagnosis and management of migraine in ten steps. Nat Rev Neurol. 2021;17(8):501-514.

3.      Friedman DI, De Ver Dye T. Migraine and the Environment. Headache. 2009;49(6):941-952.

4.      Seng EK, Martin PR, Houle TT. Lifestyle factors and migraine. Lancet Neurol. 2022;21(10):911-921.

5.      Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the Trigeminal System in Migraine. Headache. 2019;59(5):659-681.

6.      Messlinger K, Balcziak LK, Russo AF. Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators. J Neural Transm (Vienna). 2020;127(4):431-444.

7.      Edvinsson L, Villalón CM, MaassenVanDenBrink A. Basic mechanisms of migraine and its acute treatment. Pharmacol Ther. 2012;136(3):319-333.

8.      Geppetti P, Rossi E, Chiarugi A, Benemei S. Antidromic vasodilatation and the migraine mechanism. J Headache Pain. 2012;13(2):103-111.

9.      Kee Z, Kodji X, Brain SD. The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects. Front Physiol. 2018;9.

10.    Richardson JD, Vasko MR. Cellular Mechanisms of Neurogenic Inflammation. The J Pharmacol Exp Ther. 2002;302(3):839-845.

11.    Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A. The role of mast cells in migraine pathophysiology. Brain Res Rev. 2005;49(1):65-76.

12.    Suzuki K, Suzuki S, Shiina T, Kobayashi S,  Hirata K. Central Sensitization in Migraine: A Narrative Review. J Pain Res. 2022;15:2673-2682.

13.    Zobdeh F, ben Kraiem A, Attwood MM, et al. Pharmacological treatment of migraine: Drug classes, mechanisms of action, clinical trials and new treatments. Br J Pharmacol. 2021;178(23):4588-4607.

14.    Ma QP, Hill R, Sirinathsinghji D. Colocalization of CGRP with 5‐HT1B/1D receptors and substance P in trigeminal ganglion neurons in rats. Eur J Neurosci. 2001;13(11):2099-2104.

15.    Silberstein SD, Kori SH. Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine. CNS Drugs. 2013;27:385-394.

16.    Goadsby PJ, Classey JD. Evidence for serotonin (5-HT) 1B, 5-HT1D and 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience. 2003;122(2):491-498.

17.    Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183-187.

18.    Lipton RB, Goldstein J, Baggish JS, Yataco AR, Sorrentino JV, Quiring JN. Aspirin is efficacious for the treatment of acute migraine. Headache. 2005;45(4):283-292.

19.    Khazaei M, Hosseini Nejad Mir N, Yadranji Aghdam F, Taheri M, Ghafouri-Fard S. Effectiveness of intravenous dexamethasone, metoclopramide, ketorolac, and chlorpromazine for pain relief and prevention of recurrence in the migraine headache: a prospective double-blind randomized clinical trial. Neurol Sci. 2019;40:1029-1033.

20.    Dakhale GN, Sharma VS, Thakre MN, Kalikar M. Low-dose sodium valproate versus low-dose propranolol in prophylaxis of common migraine headache: a randomized, prospective, parallel, open-label study. Indian J Pharmacol. 2019;51(4):255-262.

21.    Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in migraine. Expert Review of Clinical Pharmacology. 2014;7(2):191-201.

22.    Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies—successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-350.

23.    Burstein R, Zhang X, Levy D, Aoki KR, Brin MF. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia. 2014;34(11):853-869.

24.    Halsey G, Jennings S. Axsome Therapeutics: FDA approves Symbravo for acute treatment of Migraine. Patient Care Online. January 31, 2025. Accessed July 7, 2025. https://www.patientcareonline.com/view/axsome-therapeutics-fda-approves-symbravo-for-acute-treatment-of-migraine. 

25.    Vane JR, Botting RM. Mechanism of Action of Anti-Inflammatory Drugs. Scand J Rheumatol. 1996;25(sup102):9-21.

26.    Jones A, Tepper S, Lipton R, Tabuteau H. Efficacy and Safety of AXS-07 (MoSEIC Meloxicam-Rizatriptan) for the Acute Treatment of Migraine: Results from the INTERCEPT Phase 3, Randomized, Double-blind, Placebo-controlled Trial (P14-2.004). Neurology. 2022;98(18_supplement):1112.

27.    Jones A, Tepper S, Lipton R, Tabuteau H. Efficacy and Safety of AXS-07 (MoSEIC Meloxicam-Rizatriptan) for the Acute Treatment of Migraine: Results from the MOMENTUM Phase 3, Randomized, Double-blind, Active- and Placebo-controlled Trial (P13-2.005). Neurology. 2022;98(18_supplement):3564.

28.    Jones A, Tabuteau H. Long-Term Efficacy and Safety of AXS-07 (MoSEIC Meloxicam-Rizatriptan) for the Acute Treatment of Migraine: Results from the MOVEMENT Phase 3 Trial (P11-2.003). Neurology. 2022;98(18_supplement):2915.

29.    McAllister P, Tepper S, Chhabra A, Streicher C, Parks G, Tabuteau H. EMERGE Study: An Open-label Evaluation of the Efficacy and Safety of AXS-07 (MoSEIC™ meloxicam-rizatriptan) for Migraine in Adults with Prior Inadequate Response to an Oral CGRP Inhibitor (P6-12.006). Neurology. 2024;102(7_supplement_1):5476.

Author: Michaela Price, PhD
Editor: Sy’Keria Garrison

Today, we will be discussing chronic obstructive pulmonary disease (COPD) and a new COPD treatment called Ohtuvayre (ensifentrine), which was approved on June 26, 2024 by the Food and Drug Administration (FDA) in the United States. COPD is a serious condition with a significant risk of mortality. An estimated 3 million deaths worldwide can be attributed to COPD each year.^1,2 In the United States alone, the economic cost of COPD is expected to reach $40 billion annually.^2-4

Key Highlights

• COPD is a lung condition in which patients experience respiratory symptoms (e.g. difficulty breathing, coughing, or expelling mucus by coughing or clearing one’s throat) caused by inflammation of the airways and/or damage to the alveoli (lung’s air sacs)
• COPD exacerbations (or ‘flare-ups’) are associated with a significant increase in the frequency and/or severity of symptoms
• COPD is diagnosed with spirometry, a method of assessing lung function, and an initial assessment of the patient’s airflow limitation, symptoms, history of flare-ups, and comorbidities can guide the healthcare provider’s prescription decisions
• COPD treatments include behavioral modifications (i.e. smoking cessation) and various types of pharmacological therapies
• Inhibitors of phosphodiesterase enzymes, particularly inhibitors of phosphodiesterase 3 and 4, have bronchodilator and anti-inflammatory effects that can be used to treat breathing problems
• Ohtuvayre acts as a dual phosphodiesterase 3 and phosphodiesterase 4 inhibitor, which allows it to improve COPD symptoms by relaxing the muscles around the airways and reducing lung inflammation 
• Ohtuvayre was FDA approved based on two clinical trials that found Ohtuvayre improved lung function in adults with moderate-to-severe COPD, was superior to placebo, and was generally well-tolerated

What is COPD?

In 2023, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published a report that defined COPD as a “heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.”^2,5

• Dyspnea: difficult breathing or shortness of breath
• Expectoration: the process of expelling mucus from the throat or lungs by coughing or forcefully clearing the throat
• Exacerbations of COPD: also known as flare-ups, periods of time when COPD symptoms become more severe and/or frequent than normal
• Bronchitis: inflammation of the bronchi (larger airways)
• Bronchiolitis: inflammation of the bronchioles (smaller airways)
• Emphysema: irreversible damage to the alveoli (air sacs) in the lungs

COPD Exacerbations

Exacerbations of COPD are particularly worrisome. A study that followed 101 patients with moderate to severe COPD for approximately 2.5 years reported that 90% of study participants had at least one exacerbation during the 2.5 years, with a median exacerbation rate of 2.4 exacerbations per patient per year.⁶ Exacerbations were associated with a substantial increase in dyspnea, sputum volume, sputum purulence (pus-filled sputum), colds, wheezing, sore throat, and coughing. Patients also experienced a significant decrease in lung function, as measured by the peak expiratory flow rate (PEFR), the total volume of air exhaled (forced vital capacity; FVC), and the volume of air exhaled in the first second (forced expiratory volume in one second; FEV1). Notably, the study found that the magnitude of the decrease in lung function during an exacerbation correlated with the length of time it took to recover, such that a greater decrease in function was associated with a longer recovery time. Patients were able to recover their PEFR with a median recovery time of 6 days, but 7.1% of exacerbations failed to recover their PEFR 91 days after the exacerbation onset.⁶ Thus, it is imperative that COPD therapies address exacerbation frequency in patients.

COPD Prevalence based on Diagnostic Criteria

Estimating the prevalence of COPD is complicated by the different criteria used to diagnose COPD cases. COPD is diagnosed by assessing lung function with spirometry, a common test of pulmonary function that measures the amount of air exhaled over time and assesses airflow obstruction.^2,7 Specifically, spirometry measures FEV1, FVC, and their ratio (FEV1/FVC).⁷ The GOLD guidelines recommend diagnosing COPD based on a fixed ratio of (FEV1/FVC<0.7).^2,5,8 Other guidelines adopted by the European Respiratory Society and the American Thoracic Society diagnose COPD based on the lower limit of normal (LLN) criterion where the LLN is the lower 5th percentile.^5,8 A systematic review and modeling analysis determined that, in 2019, the prevalence of COPD was between 7.6% and 10.3% worldwide in individuals 30-79 years of age.⁸ The GOLD fixed ratio yielded a global prevalence of 10.3% (approximately 391.9 million people), and the LLN criterion yielded a global prevalence of 7.6% (approximately 292.0 million people). Despite the variation in prevalence based on diagnostic criteria, COPD clearly affects a substantial portion of the adult population.

COPD Risk Factors

There are many risk factors associated with COPD. For instance, cigarette smoking is a major risk factor.^2,5 Compared to nonsmokers, individuals who smoke cigarettes are more likely to have respiratory symptoms and abnormal lung function, a larger yearly decline in the volume of air exhaled in one second (forced expiratory volume in one second; FEV1), and a higher rate of COPD mortality.^2,5,9 Air pollution and exposures to various substances like biomass, dust, chemicals, and fumes are also important environmental risk factors for COPD.^2,5,10,11 In addition, there are other risk factors, including but not limited to, genetics, advanced age, the male biological sex, low socioeconomic status, asthma, respiratory infections during childhood, abnormal lung development, and a low body mass index.^2,5,8

COPD Initial Assessment

After COPD has been diagnosed using spirometry, the choice of therapeutics is influenced by an initial assessment, which determines the “severity of airflow limitation”, “nature and magnitude of current symptoms”, “previous history of moderate and severe exacerbations”, and the “presence and type of other diseases (multimorbidity).”² The severity of airflow limitation is based on where a patient’s FEV1 value falls on the GOLD grading scale, with the severity of airflow obstruction being delineated into mild, moderate, severe, and very severe levels.² Current symptoms are assessed using a series of validated questionnaires, including the modified Medical Research Council dyspnea scale, as well as multidimensional questionnaires, such as the Chronic Respiratory Questionnaire, St. George’s Respiratory Questionnaire, COPD Assessment Test, and COPD Control Questionnaire.² A patient’s previous history of moderate and severe exacerbations is included in the initial assessment because it is the best predictor of future frequent exacerbations (frequent would be defined as at least 2 exacerbations per year), and exacerbations are worrisome because they have a substantial effect on the health of patients, worsen the decline in lung function over time, worsen the prognosis of patients, and account for a substantial portion of the healthcare costs associated with COPD.^2,12 Finally, patients with COPD typically have comorbid conditions, which ultimately impact the patient’s health outcomes.² Some common comorbidities associated with COPD are cardiovascular diseases, metabolic conditions, osteoporosis, psychiatric conditions like depression and anxiety, and lung cancer.²

COPD Treatments

Given that cigarette smoking is a major risk factor for developing COPD, smoking cessation products have an important role in improving the prognosis for individuals with COPD. Many pharmacological therapies have also been used to treat COPD, including bronchodilators (i.e. short-acting and long-acting β2-adrenergic receptor agonists), antimuscarinic drugs (i.e. short-acting and long-acting muscarinic receptor antagonists), methylxanthines (i.e. aminophylline, theophylline), anti-inflammatory agents (i.e. inhaled corticosteroids, oral glucocorticoids, phosphodiesterase 4 inhibitors, antibiotics, mucolytic agents, and antioxidant agents), and combination therapies.² These treatment options have different mechanisms, routes of administration, durations of action, adverse effects, availability, and financial costs.² All of these variables must be taken into account when prescribing treatment to patients who differ in airflow obstruction severity, the nature and magnitude of current symptoms, the history of exacerbations, comorbidities, the ability to access medications, and socioeconomic class.²

Cyclic Nucleotides, Phosphodiesterase Enzymes, and COPD

Breathing problems can occur in COPD when the muscles around the airways tighten and the lungs become inflamed. Ideally, COPD therapies should address both of these processes simultaneously by having bronchodilator and anti-inflammatory effects. Bronchodilation refers to when the airways widen and allow for increased airflow to the lungs as a result of airway smooth muscles relaxing.

Cyclic nucleotides are intracellular second messenger molecules that have an important role in a wide range of cellular processes, including promoting bronchodilation and regulating inflammation.¹³ Cyclic nucleotides, like cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are degraded by enzymes called phosphodiesterases (PDEs).¹³ PDE inhibitors prevent the degradation of cyclic nucleotides, and thus, PDE inhibitors have been used to promote bronchodilation and suppress inflammation by preventing the degradation of cyclic nucleotides.

There are 11 families of PDE enzymes.¹⁴ These enzymes differ with respect to their affinities for cAMP and cGMP, distribution within the body, function, and more. For example, PDE3 and PDE4 both hydrolyze cAMP while PDE3 is also capable of hydrolyzing cGMP.¹⁴ PDE3 and PDE4 are both expressed in airway smooth muscle, and PDE4 is expressed in nearly all inflammatory cell types.^14-16 PDE3 inhibitors relax human airways in vitro and cause bronchodilation in vivo.^14,15,17 PDE4 inhibitors relax human airways in vitro, improve pulmonary function in vivo, and reduce pro-inflammatory mediators.^13,14,16,18 Dual PDE3 and PDE4 inhibition also has bronchodilator and anti-inflammatory effects.^19,20 A clinical trial assessing the dual PDE3 and PDE4 inhibitor RPL554 (also known as ensifentrine) showed that in patients with asthma, RPL554 had bronchodilator effects that were maintained for at least 6 hours following administration of RPL554 and the bronchodilator effects did not diminish after subsequent doses on consecutive days.¹⁹ Other clinical trials demonstrated that RPL554 also produced bronchodilator effects in patients with COPD, as well as anti-inflammatory effects in healthy individuals.¹⁹ 

Ohtuvayre

On June 26, 2024, the FDA approved Ohtuvayre (ensifentrine), a new small-molecule therapeutic, as a maintenance treatment for COPD in adults.^21,22 Ohtuvayre is administered twice daily by oral inhalation via a standard jet nebulizer equipped with a mouthpiece.^21,22 The package label for Ohtuvayre notes that it can be “used to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days).”²² Ohtuvayre achieves this by acting as a dual PDE3 and PDE4 inhibitor, which allows it to prevent breathing problems by simultaneously relaxing the muscles around the airways and decreasing lung inflammation.²² Inhibiting PDE3 activity relaxes the muscles around the airways, preventing symptoms including wheezing, coughing, tightening of the chest, and shortness of breath. Inhibiting PDE4 activity primarily acts by reducing lung inflammation. 

The FDA’s approval of Ohtuvayre was based on two placebo-controlled trials: ENHANCE-1 [NCT04535986] and ENHANCE-2 [NCT04542057].^21,22 These two trials collectively enrolled 1,553 adults that had moderate-to-severe COPD, and both trials randomized the study participants to receive either Ohtuvayre or placebo in a 5:3 ratio, meaning that 5 participants were randomized to the Ohtuvayre group for every 3 participants randomized to the placebo group. The primary efficacy endpoint for these trials was a measure of pulmonary function, specifically measuring the change, between baseline and the end of treatment, in FEV1 area under the concentration-time curve over 12 hours. The end of treatment time point was measured following 12 weeks of treatment. The results of the clinical trials showed that Ohtuvayre was superior compared to placebo, as evidenced by the improvement in pulmonary function in adults with moderate-to-severe COPD. The most common side effects associated with Ohtuvayre were back pain, high blood pressure (hypertension), bladder infection (urinary tract infection), and diarrhea.^21,22 Some rare, serious side effects have been reported as well, including sudden breathing problems directly after administering Ohtuvayre and psychiatric adverse reactions like suicidal thoughts and behaviors.²¹

Given that there are hundreds of millions of people worldwide living with COPD, the pharmaceutical industry has prioritized developing therapeutics to treat the disease. It remains to be seen how Ohtuvayre will stack up against other therapeutic alternatives. Nevertheless, there is bound to be a sizable patient population that would benefit from Ohtuvayre’s FDA approval given the limitations of alternatives in terms of their accessibility, cost, and associated side effects. Although there are side effects associated with taking Ohtuvayre as well, the development of this medication provides a viable therapeutic alternative to the millions of patients worldwide who live with COPD. Furthermore, the FDA’s approval of Ohtuvayre could potentially reduce the economic burden of COPD in the United States, which is projected to reach $40 billion annually.^2-4

References

1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117-171. doi:10.1016/S0140-6736(14)61682-2.
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report. https://goldcopd.org/2023-gold-report-2/ 
3. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013;5:235-245. 
4. Zafari Z, Li S, Eakin MN, Bellanger M, Reed RM. Projecting long-term health and economic burden of COPD in the United States. Chest. 2021;159(4):1400-1410.
5. Agustí A, Celli BR, Criner GJ, et al. Global initiative for chronic obstructive lung disease report: GOLD executive summary. Eur Respir J. 2023;61:2300239. doi:10.1183/13993003.00239-2023J.
6. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-1613. doi:10.1164/ajrccm.161.5.9908022.
7. Lamb K, Theodore D, Bhutta BS. Spirometry. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 17, 2023.
8. Adeloye D, Song P, Zhu Y, Campbell H, Sheikh A, Rudan I. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med. 2022;10(5):447-458. doi:10.1016/S2213-2600(21)00511-7.
9. Kohansal R, Martinez-Camblor P, Agusti A, et al. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med. 2009;180:3–10.
10. Paulin LM, Diette GB, Blanc PD, et al. Occupational exposures are associated with worse morbidity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:557–565.
11. De Matteis S, Jarvis D, Darnton A, et al. The occupations at increased risk of COPD: analysis of lifetime job-histories in the population-based UK Biobank Cohort. Eur Respir J. 2019;54:1900186. 
12. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925-931.
13. Padda IS, Tripp J. Phosphodiesterase inhibitors. [Updated 2023 Jun 26].  In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Accessed June 13, 2025. https://www.ncbi.nlm.nih.gov/books/NBK559276/
14. Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 2014;114(5):365-376. doi:10.1111/bcpt.12209
15. Rabe KF, Tenor H, Dent G, Schudt C, Liebig S, Magnussen H. Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization. Am J Physiol. 1993;264(5 Pt 1):L458-64.doi:10.1152/ajplung.1993.264.5.L458.
16. Dent G, Poppe J, Egerland J, Marx D, Szelenyi I, Branscheid D, Magnussen H, Rabe KF. Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs. Pulmonary Pharmacology & Therapeutics. 1998;11:13-21.
17. Myou S, Fujimura M, Kamio Y, et al. Bronchodilator effects of intravenous olprinone, a phosphodiesterase 3 inhibitor, with and without aminophylline in asthmatic patients. Br J Clin Pharmacol. 2003;55(4):341-346. doi:10.1046/j.1365-2125.2003.01760.x
18. Grootendorst DC, Gauw SA, Verhoosel RM et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007;62(12):1081-1087. doi:10.1136/thx.2006.075937
19. Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013;1(9):714-727. doi:10.1016/S2213-2600(13)70187-5
20. Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther. 2006;318(2):840-848. doi:10.1124/jpet.105.099192.
21. Drug trials snapshots: Ohtuvayre. FDA. Published January 30, 2025. Accessed April 21, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-ohtuvayre 
22. Ohtuvayre. Package label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217389s000lbl.pdf 

Writer: Colin McArdle
Editor: Pari Dhayagude

Huntington’s Disease (HD) is the most common inherited neurodegenerative disorder, affecting approximately 30,000 people nationwide.¹ HD is a multimodal disorder characterized by a wide array of symptoms that are defined by motor impairments, such as involuntary movements, slurred speech and difficulty swallowing.² Non-motor impairments, such as cognitive decline, mood changes, and depression, are also observed in HD.² As an autosomal dominant disorder, HD carries a 50% inheritance risk for children of affected parents.³ Additionally, symptoms can arise earlier and earlier in age as the disease passes through each generation.⁴ Given this earlier onset pattern and caregiver costs that can reach up to $60,000 dollars annually, searching for an effective treatment for HD is becoming a major global healthcare priority.⁵

A Compromised Basal Ganglia: Understanding the Pathology in Huntington’s Disease

The onset of involuntary, rapid, and jerky movements in HD, also known as chorea, arises from dysfunction in a specific part of the brain that controls muscle movements – the basal ganglia. The basal ganglia comprises multiple brain regions that delicately coordinate the initiation and cessation of motor behaviors.⁶ One of these regions, the striatum, is particularly vulnerable to degeneration throughout disease progression. Medium spiny neurons, which make up 90% of the striatum, slowly die off in HD, resulting in compromised basal ganglia function and unregulated motor function.²

How are striatal medium spiny neurons vulnerable to degeneration? As HD is a highly heritable genetic disorder, the pathology stems from a specific mutation in the Huntingtin (Htt) gene. Located on chromosome 4, the Htt gene contains a series of cytosine-adenine-guanine (CAG) nucleotide repeats, which encode for the amino acid glutamine.⁷ In healthy patients, the Htt gene contains no more than 27 CAG repeats, resulting in normal Huntingtin protein function.⁷ However, in HD patients, the number of CAG repeats increases to 36 or more, leading to a mutated protein form.⁷ With too many glutamine repeats, the Huntingtin protein begins to misfold into a toxic aggregate that leads to neuronal toxicity and death.⁸ The degeneration of medium spiny neurons in HD additionally disturbs specific neurotransmitter signaling that regulates motor behavior. Dopamine, the neurotransmitter primarily responsible for regulating muscle movement, becomes upregulated following this structural loss, further exacerbating chorea in patients.⁹

Following the degeneration of the striatal medium spiny neurons in HD, the neurocircuitry in the basal ganglia becomes dysregulated, leading to the onset of chorea. How does this work exactly? The substantia nigra compacta (SNc) releases dopamine onto the striatum which activates two distinct neural pathways involved in motor regulation: the direct, or “GO”, pathway and the indirect, or “STOP”, pathway.¹⁰ The direct pathway, which initiates motor movement, is controlled by medium spiny neurons in the striatum that express the D1 dopamine receptor subtype. When dopamine is first released from substantia nigral neurons, it binds to D1 receptors in the striatum to activate the direct pathway. Disinhibitory signals then travel through the globus pallidus internus (GPi) and the thalamus to ultimately activate the motor cortex, initiating muscle movement in the body. The indirect pathway, which inhibits motor movement, is controlled by striatal medium spiny neurons that express the D2 dopamine receptor subtype. When activated, this pathway sends excitatory and inhibitory projections through the GPe, subthalamic nucleus (STN), globus pallidus internus (GPi), and the thalamus to suppress the motor cortex, reducing muscle movements.¹⁰

In healthy patients, the direct and indirect pathway work in balance with one another to precisely coordinate muscle movements, contractions, and balance. However, in HD, the population of D2-expressing striatal medium spiny neurons is vulnerable to degeneration, causing loss of indirect pathway function.¹¹ This consequently results in an imbalance in basal ganglia neurocircuitry, leading to the overactivation of the motor cortex and the onset of chorea.¹¹

Reducing Synaptic Packaging: How Valbenazine Normalizes Dopamine Signaling in HD

As previously noted, mutations in the Htt gene result in a distinct pathology where HD patients display compromised basal ganglia and motor function, as well as heightened dopamine signaling. How do pharmaceuticals fix these issues?  Approved by the Food and Drug Administration (FDA) in August 2023,¹² valbenazine (Ingrezza) corrects the pathology and symptoms in HD by reducing elevated dopamine levels in the brain. Mechanistically, valbenazine targets the vesicular monoamine transporter 2 (VMAT2), which is responsible for packaging dopamine into synaptic vesicles that are later released from neurons.¹³ Valbenazine acts as a VMAT2 inhibitor, blocking dopamine packaging and thereby reducing its subsequent release and binding to receptors.¹⁴ By interfering with the vesicular transport of dopamine, valbenazine normalizes overactive dopaminergic signaling in the brain, further mitigating the onset of chorea in HD patients.

KINETIC-HD: Evaluating the Therapeutic Efficacy of Valbenazine

FDA approval was supported by a double-blind, randomized, phase 3 clinical trial evaluating the safety, tolerability, and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease. Titled KINETIC-HD (Clinical Trial Number: NCT04102579), the study administered daily oral doses of up to 80 mg valbenazine or placebo to HD patients with confirmed chorea over 12 weeks.¹⁵ The primary outcome measure was the change in chorea, as measured by the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) Score. This motor assessment examines the frequency of involuntary movements across various body parts including the face, trunk, limbs, and oral-buccal-lingual region. Scores range from 0 to 28, with a higher score indicating more severe chorea. In addition to assessing treatment effects on motor activity, this clinical trial also determined whether valbenazine interacts with non-motor symptoms of HD, such as depression and anxiety.¹⁵

Following the 12-week trial period, HD patients who received valbenazine displayed an approximate 40% reduction in chorea according to their TMC scores, compared to those that received placebo.¹⁵ These results are considered both statistically and clinically significant. While alleviating motor dysfunction, valbenazine did not worsen depression or anxiety, highlighting its benefit in avoiding negative mood changes. Safety and tolerability concerns were also minimal in patients treated with valbenazine. The most prominent treatment-emergent adverse events (TEAE) were drowsiness and fatigue, experienced by approximately 15% of patients taking valbenazine.¹⁵

The Future Steps for Valbenazine in Treating Patients

The promising results of the KINETIC-HD clinical trial highlight valbenazine’s benefits in effectively treating chorea in HD patients. How is valbenazine unique when compared to the previously approved VMAT2 inhibitors for HD associated chorea, tetrabenazine and deutetrabenazine? While both tetrabenazine and deutetrabenazine effectively mitigate the onset of chorea, patients often report an increase in depression and suicidality.^16,17 Based on the results from KINETIC-HD, valbenazine is able to normalize dopamine signaling and alleviate motor dysfunction without increasing the risk of neuropsychiatric-related symptoms.¹⁵ Moving forward, researchers are currently evaluating the long-term use and safety of valbenazine in KINETIC-HD2 (Clinical Trial Number: NCT04400331).¹⁸ This open-label rollover study utilizes the participants from the original KINETIC-HD study and continues treatment for up to 104 weeks while monitoring efficacy and safety. In short, valbenazine shows significant clinical potential for managing chorea in Huntington’s disease patients, offering improved motor coordination and quality of life while minimizing safety concerns.

References:  

1. Medina A, Mahjoub Y, Shaver L, Pringsheim T. Prevalence and Incidence of Huntington’s Disease: An Updated Systematic Review and Meta-Analysis. Mov Disord. 2022;37(12):2327-2335.

2. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nature Reviews Disease Primers. 2015;1(1):15005.

3. Myers RH. Huntington’s disease genetics. NeuroRX. 2004;1(2):255-262.

4. Myers R, Madden J, Teague J, Falek A. Factors related to onset age of Huntington disease. Am J Hum Genet. 1982;34(3):481.

5. Exuzides A, Reddy SR, Chang E, et al. Healthcare utilization and cost burden of Huntington’s disease among Medicare beneficiaries in the United States. J Med Econ. 2021;24(1):1327-1336.

6. Dhawale AK, Wolff SBE, Ko R, Ölveczky BP. The basal ganglia control the detailed kinematics of learned motor skills. Nat Neurosci. 2021;24(9):1256-1269.

7. Warby SC, Montpetit A, Hayden AR, et al. CAG Expansion in the Huntington Disease Gene Is Associated with a Specific and Targetable Predisposing Haplogroup. Am J Hum Genet. 2009;84(3):351-366.

8. Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016;89(5):910-926.

9. Schwab LC, Garas SN, Drouin-Ouellet J, Mason SL, Stott SR, Barker RA. Dopamine and Huntington’s disease. Expert Rev Neurother. 2015;15(4):445-458.

10. Calabresi P, Picconi B, Tozzi A, Ghiglieri V, Di Filippo M. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci. 2014;17(8):1022-1030.

11. Galvan L, André VM, Wang EA, Cepeda C, Levine MS. Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington’s Disease. J Huntingtons Dis. 2012;1(1):17-25.

12. Van de Roovaart HJ, Nguyen N, Veenstra TD. Huntington’s Disease Drug Development: A Phase 3 Pipeline Analysis. Pharmaceuticals. 2023;16(11):1513.

13. Wimalasena K. Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev. 2011;31(4):483-519.

14. Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE. VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine). Prog Med Chem. 2018;57(1):87-111.

15. Furr Stimming E, Claassen DO, Kayson E, et al. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2023;22(6):494-504.

16. Yero T, Rey JA. Tetrabenazine (Xenazine), An FDA-Approved Treatment Option For Huntington’s Disease-Related Chorea. P T. 2008;33(12):690-694.

17. Gupta H, Perkins W, Stark C, et al. deutetrabenazine for the treatment of chorea associated with Huntington’s disease. Health Psychol Res. 2022;10(5):36040.

18. Neurocrine Biosciences. Open-Label Rollover Study for Continuing Valbenazine Administration for the Treatment of Chorea Associated With Huntington Disease. ClinicalTrials.gov identifier: NCT04400331. Updated December 24, 2024. Accessed June 11, 2025. https://clinicaltrials.gov/study/NCT04400331?cond=Huntington%27s%20Disease&intr=Valbenazine&rank=2

Writer: Colin McArdle
Editor: Misha Fini

Approximately 7.2 million Americans over the age of 65 are living with the most common form of dementia – Alzheimer’s disease (AD). Affecting 1 in 9 older adults, AD has increasingly become a financial burden to our healthcare system, as predictions estimate nearly $380 billion are used towards long-term care for patients with AD.¹ In the next 25 years, that number is estimated to reach almost $1 trillion.² As healthcare costs and the number of AD patients rise every year, scientists are eagerly searching for a therapeutic to effectively slow down the disease progression and increase quality of life. Unfortunately, the path towards reaching this goal was not as straightforward as researchers initially imagined. In reality, it took nearly twenty years of many failed clinical trials to finally solve the puzzle. Looking back, why exactly did it take so long to finally approve a novel therapeutic for AD? 

Twenty Years of Failure: What Went Wrong?

Since the year 2003, when the Food and Drug Administration (FDA) approved Memantine, an N-methly-D-aspartate (NMDA) glutamate receptor antagonist, as its latest therapeutic for AD,³ countless clinical trials have failed to effectively target and eliminate one of the fundamental pathologies in AD – amyloid-beta (Aβ) plaque. Aβ plaques are extracellular protein aggregates that exhibit toxicity in the brain by disrupting neuronal communication, exacerbating impairments in cognition and memory.⁴ Under the hypothesis that preventing Aβ plaque buildup would solve all issues in AD,⁵ researchers and clinicians were surprisingly faced with a stalemate as almost 99% of these clinical trials failed (Figure 1).^6,7 Why was there such a high failure rate? This can be narrowed down to three primary limitations in all of these studies.

The first limitation is an inadequate understanding of the disease. AD is a complex disorder that is not just defined by one single pathology. Neurofibrillary tangles that arise from hyperphosphorylated tau protein, neuroinflammation, metabolic disruptions, and vascular disturbances – all of which occur in AD – play a role in the disease either alone or in combination.⁸  This interplay of multiple pathological mechanisms is one not yet fully understood by scientists. The second limitation is the late-stage intervention approach. The majority of patients enrolled in clinical trials for AD already exhibit behavioral dysfunctions in memory and cognition. Unfortunately, the pathology in AD, Aβ plaques, tau tangles, and neuron loss, starts to develop in the brain decades before the initial onset of behavioral symptoms.⁹ This means that a significant amount of permanent damage to the brain may have already occurred prior to the beginning of the trial.

The final limitation is the lack of proper clinical outcome measures. Many previous clinical trials utilized the Alzheimer’s Disease Assessment Scale – Cognitive Test (ADAS-Cog) as the primary clinical measure of cognition. Examples include using hemorheologic agents, M1 muscarinic receptor agonists, and acetylcholinesterase inhibitors in the treatment of AD, as assessed by the ADAS-Cog.^10-12 Originally developed in 1984,¹³ the ADAS-Cog is a useful behavioral assessment to monitor cognitive changes in patients already diagnosed with AD.¹⁴ However, previous clinical trials have shown that it may not be as effective in detecting subtle cognitive changes during the precursor stage of AD – mild cognitive impairment (MCI).¹⁵ Therefore, the use of the ADAS-Cog as the primary outcome measure could yield negative results, based on the limitation that it may not accurately detect cognitive decline in early stages of the disease. Furthermore, these three limitations resulted in many barriers to overcome to approve the next therapeutic. In light of all these challenges, new therapeutic approaches were constantly being generated and tested for AD, including the immunotherapeutic monoclonal antibodies aducanumab, lecanemab, and donanemab.^16-18  

Clearing Out Toxic Plaques: How Amyloid-beta Immunotherapy Works

Before understanding how monoclonal antibodies clear the brain of Aβ plaques, it is important to first discuss how plaques develop. According to the ‘Amyloid Cascade Hypothesis,’ Aβ plaque buildup arises from a series of cleavages, or cuts, to the Amyloid Precursor Protein (APP).¹⁹ Localized predominantly in the axon terminal of the neuron, APP has differential effects on the brain depending on how it is cleaved by enzymes. Under the non-amyloidogenic, or non-disease pathway, APP is first cleaved by an enzyme known as α-secretase. Following this, another enzyme, γ-secretase, makes an additional cut to APP. The result of these two enzymes is the accumulation of soluble proteins that display a therapeutic and neuroprotective effect in the brain. Under the amyloidogenic, or disease-state pathway, APP is first cleaved by a different enzyme, β-secretase. Following cleavage by γ-secretase, this pathway results in the collection of non-soluble protein monomers that eventually aggregate together to form Aβ plaques. While there is a balance between these two pathways under normal conditions, AD displays an imbalance towards the amyloidogenic pathway. Specifically, β-secretase activity is elevated, causing a toxic buildup of Aβ plaques that lead to neurodegeneration and disrupted brain function.¹⁹

How does immunotherapy play a role in the disposal of plaques in the brain? As the name states, immunotherapy reprograms the body’s immune response to target and eliminate pathogens. In the context of AD, this form of treatment takes advantage of the brain’s resident immune cells, microglia, to locate and clear Aβ plaques.²⁰ Aducanumab, lecanemab, and donanemab all contain anti-amyloid monoclonal antibodies that are developed and programmed to specifically recognize and bind to Aβ proteins. After binding to their respective targets, these antibodies mark Aβ proteins for degradation through a process known as opsonization.²⁰ Microglia – classically known to dispose of foreign substances in the brain – respond to these ‘eat me’ signals, resulting in the engulfment and degradation of protein aggregates through a process known as phagocytosis (Figure 2).²⁰

From a mechanistic perspective, what sets these three monoclonal antibodies apart from one another? Each is uniquely engineered to recognize and target different forms of Aβ protein aggregates in the brain. Aducanumab is preferential towards early-stage aggregates with a lower molecular weight, such as Aβ fibrils, by binding to amino acids 3-7 of the Aβ peptide.²¹ Similarly, lecanamab also binds to lower-weighted aggregates such as Aβ protofibrils.²² Donanemab, on the contrary, is preferential towards high molecular weighted aggregates, specifically Aβ plaques, by binding to the N-terminal truncated pyroglutamate Aβ peptide at position 3 (pGlu3-Aβ).²³ 

Utilizing Monoclonal Antibodies in the Clinic

Aducanumab (Aduhelm)

In 2021, the FDA granted accelerated approval for aducanumab (Aduhelm) after the conclusion of two randomized, double-blind, phase 3 clinical trials that evaluated the efficacy of aducanumab in early-stage patients with AD. Titled EMERGE and ENGAGE,¹⁶ both trials were carried out under identical experimental designs such that participants received monthly intravenous (IV) infusions of either a low (3 or 6 mg/kg) or high (6 or 10 g/kg) dose of aducanumab or placebo for 76 weeks. Inclusion in both studies required participants to 1) meet the diagnostic criteria for mild AD or mild cognitive impairment (MCI) and 2) show confirmation of Aβ plaque pathology. The primary outcome measure of both EMERGE and ENGAGE was the effect of treatment on cognitive decline. To determine treatment efficacy, researchers assessed the cognitive changes from baseline measures utilizing the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. This assessment examines three domains of cognition (memory, orientation, and problem-solving) as well as three domains of daily function (community affairs, home life, and personal care). Aβ plaque buildup was also assessed as a secondary measure using ¹⁸F-florbetapir amyloid Positron Emission Tomography (PET). 

Following the 78-week trial period, secondary results indicated that, regardless of dosage, aducanumab reduced Aβ plaques in the EMERGE and ENGAGE trials by approximately 71% and 59%, respectively. Despite these positive results, the primary endpoint was only met in the EMERGE trial. Specifically, only a high dose of aducanumab in this particular trial significantly reduced cognitive decline by approximately 22% when compared to the placebo.¹⁶ Despite the statistical significance, many clinicians argue that the clinical significance of aducanumab is modest.²⁴

Lecanemab (Leqembi)

Following the results of the EMERGE and ENGAGE trials, a new monoclonal antibody was developed and approved by the FDA in January 2023 – Lecanemab (Leqembi). In the phase 3 clinical trial titled Clarity AD,¹⁷ the therapeutic efficacy of lecanemab was evaluated in patients with early-stage AD. Over the course of 18 months, patients were randomized to receive either biweekly IV infusions of 10 mg/kg lecanemab or placebo. Similar to the trial that evaluated aducanumab, the primary outcome measure was the change in cognitive decline, as determined by the CDR-SB.

The Clarity AD trial sufficiently met its primary endpoint, as lecanemab administration resulted in a robust 27% reduction in cognitive decline that was considered statistically and clinically significant. Additionally, Aβ plaque burden was reduced by approximately 68% in participants that received lecanemab. Compared to previous trials, Clarity AD brought positive news to the AD community by highlighting that monoclonal antibodies could robustly slow the disease progression in patients.¹⁷ 

Donanemab (Kisunla)

Following the success of the Clarity AD trial, the FDA approved another monoclonal antibody in July 2023 that selectively targets pre-existing Aβ plaques – Donanemab (Kisunla). The approval of donanemab for AD was determined following the positive results of the phase 3, double-blind, randomized clinical trial titled TRAILBLAZER-ALZ 2.¹⁸ Over the course of 18 months, participants were randomly selected to receive either monthly IV infusions of donanemab or placebo. Those that received donanemab began with a dose of 700 mg during the first three infusions, followed by an increase to 1400 mg per infusion through the remainder of the study.

Similar to the previously discussed trials, the primary outcome measure was the change in cognitive decline in response to treatment. However, the TRAILBLAZER-ALZ 2 utilized an alternative cognitive assessment – the integrated Alzheimer Disease Rating Scale (iADRS). This particular multidomain assessment evaluates changes in both cognition as well as daily function. At the conclusion of TRAILBLAZER-ALZ 2, donanemab reduced cognitive decline in early symptomatic AD by a robust 35% in participants with either low or high levels of neurofibrillary tau tangles. Additionally, donanemab reduced Aβ plaque buildup by approximately 88%, and interestingly, 80% of participants that received treatment sufficiently cleared plaques from the brain following the conclusion of the trial.¹⁸ 

The Next Steps for Amyloid Immunotherapy

Based on the results from the clinical trials, the development of monoclonal antibodies has proven to revolutionize therapeutics for AD. Despite the success, there are still several concerns surrounding the use of amyloid immunotherapy for patients: safety and cost. In terms of safety, a significant portion of AD patients receiving a monoclonal antibody suffered from brain edema and/or hemorrhaging, also known as Amyloid-Related Imaging Abnormalities (ARIA).²⁵ Specifically, 35%, 12.5%, and 24% of patients reported ARIA after receiving aducanumab, lecanemab, and donanemab, respectively. Aducanumab was discontinued by its manufacturer in 2024, primarily due to safety concerns.²⁶

Regardless of this roadblock, clinicians have modified treatment dosages in an attempt to reduce ARIA. In a recent clinical trial, TRAILBLAZER-ALZ 6, a modified dosage schedule of donanemab was administered such that patients gradually increased the concentration from 350 mg to 1400 mg over the course of 24 weeks. Surprisingly, when compared to the standard treatment schedule (increasing from 700 mg to 1400 mg), the modified version reduced rates of ARIA by approximately 40% while still equally reducing Aβ plaque and cognitive decline (Clinical Trial Identification Number: NCT05738486).²⁷

The other major concerns are affordability and accessibility. In light of the severe side effects, treatment with either lecanemab or donanemab comes at an exorbitant price, as each drug’s annual cost is approximately $26,000 and $32,000 without insurance, respectively.²⁸ Both therapeutics are also only approved for the treatment of early-stage AD but not late-stage. This, unfortunately, means that accessibility could be more difficult for patients who do not display any early signs of cognitive decline. To offset these hurdles, several strategies have been put in place to increase affordability and accessibility. This includes leveraging insurance companies to mitigate out-of-pocket prices and the introduction of a cost-effective treatment plan to reduce the overconsumption of therapeutics long-term. Additionally, improvement of early-stage biomarkers for AD would enhance accessibility for patients to begin earlier treatment plans when therapeutics are the most effective in alleviating symptoms.²⁹

After decades of research failure, Aβ immunotherapy represents a pivotal advancement in the development of effective therapeutics for Alzheimer’s disease. The promising results of the clinical trials investigating monoclonal antibodies further highlights the benefit of targeting Aβ plaques to slow down disease progression and improve quality of life. Furthermore, this breakthrough opens up many doors in creating novel therapeutic strategies for patients with Alzheimer’s disease and dementia.

References

1.      2025 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2025;21(4):e70235.

2.       Nandi A, Counts N, Bröker J, et al. Cost of care for Alzheimer’s disease and related dementias in the United States: 2016 to 2060. npj Aging. 2024;10(1):13.

3.      Herrmann N, Abby L, and Lanctôt K. Memantine in dementia: a review of the current evidence. Expert Opinion on Pharmacotherapy. 2011;12(5):787-800.

4.      Palop JJ, Mucke L. Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nature Neuroscience. 2010;13(7):812-818.

5.      Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nature Reviews Drug Discovery. 2022;21(4):306-318.

6.      Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer’s Research & Therapy. 2014;6(4):37.

7.      Asher S, Priefer R. Alzheimer’s disease failed clinical trials. Life Sciences. 2022;306:120861.

8.      Wilson DM, III, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186(4):693-714.

9.      van der Flier WM, de Vugt ME, Smets EMA, Blom M, Teunissen CE. Towards a future where Alzheimer’s disease pathology is stopped before the onset of dementia. Nature Aging. 2023;3(5):494-505.

10.    Black RS, Barclay LL, Nolan KA, Thaler HT, Hardiman ST, Blass JP. Pentoxifylline in Cerebrovascular Dementia. Journal of the American Geriatrics Society. 1992;40(3):237-244.

11.    FISHER A, HELDMAN E, GURWITZ D, et al. M1 Agonists for the Treatment of Alzheimer’s Disease. Annals of the New York Academy of Sciences. 1996;777(1):189-196.

12.    Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer’s disease. Jama. 1992;268(18):2523-2529.

13.    Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. The American journal of psychiatry. 1984;141(11):1356-1364.

14.    Ihl R, Ferris S, Robert P, Winblad B, Gauthier S, Tennigkeit F. Detecting treatment effects with combinations of the ADAS‐cog items in patients with mild and moderate Alzheimer’s disease. International journal of geriatric psychiatry. 2012;27(1):15-21.

15.    Benge JF, Balsis S, Geraci L, Massman PJ, Doody RS. How well do the ADAS-cog and its subscales measure cognitive dysfunction in Alzheimer’s disease? Dementia and geriatric cognitive disorders. 2009;28(1):63-69.

16.    Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease. 2022;9(2):197-210.

17.    van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388(1):9-21.

18.    Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-27.

19.    Hardy JA, Higgins GA. Alzheimer’s Disease: The Amyloid Cascade Hypothesis. Science. 1992;256(5054):184-5.

20.    Lue LF, Walker DG. Modeling Alzheimer’s disease immune therapy mechanisms: Interactions of human postmortem microglia with antibody‐opsonized amyloid beta peptide. J Neuro Res. 2002;70(4):599-610.

21.    Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Scientific Reports. 2018;8(1):6412.

22.    Johannesson M, Söderberg L, Zachrisson O, et al. Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer’s disease brains. Molecular and Cellular Neuroscience. 2024;130:103949.

23.    Alawode DOT, Heslegrave AJ, Fox NC, Zetterberg H. Donanemab removes Alzheimer’s plaques: what is special about its target? The Lancet Healthy Longevity. 2021;2(7):e395-e396.

24.    Tampi RR, Forester BP, Agronin M. Aducanumab: evidence from clinical trial data and controversies. Drugs Context. 2021;10:2021-7-3.

25.    Withington CG, Turner RS. Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer’s Disease. Front Neurol. 2022;13:862369.

26.    Jeong SY, Suh CH, Kim SJ, Lemere CA, Lim JS, Lee JH. Amyloid-Related Imaging Abnormalities in the Era of Anti-Amyloid Beta Monoclonal Antibodies for Alzheimer’s Disease: Recent Updates on Clinical and Imaging Features and MRI Monitoring. Korean J Radiol. 2024;25(8):726-41.

27.    Wang H, Serap Monkul Nery E, Ardayfio P, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimers Dement. 2025;21(4):e70062.

28.    Nguyen HV, Mital S, Knopman DS, Alexander GC. Cost-Effectiveness of Lecanemab for Individuals With Early-Stage Alzheimer Disease. Neurology. 2024;102(7):e209218.

29.    Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-76.

Author: Caryssa Drinkuth
Editor: Macy Osborne-Frazier

Postpartum depression (PPD) is a serious and potentially life-threatening condition affecting women in their third trimester and up to 12 months after childbirth. Despite affecting 10 to 20 percent of women that have recently given birth, PPD remains clinically understudied, underdiagnosed, and undertreated.¹ On August 4th, 2023, the U.S. Food and Drug Administration (FDA) approved Sage Therapeutics’ Zurzuvae (zuranolone), making it the first oral medication approved to treat PPD in adults.² In this post, we will provide an overview of PPD and the available treatment options, discuss the mechanism of action and clinical trials for Zurzuvae, and conclude with the clinical impact of Zurzuvae’s approval. 

Overview of Postpartum Depression

PPD affects 10 to 20 percent of women that have given birth within the past 12 months, though some studies estimate that this prevalence may be much higher given that only 30.8 percent of women with PPD receive a diagnosis.¹ PPD is not recognized as a unique diagnostic category but rather is classified as a subtype of Major Depressive Disorder (MDD) (“MDD with peripartum onset”) under the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).¹ The onset of PPD typically occurs either during the third trimester of pregnancy or within 4 weeks of delivery.^1,3 It is accompanied by symptoms including depressed mood, diminished interest in activities or lack of pleasure (anhedonia), feelings of worthlessness, and changes in sleep, eating, and concentration.^1,4 

Clinical identification and treatment of PPD is of particular importance because of the sensitive nature of the perinatal period (between pregnancy and up to a year after birth). Left untreated, PPD may have adverse effects on the quality of life and health of both mothers and their newborn children. Women experiencing PPD may struggle with childcare tasks, face marital issues, and have impaired ability to bond with their child.⁴ In severe cases, women may have thoughts of harming themselves or their children, with suicides accounting for 20 percent of postpartum deaths.^1,4 

Pathology

The pathophysiology of PPD is complex and not fully understood. Prevailing theories suggest that PPD is a result of a sudden drop in neurosteroid hormones including progesterone and estradiol, which are highly expressed during pregnancy but drastically reduced following childbirth.^1,4,5 Sudden withdrawal of these hormones has been associated with dysregulation of the neuroendocrine system and abnormal functioning of the hypothalamus-pituitary-adrenal (HPA) axis.⁶ The HPA axis regulates the body’s response to stress, primarily through secretion of cortisol, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH).^4,6 In the HPA pathway, an initial stressor invokes the release of CRH from paraventricular nucleus (PVN) neurons of the hypothalamus.⁷ Circulating CRH enables release of ACTH from the pituitary gland into systemic circulation, promoting synthesis and secretion of cortisol.⁷ Therefore, a prominent theory explaining the development of PPD is attributed to sudden drops in neurosteroid hormones after childbirth, leading to dysregulation of the HPA pathway and abnormal stress responses. Disinhibition of the HPA axis is suspected to contribute to PPD based on evidence demonstrating elevated levels of cortisol, CRH, and ACTH in patients diagnosed with PPD, as well as the fact that repeated stress is considered a major risk factor for depressive disorders.^4,6

Other studies have focused on how these neuroendocrine changes impair proper neurotransmission. Similarly to MDD, alterations in the neurotransmission of serotonin, dopamine, and gamma-aminobutyric acid (GABA) have been suggested to contribute to the manifestation of PPD.^1,5 Preclinical evidence has pointed to a role of reduced serotonin and dopamine levels in abnormal maternal behavior.¹ The role of serotonin in PPD is also evidenced by the fact that selective-serotonin reuptake inhibitors (SSRIs) are commonly prescribed for and effectively treat PPD, though they may require up to 6 weeks to improve depressive symptoms.^8,9 The role of GABA signaling in PPD has been supported by preclinical studies demonstrating PPD-like behaviors in mice lacking the GABA_A receptor (GABA_AR) δ subunit.¹⁰ Preclinical PPD models have also functionally linked deficits in GABA signaling to dysregulation of the HPA axis.¹⁰ Interestingly, GABA signaling is thought to be dysregulated in PPD by rapid reductions in allopregnanolone, the neuroactive metabolite of progesterone, which acts as an allosteric modulator at GABA_ARs.^11,12 Lower levels of allopregnanolone are associated with greater depression scores in late pregnancy, and increased allopregnanolone levels have been shown to be protective against PPD.¹

Various psychological and social risk factors may also be involved in the development of PPD. Mothers faced with prior negative life experiences, history of stress, anxiety, or depressive disorders, marital/familial/financial challenges, or impaired infant-mother contact may be at increased risk of developing PPD.⁴ Thus, PPD arises from a complex mixture of psychosocial, neuroendocrine, and neurotransmitter-related risks, often necessitating a combination of treatment approaches.

Diagnosis & Treatments

Diagnosis: The American College of Obstetricians and Gynecologists (ACOG) recommends screening for PPD at least once during prenatal and postpartum follow-up visits.⁸ There are currently 12 available instruments for clinical screening for PPD; the Edinburgh Postnatal Depression Scale (EPDS), which ranks depression symptoms on a scale of 0-30, is considered the gold standard for detection of PPD amongst clinicians.⁴ Despite the call for PPD screening, only 30.8% of women with PPD are diagnosed, and only 15.8% of women with a diagnosis receive treatment.¹³ Some patients and clinicians may be hesitant to initiate treatment with pharmacotherapies while breastfeeding due to concerns regarding the health of their infant.^4,8 While the risks of no treatment typically outweigh the risks of pharmacotherapies, it is important for both patients and clinicians to consider and weigh these risks on an individual basis, particularly if the infant is born premature or facing health complications.^8,9

Psychotherapy and Lifestyle Interventions: Due to the numerous psychosocial risk factors that may contribute to PPD, psychotherapies and peer support groups are common first-line treatments that have been shown to effectively reduce depressive symptoms in women with mild to moderate PPD.^4,8 Cognitive behavioral therapy (CBT), a structured, goal-oriented talk therapy that aims to identify and modify negative thoughts or behaviors, is commonly used for treatment of PPD.⁴ Interpersonal therapy (IPT), which aims to improve interpersonal relationships and role transitions that may contribute to depressive symptoms, is also commonly used to manage PPD.⁴ All psychotherapies are aimed at improving self-care, enhancing family and social support systems, and addressing negative life events or stressors.^9,14 Familial and community participation in household and childcare responsibilities is particularly helpful in alleviating stress and providing opportunities for emotional support and bonding. Evidence also demonstrates the importance of lifestyle interventions, including exercise, adequate sleep, and healthy diet, in improving depressive symptoms.⁴

Pharmacotherapies: Pharmacotherapies are often necessary and used alone or in combination with psychotherapy for patients with moderate to severe PPD. SSRIs, such as fluoxetine, sertraline, and escitalopram, are first-line pharmacotherapies for PPD.^5,9 SSRIs are non-specific to PPD but are broadly indicated to treat anxiety and depressive symptoms. SSRIs are favored compared to other antidepressant medications as they show high tolerability and minimal passage into breast milk; therefore, SSRIs are generally considered safe for mothers and their breastfed infants.⁹ Although SSRIs are acutely effective in reducing symptoms of PPD, symptom improvement may take up to 4 to 6 weeks, and few studies have examined the efficacy of protracted (>6 months) SSRI treatment on mother-infant outcomes.¹⁵

In 2019, Brexanolone (Zulresso) became the first FDA-approved pharmacotherapy specifically indicated for treatment of PPD.¹² Brexanolone is a synthetic, intravenous preparation of allopregnanolone that acts via positive allosteric modulation (PAM) of GABA_ARs.^4,8 Clinical trials with Brexanolone demonstrated significant and rapid improvement of depressive symptoms in women with PPD.^8,9 However, Brexanolone must be administered intravenously in a healthcare setting over a 60-hour period and costs more than $34,000 per patient, making treatment particularly challenging for new mothers.^3,8 Further, breastfeeding is not recommended for up to 4 days following Brexanolone infusion due to potential passage of the medication into breast milk.⁸ Because of this, implementation of Brexanolone as a treatment for PPD has been limited, but its approval has promoted a growing interest in GABA_AR PAM as a treatment for PPD.

Mechanism of Action

Zurzuvae, like Brexanolone, is a synthetic preparation of allopregnanolone that exerts its antidepressant actions through selective PAM of GABA_ARs. In this sense, Zurzuvae mimics the endogenous effects of allopregnanolone and acts to supplement the severe drop in allopregnanolone following birth that contributes to depressive symptoms. Although not fully understood, ongoing studies are attempting to elucidate the antidepressant effects of GABA_AR PAM. PAM at synaptic and extrasynaptic GABA_ARs is known to prolong the opening time of the GABA_AR chloride ion channel.^12,16 This modulatory activity increases the efficacy of GABA at GABA_ARs, potentiating the inhibition of GABA_AR-containing neurons.¹⁶ Increased GABAergic inhibitory tone may, in turn, normalize disruptions in the function of the HPA axis that are implicated in PPD. Specifically, inhibitory inputs from GABAergic neurons projecting to the PVN, a key region involved in regulation of the HPA axis, may inhibit release of pro-stress hormones like CRH, ACTH, and cortisol, resulting in anxiolytic and antidepressant effects.^11,17

Unlike SSRIs, the antidepressant effects of Zurzuvae are fast-acting, delivering significant clinical improvement within a few days of treatment.^10,18 In contrast to Zulresso, which is cost-prohibitive and must be administered in a healthcare setting, Zurzuvae is less expensive (~$16,000 for 2 weeks but covered by most insurers¹⁹) and may be taken at home. Zurzuvae is available as a 50 mg oral pill, intended to be taken nightly over 14 days.^2,8 Zurzuvae may have central nervous system depressant effects, including headache, somnolence (drowsiness), and dizziness, thus patients should not operate motor vehicles or use other substances that depress the central nervous system (e.g. alcohol, opioids, tricyclic antidepressants) for at least 12 hours following dosing. Zuranolone passes into breast milk with a relevant infant dose lower than that of SSRIs; however, due to a lack of relevant data, patients are recommended to use caution and consult with their provider if they are breastfeeding during treatment.⁸

Clinical Trials

The safety and efficacy of Zurzuvae was tested in two phase 3 randomized, double-blinded, placebo-controlled, multicenter studies. These two studies enrolled a total of 361 women who were between the ages of 18 and 45 years old, less than 6 months postpartum, and diagnosed with a major depressive episode without psychosis occurring as early as the third trimester of pregnancy or as late as 4 weeks postpartum.^10,18 The severity of PPD was determined by baseline scoring of depressive symptoms on a 17-item Hamilton Rating Scale for Depression (HAMD-17). Women with baseline HAMD-17 scores of 26 or higher were eligible to participate in the study.^10,18 Participants were not permitted to breastfeed during treatment or for 1 week following treatment.^10,18 Participants were randomized 1:1 such that an equal number of participants received either 50 mg/day of Zurzuvae or placebo orally once daily for 14 days.¹⁸ Changes in HAMD-17 scores between baseline and day 15 were used as the primary endpoint to assess efficacy of Zurzuvae treatment. Secondary endpoints included HAMD-17 responses at days 3, 8, 21, and 45.^10,18 Safety and tolerability were evaluated by the occurrence of adverse events, vital signs, clinical laboratory measurements, and electrocardiogram. Both clinical studies demonstrated statistically significant improvement in depressive symptoms at the primary endpoint following Zurzuvae treatment.^10,18 The response was rapid and sustained, with patients receiving Zurzuvae showing significant symptom improvement beginning 3 days into treatment and lasting up to 45 days (4 weeks after treatment ended).¹⁸

Zurzuvae was generally well-tolerated by participants. The most commonly reported adverse effects included somnolence, headache, dizziness, sedation, and diarrhea.^10,18 No clinically significant changes in vital signs, clinical laboratory measurements, or electrocardiogram readings were observed.^10,18 Altogether, the FDA approved Zurzuvae based on a favorable safety profile, high tolerability, and meaningful reductions in the severity of depressive symptoms following 2 weeks of once-daily treatment. Further studies will be necessary to determine the safety of breastfeeding during Zurzuvae treatment and sustainability of the treatment response beyond 45 days.^3,10,18 

Clinical Significance

Few women with PPD receive a diagnosis, and even fewer receive adequate treatment. The FDA’s approval of Zurzuvae marks a promising step in the development of novel pharmacological treatments for the management of PPD. To date, Zurzuvae is the only oral medication specifically indicated for treatment of PPD. Zurzuvae may be self-administered at home, making this medication particularly useful for new mothers that do not have the time or resources to seek treatment in a healthcare setting. Further, Zurzuvae’s fast-acting antidepressant effects may prove promising for patients with moderate to severe PPD that require more rapid symptom relief than can be accomplished with SSRIs.

Zurzuvae and Brexanolone are also the first neurosteroid medications to receive FDA approval, opening the door to the possibilities of neurosteroid-based therapies as treatment options for other mental health conditions. For conditions involving protracted stress, including MDD and post-traumatic stress disorder (PTSD), allopregnanolone may be a promising treatment.¹¹ Allopregnanolone analogs (e.g. SAGE-217) are actively being investigated for the treatment of MDD and have shown promise in initial clinical trials.¹¹ Thus, neurosteroid-based therapeutics may become a powerful tool for the treatment of stress-related disorders.

Publication Licenses

1. Created in BioRender. Drinkuth, C. (2025) https://BioRender.com/v557o9y
2. Created in BioRender. Drinkuth, C. (2025) https://BioRender.com/k22jvil

Reference list

1. Payne JL, Maguire J. Pathophysiological mechanisms implicated in postpartum depression. Front Neuroendocrinol. 2019;52:165-180. doi:10.1016/j.yfrne.2018.12.001

2. U.S. Food & Drug Administration. FDA Approves First Oral Treatment for Postpartum Depression. FDA News Release. Published August 4, 2023. Accessed May 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression#:~:text=Today%2C%20the%20U.S.%20Food%20and,the%20later%20stages%20of%20pregnancy. 

3. Oliveira JA, Eskandar K, Freitas MAA, Philip CE. Zuranolone for postpartum depression: a systematic review and meta-analysis of two randomized studies. Rev Bras Ginecol Obstet. 2024;46. doi:10.61622/rbgo/2024rbgo79

4. Khamidullina Z, Marat A, Muratbekova S, et al. Postpartum Depression Epidemiology, Risk Factors, Diagnosis, and Management: An Appraisal of the Current Knowledge and Future Perspectives. J Clin Med. 2025;14(7). doi:10.3390/jcm14072418

5. Suryawanshi O, Pajai S. A Comprehensive Review on Postpartum Depression. Cureus. 2022;14(12):e32745. doi:10.7759/cureus.32745

6. Brummelte S, Galea LA. Depression during pregnancy and postpartum: contribution of stress and ovarian hormones. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(5):766-76. doi:10.1016/j.pnpbp.2009.09.006

7. Herman JP, McKlveen JM, Ghosal S, et al. Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol. 2016;6(2):603-21. doi:10.1002/cphy.c150015

8. Moore Simas TA, Whelan A, Byatt N. Postpartum Depression-New Screening Recommendations and Treatments. JAMA. 2023;330(23):2295-2296. doi:10.1001/jama.2023.21311

9. Stewart DE, Vigod SN. Postpartum Depression: Pathophysiology, Treatment, and Emerging Therapeutics. Annu Rev Med. 2019;70:183-196. doi:10.1146/annurev-med-041217-011106

10. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(9):951-959. doi:10.1001/jamapsychiatry.2021.1559

11. Almeida FB, Pinna G, Barros HMT. The Role of HPA Axis and Allopregnanolone on the Neurobiology of Major Depressive Disorders and PTSD. Int J Mol Sci. 2021;22(11). doi:10.3390/ijms22115495

12. Cutler AJ, Mattingly GW, Maletic V. Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder. Transl Psychiatry. 2023;13(1):228. doi:10.1038/s41398-023-02514-2

13. Kaufman Y, Carlini SV, Deligiannidis KM. Advances in pharmacotherapy for postpartum depression: a structured review of standard-of-care antidepressants and novel neuroactive steroid antidepressants. Ther Adv Psychopharmacol. 2022;12:20451253211065859. doi:10.1177/20451253211065859

14. Le J, Alhusen J, Dreisbach C. Screening for Partner Postpartum Depression: A Systematic Review. MCN Am J Matern Child Nurs. 2023;48(3):142-150. doi:10.1097/NMC.0000000000000907

15. De Crescenzo F, Perelli F, Armando M, Vicari S. Selective serotonin reuptake inhibitors (SSRIs) for post-partum depression (PPD): a systematic review of randomized clinical trials. J Affect Disord. 2014;152-154:39-44. doi:10.1016/j.jad.2013.09.019

16. Zorumski CF, Paul SM, Covey DF, Mennerick S. Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiol Stress. 2019;11:100196. doi:10.1016/j.ynstr.2019.100196

17. Camille Melon L, Maguire J. GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function. J Steroid Biochem Mol Biol. 2016;160:196-203. doi:10.1016/j.jsbmb.2015.11.019

18. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the Treatment of Postpartum Depression. Am J Psychiatry. 2023;180(9):668-675. doi:10.1176/appi.ajp.20220785

19. Policy Center for Maternal Mental Health. One Year Later: How Insurers Are Covering Zurzuvae, the First Postpartum Depression Pill. Published December 4, 2024. Accessed May 25, 2025. https://policycentermmh.org/one-year-later-how-insurers-are-covering-zurzuvae-the-first-postpartum-depression-pill/#:~:text=All%20Six%20Large%20Insurers%20Now,Manager%20(PBM)%20drug%20formularies. 

Author: Macy Osborne-Frazier
Editor: Anna Goddard

This article will cover the use of the immune checkpoint inhibitor (ICI)  pembrolizumab to treat endometrial cancer (EC). This drug, developed by Merck and sold under the brand name KEYTRUDA, was originally approved to be used as a single agent by the Food and Drug Administration (FDA) to treat mismatch repair deficient (MMRd) ECs on March 21, 2022.¹ More recently, on June 17, 2024, pembrolizumab in combination with the chemotherapies carboplatin and paclitaxel followed by single agent pembrolizumab was approved to treat primary advanced or recurrent ECs.² Here, we discuss the treatment of EC, the mechanism of action of ICIs, and the efficacy and side effects of ICI treatment in EC.

Overview of Endometrial Cancer

Endometrial cancer (EC) is a cancer of the epithelial lining of the uterus, most often attributed to an abundance of estrogen, a primary growth signal in the uterus.³ EC is the most common gynecologic malignancy in developed nations and is the cancer most closely associated with obesity.^4,5 Unlike most cancer types, both the incidence rates, or the amount of people being diagnosed, and mortality rates of EC are rising.⁵ This year alone, it is estimated that 69,120 women in the United States will be diagnosed with EC and 13,860 deaths will be attributed to EC.⁵  This rise has partially contributed to the global rise in obesity rates; however, many of the mechanisms through which the cancer develops and survives remain unclear, making it difficult to develop targeted treatment options. EC primarily effects postmenopausal women, but EC rates in women under the age of 50 are also steadily rising.⁶ One of the most common symptoms of EC is irregular vaginal bleeding, a symptom often overlooked by women, especially those that are pre-menopausal.⁷

Approximately 30% of EC cases diagnosed are MMRd.⁸ Mismatch repair functions repair mistakes that occur when cells copy DNA during cell replication.⁹ MMRd endometrial tumors arise from cells that lack functional mismatch repair proteins, either by spontaneous hypermethylation of the promoter sequence, which inhibits proteins from binding the DNA and expressing the mismatch repair genes, or inherited mutations in one or more of the genes encoding mismatch repair proteins.¹⁰ MMRd tumors display a hypermutated phenotype due to the inability to repair DNA mismatches.¹⁰ This hypermutated phenotype often correlates with very high tumor mutational burdens (TMBs) in ECs that are MMRd (Figure 1).^11,12 High TMBs mean the tumor has many mutations that can be presented to the immune system to generate an anti-tumor response, often times correlating with improved survival.¹³ Given that pembrolizumab was approved for MMRd tumors with high TMBs, such as gastric and colorectal cancers, ICIs are considered excellent treatment options for MMRd ECs.^13,14

Treatment Options for Endometrial Cancer

Subtyping of EC has encouraged targeted options for EC treatment, such as the use of ICIs for MMRd tumors; however, the majority of EC cases are still treated with traditional, cytotoxic chemotherapies.¹⁵ Frontline therapy for EC is often a doublet of carboplatin and paclitaxel, chemotherapies which stop cancer cell division, with a success rate of ~47% in advanced EC cases.¹⁶ The success rate of chemotherapy following recurrence drops starkly to ~15%.¹⁷ If EC is detected early, the most common treatment method is a complete hysterectomy, often including removal of the surrounding lymph nodes and ovaries.¹⁸ For high-risk ECs, secondary radiation therapy is common following hysterectomy.¹⁹

Several clinical trials have evaluated the addition of adjuvant chemotherapy along with radiotherapy and have reported conflicting results.²⁰ Both the NSGO−9501/ EORTC−5591-trial and the PORTEC-3 trial reported increased recurrence-free survival with the addition of adjuvant chemotherapy.^21,22 However, treatment-related morbidity and toxicities were significantly higher in the chemoradiation group of the PORTEC-3 trial, with late morbidity occurring in 25% of patients and late toxicity occurring in 22-26% of patients depending on the radiation method.²¹ On the other hand, the GOG-249 and GOG-258 trials reported no significant increases in recurrence-free survival with the addition of chemotherapy.^23,24 As previously mentioned, a rise in pre-menopausal EC diagnoses has been noted.⁶ Given that hysterectomies result in complete loss of fertility and cytotoxic chemotherapies are often accompanied by unfavorable side effects, interest in more targeted treatment modalities, such as ICIs, has been high.

Immune Checkpoint Inhibitor Mechanism of Action

The rising interest in using ICIs to treat ECs with high TMBs has led to the FDA approval of pembrolizumab to treat MMRd and primary advanced or recurrent ECs.^25,26 Pembrolizumab is a type of ICI that inhibits the PD-1/PD-L1 pathway and is already approved to treat multiple types of solid tumors.²⁷ Cancers with high TMBs, such as MMRd ECs, attract an immune response as the high number of mutations generates neoantigens to present to immune cells.^11,12 When a circulating T cell recognizes and binds to a neoantigen expressed by the tumor cell, a cytotoxic immune response results in the killing of the tumor cell.²⁸ In addition, cytokines released from the activated T cell recruit more immune cells to the tumor.²⁹ To evade this interaction with T cells, tumors can upregulate expression of the PD-L1 and PD-L2 ligands on the cell membrane.³⁰ PD-L1 and PD-L2 ligands interact with the PD-1 receptor expressed on the surface of T cells.³⁰ This interaction inhibits the T cell response against the tumor cells, allowing the tumor to evade detection of T cells.³⁰ Pembrolizumab is an anti-PD-1 antibody that binds to PD-1 on tumor cells, which inhibits PD-L1 or PD-L2 from interacting with PD-1 and, therefore, restores T cell mediated killing of tumor cells (Figure 2).²⁷

Efficacy and Side Effects of Pembrolizumab in Treating Endometrial Cancer

In 2022, pembrolizumab was approved for treating MMRd ECs that had disease progression following chemotherapy treatment and were not candidates for surgery.¹ This approval was based on the results of cohorts D and K of the Keynote-158 (NCT02628067) trial.^1,13,25 This non-randomized trial enrolled endometrial, gastric, and small intestine MMRd cancer patients that had previously received treatment.^13,25 Of the eligible EC patients, the objective response rate was 48% in patients that received 200 mg of pembrolizumab once every 3 weeks for 35 cycles.^13,25 This includes 11 patients that had a complete response, defined by the disappearance of all targeted lesions, to pembrolizumab treatment at a median follow-up time of 16 months.^13,25 Of the patients that did not respond, progression-free survival was 13.1 months compared to a progression-free survival of 10 months in patients treated with chemotherapies.^13,17,25 No fatal adverse events (AEs) were reported, but 68% of enrolled patients reported an AE.^13,25 The most commonly reported AEs were itching, fatigue, and diarrhea.^13,25 Only 12% of patients had more serious grade 3 or grade 4 AEs, defined as medically severe events (grade 3) and life-threatening events (grade 4), most commonly hyperglycemia, or high sugar, and reduced lymphocyte counts.^13,25 All grade 4 AEs resolved, and only 7% of patients discontinued treatments as a result of AEs.^13,25

In 2024, pembrolizumab taken with carboplatin and paclitaxel, followed by single-agent pembrolizumab was approved for primary advanced or recurrent ECs, regardless of mismatch repair status. The approval was based on the results of the KEYNOTE-868/NRG-GY018 (NCT03914612) study.² This was a randomized, double-blind trial, meaning neither participant nor researcher knew which treatment the patient was receiving. 816 advanced stage or recurrent EC patients were assigned to either the pembrolizumab plus chemotherapy or placebo plus chemotherapy arm.²⁶ Patients were divided based on their mismatch repair status with an MMRd cohort and mismatch repair proficient (MMRp) cohort.²⁶ Pembrolizumab (400 mg) was given every 6 weeks for 14 cycles.²⁶ After 12 months, progression-free survival in the MMRd cohort was estimated to be greater than 36 months in the pembrolizumab group and 7.6 months in the placebo group.²⁶ In the MMRp cohort, the median progression-free survival was 13.1 months in the pembrolizumab group and 8.7 months in the placebo group.²⁶ AEs were similar regardless of mismatch repair status, with the most common AEs being fatigue, neuropathy, anemia, and nausea.²⁶ Intravenous infusion reactions occurred in approximately 14% of patients in both the MMRd and MMRp cohorts.²⁶ Within the MMRd cohort, only 1 (0.9%) AE resulted in death. In the MMRp cohort, 6 (2.2%) AEs resulted in death.²⁶

Taken together, pembrolizumab is an exciting treatment option for MMRd and advanced or recurrent ECs. ICIs are generally well-tolerated and have milder side effects than many chemotherapies. The option for a fertility-sparing treatment is also particularly exciting as the age of EC diagnosis continues to trend towards younger patients. The approval and success of pembrolizumab in MMRd ECs also paves the way for ICI treatment in other MMRd cancer types.

References

1.    U.S. Food and Drug Administration. FDA approves pembrolizumab for advanced endometrial carcinoma. March 21, 2022. Accessed April 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-endometrial-carcinoma#:~:text=On%20March%2021%2C%202022%2C%20the,for%20curative%20surgery%20or%20radiation.

2.    U.S. Food and Drug Administration. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. June 17, 2024. Accessed April 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma

3.    Rodriguez AC, Blanchard Z, Maurer KA, Gertz J. Estrogen Signaling in Endometrial Cancer: a Key Oncogenic Pathway with Several Open Questions. Horm Cancer. 2019;10(2-3):51-63. doi:10.1007/s12672-019-0358-9

4.    Onstad MA, Schmandt RE, Lu KH. Addressing the role of obesity in endometrial cancer risk, prevention, and treatment. J Clin Oncol. 2016;34(35):4225-4230. doi:10.1200/JCO.2016.69.4638

5.    Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820

6.    Liu L, Habeshian TS, Zhang J, et al. Differential trends in rising endometrial cancer incidence by age, race, and ethnicity. JNCI Cancer Spectr. 2023;7(1). doi:10.1093/jncics/pkad001

7.    Braun MM, Overbeek-Wager EA, Grumbo RJ. Diagnosis and Management of Endometrial Cancer. Am Fam Physician. 2016;93(6):468-474.

8.    Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. doi:10.1038/nature12113

9.    Li G-M. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18(1):85-98. doi:10.1038/cr.2007.115

10.   Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J. Gynecological cancers caused by deficient mismatch repair and microsatellite instability. Cancers (Basel). 2020;12(11). doi:10.3390/cancers12113319

11.   Kim T-M, Laird PW, Park PJ. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell. 2013;155(4):858-868. doi:10.1016/j.cell.2013.10.015

12.   Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. doi:10.1186/s13073-017-0424-2

13.   Maio M, Ascierto PA, Manzyuk L, et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022;33(9):929-938. doi:10.1016/j.annonc.2022.05.519

14.   Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. doi:10.1126/science.aan6733

15.   Corr B, Cosgrove C, Spinosa D, Guntupalli S. Endometrial cancer: molecular classification and future treatments. bmjmed. 2022;1(1):e000152. doi:10.1136/bmjmed-2022-000152

16.   Sovak MA, Dupont J, Hensley ML, et al. Paclitaxel and carboplatin in the treatment of advanced or recurrent endometrial cancer: a large retrospective study. Int J Gynecol Cancer. 2007;17(1):197-203.

17.   Rubinstein M, Halpenny D, Makker V, Grisham RN, Aghajanian C, Cadoo K. Retreatment with carboplatin and paclitaxel for recurrent endometrial cancer: A retrospective study of the Memorial Sloan Kettering Cancer Center experience. Gynecol Oncol Rep. 2019;28:120-123. doi:10.1016/j.gore.2019.04.002

18.   Sonoda Y. Surgical treatment for apparent early stage endometrial cancer. Obstet Gynecol Sci. 2014;57(1):1-10. doi:10.5468/ogs.2014.57.1.1

19.   Klopp A, Smith BD, Alektiar K, et al. The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2014;4(3):137-144. doi:10.1016/j.prro.2014.01.003

20.   van den Heerik ASVM, Horeweg N, de Boer SM, Bosse T, Creutzberg CL. Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy. Int J Gynecol Cancer. 2021;31(4):594-604. doi:10.1136/ijgc-2020-001822

21.   Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet. 2000;355(9213):1404-1411. doi:10.1016/s0140-6736(00)02139-5

22.   Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer–results from two randomised studies. Eur J Cancer. 2010;46(13):2422-2431. doi:10.1016/j.ejca.2010.06.002

23.   Randall ME, Filiaci V, McMeekin DS, et al. Phase III Trial: Adjuvant Pelvic Radiation Therapy Versus Vaginal Brachytherapy Plus Paclitaxel/Carboplatin in High-Intermediate and High-Risk Early Stage Endometrial Cancer. J Clin Oncol. 2019;37(21):1810-1818. doi:10.1200/JCO.18.01575

24.   Matei D, Filiaci V, Randall ME, et al. Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer. N Engl J Med. 2019;380(24):2317-2326. doi:10.1056/NEJMoa1813181

25.   O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol. 2022;40(7):752-761. doi:10.1200/JCO.21.01874

26.   Esk R, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med. 2023;388(23):2159-2170.

27.   Merck. Mechanism of Action: KEYTRUDA® (pembrolizumab): PD⁠-⁠1 Receptor Blockade. Accessed April 16, 2025. https://www.keytrudahcp.com/resources/mechanism-of-action/

28.   Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359-367. doi:10.1038/s41416-020-01048-4

29.   Zhang Y, Guan X-Y, Jiang P. Cytokine and Chemokine Signals of T-Cell Exclusion in Tumors. Front Immunol. 2020;11:594609. doi:10.3389/fimmu.2020.594609

30.   Wu Y, Chen W, Xu ZP, Gu W. PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Front Immunol. 2019;10:2022. doi:10.3389/fimmu.2019.02022

Publication Licenses for Figures:

Figure 1: Created in BioRender. Osborne-Frazier, M. (2025) https://BioRender.com/n4vy3sj 

Figure 2: Created in BioRender. Osborne-Frazier, M. (2025) https://BioRender.com/wox4ibn

Author: Misha Fini 
Editor: Morgan McCullough 

What is Cystic Fibrosis?

Cystic fibrosis (CF) is a genetic disease caused by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein resides on the apical surface of epithelial cells and functions as a cyclic adenosine monophosphate (AMP)-dependent ion channel, modulating the flux of ions into and out of the cell.^1,2 More specifically, the CFTR protein regulates movement of chloride (Cl^–) and bicarbonate anions out of the cell, while the epithelial sodium channel (ENaC) allows for movement of positive sodium ions (Na⁺) into lung epithelial cells. Dysfunction of this CFTR channel allows for the buildup of ions inside the cell, causing water (H₂O) from the mucus layer to permeate in, thickening the mucus layer, and making it difficult to clear from the lungs (Figure 1). This can lend itself to pulmonary infections due to dysfunctional mucociliary clearance. This gene is essential in maintaining proper hydration and mucus production, especially in the lungs, pancreas, intestines, and reproductive organs.

The clinical manifestations of CF display variability such as multi-organ disease states, leading to renal failure, intestinal issues, pancreatic insufficiency, reproductive complications, and most commonly pulmonary obstruction.² Disease severity, in part, is determined by each patient’s mutational landscape of the CFTR gene.^1,2,3 Thus far, about 2,000 mutational variants of the CFTR gene have been recorded. The severity of clinical manifestations is dependent upon the mutational status, leading to partial or total loss of function of the CFTR protein.^3,4,5

Patients with CF struggle with frequent hospitalizations associated with pulmonary obstruction and lung infections due to their inability to clear mucus from their lungs. The dehydration of the mucus layer (Figure 1) leads to mucus plugging the airway, bacterial colonization, and large-scale inflammation in the lungs, leading to fibrosis of the tissue and eventually pulmonary impairment.^2,4,6 While these complications can occur, the life expectancy of patients with CF has drastically increased from 11 years in the 1980s to 60 years in present day with the advancement of therapeutic modulators.^7,8

Therapeutic Landscape for Cystic Fibrosis

Traditionally, CF treatment only involved treating symptoms resulting from the disease. However, since 2012, CFTR modulators have become available for patients who carry certain mutations of the CFTR gene.

Ivacaftor became the first CFTR modulator approved by the Food and Drug Administration (FDA) in 2012. This drug was most commonly used for the G551D mutation where the glycine at position 551 of the protein is replaced with aspartic acid. This is classified as a class III mutation where the CFTR protein reaches the cell surface but does not function properly. It is one of the most common CFTR mutations. Ivacaftor was able to improve lung functionality. Ivacaftor binds to the CFTR protein and aids in maintaining the channel’s open conformation, allowing ions to pass through.¹¹ In 2017, the drug was approved for an additional 23 mutations with partial functionality of the CFTR protein.^11,12  While this was a breakthrough for many CF patients, Ivacaftor was only able to treat about 10% of all CF patients due to the diversity of the CFTR gene mutations.¹¹

The most common mutation for CF patients is the F508del. This mutation is a deletion of phenylalanine at position 508 of the protein, leading to a loss-of-function. While Ivacaftor alone is not effective for treating CF patients with this mutation, it is effective when used in combination with another CFTR modulators.^11,12  Other modulators have been studied for this mutation such as Lumacaftor (known as VX -809 during its investigational phase), which was used as monotherapy. Lumacaftor alone did not have efficacy in symptom treatment, but it was able to increase surface expression of the CFTR protein.¹³ Lumacaftor used in combination with Ivacaftor was able to provide long-term therapeutic benefit by slowing down lung deterioration. Lumacaftor helped increase surface expression of CFTR while Ivacaftor aided in keeping the ion channel open.^14,15  In a similar fashion, Tezacaftor in combination Ivacaftor achieves the same effect. Tezacaftor aids in trafficking the CFTR protein to the cell surface, and Ivacaftor aids in keeping the ion channel in an open conformation.¹⁶ In 2019, a triple combination of modulators (Elexacaftor-Tezacaftor-Ivacaftor) was approved, which has broadened the therapeutic landscape for CF patients even more.¹⁷ With the advent, combination, and  approval of these modulators, treatment has expanded to 90% of CF patients. While these drug treatments have been revolutionary in expanding options to patients, the side effects, accessibility, and efficacy of these treatments can be improved upon. In addition, 10% of patients who do not have compatible mutations for these modulators are not able to receive them, leaving an untreated population of CF patients.

ReCode Therapeutics and mRNA therapy for CF Patients

ReCode Therapeutics is a clinical-stage company specializing in precision delivery of mRNA for genetic diseases.  The RCT2100 is an inhaled nebulized mRNA delivery platform using ReCode’s proprietary selective organ targeting lipid nanoparticle (SORT LNP).¹⁸ Traditional lipid nanoparticles are comprised of a sterol, pegylated lipid, ionizable cationic lipid, and phospholipids. When an LNP product is administered, it is usually trafficked to the liver, missing key organs of interest for targeted therapy. ReCode’s SORT LNP has two additional modified lipids and a proprietary lipid mixture in its structure that allows it not to be taken up by the liver and instead delivers it to targeted organs such as the lungs.¹⁸

Currently underway is a multipart phase 1 clinical trial using the RCT2100 mRNA therapeutic platform to give a healthy copy of the CFTR gene to patients via nebulizer administration.¹⁹ This is the first-in-human study of RCT2100 mRNA in SORT LNP formulation. In part 1, healthy participants of any gender from 18-55 years of age with BMI of 16-32 kg/m², and an forced lung expiratory volume in one second (FEV1) of at least 80% will be considered to assess biodistribution, tolerability, and safety of the drug.²⁰ In part 1, RCT2100 will be supplied in varying dose strengths administered via oral inhalation using a nebulizer.²⁰ 

In part 2, patients with a confirmed CF diagnosis and a FEV1 between 40% and 100% will be considered.²⁰ Patients who are and are not eligible for CFTR modulators are able to participate, but they must not be taking CFTR modulators over the course of the clinical trial.²⁰ In part 2, patients will be given RCT2100 at varying dose strengths administered via oral inhalation using a nebulizer for 4 weeks or at a single dose strength for 12 weeks.²⁰ 

The readout of both parts of the trial involve clinically defined adverse events, such as increased fatigue, seizures, headaches, or injuries, and serious adverse events, which would involve hospitalizations, disability, or death.²⁰

The goal of this new drug is to aid the 10% of patients who have missense mutations and are not eligible for the current modulators on market.²⁰ If this drug makes it to market, this would be another breakthrough in treating CF patients.

References:

1. Ooi CY, Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. Journal of Cystic Fibrosis. 2012;11(5):355-362. doi:10.1016/j.jcf.2012.05.001

2.  Mall MA, Burgel PR, Castellani C, Davies JC, Salathe M, Taylor-Cousar JL. Cystic fibrosis. Nat Rev Dis Primers. 2024;10(1):53. doi:10.1038/s41572-024-00538-6

3. Farinha CM, Callebaut I. Molecular mechanisms of cystic fibrosis – how mutations lead to dysfunction and guide therapy. Biosci Rep. 2022;42(7):BSR20212006. doi:10.1042/BSR20212006

4. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16(1):45-56. doi:10.1038/nrg3849

5. Cutting GR. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Annals of the New York Academy of Sciences. 2010;1214(1):57-69. doi:10.1111/j.1749-6632.2010.05879.x

6. Livraghi A, Randell SH. Cystic Fibrosis and Other Respiratory Diseases of Impaired Mucus Clearance. Toxicol Pathol. 2007;35(1):116-129. doi:10.1080/01926230601060025

7. McBennett KA, Davis PB, Konstan MW. Increasing life expectancy in cystic fibrosis: Advances and challenges. Pediatric Pulmonology. 2022;57(S1). doi:10.1002/ppul.25733

8. Cystic fibrosis foundation. Understanding Changes in Life Expectancy. Cystic Fibrosis Foundation. Accessed April 20, 2025. https://www.cff.org/managing-cf/understanding-changes-life-expectancy

9. Bierlaagh MC, Muilwijk D, Beekman JM, Van Der Ent CK. A new era for people with cystic fibrosis. Eur J Pediatr. 2021;180(9):2731-2739. doi:10.1007/s00431-021-04168-y

10. Burgener EB, Moss RB. Cystic fibrosis transmembrane conductance regulator modulators: precision medicine in cystic fibrosis. Curr Opin Pediatr. 2018;30(3):372-377. doi:10.1097/MOP.0000000000000627

11. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N Engl J Med. 2011;365(18):1663-1672. doi:10.1056/NEJMoa1105185

12. Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation. Chest. 2012;142(3):718-724. doi:10.1378/chest.11-2672

13. Clancy JP, Rowe SM, Accurso FJ, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax. 2012;67(1):12-18. doi:10.1136/thoraxjnl-2011-200393

14.Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(18):1783-1784. doi:10.1056/NEJMc1510466

15.Konstan MW, McKone EF, Moss RB, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. The Lancet Respiratory Medicine. 2017;5(2):107-118. doi:10.1016/S2213-2600(16)30427-1

16. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. doi:10.1056/NEJMoa1709846

17. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-1819. doi:10.1056/NEJMoa1908639

18.  ReCode Therapeutics. ReCode Therapeutics -The Next Generation of Genetic Medicine Delivery. ReCode Therapeutics. Published June 14, 2022. Accessed April 20, 2025. https://recodetx.com/science/

19. ReCode Therapeutics. ReCode Therapeutics Announces First Participants Dosed in a Phase 1 Healthy Volunteer Clinical Study of Inhaled mRNA-Based Genetic Medicine, RCT2100, for the Treatment of Cystic Fibrosis. ReCode Therapeutics. Published February 21, 2024. Accessed April 20, 2025. https://recodetx.com/recode-therapeutics-announces-first-participants-dosed-in-a-phase-1-healthy-volunteer-clinical-study-of-inhaled-mrna-based-genetic-medicine-rct2100-for-the-treatment-of-cystic-fibrosis/

20. ReCode Therapeutics. A Phase 1 Study Evaluating Safety and Tolerability of RCT2100 in Healthy Participants and in Participants With CF. Clinicaltrials.gov identifier: NCT06237335. Updated March 5, 2025. Accessed April 18, 2025. https://clinicaltrials.gov/study/NCT06237335?term=RCT2100&rank=1

21. Hansson GC. Mucus and mucins in diseases of the intestinal and respiratory tracts. J Intern Med. 2019;285(5):479-490. doi:10.1111/joim.12910

Author: Pari Dhayagude
Editor: Sarah Sizer, PhD

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by recurrent episodes of complete or partial upper airway collapse, leading to abnormal breathing and oxygen desaturation during sleep.¹ OSA affects an estimated 10-30% of adults worldwide, with hundreds of thousands of cases remaining undiagnosed.² In December 2024, the Food and Drug Administration (FDA) approved Zepbound (tirzepatide) for the treatment of moderate to severe OSA, making it the first medication specifically approved to treat obstructive sleep apnea.³ While Zepbound was initially FDA approved for the treatment of chronic weight management in adults with obesity in 2023, it has shown efficacy in improving OSA symptoms.^4,5 Although further research is needed to explore its efficacy in non-overweight patients, Zepbound is a novel treatment option for patients who are overweight with OSA who may not respond adequately to other interventions.

Overview of Obstructive Sleep Apnea

Sleep-disordered breathing includes a spectrum of sleep-related breathing disorders affecting approximately 1 billion people worldwide, with OSA being the most prevalent form.^6,7 According to the American Academy of Sleep Medicine International Classification of Sleep Disorders – Third Edition (ICSD-3), OSA is defined by recurrent episodes of partial (hypopneas) or complete (apneas) upper airway obstruction during sleep, resulting in oxygen desaturation, breathing disruptions, and brief arousal from sleep.⁸ Individuals with OSA generally experience symptoms such as excessive daytime sleepiness, loud snoring, fatigue, difficulty concentrating, and waking up during the night gasping or choking.⁸ When left untreated, OSA is an independent risk factor for several cerebrovascular and cardiovascular diseases.⁹ While anyone can develop OSA, about 40% of individuals with OSA are obese.²⁸ Comorbidities with OSA include cardiovascular disease, hypertension, metabolic conditions, and type 2 diabetes, which can exacerbate symptoms and complicate treatment.¹⁰ Despite advances in understanding OSA, traditional treatments such as continuous positive air pressure (CPAP) face challenges, with approximately 30-40% of patients not complying with treatment, highlighting the need for alternative treatment options.¹¹

The severity of OSA is classified based on the apnea-hypopnea index (AHI), which measures the number of breathing disruptions per hour of sleep through an at-home sleep apnea test.¹² The AHI score captures the frequency of breathing disruptions, where a higher score indicates more severe sleep apnea (Figure 1). AHI severity falls into three categories: mild with 5-14 events per hour of sleep, moderate with 15-30 events per hour of sleep, and severe with greater than 30 events per hour of sleep. Patients with moderate to severe OSA generally present with more pronounced symptoms, including loud snoring, morning headaches, and cognitive impairment. Additionally, individuals with severe OSA have higher rates of cardiovascular complications, metabolic dysfunction, and neurocognitive disorders.² Current research on OSA treatment focuses on personalized approaches that consider the anatomical and non-anatomical features contributing to this disorder.

Pathophysiology

OSA arises from anatomical and physiological features leading to airway collapse during sleep.¹⁴ The human upper airway contains a collapsible portion between the hard palate and larynx that is essential for speech, swallowing, and breathing. A narrow airway can make an individual more prone to collapse, and imaging studies have confirmed that patients with OSA generally have a reduced airway size.¹⁵ Additional research has also found altered soft tissue arrangement as a risk factor for airway obstruction in these individuals, placing the upper airway at risk for collapse.¹⁵ These upper airway anatomical differences do not impact the individual during wakefulness because upper airway dilator muscles compensate for the anatomical vulnerability to maintain airway patency.¹⁶ However, at sleep onset, the loss of muscle tone leads to airway obstruction, causing repeated apneas and hypopneas that disrupt sleep stages. The genioglossus muscle, a muscle critical for maintaining airway patency, has higher activity in OSA patients during wakefulness but loses tone during the transition to sleep and exacerbates breathing instability.¹⁶ As a result, individuals with OSA often experience cortical arousals, which are short awakenings that prevent deep sleep, increase daytime fatigue, and impair cognitive function. Another contributor to OSA pathophysiology is reduced lung volume, which decreases airway stability by decreasing the downward pull on upper airway structures that keep them open, known as caudal traction.¹⁷ Changes in lung volume affect upper airway resistance, especially in individuals with OSA, where reduced lung volume increases collapsibility. Interventions that enhance expiratory lung volume improve airway stability and reduce sleep-disordered breathing, but further studies are needed to understand the underlying mechanisms.¹⁴ All together, anatomical susceptibility, muscle dysfunction, and reduced lung volume create the conditions for recurrent airway obstruction seen in OSA.

Current Available Treatments and Limitations

Positive Airway Pressure Therapy

Positive airway pressure (PAP) therapy remains the gold standard treatment for moderate to severe OSA, in which the patient wears a mask to sleep and a machine delivers a stream of air to keep airways open while sleeping.¹⁸ The most commonly prescribed form of PAP is continuous positive airway pressure (CPAP), where the air pressure is continuous and greater than the surrounding air.¹⁸ The fixed pressure delivered from the CPAP machine acts as a pneumatic splint, maintaining upper airway patency throughout sleep. While CPAP machines are highly effective when used consistently, approximately 30% of patients discontinue treatment within the first year due to mask discomfort, pressure intolerance, and noise disturbances.¹⁹ Additionally, CPAP therapy requires nightly use for continued benefit and addresses the symptoms of OSA rather than the underlying causes.

Oral Device

Another treatment option for OSA is oral appliance therapy, which involves using custom-fit devices designed to keep the throat open while sleeping. These devices open the airway by bringing the lower jaw forward or holding the tongue in a different position. Oral devices work best in individuals with mild to moderate OSA, showing poorer efficacy in those with severe OSA.¹⁸ They are generally more comfortable, portable, and well-tolerated than PAP devices, but long-term side effects include temporomandibular joint pain and dental occlusion changes.¹⁸

Surgical Procedures

If other therapies do not render effective results, various surgical options are considered for moderate to severe OSA. Surgical approaches target specific anatomical sites of obstruction in the upper airway²⁰. Options include minimally invasive procedures such as radiofrequency ablation of the soft palate or tongue. Alternatively, more invasive procedures can be used, like maxillomandibular advancement to move the jaw and uvulopalatopharyngoplasty to remove tissue from the back of the mouth and top of the throat.²⁰ Surgical procedures are used as a final resort due to pain, risk of infection, higher costs, and long recovery times.²⁰

Lifestyle Modifications

Non-invasive approaches for OSA include weight loss, exercise, and positional therapy for sleeping.¹⁸ Excess weight is one of the strongest factors influencing both the risk and severity of OSA.²¹ One study found that a 10% weight loss predicts a 26% decrease in AHI, reducing the severity of OSA.²¹ Positional therapy is a behavioral treatment that prevents supine sleep, which often worsens airway collapse, by using devices worn around the waist and back to encourage side sleeping.^18,29 Lifestyle changes alone are often insufficient for more moderate to severe OSA, and weight-loss management program adherence is also challenging, with several patients regaining weight over time.²¹ Still, excess weight remains the most significant modifiable risk factor for OSA, with 40% of patients being obese.⁹ Given the relationship between weight and OSA, there is a critical need for therapeutic approaches that can effectively address both conditions simultaneously.

Zepbound (Tirzepatide) Mechanism of Action

Zepbound works to treat OSA primarily by promoting significant weight loss, which in turn helps combat some of the anatomical factors contributing to airway obstruction during sleep. Zepbound is a dual agonist for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) receptors, mimicking the effects of incretin hormones naturally produced in the gastrointestinal tract.^22,23 The GIP pathway plays a role in insulin sensitivity and the metabolism of fat, and the GLP-1 pathway promotes satiety and decreases appetite (Figure 2).²³ 

GLP-1 Pathway

GLP-1 receptors are widely expressed in the central nervous system, particularly in the arcuate nucleus (ARC), paraventricular nucleus (PVN) of the hypothalamus, and brainstem regions such as the nucleus tractus solitarius.²⁴ β-cells in the pancreas and enteroendocrine L-cells in the gastrointestinal tract also contain GLP-1 receptors. In the hypothalamus, GLP-1 receptor activation promotes satiety, reducing hunger signals and curbing food intake, while in the brainstem, enhanced signaling reinforces these satiety cues through different afferent pathways.²⁴ Peripherally, GLP-1 receptor activation in the gastrointestinal tract slows down the rate at which food leaves the stomach, and activation in the pancreas augments insulin release.²⁴ Activation of this GLP-1 pathway leads to weight loss and reduces OSA symptoms by reducing adipose tissue around the neck and upper airway.

GIP Pathway

Zepbound also targets GIP receptors found on pancreatic β-cells. Upon activation, these receptors boost insulin release and maintain glucose homeostasis.²⁴ They also encourage blood flow to adipose tissue and increase adipocyte metabolism via lipolysis and lipid uptake.²⁴ By enhancing insulin sensitivity, the GIP pathway contributes indirectly to weight reduction, supporting the overall reduction in upper airway fat deposition and amelioration of OSA symptoms.

Administration and Dosage

Clinically, Zepbound is administered as a once-weekly subcutaneous injection with a 2.5 mg starting dose for 4 weeks, followed by 5 mg for another 4 weeks, and gradually increasing to a maintenance dose between 7.5 mg to the maximum dose of 15 mg.²⁵ Administering GLP-1 receptor agonists via a subcutaneous injection allows for direct absorption into the bloodstream. Compared to nightly PAP therapy, the convenient dosing schedule offers a significant advantage for patient adherence, long-term compliance, and discrete use.

Clinical Trials

Several clinical trials have demonstrated the safety and efficacy of Zepbound for OSA, leading to its recent FDA approval. Prior to its approval for OSA, the FDA approved Zepbound to treat obesity.⁴ In the pivotal SURMOUNT-1 phase 3 clinical trial for weight management, researchers conducted a double-blind, randomized controlled trial (RCT) in over 2500 adults with a body mass index (BMI) of 30 or more, or 27 or more with a weight-related complication, to investigate whether once-weekly Zepbound at either 5, 10, or 15 mg doses for 72 weeks would reduce weight compared to placebo.²⁶ Between baseline and the end of treatment, they found a mean percentage change in weight of -15%, -19.5%, and -20.9% at the three respective doses and a -3.1% change with placebo.²⁶ However, adverse events did cause 4.3-7.1% of participants taking Zepbound and 2.6% of participants taking the placebo to discontinue their treatment, highlighting the need to investigate gastrointestinal adverse reactions such as abdominal pain, nausea, and constipation.²⁶ 

The SURMOUNT-OSA trials also demonstrated the efficacy of Zepbound in the treatment of OSA. Two phase 3, double-blind RCTs that enrolled adults with moderate-to-severe OSA and obesity were conducted.²⁷ The first trial had participants who were not on PAP therapy at baseline, while participants who were on PAP at baseline were placed in the second trial. For 52 weeks, participants received either the maximum tolerated dose of tirzepatide (10 or 15 mg) or a placebo. AHI was measured at baseline, and the primary endpoint was the change in AHI following the trial.²⁷ The mean baseline AHI in trials 1 and 2 were 51.5 and 49.5 events per hour, respectively. After 52 weeks, the mean change in AHI for trials 1 and 2 was -25.3 and -29.3 events per hour with tirzepatide and -5.3 and -5.5 events per hour with placebo, respectively.²⁷ In addition to AHI reduction, treatment was also associated with significant improvements in oxygen saturation during sleep, decreased daytime sleepiness, and reduced hypoxic burden.²⁷ These trial results show that Zepbound offers a novel pharmacological approach to OSA management, offering significant improvements in sleep-disordered breathing for patients with excess weight.

Conclusion

The FDA approval of Zepbound for OSA represents a landmark advancement in managing sleep-disordered breathing, being the first pharmacological drug available for this condition. By offering a drug that addresses multiple aspects of OSA pathophysiology, Zepbound provides an option for patients who do not respond well to PAP therapy. Additionally, the once-weekly administration may enhance long-term adherence compared to traditional OSA treatments.

References

1. Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Engl J Med. 1996;334(2):99-104. doi:10.1056/NEJM199601113340207
2. Gottlieb DJ, Punjabi NM. Diagnosis and Management of Obstructive Sleep Apnea: A Review. JAMA. 2020;323(14):1389-1400. doi:10.1001/jama.2020.3514
3. FDA. FDA Approves New Medication for Obstructive Sleep Apnea. U.S. Food and Drug Administration. Published December 20, 2024. Accessed April 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea
4. FDA. FDA Approves New Medication for Chronic Weight Management. U.S. Food and Drug Administration. Published November 8, 2023. Accessed April 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
5. Lilly. What is Zepbound. Zepbound.lilly.com. Accessed April 24, 2025. https://zepbound.lilly.com/weight/what-is-zepbound?utm_id=bi_cmp-506118382_adg-1272136592596011_ad-79508643410791_kwd-79509032322779%3Aloc-190_dev-c_ext-8864887765627_prd-_sig-d9341fa1aa071b38562377b0b3461c69&campaign=506118382&adgroup=1272136592596011&ad=79508643410791&utm_keyword=kwd-79509032322779%3Aloc-190&msclkid=d9341fa1aa071b38562377b0b3461c69&utm_source=bing&utm_medium=cpc&utm_campaign=US_DTC_Zepbound_Brand_Support_Tier-1&utm_term=how%20does%20zepbound%20work&utm_content=Zepbound%20Instructions&dclid=CjgKEAjw8cHABhC18dnXgpXY0DUSJAAzaKxbwKDTBK98qe00y6LsHe9EwFgrW_5nsaenHyQovkQxJvD_BwE&redirect-referrer=https%3A%2F%2Fwww.bing.com%2F
6. Foldvary-Schaefer NR, Waters TE. Sleep-Disordered Breathing. Continuum (Minneap Minn). 2017;23(4, Sleep Neurology):1093-1116. doi:10.1212/01.CON.0000522245.13784.f6
7. Lyons MM, Bhatt NY, Pack AI, Magalang UJ. Global burden of sleep-disordered breathing and its implications. Respirology. 2020;25(7):690-702. doi:10.1111/resp.13838
8. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014.
9. Jehan S, Zizi F, Pandi-Perumal SR, et al. Obstructive Sleep Apnea and Obesity: Implications for Public Health. Sleep Med Disord. 2017;1(4):00019.
10. Bonsignore MR, Baiamonte P, Mazzuca E, Castrogiovanni A, Marrone O. Obstructive sleep apnea and comorbidities: a dangerous liaison. Multidiscip Respir Med. 2019;14:8. doi:10.1186/s40248-019-0172-9
11. Rotenberg BW, Murariu D, Pang KP. Trends in CPAP adherence over twenty years of data collection: a flattened curve. J Otolaryngol Head Neck Surg. 2016;45(1):43. doi:10.1186/s40463-016-0156-0
12. Sleep Foundation. Understanding the Apnea-Hypopnea Index. sleepfoundation.org. Published January 27, 2025. Accessed May 1, 2025. https://www.sleepfoundation.org/sleep-apnea/ahi
13. Kline LR. Clinical Presentation and Diagnosis of Obstructive Sleep Apnea in Adults. UpToDate. June 7, 2023. Accessed May 1, 2025. https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-obstructive-sleep-apnea-in-adults
14. Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008;5(2):144-153. doi:10.1513/pats.200707-114MG
15. Schwab RJ, Gupta KB, Gefter WB, Metzger LJ, Hoffman EA, Pack AI. Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med. 1995;152(5 Pt 1):1673-1689. doi:10.1164/ajrccm.152.5.7582313
16. Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest. 1992;89(5):1571-1579. doi:10.1172/JCI115751
17. Tagaito Y, Isono S, Remmers JE, Tanaka A, Nishino T. Lung volume and collapsibility of the passive pharynx in patients with sleep-disordered breathing. J Appl Physiol (1985). 2007;103(4):1379-1385. doi:10.1152/japplphysiol.00026.2007
18. Mayo Clinic. Obstructive sleep apnea – Diagnosis and treatment. mayoclinic.org. Published July 14, 2023. Accessed May 1, 2025. https://www.mayoclinic.org/diseases-conditions/obstructive-sleep-apnea/diagnosis-treatment/drc-20352095
19. Bakker JP, Weaver TE, Parthasarathy S, Aloia MS. Adherence to CPAP: What Should We Be Aiming For, and How Can We Get There? Chest. 2019;155(6):1272-1287. doi:10.1016/j.chest.2019.01.012
20. Carvalho B, Hsia J, Capasso R. Surgical therapy of obstructive sleep apnea: a review. Neurotherapeutics. 2012;9(4):710-716. doi:10.1007/s13311-012-0141-x
21. St-Onge MP, Tasali E. Weight Loss Is Integral to Obstructive Sleep Apnea Management. Ten-Year Follow-up in Sleep AHEAD. Am J Respir Crit Care Med. 2021;203(2):161-162. doi:10.1164/rccm.202007-2906ED
22. Lilly. How Zepbound works. Zepbound.lilly.com. Accessed May 1, 2025. https://zepbound.lilly.com/hcp/how-zepbound-works?utm_id=bi_cmp-506118389_adg-1268838058352184_ad-79302487045031_kwd-79302874920099%3Aloc-190_dev-c_ext-_prd-_sig-c3c3cde52fc31dd9485da5f1c175902f&campaign=506118389&adgroup=1268838058352184&ad=79302487045031&utm_keyword=kwd-79302874920099%3Aloc-190&msclkid=c3c3cde52fc31dd9485da5f1c175902f&utm_source=bing&utm_medium=cpc&utm_campaign=US_HCP_Zepbound_Brand_Education_Tier-1&utm_term=zepbound%20mechanism%20of%20action&utm_content=Zepbound%20-%20MOA
23. Afridi Z, Farhan K, Fahad F, Khan MWZ, Salomon I. Tirzepatide: a dual-action solution for obstructive sleep apnea and obesity. Ann Med Surg (Lond). 2024;87(2):436-437. doi:10.1097/MS9.0000000000002975
24. Lempesis IG, Liu J, Dalamaga M. The catcher in the gut: Tirzepatide, a dual incretin analog for the treatment of type 2 diabetes mellitus and obesity. Metabol Open. 2022;16:100220. doi:10.1016/j.metop.2022.100220
25. Lilly. Explore Zepbound dosing. Zepbound.lilly.com. Accessed May 1, 2025. https://zepbound.lilly.com/hcp/dosage
26. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
27. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity [published correction appears in N Engl J Med. 2024 Oct 17;391(15):1464. doi: 10.1056/NEJMx240005.]. N Engl J Med. 2024;391(13):1193-1205. doi:10.1056/NEJMoa2404881
28. Esmaeili N, Gell L, Imler T, et al. The relationship between obesity and obstructive sleep apnea in four community-based cohorts: an individual participant data meta-analysis of 12,860 adults. EClinicalMedicine. 2025;83:103221. doi:10.1016/j.eclinm.2025.103221
29. American Academy of Sleep Medicine. Positional Therapy – Sleep Education by the AASM. sleepeducation.org. Published November 2020. Accessed May 8, 2025. https://sleepeducation.org/patients/positional-therapy/#:~:text=Positional%20therapy%20is%20a%20behavioral%20strategy%20to%20treat,sleep%20doctor%20might%20recommend%20positional%20therapy%20for%20you.

Publication License

Figure 2: Created in BioRender. Dhayagude, P. (2025) https://BioRender.com/oizrw3x

Author: Sarah Sizer, Ph.D.
Editor: Kylie VanDerMolen

This article will describe Datroway (datopotamab deruxtecan-dlnk), an antibody-drug conjugate (ADC) developed by the pharmaceutical companies AstraZeneca and Daiichi Sankyo. In January 2025, the Food and Drug Administration (FDA) approved Datroway for the treatment of  metastatic HR⁺/HER2^– breast cancer.¹ The FDA approval was based on data from a phase 3 clinical trial demonstrating that Datroway significantly improved progression-free survival rates following 9 and 12 months of treatment in comparison to the clinician’s choice of chemotherapy.² In this article, I describe the increasing global incidence of breast cancer and the disproportionate disease burden on women living in low and middle-income countries. I provide an overview of breast cancer subtypes and staging, outline Datroway’s mechanism of action, and summarize the results of Datroway’s phase 3 clinical trial. Finally, I discuss the importance of breast cancer research funding through the National Institutes of Health (NIH).

Breast Cancer: A Global Problem

The incidence of breast cancer is growing at alarming rates globally. 2.3 million people received their first breast cancer diagnosis in 2022, and epidemiologists estimate that this statistic will increase to 3.2 million new diagnoses annually by 2050.³ Breast cancer incidence rates are lower in women living in low and medium-income countries, yet their mortality rates are disproportionately higher due to limited access to clinicians and treatments, financial concerns, religious beliefs, and stigma.^4,5 For example, the survival rate for breast cancer surpasses 90% in high-income countries compared to 66% in India and 40% in sub-Saharan Africa.⁶ Global policy efforts are underway to combat escalations in breast cancer-related mortality in low and medium-income countries. In 2021, the World Health Organization (WHO) established the Global Breast Cancer Initiative (GBCI) to address inequities in breast cancer prognosis through public health education, early screening, timely diagnosis, and comprehensive treatment.⁶ While the GBCI aims to prevent 2.5 million global breast cancer deaths by 2040, there are significant logistical challenges in implementing a program of this scale, including staffing healthcare workers, building primary healthcare clinics or pathology laboratories, and creating breast cancer databases and surveillance systems.⁷ The Pfizer Foundation recently pledged $15 million in partnership with non-profit agencies to improve health infrastructure to treat breast cancer in sub-Saharan Africa, which exemplifies the collaborative effort that will be necessary to achieve GBCI objectives and will further require the participation of governments, United Nations agencies, and partnering organizations.⁸

Some countries, such as Mexico and the United States, have implemented policies that have proven to be successful in increasing access to breast cancer treatment. In 2007, the Mexican government’s health insurance plan Seguro Popular began covering breast cancer medical costs through the Fund for Protection Against Catastrophic Expenses (FPGC). Although there are limitations of the breast cancer treatment under Seguro Popular, including regional differences in treatment, low investment in preventative measures, and lack of access to medications, this policy has led to a 50% reduction in the breast cancer treatment gap across Mexico by diminishing barriers to treatment for many Mexican women.^9,10 In the 1990s, the United States Congress passed the Breast and Cervical Cancer Prevention Treatment Act, which established the Center for Disease Control’s (CDC) National Breast and Cervical Cancer Early Detection Program (NBCCEDP) and allows states to use Medicaid to cover treatment for women diagnosed with breast cancer through the program. Since its inception in 1991, the NBCCEDP has served 6.4 million women in underserved communities and has given 16.5 million screening examinations across the United States.¹¹ Between 1991 and 2006, it is estimated that the NBCCEDP has saved 369,000 life-years in women from low-income households.¹² These examples in Mexico and the United States illustrate that through significant financial investment and public policy changes, government programs can increase the availability of breast cancer education, early screening, and diagnostic services to improve health outcomes.^9,13

Diversity in Breast Cancer Staging, Subtypes, and Treatment

Breast cancer occurs when a cell within the breast lobules, ducts, or nipple begins to proliferate uncontrollably, forming a mass of cancer cells known as a tumor. As the tumor grows, breast cancer cells spread regionally to the lymph nodes before metastasizing and traveling through the bloodstream to either the bones, lungs, liver, or brain. Mortality from breast cancer metastasis is often associated with related complications like organ failure or due to comorbid conditions like cardiovascular disease.^14–16 Metastasis reduces the 5-year relative breast cancer survival rate to 32% compared to 87% and 99% in regional and localized breast cancers, respectively.¹⁶ The gap in survival rates between localized and metastatic breast cancer highlights the need for early prevention, including clinical breast exams and routine breast self-exams. This is especially true among women under 40 years old, whose incidence of breast cancer is increasing and who are typically ineligible for annual x-rays of the breast tissue called mammograms.¹⁷

Breast cancer is a heterogeneous disease where tumor subtypes exhibit differential “disease presentation, patterns of metastasis, drug sensitivity, timing of recurrence, and prognosis.”¹⁸ A biopsy and immunohistochemical staining of the breast tissue is necessary to categorize the breast cancer stage and subtype to inform the treatment plan. Clinicians use the Tumor, Nodes, and Metastasis (TNM) system by the American Joint Committee on Cancer (AJCC) to determine the breast cancer stage from factors like the tumor size, spread to the lymph nodes, metastasis to the organs, receptor expression, and cancer grade.¹⁹ Breast cancer stage ranges from Stage 0 carcinoma in situ to Stage IV metastatic, where stage 0 is defined as early stage pre-invasive breast cancer and stage IV metastatic is defined as advanced stage with spread to distant organs. Breast cancer subtype depends on whether genetic mutations cause the cancer cells to upregulate specific receptors that mediate abnormal cell growth and proliferation.^20–22 These receptors are hormone receptors (HR), such as estrogen receptors (ER) and progesterone receptors (PR), and the human epidermal growth factor receptor 2 (HER2). The four major breast cancer subtypes are Luminal A (ER⁺/PR⁺/HER2^–), Luminal B (ER⁺/PR^∓/HER2^∓), HER2⁺ (ER^–/PR^–/HER⁺), and triple-negative breast cancer (ER^–/PR^–/HER2^–) (Figure 1).²³ Despite some overlap in Luminal A and Luminal B expression patterns, these breast cancer subtypes are distinguishable based on the expression of the cell proliferation marker Ki-67. Luminal B breast cancer cells express higher levels Ki-67, grow faster, and therefore require more aggressive forms of treatment than Luminal A.²⁴ Classifying the breast cancer stage and subtype is complex and dependent on multiple factors, but assessing the tumor type is necessary to develop the most effective and personalized treatment plan with the diversity of available options.

While an individual’s treatment typically involves a combination of surgery (i.e., lumpectomy or mastectomy), radiation, or chemotherapy, the breast cancer subtype also guides decisions about which oral and intravenous medications clinicians will prescribe as part of the treatment plan. HR⁺ tumors have more available treatment options because they are responsive to endocrine therapies that prevent hormone-mediated proliferation of breast cancer cells. The main classes of endocrine therapies commonly prescribed to treat HR⁺ breast cancers are selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors. SERMs block estrogen from binding to its receptor, SERDs promote ER degradation, and aromatase inhibitors inhibit estrogen synthesis. Less commonly prescribed therapies are progesterone receptor modulators (PRMs), which have mixed efficacy and side effects.²⁵ Since HER2⁺ tumors are less responsive to endocrine therapies, they are typically treated with HER2-targeted monoclonal antibodies (i.e., trastuzumab and pertuzumab) to prevent the initiation of HER2-mediated signaling. Although HER2⁺ breast cancer is more aggressive than other subtypes, the lack of receptor expression in triple-negative breast cancer makes it the most difficult to treat with available therapies. Consequently, triple-negative breast cancer has the lowest 5-year relative survival rate of all breast cancers.²⁶

Metastatic (Stage IV) HR⁺/HER2^– Breast Cancer and Datroway

Approximately 70% of breast cancer cases are HR⁺/HER2^– (Luminal A, subset of Luminal B). This subtype has the most favorable 5-year relative breast cancer survival rate; however, 30% of all early stage HR⁺/HER2^– breast cancer patients will ultimately develop metastatic (Stage IV) HR⁺/HER2^– breast cancer.²⁷ While endocrine therapies serve as a first-line treatment against metastatic HR⁺/HER2^– breast cancer, some women are immediately resistant to endocrine therapies (15-20%), while others develop resistance over time (30-40%).^26,28 Resistance to endocrine therapies occurs through multiple mechanisms but ultimately results in the ability of cancer cells to continue to proliferate despite the inhibition of ER function.²⁶ Since endocrine therapies lack efficacy for a significant percentage of the treatment population, there is a need for additional therapies to treat metastatic HR⁺/HER2^– breast cancer.

A newer drug class for HR⁺/HER2^– breast cancer is cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, which disrupt the  progression of the cell cycle and enhance the immune response against cancerous cells.²⁹ The first CDK4/6 inhibitor, palbociclib, was FDA-approved for HR⁺/HER2^– breast cancer based on a phase 3 clinical trial, which found that palbociclib in combination with endocrine therapy significantly lengthened the time of progression-free survival compared to endocrine therapy alone.^30,31 However, palbociclib has been associated with multiple adverse drug events, including myelosuppression, venous thrombosis, skin toxicity, and interstitial lung disease.^30,32,33 While CDK4/6 inhibitors reduce tumor progression for many people living with HR⁺/HER2^– breast cancer, these drugs are associated with significant risks and potentially life-threatening side effects.

Antibody-drug conjugates (ADC) are the next generation of cancer treatments that are FDA-approved for a variety of cancers, including triple-negative breast cancer,³⁴ HER2⁺ breast cancer,³⁵ and lung cancer.³⁶ ADCs contain a monoclonal antibody linked to a cytotoxic agent that specifically targets and kills cancer cells. Datroway (datopotamab deruxtecan-dlnk) is an ADC recently approved by the FDA to treat metastatic HR⁺/HER2^– breast cancer for individuals that are unresponsive to endocrine-based therapy and chemotherapy.¹ The monoclonal antibody, datopotamab, binds to a specific epitope of a protein upregulated by cancer cells called the trophoblast cell surface antigen 2 (TROP2). TROP2 is a receptor that regulates intracellular calcium concentrations and is typically expressed at low levels in epithelial cells within the heart, liver, kidney, and lungs. Overexpression of TROP2 occurs in all breast cancer subtypes and leads to the activation of multiple signaling pathways that promote “tumor proliferation, growth, invasion, metastasis, and resistance to treatments.”^37–43 Datopotamab recognizes and binds to TROP2, and the breast cancer cell internalizes the drug through endocytosis, where it is then trafficked to the lysosomes for processing. Lysosomal proteases cleave the linker that connects the monoclonal antibody and the cytotoxic agent, releasing the cytotoxic agent known as a topoisomerase I inhibitor. Since topoisomerase I is an enzyme that cleaves and rejoins DNA during DNA replication to relieve tension, inhibition of this enzyme results in DNA breaks and loss of DNA replication. Loss of these cellular processes leads to cell cycle arrest, activation of pro-apoptotic cellular pathways, and eventually apoptosis (Figure 2).⁴⁴ The ability of ADCs like Datroway to target the destruction of breast cancer cells using monoclonal antibodies reduces unwanted side effects associated with other anti-cancer therapeutics due to their lack of specificity. This makes ADCs a promising avenue for the development of other types of cancer treatments.

The FDA approved Datroway based on data from the open-label phase III clinical trial comparing intravenous Datroway to the clinician’s choice of chemotherapy (eribulin/vinoelbine/capecitabine/gemcitabine). Open-label clinical trials are studies where patients and healthcare providers know the treatment they are receiving. The open-label phase III clinical trial consisted of 732 people with HR⁺/HER2^– breast cancer between the ages of 28-86 and measured progression-free survival and overall survival as the primary endpoints. Datroway caused a 37.5% improvement in progression-free survival at 9 months and a 25.5% improvement at 12 months, whereas chemotherapy caused an 18.7% improvement in progression-free survival at 9 months and 14.6% at 12 months.⁴¹ Although there were no significant differences between Datroway and chemotherapy in overall survival (Datroway 36.4% vs. chemotherapy 22.9%), it has a favorable safety profile, with the most common side effects being nausea and stomatitis (inflammation within the mouth).⁴⁵ Datroway is also currently in clinical trials to investigate its effectiveness in treating triple-negative breast cancer and lung cancer.⁴⁶

Outlook: Breast cancer research funding

The diversity of drugs within the breast cancer treatment landscape is a direct result of significant investment in breast cancer research in the United States. Breast cancer research is funded through multiple sources, including the National Cancer Institute (NCI) within the NIH, the Breast Cancer Research Foundation, and the Susan G. Komen Foundation. This funding is critical to advance our understanding of breast cancer pathogenesis and to further refine the current standard of care for women who are diagnosed with breast cancer. While this investment has proven to be successful in improving the 5-year relative survival rate of women with early-stage breast cancer compared to thirty years ago, funding biomedical research is necessary to improve survival rates among women with metastatic breast cancer and women living in low and medium-income countries.^3,13

References

1. FDA Approves Datopotamab Deruxtecan-Dlnk for Unresectable or Metastatic, HR-Positive, HER2-Negative Breast Cancer. Food and Drug Administration. January 17, 2025. Accessed April 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast#:~:text=On%20January%2017%2C%202025%2C%20the,epidermal%20growth%20factor%20receptor%202%20(

2. Bardia A, Jhaveri K, Kalinsky K, et al. TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2– breast cancer. Future Oncol. 2024;20(8):423-436. doi:10.2217/fon-2023-0188

3. Kim J, Harper A, McCormack V, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 2025;31:1154-1162. doi:10.1038/s41591-025-03502-3

4. Akuoko CP, Armah E, Sarpong T, Quansah DY, Amankwaa I, Boateng D. Barriers to early presentation and diagnosis of breast cancer among African women living in sub-Saharan Africa. Sapino A, ed. PLOS ONE. 2017;12(2):e0171024. doi:10.1371/journal.pone.0171024

5. Aizenman N. The breast cancer burden in lower income countries is even worse than we thought. Natl Public Ratio. February 1, 2024. Accessed April 13, 2025. https://www.npr.org/sections/goatsandsoda/2024/02/01/1228089751/the-breast-cancer-burden-in-lower-income-countries-is-even-worse-than-we-thought

6. Global Breast Cancer Initiative Implementation Framework: Assessing, Strengthening and Scaling-Up of Services for the Early Detection and Management of Breast Cancer. Executive Summary. 1st ed. World Health Organization; 2023.

7. Ong SK, Haruyama R, Yip CH, et al. Feasibility of monitoring Global Breast Cancer Initiative Framework key performance indicators in 21 Asian National Cancer Centers Alliance member countries. eClinicalMedicine. 2024;67:102365. doi:10.1016/j.eclinm.2023.102365

8. The Pfizer Foundation Provides $15 Million Investment to Improve Breast Cancer Care in Sub-Saharan Africa. Pfizer. January 17, 2025. Accessed April 16, 2025. https://www.pfizer.com/news/announcements/pfizer-foundation-provides-15-million-investment-improve-breast-cancer-care-sub

9. Unger-Saldaña K, Contreras-Manzano A, Lamadrid-Figueroa H, et al. Reduction in the Treatment Gap for Breast Cancer in Mexico under Seguro Popular , 2007 to 2016. Health Syst Reform. 2022;8(1):e2064794. doi:10.1080/23288604.2022.2064794

10. Reynoso-Noverón N, Villarreal-Garza C, Soto-Perez-de-Celis E, et al. Clinical and Epidemiological Profile of Breast Cancer in Mexico: Results of the Seguro Popular. J Glob Oncol. 2017;3(6):757-764. doi:10.1200/JGO.2016.007377

11. About the National Breast and Cervical Cancer Early Detection Program. Center for Disease Control. September 19, 2024. Accessed April 16, 2025. https://www.cdc.gov/breast-cervical-cancer-screening/about/index.html

12. Hoerger TJ, Ekwueme DU, Miller JW, et al. Estimated Effects of the National Breast and Cervical Cancer Early Detection Program on Breast Cancer Mortality. Am J Prev Med. 2011;40(4):397-404. doi:10.1016/j.amepre.2010.12.017

13. Taylor C, McGale P, Probert J, et al. Breast cancer mortality in 500 000 women with early invasive breast cancer diagnosed in England, 1993-2015: population based observational cohort study. BMJ. June 13, 2023:e074684. doi:10.1136/bmj-2022-074684

14. Riihimäki M, Thomsen H, Brandt A, Sundquist J, Hemminki K. Death causes in breast cancer patients. Ann Oncol. 2012;23(3):604-610. doi:10.1093/annonc/mdr160

15. Afifi AM, Saad AM, Al‐Husseini MJ, Elmehrath AO, Northfelt DW, Sonbol MB. Causes of death after breast cancer diagnosis: A US population‐based analysis. Cancer. 2020;126(7):1559-1567. doi:10.1002/cncr.32648

16. Stage 4 Breast Cancer Overview. The National Breast Cancer Foundation. May 20, 2024. Accessed April 16, 2025. https://www.nationalbreastcancer.org/breast-cancer-stage-4/#:~:text=According%20to%20the%20American%20Cancer,is%20considered%20distant%20breast%20cancer.

17. Xu S, Murtagh S, Han Y, Wan F, Toriola AT. Breast Cancer Incidence Among US Women Aged 20 to 49 Years by Race, Stage, and Hormone Receptor Status. JAMA Netw Open. 2024;7(1):e2353331. doi:10.1001/jamanetworkopen.2023.53331

18. Fasching PA, Kreipe H, Del Mastro L, et al. Identification of Patients with Early HR+ HER2− Breast Cancer at High Risk of Recurrence. Geburtshilfe Frauenheilkd. 2024;84(02):164-184. doi:10.1055/a-2238-3199

19. Breast Cancer Stages. The American Cancer Society. November 8, 2021. Accessed April 17, 2025. https://www.cancer.org/cancer/types/breast-cancer/understanding-a-breast-cancer-diagnosis/stages-of-breast-cancer.html

20. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/neu Oncogene. Science. 1987;235(4785):177-182. doi:10.1126/science.3798106

21. Henry JA, Nicholson S, Farndon JR, Westley BR, May FE. Measurement of oestrogen receptor mRNA levels in human breast tumours. Br J Cancer. 1988;58(5):600-605. doi:10.1038/bjc.1988.267

22. Holst F, Stahl PR, Ruiz C, et al. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet. 2007;39(5):655-660. doi:10.1038/ng2006

23. Orrantia-Borunda E, Anchondo-Nuñez P, Acuña-Aguilar LE, Gómez-Valles FO, Ramírez-Valdespino CA. Subtypes of Breast Cancer. In: Department of Medical Education, Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, FL, USA, Mayrovitz HN, eds. Breast Cancer. Exon Publications; 2022:31-42. doi:10.36255/exon-publications-breast-cancer-subtypes

24. Feeley LP, Mulligan AM, Pinnaduwage D, Bull SB, Andrulis IL. Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information. Mod Pathol. 2014;27(4):554-561. doi:10.1038/modpathol.2013.153

25. Robertson JFR, Willsher PC, Winterbottom L, Blamey RW, Thorpe S. Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer. Eur J Cancer. 1999;35(2):214-218. doi:10.1016/S0959-8049(98)00388-8

26. Gutierrez MC, Detre S, Johnston S, et al. Molecular Changes in Tamoxifen-Resistant Breast Cancer: Relationship Between Estrogen Receptor, HER-2, and p38 Mitogen-Activated Protein Kinase. J Clin Oncol. 2005;23(11):2469-2476. doi:10.1200/JCO.2005.01.172

27. Cancer Stat Facts: Female Breast Cancer Subtypes. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed April 17, 2025. https://seer.cancer.gov/statfacts/html/breast-subtypes.html

28. Anurag M, Ellis MJ, Haricharan S. DNA damage repair defects as a new class of endocrine treatment resistance driver. Oncotarget. 2018;9(91):36252-36253. doi:10.18632/oncotarget.26363

29. Deng J, Wang ES, Jenkins RW, et al. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov. 2018;8(2):216-233. doi:10.1158/2159-8290.CD-17-0915

30. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925-1936. doi:10.1056/NEJMoa1607303

31. Palbociclib (IBRANCE). Food and Drug Administration. March 31, 2017. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/palbociclib-ibrance 

32. Silvestri M, Cristaudo A, Morrone A, et al. Emerging Skin Toxicities in Patients with Breast Cancer Treated with New Cyclin-Dependent Kinase 4/6 Inhibitors: A Systematic Review. Drug Saf. 2021;44(7):725-732. doi:10.1007/s40264-021-01071-1

33. Raschi E, Fusaroli M, Ardizzoni A, Poluzzi E, De Ponti F. Thromboembolic Events with Cyclin-Dependent Kinase 4/6 Inhibitors in the FDA Adverse Event Reporting System. Cancers. 2021;13(8):1758. doi:10.3390/cancers13081758

34. FDA Grants Regular Approval to Sacituzumab Govitecan for Triple-Negative Breast Cancer. Food and Drug Administration. April 8, 2021. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-sacituzumab-govitecan-triple-negative-breast-cancer

35. FDA Grants Accelerated Approval to Fam-Trastuzumab Deruxtecan-Nxki for Unresectable or Metastatic HER2-Positive Solid Tumors. Food and Drug Administration. April 5, 2024. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

36. FDA Grants Accelerated Approval to Fam-Trastuzumab Deruxtecan-Nxki for HER2-Mutant Non-Small Cell Lung Cancer. Food and Drug Administration. August 16, 2022. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung

37. Aslan M, Hsu EC, Garcia-Marques FJ, et al. Oncogene-mediated metabolic gene signature predicts breast cancer outcome. Npj Breast Cancer. 2021;7(1):141. doi:10.1038/s41523-021-00341-6

38. Liu L, Meng T, Zheng X, et al. Transgelin 2 Promotes Paclitaxel Resistance, Migration, and Invasion of Breast Cancer by Directly Interacting with PTEN and Activating PI3K/Akt/GSK-3β Pathway. Mol Cancer Ther. 2019;18(12):2457-2468. doi:10.1158/1535-7163.MCT-19-0261

39. Boucher MJ, Morisset J, Vachon PH, Reed JC, Lainé J, Rivard N. MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem. 2000;79(3):355-369.

40. Dajti G, Serra M, Cisternino G, et al. Prognostic Role of p53 Immunohistochemical Status in Invasive Breast Cancer. A Retrospective Review of 1387 Cases With Luminal-Like/Her2 Negative Breast Tumors. The Oncologist. 2024;29(5):384-391. doi:10.1093/oncolo/oyad309

41. Helbig G, Christopherson KW, Bhat-Nakshatri P, et al. NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4. J Biol Chem. 2003;278(24):21631-21638. doi:10.1074/jbc.M300609200

42. Cubas R, Zhang S, Li M, Chen C, Yao Q. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer. 2010;9(1):253. doi:10.1186/1476-4598-9-253

43. Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene. 2003;22(19):2869-2881. doi:10.1038/sj.onc.1206427

44. Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6(10):789-802. doi:10.1038/nrc1977

45. Bardia A, Jhaveri K, Im SA, et al. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025;43(3):285-296. doi:10.1200/JCO.24.00920

46. DATROWAY® (Datopotamab Deruxtecan-Dlnk) Approved in the US for Patients with Previously Treated Metastatic HR-Positive, HER2-Negative Breast Cancer. AstraZeneca. January 17, 2025. Accessed April 18, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/datroway-datopotamab-deruxtecan-dlnk-approved-in-the-us-for-patients-with-previously-treated-metastatic-hr-positive-her2-negative-breast-cancer.html#:~:text=DATROWAY%20clinical%20development%20program,anticancer%20treatments%20in%20various%20settings.

Publication Licenses for Figures:

Figure 1: Created in BioRender. Sizer, S. (2025) https://BioRender.com/niqf31i 

Figure 2: Created in BioRender. Sizer, S. (2025) https://BioRender.com/8k4p45d 

Author: Michaela Price, PhD 
Editor: Rachel VanKeulen-Miller

Today, we will discuss the histone deacetylase inhibitor Duvyzat (givinostat). In March 2024, the U.S. Food and Drug Administration (FDA) approved Duvyzat as the first nonsteroidal drug to treat Duchenne muscular dystrophy (DMD).¹

Key takeaways

• DMD is a severe X-linked recessive disorder that is caused by a mutation in the dystrophin gene, which leads to a lack of functional dystrophin protein
• DMD is characterized by many symptoms, including, but not limited to, muscle wasting, delayed/impaired motor skills, pseudohypertrophy, flexion contracture, cognitive and behavioral impairments, dilated cardiomyopathy, and impaired breathing
• Prior to Duvyzat’s approval, the FDA-approved therapies for treating DMD were corticosteroids, recombinant gene therapy, and antisense oligonucleotides. However, the side effects from these therapies may be intolerable to some patients, gene therapies are expensive, and antisense oligonucleotides are mutation-specific, all of which limits the number of patients that can use each of these therapies
• Duvyzat’s approval was based on a randomized, double-blind, placebo-controlled phase 3 clinical trial that found Duvyzat was superior to placebo in maintaining muscle function
• Duvyzat qualified for 4 of the FDA’s special programs that incentivize the development of products that treat, prevent, or diagnose serious and/or rare disorders and earned the benefits associated with those programs

Duchenne muscular dystrophy

What is DMD?

DMD is one of the many muscular dystrophy diseases. Muscular dystrophy diseases are genetic diseases that cause progressive muscle weakness and degeneration.² DMD is the most common form of muscular dystrophy in children.^1,2

What causes DMD?

DMD is caused by a mutation in the dystrophin (DMD) gene, which is located on the X chromosome.^2-5 The mutation can be inherited in an X-linked recessive pattern or occur spontaneously during cell division.^3,5 The mutation prevents the production of functional dystrophin protein,^2,4,5 which is primarily localized to skeletal and cardiac muscles.^2-4 

What is the role of dystrophin in healthy individuals?

In skeletal and cardiac muscles, dystrophin interacts with a protein complex, and together they connect the cytoskeleton of the muscle cell to the extracellular matrix, which helps structure, strengthen, and protect muscle fibers when they contract and relax.^4,5 Muscle contraction generates mechanical stress that is manageable under normal conditions, but it can damage muscle when functional dystrophin is absent.⁵

What happens when an individual lacks functional dystrophin?

Without functional dystrophin, skeletal and cardiac muscle cells become progressively more damaged, weaken, and eventually die with repetitive use.^4,5 A small amount of dystrophin is located in neurons; however, the function of the dystrophin protein in neurons has been studied considerably less than its contribution to muscle function.⁴

How many individuals are affected by DMD?

Although DMD affects less than 50,000 individuals in the United States, it remains the most common form of muscular dystrophy in children.^1-3

Who does DMD affect?

Since DMD is an X-linked recessive disease, it occurs almost exclusively in males.^1-5 Some estimate that the prevalence of DMD is less than 10 cases per 100,000 males and less than 1 case per 1,000,000 females.⁵ Another estimate suggests the prevalence of DMD in males is closer to 1 in 3,300.⁶

What are the symptoms of DMD?

DMD symptoms often appear during early childhood.^2,3,5 In the early stages of DMD, the child may have^3,5:

• Muscle weakness
• Delayed motor skills (e.g. sitting, standing, walking)
• Frequent falls and clumsiness
• Waddling gait
• Delayed speech and language development

Other common symptoms of DMD include^1-5 :

• Progressive muscle wasting (decreased size and strength)
• Loss of reflexes
• Impaired gross motor function (e.g. difficulty walking, running, jumping, climbing stairs, or standing from a seated position)
• Pseudohypertrophy (muscles that appear enlarged due to an accumulation of fat and connective tissue, most often affecting calf muscles)
• Flexion contracture (a permanently flexed joint that cannot be fully straightened as a result of structural changes to the muscle, tendons, ligaments, or skin)
• Weakened diaphragm muscles leading to impaired breathing and coughing
• Respiratory infections
• Swallowing problems
• Bone thinning
• Scoliosis (abnormally curved spine)
• Cognitive and behavioral impairments
• Dilated cardiomyopathy 

Patients typically require wheelchairs at around 10 to 12 years of age and ventilation around 20 years of age.⁵ 

What is the life expectancy for individuals with DMD?

Sources estimate life expectancy to be between 20 and 40 years old for individuals with DMD; however, recent advancements in diagnostic and therapeutic tools have improved the life expectancy dramatically over recent years.^1,2,5 A study in France reported a similar pattern in which median life expectancy was approximately 25.77 years of age for people born before 1970 and 40.95 years for people born after 1970.^5,7 Often the direct cause of death is cardiac and/or respiratory failure due to disease progression.^5,6 

Therapies on the market for treating DMD prior to Duvyzat’s approval

There were several types of treatments on the market for DMD prior to the approval of Duvyzat in March 2024, such as corticosteroids, recombinant gene therapy, and antisense oligonucleotides. Corticosteroids target pathogenic processes while the recombinant gene therapy approach introduces micro-dystrophin into the body, and antisense oligonucleotides use short, modified nucleic acid strands to make the nonfunctional dystrophin semi-functional. 

Corticosteroids

Corticosteroids are intended to improve disease progression by improving muscle strength, motor function, and survival.⁵ They also delay the loss of ambulation, the reduction in pulmonary function, and the onset of cardiomyopathy.⁵ Figure 1 lists the year that the drug was approved, what it was approved for, and the common side effects for three corticosteroids, including Emflaza (deflazacort), Prednisone, and Agamree (vamorolone). Corticosteroids can also produce other side effects, including, but not limited to, endocrine dysfunction, increased risk for new infections, increased risk for worsening current infections, heart and kidney dysfunction, gastrointestinal perforations, serious skin rashes, behavioral and mood changes, low bone mineral density, eye problems (e.g. cataracts, infections, glaucoma), stunted growth, increased risk of muscle disease (myopathy), blood clots, and, in rare cases, anaphylaxis.^8,9 Although corticosteroids have been effective at improving muscle strength, the side effects may make the treatment intolerable for some individuals.

Elevidys (delandistrogene moxeparvovec-rokl)

Elevidys is a recombinant gene therapy that received Accelerated Approval in June 2023 and then traditional approval in June 2024 following a confirmatory study.⁶ Elevidys is FDA-approved to treat DMD in patients that are at least 4 years of age and have a confirmed DMD gene mutation. This gene therapy delivers a gene that encodes Elevidys micro-dystrophin protein, which is only a third of the length of the full dystrophin protein, via a single intravenous dose. Figure 2 shows the common side effects of Elevidys. In addition, some patients taking Elevidys experienced severe immune-mediated myositis (muscle inflammation), myocarditis (heart muscle inflammation), and elevated troponin-I levels in the blood (indicative of heart muscle injury).⁶ The micro-dystrophin protein is capable of treating DMD with a single dose, which makes it appealing to patients. However, side effects and the financial cost associated with gene therapies may make this therapy intolerable or unaffordable for some patients. The cost for gene therapies ranges from $65,000 to $3.5 million, which presents a massive challenge for stakeholders.¹²

Antisense oligonucleotides

Antisense oligonucleotides (ASOs) are short, modified nucleic acid strands.⁵ ASOs treat DMD by binding to a specific exon of the dystrophin gene and promoting exon skipping.⁵ This produces semi-functional dystrophin and reduces symptom severity.^4,5 ASOs are intended to promote exon skipping for specific DMD gene mutations, and thus have a limited treatment population.⁵ ASOs are typically administered intravenously on a weekly basis for DMD treatments, which may become a burden to some individuals that have difficulty making the weekly trip to their healthcare provider.^13-16 Examples of ASOs that are approved to treat DMD include Amondys 45 (casimersen), Exondys 51 (eteplirsen), Vyondys 53 (golodirsen), and Viltepso (viltolarsen).^13-16 Figure 3 shows which exon is skipped and the common side effects reported for each of the ASOs.

The FDA approval of Duvyzat

Duvyzat is administered orally twice daily with food.¹ It is a nonsteroidal drug that acts by inhibiting histone deacetylase (HDAC).¹ HDAC is an enzyme that removes acetyl groups from lysine residues on proteins called histones.¹⁷ Histone proteins have DNA wrapped around them, which together form a nucleosome. Nucleosomes fold together into chromatin fibers, which then coil and condense further into a chromosome. Histones can undergo epigenetic modifications like acetylation (adding acetyl groups) or deacetylation (removing acetyl groups), which alters how histones and DNA interact. If histones and DNA are tightly wound into ‘closed’ chromatin, transcription is blocked because RNA polymerase cannot access the tightly wound, ‘closed’ chromatin. However, if the histones and DNA are less compact (‘open’ chromatin) RNA polymerase can access the genes for transcription.¹⁷ Histone acetylation is typically associated with open chromatin and transcription whereas histone deacetylation is associated with closed chromatin and transcription is suppressed.^17,18 Therefore, drugs that inhibit histone deacetylation (HDAC inhibitors) would ultimately promote transcription via open chromatin. HDAC inhibitors are most well-known as anticancer drugs,¹⁷ but they have shown significant promise in treating Duchenne muscular dystrophy as well.

Preclinical Data

Preclinical studies suggest that HDAC inhibitors can restore muscle function and minimize signs of DMD in a mouse model. One study showed that the force produced by stimulating muscles in vitro is significantly lower in a mouse model of DMD compared to wildtype mice.¹⁹ An HDAC inhibitor restored the force produced in a mouse model of DMD.¹⁹ Additionally, a mouse model of DMD became exhausted quicker in a treadmill test than wildtype mice, and HDAC inhibitor treatment increased the time to exhaustion.¹⁹ Similarly, compared to control-treated mice, Duvyzat increased the weight and size of muscles, reduced fibrosis and fatty infiltration of the muscles, reduced inflammation, and increased skeletal muscle function as measured by a treadmill performance test in a mouse model of DMD.²⁰ Therefore, in vitro and in vivo studies in mice support the use of HDAC inhibitors for treating DMD.

Phase 2 Clinical Trial

Clinical studies also suggested HDAC inhibitors like Duvyzat had the potential to treat DMD in humans. An open-label phase 2 study sponsored by Italfarmaco S.p.A. included 20 adolescent boys (ages 7 to <11 years) with a DMD diagnosis.²¹ In this study, all participants had been taking corticosteroids for at least 6 months and were ambulatory with a 6-minute walk distance of at least 250 meters. All end of treatment measures were taken after at least one year of treatment with Duvyzat.²¹

Primary Objective: The primary objective of the trial was to determine whether Duvyzat could prevent the histological signs of DMD between baseline and the end of treatment using muscle biopsies.²¹ The histological signs that were evaluated included the muscle fiber area fraction, cross-sectional area, necrosis, hypercontracted fibers, fatty replacement, and fibrosis. The study showed that the mean muscle fiber area fraction and cross-sectional area increased by 29.1% and 77.7%, respectively. There was also a significant decrease in the number of necrotic and hypercontracted fibers, fat replacement, and fibrosis (endomysial and perimysial).²¹

Secondary Objectives: One secondary objective of the trial was to examine safety and tolerability by monitoring adverse events, as well as assessing various lab tests, physical parameters, vital signs, and more.²¹ The phase 2 study found that the 37.5 mg dose was the maximum tolerated dose and that dose could be lowered to 25 mg to reduce adverse events. The most common adverse events were reduced platelet counts and diarrhea. Serious adverse events included reduced platelet counts, rhabdomyolysis (rapid breakdown of damaged muscle) when anesthetized for the muscle biopsy, and tibioperoneal fracture. The company claims that the decreased platelet counts was the only serious adverse event to be linked to the drug. In addition, secondary objectives also included assessments testing muscle function like the 6-minute walk test (6MWT), North Star Ambulatory Assessment (NSAA), and the Performance of Upper Limb comparing measurements between baseline and the end of treatment. They also discovered that the 6MWT and NSAA score were correlated with muscle fiber area fraction and total fibrosis.²¹

Despite the promising results, all of the muscle biopsies revealed dystrophin was not present at baseline or at the end of the study.²¹ Therefore, Duvyzat is capable of preventing the histological signs of DMD without restoring functional dystrophin. Since Duvyzat is acting downstream of the genetic mutations and therefore is not mutation-specific, it can be used by the entire patient population unlike antisense oligonucleotides.²¹

Phase 3 Clinical Trial

The FDA approved Duvyzat to treat DMD in patients ages 6 years and older based on data obtained in a randomized, double-blind, placebo-controlled phase 3 clinical trial.^1,22 The phase 3 study lasted 18 months and tested the efficacy and safety of Duvyzat in ambulatory, male patients with DMD (ages ≥6 years). Notably, all study participants had a stable background therapy of steroids (the standard of care), and they continued to take steroid treatment for the entire study.²² The study enrolled 179 male patients with DMD, and the efficacy results were based on 120 male patients.²²

Primary Objective: The primary efficacy endpoint in the clinical trial was the change in muscle function between baseline and month 18 as measured by the four stair climb.^1,22 The trial showed that the patients receiving Duvyzat took 1.25 seconds longer to climb four stairs at month 18 compared to baseline.¹ In comparison, the placebo-treated group increased the four stair climb duration by 3.03 seconds between baseline and month 18.¹ Thus, Duvyzat was superior to placebo since Duvyzat-treated patients declined in muscle function significantly less than placebo-treated patients.^1,22

Secondary Objectives: The second efficacy endpoint was the change in physical function from baseline to month 18 as measured by the NSAA.¹ The NSAA is a scale used to measure motor function in patients with DMD who are ambulatory.¹ Duvyzat-treated patients had significantly less decline in their NSAA score between baseline and month 18 compared to placebo-treated patients.¹ The clinical study also reported common adverse events that appeared in at least 10% of the patients treated with Duvyzat, such as diarrhea, abdominal pain, thrombocytopenia (low platelet count, which may increase the risk of excessive bleeding), nausea/vomiting, elevated triglycerides, and fever.^1,22 Duvyzat comes with a warning for low platelets, elevated triglycerides, and diarrhea, which may necessitate lowering the dose of Duvyzat or discontinuing treatment altogether.^1,22,23 There is also a warning for possible QT prolongation, which increases the risk for ventricular arrhythmias.^22,23 

Based on these data, the FDA approved Duvyzat for market authorization in March 2024.^1,24 The FDA is requiring the sponsor to complete postmarketing studies, including carcinogenicity studies in rodents, a prospective observational study lasting at least 5 years (to determine the risk for thrombocytopenia and severe bleeding), and a clinical trial (to determine how hepatic impairment impacts Duvyzat effects compared to normal hepatic function).²⁴

FDA’s Special Programs

Duvyzat qualified for several of the FDA’s special programs that incentivizes sponsors to develop products that diagnose, treat, or prevent serious and/or rare disorders, including a fast track designation, priority review, an orphan drug designation, and a rare pediatric disease designation.¹ Duvyzat’s sponsor, Italfarmaco S.p.A., was granted certain benefits for meeting these criteria. If a product treats a serious condition and fills an unmet medical need, it qualifies for the fast track designation.²⁵ The sponsor earns several benefits, including meeting and communicating with the FDA more often, receiving rolling review, and, if other criteria are met, following the Accelerated Approval pathway and receiving priority review.²⁵ Priority review shortens the time period in which the FDA reviews applications from 10 months to 6 months, and a product qualifies when it treats a serious condition and is a significant improvement over standard therapies.²⁶ A product qualifies for the orphan drug designation if it treats a rare disease (a disease that affects less than 200,000 people in the United States) or the expected sales are outweighed by the cost to develop the product.²⁷ When a product receives an orphan drug designation, their sponsor benefits from tax credits, fee exemptions, and potential market exclusivity for 7 years.²⁸ Finally, the rare pediatric disease designation requires that the product treat a serious pediatric condition (a condition which primarily impacts pediatric patients) that is rare.^29,30 A sponsor will then receive a voucher when the product is approved, and they may use that voucher to receive priority review on another application for a product that ordinarily would not qualify for priority review.^24,29,30

Altogether, Duvyzat is a major advancement in treating DMD. It provides vital relief to patients and improves their quality of life substantially. Although Duvyzat is not without its own side effects, it remains a viable alternative to patients that may experience side effects from corticosteroids, recombinant gene therapies, and antisense oligonucleotides. In addition, Duvyzat may be more accessible to patients since it is unlikely to be as expensive as gene therapies like Elevidys, which costs $3.2 million for the single dose.³¹ Moreover, antisense oligonucleotides are mutation-specific, which limits their use significantly, whereas Duvyzat can be used in a larger portion of the patient population. Time will tell how much impact Duvyzat has in comparison to its alternatives, but regardless, individuals with DMD will surely benefit from the development of Duvyzat.

References

1. FDA approves nonsteroidal treatment for Duchenne Muscular Dystrophy [Press Announcement]. FDA. Published March 21, 2024. Accessed February 18, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-nonsteroidal-treatment-duchenne-muscular-dystrophy 
2. Muscular dystrophy. NINDS. Updated December 19, 2024. Accessed February 18, 2025. https://www.ninds.nih.gov/health-information/disorders/muscular-dystrophy 
3. Duchenne muscular dystrophy. Genetic and Rare Diseases Information Center. Updated January 2025. Accessed February 19, 2025. https://rarediseases.info.nih.gov/diseases/6291/duchenne-muscular-dystrophy
4. DMD gene. MedlinePlus. Updated February 1, 2017. Accessed February 19, 2025. https://medlineplus.gov/genetics/gene/dmd/ 
5. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi:10.1038/s41572-021-00248-3.
6. FDA expands approval of gene therapy for patients with Duchenne Muscular Dystrophy [Press Announcement]. FDA. Published June 20, 2024. Accessed February 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy 
7. Kieny P, Chollet S, Delalande P, Le Fort M, Magot A, Pereon Y, Perrouin Verbe B. Evolution of life expectancy of patients with Duchenne muscular dystrophy at AFM Yolaine de Kepper centre between 1981 and 2011. Ann Phys Rehabil Med. 2013;56(6):443-454.
8. FDA approves drug to treat Duchenne muscular dystrophy [Press Announcement]. FDA. Published February 9, 2017. Updated March 28, 2018. Accessed February 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-duchenne-muscular-dystrophy
9. Agamree. Package insert. Catalyst Pharmaceuticals; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215239s000lbl.pdf 
10. Griggs RC, Miller JP, Greenberg CR, et al. Efficacy and safety of deflazacort vs prednisone and placebo for Duchene muscular dystrophy. Neurology. 2016;87:2123-2131.
11. Dang UJ, Damsker JM, Guglieri M, et al. Efficacy and safety of vamorolone over 48 weeks in boys with Duchenne muscular dystrophy. Neurology. 2024;102:e208112. doi:10.1212/WNL.0000000000208112.
12. Horrow C, Kesselheim AS. Confronting high costs and clinical uncertainty: Innovative payment models for gene therapies. Health Aff (Millwood). 2023;42(11):1532-1540. doi:10.1377/hlthaff.2023.00527.
13. Amondys 45. Package insert. Sarepta Therapeutics Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213026s008lbl.pdf 
14. Exondys 51. Package insert. Sarepta Therapeutics Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206488s035lbl.pdf 
15.  Vyondys 53. Package insert. Sarepta Therapeutics Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/211970s010s011lbl.pdf 
16. Viltepso. Package insert. Nippon Shinyaku; 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212154s002lbl.pdf 
17. Park SY, Kim JS. A short guide to histone deacetylases including recent progress on class II enzymes. Experimental & Molecular Medicine. 2020;52:204-212. doi:10.1038/s12276-020-0382-4
18. Farr GH, Morris M, Gomez A, Pham T, Kilroy E, Parker EU, Said S, Henry C, Maves L. A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy. Skeletal Muscle. 2020;10:29. doi:10.1186/s13395-020-00251-4
19. Minetti GC, Colussi C, Adami R, Serra C, Mozzetta C, Parente V, Fortuni S, Straino S, Sampaolesi M, Di Padova M, Illi B, Gallinari P, Steinkühler C, Capogrossi MC, Sartorelli V, Bottinelli R, Gaetano C, Puri PL. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med. 2006;12:1147-1150. doi:10.1038/nm1479.
20. Consalvi S, Mozzetta C, Bettica P, Germani M, Fiorentini F, Del Bene F, Rocchietti M, Leoni F, Monzani V, Mascagni P, Puri PL, Saccone V. Preclinical studies in the mdx mouse model of Duchenne muscular dystrophy with the histone deacetylase inhibitor Givinostat. Molecular Medicine. 2013;19:79-87.
21. Bettica P, Petrini S, D’Oria V, D’Amico A, Catteruccia M, Pane M, Sivo S, Magri F, Brajkovic S, Messina S, Viga GL, Gatti B, Moggio M, Puri PL, Rocchetti M, De Nicolao G, Vita G, Comi GP, Bertini E, Mercuri E. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscular Disorders. 2016;26:643-649.
22. Drug Trials Snapshot: Duvyzat. FDA. Updated June 7, 2024. Accessed April 1, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-duvyzat
23. Duvyzat. Package insert. Italfarmaco S.p.A.; 2024.  https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217865Orig1s000lbl.pdf 
24. Approval Letter NDA 217865. FDA. Published March 21, 2024. Accessed April 2, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/217865Orig1s000ltr.pdf 
25. Fast track. FDA. Updated August 13, 2024. Accessed December 12, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track 
26. Priority review. FDA. Updated January 4, 2018. Accessed December 12, 2024.  https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review
27. Orphan drug act – relevant excerpts. FDA. Updated March 9, 2018. Accessed December 12, 2024. https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drug-act-relevant-excerpts 
28. Designating an orphan product: Drugs and biological products. FDA. Updated August 12, 2024. Accessed December 12, 2024.  https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products 
29. Rare pediatric disease designation and priority review voucher programs. Updated September 27, 2024. Accessed December 12, 2024.  https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/rare-pediatric-disease-designation-and-priority-review-voucher-programs 
30. Guidance for industry: Rare pediatric disease priority review vouchers. FDA. Published July 2019. Accessed January 24, 2025. https://www.fda.gov/media/90014/download 
31. Fidler B. Sarepta prices Duchenne gene therapy at $3.2M. Biopharma Dive. Published June 22, 2023. Accessed April 4, 2025. https://www.biopharmadive.com/news/sarepta-duchenne-elevidys-price-million-gene-therapy/653720/

Publication License

Figure 4: Created in BioRender. Price, M. (2025) https://BioRender.com/8ulanyt