Category: The Pipeline Blog

Author: Joe Krzeski 
Editor: Rachel VanKeulen-Miller 

Precision medicine seeks to improve patient outcomes by subclassifying diseases based on their molecular and genetic characteristics with the ultimate goal of developing novel and targeted therapies.¹ A notable example of precision medicine is the stratification of breast cancer into distinct subtypes, rather than a singular disease. This shift led to personalized treatment strategies for each subtype and has improved outcomes for breast cancer patients.² While precision medicine holds great promise across a broad range of conditions, it faces distinct challenges in the area of rare diseases, or disorders affecting fewer than 200,000 individuals in the United States. Though each rare disease is individually uncommon, there are an estimated 7,000 to 10,000 rare diseases that collectively impact approximately 30 million Americans.³ Unfortunately, very few rare diseases have approved disease-modifying treatments from the Food and Drug Administration (FDA) and precision medicine for rare diseases has been hindered, in part, by economic constraints and the biological complexity of each disorder. Despite these challenges, the past decade has seen promising developments—most notably the emergence of antisense oligonucleotides (ASOs), a therapeutic modality that offers new hope for personalized treatments of rare diseases.^4,5 

Challenges for precision medicine for rare diseases 

Like many areas of therapeutic development, precision medicine for rare diseases is often constrained by economic challenges. On average, bringing a new therapy to patients takes 20 years and demands around $700 million in investment.⁶ Moreover, there is inherent risk in this process as only about 10% of therapies successfully progress from Phase I clinical trials to FDA approval.⁷ Therapeutic developers are frequently incentivized to target conditions with larger patient populations to ensure a viable return on investment. As a result, precision medicine for rare diseases often lacks sufficient investment. Nevertheless, a number of industry, academic, and nonprofit organizations remain committed to advancing treatments for rare diseases.^8,9 These organizations are partly driven by incentives from the Orphan Drug Act, which provides tax credits and market exclusivity to companies with potential treatments for rare diseases.¹⁰ 

In addition to economic factors, the biological complexity of rare diseases hinders precision medicine. Many rare diseases stem from genetic mutations, often involving mutations within a single gene.¹¹ However, even within single-gene disorders, the types of mutations can vary widely. An example of this is Angelman syndrome (AS), a rare neurodevelopmental disorder characterized by intellectual disability, epilepsy, and motor problems.¹² AS is caused by deletions or mutations in a particular gene called UBE3A, which generates a protein necessary for the removal of other proteins. Full deletions of the UBE3A gene, which result in the complete absence of UBE3A protein, are generally linked to more severe symptoms compared to missense mutations that alter a single amino acid, which result in a non-functional UBE3A protein. Still, there are other types of mutations that contribute to AS pathology.¹³ The diversity of these UBE3A mutations subclassifies a rare disease into even rarer subtypes (Figure 1). While treatment strategies can be developed to overcome this challenge, each subtype may require unique and targeted treatments.

Antisense oligonucleotides (ASOs) pave the way  

Regulators, industry partners, academics, and interest groups have leveraged ASOs to overcome the challenges facing therapeutic development for rare diseases. ASOs are small, synthetic strands of nucleotides that can be engineered to bind specific regions of RNA (ribonucleic acid).^14,15 The safety and efficacy profile of this therapeutic class is underscored by FDA-approval of thirteen ASOs since 1998, including ones developed for rare diseases. A major advantage of ASOs is that they are highly customizable and can be designed to treat a variety of genetic predispositions.⁵  

These factors culminated in the development of the first ASO designed to treat a single patient—a young girl diagnosed with neuronal ceroid lipofuscinosis 7 (CLN7 disease).¹⁶ CLN7 disease is a rare genetic disorder that affects ~1:100,000 individuals and is caused by mutations in the MFSD8 gene that result in severe neurodegeneration, seizures, and early-life mortality.¹⁷ This particular patient had a unique mutation in the MFSD8 gene that was amenable to ASO treatment. In 2017, under the leadership of Dr. Timothy Wu at Boston Children’s Hospital, a dedicated team of scientists and clinicians developed an ASO called milasen in just ten months as a treatment. Milasen was administered through an expanded access Investigational New Drug (IND) application, which permits the use of non-FDA-approved therapeutics for life-threatening conditions with no other treatment options. While the patient unfortunately passed away due to the natural progression of CLN7 disease, milasen reduced both the frequency and duration of the patient’s seizures.¹⁶ Milasen represents a pioneering effort in personalized medicine—ushering in new possibilities for treating rare genetic diseases. 

Since the development of milasen, additional ASOs have been created to treat rare diseases, particularly in single patients. In 2019, an ASO called jacifusen was used to treat a rare and aggressive form of amyotrophic lateral sclerosis (ALS). Although the patient ultimately passed away due to the natural course of the disease, jacifusen showed potential in slowing the progression of symptoms.¹⁸ This encouraging result has spurred a clinical trial to evaluate the safety and efficacy of jacifusen in a broader ALS patient population.¹⁹ This case highlights how insights from individualized treatments can inform and scale therapeutic approaches for larger groups. Overall, ASOs are advancing personalized medicine for rare diseases by driving innovation and expanding treatment options. 

References: 

1.    Ashley EA. Towards precision medicine. Nat Rev Genet. 2016;17(9):507-522. doi:10.1038/nrg.2016.86 

2.    Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. doi:10.1038/s41572-019-0111-2 

3.    RARE Disease Facts – Global Genes. Accessed March 27, 2025. https://globalgenes.org/rare-disease-facts/ 

4.    Lauffer MC, van Roon-Mom W, Aartsma-Rus A, N = 1 Collaborative. Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders. Commun Med (London). 2024;4(1):6. doi:10.1038/s43856-023-00419-1 

5.    Wijnant KN, Nadif Kasri N, Vissers LE. Systematic analysis of genetic and phenotypic characteristics reveals antisense oligonucleotide therapy potential for one-third of neurodevelopmental disorders. BioRxiv. March 20, 2025. doi:10.1101/2025.03.20.644369 

6.    Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844-853. doi:10.1001/jama.2020.1166 

7.    Mullard A. Shifts in the clinical trial landscape. Nat Rev Drug Discov. 2024;23(4):239. doi:10.1038/d41573-024-00048-w 

8.    Levine JA, Stemitsiotis C. De-risking rare disease acquisitions: a win-win-win for patients, biotech and investors. Nat Rev Drug Discov. 2024;23(1):10-11. doi:10.1038/d41573-023-00190-x 

9.    Crooke ST. Addressing the Needs of Patients with Ultra-Rare Mutations One Patient at a Time: The n-Lorem Approach. Nucleic Acid Ther. 2022;32(2):95-100. doi:10.1089/nat.2021.0046 

10.   Designating an Orphan Product: Drugs and Biological Products | FDA. Accessed April 29, 2025. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products 

11.   Sanders SJ, Sahin M, Hostyk J, et al. A framework for the investigation of rare genetic disorders in neuropsychiatry. Nat Med. 2019;25(10):1477-1487. doi:10.1038/s41591-019-0581-5 

12.   Buiting K, Williams C, Horsthemke B. Angelman syndrome – insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016;12(10):584-593. doi:10.1038/nrneurol.2016.133 

13.   Keute M, Miller MT, Krishnan ML, et al. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021;26(7):3625-3633. doi:10.1038/s41380-020-0858-6 

14.   Bennett CF. Therapeutic antisense oligonucleotides are coming of age. Annu Rev Med. 2019;70:307-321. doi:10.1146/annurev-med-041217-010829 

15.   Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018;14(1):9-21. doi:10.1038/nrneurol.2017.148 

16.   Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019;381(17):1644-1652. doi:10.1056/NEJMoa1813279 

17.   Mole SE. The neuronal ceroid lipofuscinoses. In: Noebels JL, Avoli M, Rogawski MA, Vezzani A, Delgado-Escueta AV, eds. Jasper’s Basic Mechanisms of the Epilepsies. 5th ed. Oxford University Press; 2024. doi:10.1093/med/9780197549469.003.0050 

18.   Promising ALS Therapy Moves Closer to Clinic | Columbia University Irving Medical Center. 2025; Accessed March 27, 2025. https://www.cuimc.columbia.edu/news/promising-als-therapy-moves-closer-clinic 

19.   Study Details | FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS) | ClinicalTrials.gov. Accessed March 23, 2025. https://clinicaltrials.gov/study/NCT04768972#study-plan  

Author: Pari Dhayagude
Editor: Phoebe Tchoua

Treatment-resistant depression (TRD) is one of the most difficult psychiatric disorders to treat. It  occurs when a patient is unresponsive to two or more antidepressant regimens following adequate dosing, duration, and adherence.¹ In 2019, the FDA approved Spravato (esketamine), a nasal spray developed by Janssen Pharmaceuticals, for use alongside oral antidepressants to treat TRD.² Recently, Spravato has emerged as a potential monotherapy option. Although further research is needed, Spravato provides a new treatment avenue for patients with TRD.³

Overview of Major Depressive Disorder and Treatment-Resistant Depression

Major depressive disorder (MDD) affects over 21 million adults in the United States (US), making it one of the most common mental health disorders.⁴ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), MDD is characterized by having at least two weeks of depressed mood or inability to feel joy (anhedonia), accompanied by symptoms, such as changes in sleep, eating, concentration, and feelings of worthlessness.⁵ Individuals with MDD often experience comorbidities, such as anxiety and substance use disorders, which often exacerbates the severity of symptoms and makes treatment more difficult.^6,7 Despite advances in understanding the onset and progression of MDD, traditional treatments are ineffective for 30% of people with depression, highlighting the need for novel treatments that offer rapid, sustained relief for those who do not respond to traditional treatment.¹

Patients with MDD who do not respond to standard treatment are often referred to as having TRD. A TRD diagnosis follows after a failure at least two different first-line antidepressants (such as selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs)) fail to significantly alleviate their depressive symptoms.^1,8 However, the lack of a clear universal definition of TRD continues to hinder both the development of treatments and patient access to care. Generally, this subpopulation with TRD have similar symptoms, such as a depressed mood and disruptions with sleep, as those with MDD, but the severity is greater. Additionally, individuals with TRD tend to present with increased anhedonia, recurrent MDD episodes, anxiety, suicidal ideation, and physical comorbidities such as metabolic syndrome and type 2 diabetes.^9,10,11 Current research on the treatment of TRD focuses on personalized approaches and novel pharmacological interventions over standard medications.

Pathology

The pathophysiology of MDD is not fully understood, but several studies suggest that alterations in monoaminergic neurotransmission of serotonin, norepinephrine, and dopamine significantly contribute to its clinical manifestations.¹² Specifically, reduced synaptic availability of these neurotransmitters has been linked to symptoms often seen in individuals with MDD, including lower mood, diminished motivation, and impaired cognitive function. SSRIs and SNRIs focus on correcting the dysregulation in monoaminergic transmission by preventing reuptake of these neurotransmitters. In recent years, there has been growing attention from researchers and agencies, such as the National Institute on Mental Health (NIMH), toward understanding the complex molecular, cellular, and circuit-level imbalances that underlie MDD and TRD. 

Emerging research has identified disruptions in glutamatergic transmission, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and inflammatory signaling as significant contributors to both MDD and TRD.^13,14 Chronic stress and elevated cortisol levels can trigger neuroinflammatory cascades, leading to neuronal atrophy and impaired plasticity in the hippocampus and prefrontal cortex.¹⁵ In TRD, these underlying disruptions are often more pronounced, limiting the effectiveness of interventions that primarily target monoaminergic pathways. This complex and multifaceted physiology requires newer interventions that target novel molecular mechanisms that can offer relief for patients who do not respond to traditional monoaminergic-based treatments.

Current Available Treatments and Limitations

Pharmacotherapy

Pharmacological treatments for MDD and TRD span several medication classes, each targeting different aspects of monoaminergic dysregulation. First-line treatments generally include SSRIs, such as fluoxetine, sertraline, and escitalopram, due to their efficacy and milder side effects. They act by binding to serotonin transporters on the presynaptic neuron, which prevents the reuptake of serotonin and increases its availability.¹⁶ For patients who do not respond to SSRIs, SNRIs such as duloxetine may be used as an alternative. SNRIs prevent the reuptake of both serotonin and norepinephrine, potentially addressing a wider range of depressive symptoms.¹⁷ Other pharmacotherapies such as tricyclic antidepressants present alternative mechanisms that may be advantageous in patients who have not responded to first-line treatments, but their anticholinergic activity and risk of overdose may cause adverse side effects.¹⁸ A key limitation of antidepressants is that they can take several weeks before a significant therapeutic effect is achieved, and over a third of patients, including those with TRD, do not respond to these treatments.¹⁹

Behavioral Therapies

Non-pharmacological therapies can serve as complementary or as alternative treatments for individuals with MDD and TRD. This includes interventions like cognitive behavioral therapy, mindfulness-based therapy, and lifestyle modifications such as incorporating exercise and improving sleep hygiene.²⁰ However, individuals with TRD generally do not respond adequately from standalone behavioral therapies and often require additional interventions to alleviate symptoms. 

Somatic Therapies

Somatic therapies are often used for individuals with TRD when standard pharmacological and behavioral interventions fail to provide sufficient relief. Electroconvulsive therapy (ECT) is a common and effective intervention for severe depression, particularly in individuals presenting with suicidality or psychotic symptoms. The procedure involves administering an electrical current through the scalp to induce a brief seizure and has been shown to be about 60% successful in producing short-term relief.²¹ However, ECT is associated with several side effects and a $15,000 cost for a full course of treatment.²¹ Transcranial magnetic stimulation (TMS), a noninvasive procedure that applies magnetic pulses to the prefrontal cortex, may be a more viable alternative to ECT. However, the efficacy of reducing symptoms in people with TRD remains inconclusive, and patients need to receive treatment 5 days per week, increasing patient burden.²¹ Given the limitations of both ECT and TMS—including side effects, high costs, inconsistent efficacy, and significant time commitments—there remains a critical need for more accessible, effective, and well-tolerated treatment options for individuals with TRD.

Spravato (Esketamine) Mechanism of Action

Esketamine, the S-enantiomer of racemic ketamine, provides a different mechanism of action compared to other traditional antidepressant treatments by targeting the glutamatergic system. Instead of blocking monoamine reuptake, esketamine works as a non-selective, non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, an ionotropic glutamate receptor, preferentially targeting those located on GABA interneurons.²² Inhibiting NMDA receptors on GABA interneurons leads to the disinhibition of glutamatergic neuron activity and an acute increase in glutamate release from glutamatergic neurons. In turn, this causes increased stimulation of postsynaptic AMPA receptors, creating a signaling cascade to boost brain-derived neurotrophic factor (BDNF).²² BDNF plays an important role in regulating synaptic formation and maintaining synaptic connections and is critical in synaptic plasticity.²³ Unlike traditional antidepressants which can take several weeks to show effects, esketamine can deliver significant clinical improvement within hours to days, making it a vital therapeutic candidate for TRD and urgent interventions in emergency care settings.²⁴

Clinically, esketamine is available as a 58 or 84 mg intranasal spray (Spravato) designed for self-administration under direct medical supervision. Due to its possible side effects like transient dissociation and sedation, patients must remain at the treatment center for a few hours following administration, during which vital signs and mental assays are regularly taken. Generally, Spravato is administered twice a week for the first four weeks of treatment, followed by weekly maintenance sessions for weeks five through eight, and then on an as-needed basis.²⁵ Until 2025, FDA-approved guidelines required Spravato to be used alongside an oral antidepressant.² However, Johnson & Johnson recently received approval to use Spravato as a standalone monotherapy for TRD, marking a significant advancement in the pharmacological management of TRD.³ 

Clinical Trials

Several clinical trials have investigated esketamine as a treatment for individuals with TRD or severe depression, reaching a consensus on its efficacy and general tolerability.²⁸ One randomized clinical trial conducted by Janssen R&D and academic collaborators evaluated the efficacy of 3 different doses of intranasal esketamine (28, 56, and 84 mg) versus placebo combined with oral antidepressants in 67 participants.²⁹ The results showed a significant ascending dose-response relationship with higher doses correlating to greater reductions in depression scores.²⁹ Most notably, they found a rapid decrease in depressive symptoms with a mean decrease within 8 days of treatment.²⁹ Additionally, sustained improvements continued after reduced dosing frequency, and response and remissions rates favored the esketamine-treated groups, particularly the 84 mg dose group.²⁹ Adverse events in this trial were rare with 5% of esketamine-treated participants discontinuing treatment during the double-blind phase and 2% during the open-label phase.²⁹

Janssen R&D conducted its first Phase 4 clinical trial to evaluate the efficacy and safety of Spravato nasal spray as a monotherapy for TRD.³⁰ This randomized, double-blind, placebo-controlled trial involved 478 participants, of whom 379 met criteria for non-responsiveness to prior treatments and received medication. The findings revealed that the 56 and 84 mg doses of Spravato significantly improved depressive symptoms compared to placebo.³⁰ Results began to show about 24 hours after the first dose, indicating a rapid reduction in depressive symptoms similar to previous trials combining esketamine with an oral antidepressant.^29,30 The study suggests that Spravato could be an effective standalone option for patients with TRD, especially when conventional treatments fail and alternate treatments are more invasive. 

Economic Impact

The societal and economic burden of TRD remains high with the most expenses coming from direct expenses (e.g., prescription drug costs, clinician visits, inpatient care) and indirect expenses (e.g., lost productivity and disability).²⁶ One study estimated the national economic burden of TRD to be between $29 to 48 billion annually, assuming that 12-20% of the individuals have TRD.²⁷ On average, individuals with TRD face an annual incremental productivity cost exceeding $6,000 annually compared to individuals without MDD.²⁶ Additionally, unemployment among individuals with TRD results in an estimated $8.7 billion in cost to US taxpayers.²⁶ Emerging alternative treatments like Spravato offer hope for individuals with TRD who have not responded to traditional treatments. By enhancing brain plasticity and providing rapid symptom relief, Spravato not only offers an effective therapeutic option for patients, but it also has the potential to reduce the economic impact associated with TRD.

References

1. McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394-412. doi:10.1002/wps.21120
2. ‌FDA. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. U.S. Food and Drug Administration. Published March 5, 2019. Accessed March 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication- treatment-resistant-depression-available-only-certified
3. ‌SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. JNJ.com. Published January 21, 2025. Accessed March 22, 2025. https://www.jnj.com/media-center/press-releases/spravato-esketamine-approved-in-the-u-s-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression
4. ‌NIMH. Major Depression. www.nimh.nih.gov. Updated July 2023. Accessed March 23, 2025.. https://www.nimh.nih.gov/health/statistics/major-depression#part_2630
5. ‌American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders. 2013;5(5). doi:10.1176/appi.books.9780890425596
6. Hirschfeld RM. The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care. Prim Care Companion J Clin Psychiatry. 2001;3(6):244-254. doi:10.4088/pcc.v03n0609
7. ‌Swendsen JD, Merikangas KR. The comorbidity of depression and substance use disorders. Clin Psychol Rev. 2000;20(2):173-189. doi:10.1016/s0272-7358(99)00026-4
8. U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Major Depressive Disorder: Developing Drugs for Treatment. Guidance for Industry. Revision 1. U.S. Department of Health and Human Services; June 2018. Accessed March 23, 2025. https://www.fda.gov/media/113988/download
9. Rashidian H, Subramaniapillai M, Park C, et al. Changes in insulin resistance following antidepressant treatment mediate response in major depressive disorder. J Psychopharmacol. 2023;37(3):313-317. doi:10.1177/02698811221132473
10. McIntyre RS, Schaffer A, Beaulieu S. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid conditions. Ann Clin Psychiatry. 2012;24(1):2-3.
11. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should Depressive Syndromes Be Reclassified as “Metabolic Syndrome Type II”?. Ann Clin Psychiatry. 2007;19(4):257-264. doi:10.1080/10401230701653377
12. Jiang Y, Zou D, Li Y, et al. Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders. Pharmaceuticals (Basel). 2022;15(10):1203. doi:10.3390/ph15101203
13. Zunszain PA, Hepgul N, Pariante CM. Inflammation and depression. Curr Top Behav Neurosci. 2013;14:135-151. doi:10.1007/7854_2012_211
14. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31(9):464-468. doi:10.1016/j.tins.2008.06.006
15. Liu W, Ge T, Leng Y, et al. The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural Plast. 2017;2017:6871089. doi:10.1155/2017/6871089
16. Lane R, Baldwin D, Preskorn S. The SSRIs: advantages, disadvantages and differences. J Psychopharmacol. 1995;9(2 Suppl):163-178. doi:10.1177/0269881195009002011
17. Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014;11(3-4):37-42.
18. Moraczewski J, Awosika AO, Aedma KK. Tricyclic Antidepressants. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 17, 2023.
19. Ruberto VL, Jha MK, Murrough JW. Pharmacological Treatments for Patients with Treatment-Resistant Depression. Pharmaceuticals (Basel). 2020;13(6):116. doi:10.3390/ph13060116
20. Karrouri R, Hammani Z, Benjelloun R, Otheman Y. Major depressive disorder: Validated treatments and future challenges. World J Clin Cases. 2021;9(31):9350-9367. doi:10.12998/wjcc.v9.i31.9350
21. Cusin C, Dougherty DD. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS [published correction appears in Biol Mood Anxiety Disord. 2013;3(1):1. doi:10.1186/2045-5380-3-1.]. Biol Mood Anxiety Disord. 2012;2:14. doi:10.1186/2045-5380-2-14
22. Vasiliu O. Esketamine for treatment‑resistant depression: A review of clinical evidence (Review). Exp Ther Med. 2023;25(3):111. doi:10.3892/etm.2023.11810
23. Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223-250. doi:10.1007/978-3-642-45106-5_9
24. Fu DJ, Ionescu DF, Li X, et al. Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191. doi:10.4088/JCP.19m13191
25. Dosage and Administration of SPRAVATO – Duration of Therapy. Jnjmedicalconnect.com. Published 2025. Accessed April 1, 2025. https://www.jnjmedicalconnect.com/products/spravato/medical-content/dosage-and-administration-of-spravato-duration-of-therapy
26. ‌Zhdanava M, Pilon D, Ghelerter I, et al. The Prevalence and National Burden of Treatment-Resistant Depression and Major Depressive Disorder in the United States. J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699
27. Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv. 2014;65(8):977-987. doi:10.1176/appi.ps.201300059
28. Papakostas GI, Salloum NC, Hock RS, et al. Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis. J Clin Psychiatry. 2020;81(4):19r12889. doi:10.4088/JCP.19r12889
29. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189
30. Janik A, Qiu X, Lane R, et al. Efficacy and safety of esketamine nasal spray as monotherapy in adults with treatment-resistant depression: a randomized, double-blind, placebo-controlled study. Presented at: American Psychiatric Nurses Association 38th Annual Conference; October 9-12, 2024; Louisville, KY.

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Figure 2: Created in BioRender. Dhayagude, P. (2025) https://BioRender.com/thiraz6

Author: Lilly Baker
Editor: Phoebe Tchoua

On November 21, 2023, MTX325 was approved by the Medicines and Healthcare Products Regulatory Agency in the United Kingdom to enter a Phase 1 clinical study for Parkinson’s disease.¹ This approval marks the first time that a selective mitophagy enhancer—a drug that promotes the removal of damaged mitochondria—is being tested as a disease-modifying therapeutic. In this post, we (1) discuss how mitochondrial dysfunction contributes to Parkinson’s disease, (2) explore the therapeutic rationale behind mitophagy enhancement, (3) provide a mechanistic overview of ubiquitin-dependent mitophagy, and (4) explain how MTX325 targets this pathway to progress into early clinical development. 

Mitochondrial Dysfunction and Parkinson’s Disease

Cellular health and longevity hinges on mitochondrial function. These dynamic organelles produce 90% of the cell’s energy, synthesize essential metabolites, maintain calcium homeostasis, and even regulate cell death.² Each cell contains hundreds to thousands of mitochondria, with highly active neurons housing upwards of 2 million.³ Consequently, it should come as no surprise that mitochondrial dysfunction has been linked to the pathophysiology of many chronic diseases, like neurodegeneration (e.g., Parkinson’s disease) and heart failure.⁴

Parkinson’s disease (PD) is a progressive neurodegenerative disorder where dopamine-producing neurons in the brain’s substantia nigra die off.⁵ Due to the lack of dopamine, symptoms manifest through various motor troubles and cognitive decline, like tremors, muscle stiffness, depression, and memory loss.⁶ Age is the primary risk factor for developing PD, with an average onset at 60 years.⁷ Nearly 10 million people are affected worldwide, and as the population ages, that number is expected to exceed 25 million by 2050.^7,8 In the United States alone, the total economic burden of PD is estimated to be $52 billion annually and therapeutic surgery can cost up to $100,000 per person.⁷ Current treatments approved by the U.S. Food and Drug Administration (FDA), such as levodopa, replenish dopamine levels and help manage symptoms but do not slow disease progression.⁶ Hence, there is a significant unmet need for disease-modifying therapies.

PD is inherently heterogeneous. Its sporadic and inherited causes, varying clinical presentations, and convoluted pathophysiology have challenged the development of target-/group- and individual-specific disease-modifying therapies.⁹ However, mounting genetic analyses, post-mortem studies, and functional assays have begun to shed light on mitochondria as a promising therapeutic avenue. 

Autosomal recessive mutations in the genes parkin RBR E3 ubiquitin protein ligase (PRKN) and PTEN-induced kinase 1 (PINK1) make up the majority of inherited early-onset PD cases.⁵ This is significant because the proteins encoded by these genes facilitate the autophagic clearance of dysfunctional mitochondria, a quality control mechanism called mitophagy. Thus, mutations in PRKN and PINK1 disrupt mitophagy and cause damaged mitochondria to accumulate within cells.

The first time damaged mitochondria were linked to PD was through post-mortem studies on individuals who developed the condition after injecting themselves with synthetic heroin contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).¹⁰ MPTP is a potent neurotoxin that disrupts complex I of the electron transport chain, the mitochondria’s energy motor. The discovery of MPTP-induced PD led to major breakthroughs that indicated how the downstream effects of mitochondrial damage—such as reduced adenosine triphosphate (ATP) production and increased reactive oxygen species (ROS)—drive PD progression.¹¹ 

The main pathological feature of PD is the buildup of toxic α-synuclein, a protein that forms into insoluble fibrils called Lewy bodies.⁵ A major problem with α-synuclein accumulation is that it hinders mitochondrial function. The binding of α-synuclein aggregates to mitochondria can exacerbate mitochondrial damage. As a result, ROS production increases and ATP depletes, which can lead to the release of mitochondrial deoxyribonucleic acid (DNA) and subsequent activation of inflammatory pathways. Additionally, calcium homeostasis can become disrupted, which impairs synaptic plasticity (i.e. the ability to strengthen neural connections).¹²  Together, these events converge to trigger the death of dopaminergic neurons and elicit PD (Figure 1). Given that there are several interconnected PD mechanisms downstream of mitochondrial dysfunction, therapies targeting damaged mitochondria may offer a novel and holistic approach at slowing disease progression.

Leveraging Mitophagy 

The enormous societal burden associated with PD will continue to grow with no available disease-modifying therapies. Given that research has been highlighting the intricate role of mitochondria in PD, the development of novel therapies is expected to surge. Reflecting the high demand, the global market for mitochondrial-targeted drugs for central nervous system (CNS) indications, including PD, is projected to reach $2.5 billion by 2029. That is a staggering compound annual growth rate of 97% from 2023 to 2029.¹³

The current attempts to target mitochondrial dysfunction have so far been indirect and have failed to confer long-term clinical benefits.¹² For example, in a Phase II trial, the antioxidant coenzyme Q10 (CoQ10) showed promise at high doses (1.2 g/day) in slowing functional decline in early PD patients over two months.¹⁴ However, a subsequent 16-month Phase III trial found no significant benefit when 600 patients with early PD received 1.2 g/day, 2.4 g/day, or a placebo.¹⁵ A more specific approach was developed with MitoQ, a synthetic mitochondria-targeted version of CoQ10, but its long-term clinical benefit still remains unclear.^16,17

Additionally, epidemiological studies revealed that the risk of developing PD was reduced when using glucagon-like peptide-1 (GLP-1) agonists like exenatide.¹² More promisingly, exenatide administration enabled neuroprotection in preclinical PD mouse models and improved motor symptoms in a 48-week placebo-controlled clinical trial.^18,19 However, a Phase III clinical study funded by Britain’s National Institute for Health and Care Research reported that a 96-week trial testing exenatide in PD patients provided no significant benefit.²⁰ A major factor in these results is that the mechanism of action of exenatide in targeting PD is unclear.²⁰ 

The brain is an organ with a high metabolic rate, accounting for 20% of the body’s total energy expenditure.¹¹ Since mature neurons do not divide, they cannot dilute damaged mitochondria through cell division. Instead, neurons must rely on quality control mechanisms like mitophagy to clear dysfunctional mitochondria and remain functional. Moreover, the significant bioenergetic and metabolic requirements of dopaminergic neurons make them especially vulnerable to mitochondrial stress. Consistent with this, in vivo mouse studies using mitophagy reporters have shown that dopaminergic neurons exhibit high mitophagy levels.²¹ This largely underlies why defective mitophagy has been implicated in synaptic dysfunction in the early pathophysiology of PD.²² Additionally, as mentioned earlier, the genes PINK1 and PRKN are key regulators of mitophagy and are commonly mutated in patients with PD. Given that mitophagy is crucial for neuronal health and deficits in this process are genetically driven, enhancing mitophagy offers a promising therapeutic approach for treating both inherited and sporadic forms of PD. 

Non-selective mitophagy enhancers are currently being pursued as a means of targeting the root cause of mitochondrial dysfunction in PD. In fact, the immunosuppressant rapamycin and the supplement nicotinamide riboside have both shown positive outcomes in preclinical studies and Phase 1 trials.^23,24 However, the action of these agents is pleiotropic and not well understood. Similar to exenatide, rapamycin and nicotinamide riboside may encounter challenges in later clinical trials due to the lack of a fully characterized mechanism of action in targeting PD.²⁵

Ubiquitin-Mediated Mitophagy

New targeted therapeutics addressing mitochondria damage are beginning to emerge as our understanding of the molecular components that regulate mitophagy become clearer. The PINK1-Parkin pathway represents the most promising therapeutic avenue due to its highly characterized ubiquitination mechanism. Landmark studies have shown that damaged mitochondria are cleared from the cell through the coordinated activity of the serine/threonine (Ser/Thr) kinase PINK1 and the ubiquitin E3 ligase Parkin (Figure 2).²⁵ This process tags damaged mitochondria with ubiquitin, which enables its recognition and clearance by autophagic machinery. Additionally, ubiquitin-specific peptidase 30 (USP30), a deubiquitylating enzyme, has been identified as a negative regulator of this pathway by removing ubiquitin chains.²⁵  Since PINK1 promotes mitophagy and USP30 inhibits it, both have become key targets for small molecule intervention. Moreover, the PINK1 activator ABBV-1088 (Mitokinin/AbbVie) and the USP30 inhibitor MTX325 (Mission Therapeutics) are both entering Phase 1 clinical trials as the first selective mitophagy enhancers to treat PD.^25,26

MTX325: From Bench to Bedside

In late 2023, the UK-based biotech company Mission Therapeutics (Mission) published a pivotal preclinical study using a mouse model of PD that conveyed the translational capabilities of MTX325. They found that genetic knockdown of USP30 increased CNS mitophagy, protected against dopaminergic neuron loss, and reduced α-synuclein aggregation. More importantly, they found that pharmacological USP30 inhibition via MTX325 similarly showed dose-dependent protection against dopaminergic neuron loss and α-synuclein aggregation, as well as the prevention of inflammatory responses.²⁷

Building on promising preclinical data, Mission launched Phase 1 of its multi-part and adaptive clinical study of MTX325 in March 2024. This first-in-human study enrolled up to 160 adults across the UK, including healthy volunteers and PD patients.²⁶  The trial began with single and multiple dose ascending stages in healthy volunteers and extended to elderly non-PD participants in June 2024 to control for age-related effects. Early data from these cohorts have revealed that MTX325 has a good safety profile, pharmacokinetics, and CNS penetration.²⁸ Backed by funding from The Michael J. Fox Foundation for Parkinson’s Research and Parkinson’s UK, a 28-day dosing of MTX325 in PD patients is expected to begin in early 2025. The goal for this cohort is to observe how MTX325 modulates PD biomarkers, although it’s unclear what specific biomarkers Mission is pursuing.²⁸

The most common limitation to the success of early PD clinical trials is the lack of reliable, inexpensive, and non-invasive biomarkers.²⁹ Without an accurate PD biomarker, tracking target engagement, monitoring disease progression, and optimizing patient stratification is nearly impossible. However, recent data from Mitokinin suggest that mitophagy activation can be detected in cerebrospinal fluid (CSF) and blood plasma by measuring phosphorylated ubiquitin at serine 65 (p-Ser65-Ub) using immunodetection techniques.^25,30 Having a molecular readout for mitophagy levels will significantly aid in evaluating early proof of concept for MTX325. Additionally, an α-synuclein seed amplification assay is being developed to quantify α-synuclein aggregation in skin samples, a more accessible tissue than CSF. If MTX325 demonstrates the same ability to reduce α-synuclein aggregation in people with PD as seen in its preclinical studies, then the combined use of p-Ser65-Ub and α-synuclein as biomarkers could potentially expedite its regulatory approval process.²⁵ However, the stage of development for these biomarkers and how they will be integrated into clinical strategy remain unclear.

Despite early clinical uncertainties, small molecule USP30 inhibitors still represent a promising therapeutic approach due to their potential to treat multiple disease indications. Another area of interest is employing mitophagy enhancement to protect kidney health, as this organ also has high metabolic demands and selective sensitivities to mitophagy defects. In fact, the U.S. Food and Drug Administration has approved MTX652, a peripherally-restricted USP30 inhibitor, to enter a phase II clinical trial to treat acute kidney injury following cardiac surgery.³¹

Thanks to advancements in basic science, we now have a deep understanding of how mitochondria are implicated in a variety of hard-to-treat diseases. But the real challenge lies in successfully translating these insights into the clinic. MTX325 and MTX652 are the first mitophagy enhancers to enter clinical trials; therefore, the utility of mitophagy enhancement as a therapeutic strategy greatly depends on their clinical outcomes. Looking ahead, this field is poised to evolve over the coming years as we gather more clinical data, validate alternative mitophagy targets, and develop new selective agents. Although it’s too early to tell, enhancing mitophagy could revolutionize how we combat chronic diseases— that is, by harnessing our cells’ own quality control mechanisms to restore mitochondrial health. 

References

1. Mission Therapeutics Ltd. Phase I trial code: RD 787.36057 (MTX325-101). ISRCTN Registry. Published February 6, 2025. Accessed April 14, 2025. https://doi.org/10.1186/ISRCTN20898392
2. Clark EH, Vázquez de la Torre A, Hoshikawa T, Briston T. Targeting mitophagy in Parkinson’s disease. J Biol Chem. 2021;296:100-209. doi:10.1074/jbc.REV120.014294
3. Misgeld T, Schwarz TL. Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture. Neuron. 2017;96(3):651-666. doi:10.1016/j.neuron.2017.09.055.
4. Murphy MP, Hartley RC. Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov. 2018;17(12):865-886. doi:10.1038/nrd.2018.174
5. Kouli A, Torsney KM, Kuan WL. Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis. In: Stoker TB, Greenland JC, eds. Parkinson’s Disease: Pathogenesis and Clinical Aspects. Brisbane (AU): Codon Publications; December 21, 2018. doi:10.15586/codonpublications.parkinsonsdisease.2018.ch1
6. Parkinson’s Disease. National Institute of Neurological Disorders and Stroke. Updated March 5, 2025. Accessed March 15, 2025. https://www.ninds.nih.gov/health-information/disorders/parkinsons-disease
7. Statistics. Parkinson’s Foundation. Accessed March 15, 2025. https://www.parkinson.org/Understanding-Parkinsons/Statistics.
8. Projected Parkinson’s disease cases worldwide set to hit 25 million by 2050. Healio. Published March 06, 2025. Accessed March 15, 2025. https://www.healio.com/news/primary-care/20250306/projected-parkinsons-disease-cases-worldwide-set-to-hit-25-million-by-2050
9. Mari Z, Mestre TA. The Disease Modification Conundrum in Parkinson’s Disease: Failures and Hopes. Front Aging Neurosci. 2022;14:810860. Published 2022 Feb 28. doi:10.3389/fnagi.2022.810860
10. Nonnekesa J, Postb B, Tetrudc J,  Langstonc W. MPTP-Induced Parkinsonism: An Historical Case Series. The Lancet Neurology 2018, 17 (4), 300–301. doi:10.1016/s1474-4422(18)30072-3.
11. Moreira PI, Zhu X, Wang X, et al. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta. 2010;1802(1):212-220. doi:10.1016/j.bbadis.2009.10.007
12. Henrich MT, Oertel WH, Surmeier DJ, Geibl FF. Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential. Mol Neurodegener. 2023;18(1):83. Published 2023 Nov 11. doi:10.1186/s13024-023-00676-7
13.  From Lab to Market: The Future of Mitochondrial Function in Neurodegeneration Therapy. Sygnature Discovery. Accessed March 15, 2025. https://www.sygnaturediscovery.com/news-and-events/blog/from-lab-to-market-the-future-of-mitochondrial-function/
14.  Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol. 2004;188(2):491-494. doi:10.1016/j.expneurol.2004.05.003
15. Parkinson Study Group QE3 Investigators, Beal MF, Oakes D, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014;71(5):543-552. doi:10.1001/jamaneurol.2014.131
16. Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG. Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta. 2014;1842(8):1282-1294. doi:10.1016/j.bbadis.2013.09.007
17. Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O’Sullivan JD, Fung V, Smith RA, Murphy MP, Taylor KM. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Movement Disorder Society. 2010;25:1670–1674. doi:10.1002/mds.23148.
18. Dahiya S, Tisch S, Greenfield J. The effect of GLP-1 receptor agonists in pre-clinical rodent models of Parkinson’s disease: a systematic review and meta-analysis. Clin Park Relat Disord. 2022;6:100133.
19. Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:1664–75.
20. Vijiaratnam N, Girges C, Auld G, et al. Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson’s disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial. Lancet. 2025;405(10479):627-636. doi:10.1016/S0140-6736(24)02808-3
21.  McWilliams TG, Prescott AR, Montava-Garriga L, et al. Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand. Cell Metab. 2018;27(2):439-449.e5. doi:10.1016/j.cmet.2017.12.008
22. Henrich MT, Oertel WH, Surmeier DJ, Geibl FF. Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential. Mol Neurodegener. 2023;18(1):83. Published 2023 Nov 11. doi:10.1186/s13024-023-00676-7
23. Zheng W, Li K, Zhong M, et al. Mitophagy activation by rapamycin enhances mitochondrial function and cognition in 5×FAD mice. Behav. Brain Res. 2024;463:114889. doi:10.1016/j.bbr.2024.114889
24. Berven H, Kverneng S, Sheard E, et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nat. Commun. 2023;14(1):7793. doi:10.1038/s41467-023-43514-6
25.  Antico O, Thompson PW, Hertz NT, Muqit MMK, Parton LE. Targeting mitophagy in neurodegenerative diseases. Nat Rev Drug Discov. 2025;24(4):276-299. doi:10.1038/s41573-024-01105-0
26. Phase I trial code: RD 787.36057 (MTX325-101) ISRCTN. Accessed April 1, 2025. https://www.isrctn.com/ISRCTN20898392 
27.  Fang TZ, Sun Y, Pearce AC, et al. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Nat Commun. 2023;14(1):7295. Published 2023 Nov 13. doi:10.1038/s41467-023-42876-1
28. Mission Therapeutics awarded $5.2m from The Michael J. Fox Foundation and Parkinson’s UK to advance potential disease-modifying treatment MTX325. Prnewswire. Published July 2, 2024. Accessed April 1, 2025. https://www.prnewswire.com/news-releases/mission-therapeutics-awarded-5-2m-from-the-michael-j-fox-foundation-and-parkinsons-uk-to-advance-potential-disease-modifying-treatment-mtx325–302187338.html
29. Angeliki Z, Thomas GEC, Zetterberg H, Weil RS. Neuroimaging and Fluid Biomarkers in Parkinson’s Disease in an Era of Targeted Interventions. Nature Communications 2024;15(1). doi:10.1038/s41467-024-49949-9.
30. Chin RM, Rakhit R, Ditsworth D, et al. Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models. Preprint. bioRxiv. 2023;2023.02.14.528378. Published 2023 Feb 15. Accessed April 1, 2025. doi:10.1101/2023.02.14.528378
31. Dunmore R, Haines Z, Williams R, et al. Abstract 4135531: The ubiquitin-specific protease 30 inhibitor, MTX652, attenuates cardiac dysfunction and remodelling in a murine model of transverse aortic constriction. Circulation. 2024;150(Suppl_1):A4135531. doi:10.1161/circ.150.suppl_1.4135531

Publication Licenses

Figure 1. Created in BioRender. Baker, L. (2025) https://BioRender.com/geovomz

Figure 2. Created in BioRender. Baker, L. (2025) https://BioRender.com/vzoefyc

Figure 3. Created in BioRender. Baker, L. (2025) https://BioRender.com/r4p1j16

Author: Kylie VanDerMolen
Editor: Ashley Aguillard

Today, I will be discussing rapamycin and its various analogs, called “rapalogs,” that have been developed for improved pharmacological properties and therapeutic uses. There are seven brand name rapamycin/rapalog therapeutics (five generics) that have been approved by the U.S. Food and Drug Administration (FDA) mainly as immunosuppressants or cancer/tumor inhibitors; however, there is a broad range of ongoing research to expand the use of these drugs to treat various other conditions, such as metabolic, neurodegenerative, and age-related diseases. I will start with an introduction to rapamycin and the pathophysiological significance of its target protein, mechanistic Target Of Rapamycin (mTOR). I will then cover the approved rapamycin and rapalog therapeutics, briefly touch on a category of rapamycin-related medical devices, and finally, discuss the future of this class of drugs and the ongoing studies intended to expand the range of their therapeutic use.

Introduction to rapamycin and mTOR signaling

The discovery of rapamycin dates back to a 1964 Canadian expedition to the Chilean territory of Easter Island, called Rapa Nui (Rapamycin’s namesake), from which researchers collected soil samples to study the diversity of microorganisms on the island in an effort to uncover novel natural products.¹ The Gram-positive bacterial species Streptomyces hygroscopicus was isolated and found to produce rapamycin, a molecule later determined to be an antibiotic and antifungal with immunosuppressive and antiproliferative effects on cells.^1,2 Further studies revealed that rapamycin is a potent inhibitor of a protein kinase named for this interaction – mechanistic Target Of Rapamycin (mTOR).² Protein kinases add a phosphate group to target substrates (i.e. other proteins) to alter their activity. This process is a key component of protein signaling pathways that ultimately lead to the regulation of important biological processes. mTOR exists in two complexes (mTORC1 and mTORC2), which are distinguished by their inclusion of distinct proteins (see Figure 1). Notably, rapamycin is thought to be a specific inhibitor of mTORC1 through formation of a complex with Fk506-binding protein 12 kDa (FKBP12) that disrupts the ability of mTORC1 to interact with its substrates (otherwise known as allosteric inhibition).² However, chronic treatment of some cell types with rapamycin has been proposed to also inhibit mTORC2.²

Since its initial identification as the mechanism of the valuable properties of rapamycin, mTOR signaling has become considered a key regulator of biological processes necessary for cell growth and proliferation, particularly in metabolic anabolism, or the building of complex biological molecules (macromolecules).^2,3 mTORC1 has been well-characterized as a key nutrient sensor, integrating signals about nutrient availability to navigate the generation of the building blocks of cells, such as proteins and fats. Less is known about mTORC2, but it is also thought to use similar signals to contribute to the production of macromolecules and regulation of cell proliferation and survival.² Overactive mTOR signaling can lead to over-proliferation of cells that become cancerous. The genes TSC1 and TSC2 (Tuberous Sclerosis Complex 1 and 2) encode for proteins that inhibit mTORC1, thereby regulating tumor suppression.² Because of its robust regulation of cell proliferation, inhibition of mTOR signaling has become a prominent mechanism for anti-cancer and anti-tumor therapeutics.³ Additionally, mTOR inhibitors are useful for suppressing unwanted cell proliferation that promotes rejection of organ transplants and other conditions associated with the genetic disease caused by mutations in the TSC1 and TSC2 genes.² However, inhibition of mTOR also has promising anti-aging and lifespan extending effects, which has led to ongoing clinical trials to expand their approval into treatment for age-related diseases.² The anti-aging effects of mTOR inhibition by rapamycin are, in part, attributed to its activation of a process called autophagy, which removes unwanted cellular debris and damaged proteins and organelles.⁴ These components are thought to accumulate with age and cause negative effects associated with disease.⁴ I will discuss some ongoing clinical trials and promising results in the conclusion of this post.

Sirolimus: the first FDA approval of rapamycin

Sirolimus systemic

Rapamune

The FDA first approved rapamycin, also known by its generic name, sirolimus, under the brand name Rapamune to Wyeth-Ayerst Research (acquired by Pfizer in 2009) in 1999 as an oral solution and in 2000 as an oral tablet for the prevention of organ rejection in kidney transplant patients.⁵ When a patient receives an organ transplant, the body may recognize foreign molecules, or antigens, from the donor organ via specialized immune cells called T cells.^6,7 T cells trigger the immune response, which ultimately leads to the neutralization and destruction of cells with the foreign antigen via antibodies.⁷ This can cause organ damage and ultimately lead to organ failure.⁶ Treatment with immunosuppressive agents inhibits this immune response and significantly reduces the risk of rejection. Therefore, organ donor recipients are prescribed lifelong immunosuppressive intervention.⁶ Sirolimus effectively restricts the proliferation of immune T cells through inhibition of mTORC1, thus reducing the attack on the donor organ by the immune system.³ Pfizer later expanded the indicated use of Rapamune in 2015 when the FDA approved its use for the treatment of lymphangioleiomyomatosis (LAM).⁸ LAM is a rare, progressive disease that affects the lungs primarily, but also kidney and lymphatic system function.⁹ LAM symptoms occur due to abnormal cell growth in the affected tissues, leading to respiratory dysfunction, cysts, and tissue damage.⁹ Sirolimus combats this cell growth via inhibition of pro-growth mTORC1 signaling to help stabilize lung function. Importantly, Rapamune became the first approved treatment for this condition.⁸ The brand name drug, Rapamune, was discontinued by Pfizer in 2023 after a determination that the availability of generic sirolimus was sufficient to meet the therapeutic need in the U.S.¹⁰

Sirolimus protein-bound systemic

Fyarro

Sirolimus has also been approved for the most common area of indication for rapamycin/rapalogs – cancer treatment. Aadi Bioscience developed a sirolimus protein-bound particle for injectable suspension (albumin-bound) to treat local, advanced malignant perivascular epithelioid cell tumors (PEComa) associated with blood vessel walls that are unresectable or metastatic. This therapeutic was approved under the brand name Fyarro in 2021 by the FDA.¹¹ PEComa is a rare, aggressive connective tissue cancer that is frequently driven by mTOR overactivation caused by mutations in TSC1 and TSC2, leading to cell over-proliferation and tumor formation.¹² Fyarro utilizes a technology called nanoparticle albumin-bound (nab) particles, meaning that sirolimus molecules are attached to small particles of albumin (a naturally occurring protein in human blood).^12,13 This technique is particularly useful for therapeutics that are not very soluble in blood and those that are highly toxic, like anticancer drugs.¹³ Nab technology allows for improved drug delivery due to its natural compatibility with movement through the bloodstream. Importantly, sirolimus nab particles have significantly higher specificity, efficacy, and potency than oral mTOR inhibitors in nonclinical studies of human bladder cancer tumors in mice.^12,13

Sirolimus topical

Hyftor

The most recent FDA approval of rapamycin is a topical sirolimus (0.2%) manufactured as a gel that was developed by Nobelpharma and approved by the FDA in 2022 for the treatment of facial angiofibroma associated with Tuberous Sclerosis Complex (TSC).^14,15. TSC is a rare genetic condition caused by mutations in the TSC1 and TSC2 genes that leads to benign tumor growth in many tissues, including the brain, kidneys, eyes, and most commonly, the skin.¹⁵  These skin tumors (facial angiofibromas), while noncancerous, can lead to bleeding, nasal blockage, or other disfigurement and occur in 75-80% of TSC patients.¹⁵ Hyftor was developed as a topical, non-invasive treatment option for this symptom of TSC. This met a major unmet need in the treatment landscape for TSC-associated facial angiofibromas, as other existing interventions involve invasive procedures that often require anesthesia.¹⁵

Rapalogs – altering rapamycin for improved efficacy and expanded indications

Oral rapamycin, while efficacious in both the prevention of kidney transplant rejection and stabilization of lung function in LAM, is considered to have low and variable oral bioavailability.¹⁶ To improve its therapeutic use, researchers have generated alternate versions of this compound, called analogs, that enhance its pharmacological properties. Two analogs of rapamycin, or rapalogs, have been FDA approved – everolimus and temsirolimus. All rapalogs share the exact same chemical structure that interacts with FKBP12, except for a change to the chemical group of the carbon at the 40^th position (C40).¹⁷ These small alterations allow for improvements in the compound’s properties. Comparative pharmacokinetic studies demonstrated that everolimus has improved absorption and oral bioavailability in comparison to sirolimus, as well as improved systemic clearance.¹⁷ Additionally, everolimus and sirolimus may have differential access to tissues and organelles. For example, it’s been suggested that everolimus can affect mitochondrial function in the brain, while sirolimus cannot.¹⁸ This may allow for treatment of different indications.¹⁷ On the other hand, sirolimus is thought to have superior absorption through the skin, hence its beneficial effects as a topical gel for TSC-associated skin conditions.¹⁷ Temsirolimus has significantly better solubility and stability than sirolimus, allowing for its formulation as an intravenous injection.^17,18 This route of administration permits almost complete bioavailability by avoiding metabolism through the digestive system and liver.^17,18 Additionally, its immunosuppressive effects are minimized under a weekly injection dose schedule, allowing for reduced undesirable side effects in indications like cancer.¹⁸ These chemical advancements have allowed for expanded approvals of rapamycin and its analogs to treat more diseases with better efficacy and fewer adverse effects.

Everolimus systemic

Afinitor/Afinitor Disperz, Zortress

Everolimus is approved by the FDA for the treatment of several types of tumors, multiple TSC-associated conditions, and as an immunosuppressant for the prevention of kidney or liver transplant rejection.

Cancer
Novartis first got FDA approval for Afinitor (an oral tablet) in 2009 for the treatment of advanced kidney cancer (renal cell carcinoma (RCC)) after treatment failure with other therapeutics (sunitinib or sorafenib).^19,20. In 2011, Afinitor was approved to treat advanced progressive neuroendocrine tumors of pancreatic origin (PNET) that were locally advanced, metastatic, or unable to be resected.^19,20 This was a monumental approval as this indication had not seen a new treatment approved in nearly 30 years. Novartis subsequently gained approval to treat well-differentiated, progressive, nonfunctional gastrointestinal and lung neuroendocrine tumors (NET) with the same criteria in 2016.^19,20. Afintor was also approved to treat advanced breast cancer in 2012. Specifically, this approval is to treat hormone receptor-positive, HER2-negative breast cancer in combination with Aromasin (exemestane) for use in postmenopausal women with recurrent or progressing cancer after treatment with other therapeutics (letrozole or anastrozole).^19,20

TSC-associated conditions
In 2010, Afinitor first became approved to treat TSC-associated subependymal giant cell astrocytoma (SEGA), a slow-growing, but potentially fatal, brain tumor in TSC patients that could not be treated by surgery.^19,20 Novartis also developed a pediatric-specific dosage of Afinitor called Afintor Disperz, which is an oral suspension of everolimus, or a dissolvable tablet.^19,20 This formulation was approved for the same indication in patients 1 year and older in 2012. Afintor Disperz was also approved in 2018 to treat TSC-associated partial-onset seizures in patients 2 years and older.^19,20 Afinitor approval was expanded in 2012 for the first non-surgical intervention for TSC-associated benign kidney tumors (renal angiomyolipomas), which are highly prevalent among TSC patients (80%) and could become life-threatening.^19,20

Organ transplant
Novartis, who owns all of the FDA-approved everolimus therapeutics currently available, also gained approval in 2010 for Zortress, an everolimus oral tablet for preventing rejection of kidney transplants in adults that are not at high immunologic risk.²¹ This approval was expanded to include liver transplants in 2013, making Zortress the first immunosuppressive agent approved for liver transplant patients in over ten years.²² Novartis also has an everolimus immunosuppressant for kidney, heart, and lung transplant rejection prevention in adults with low to moderate immunological risk that was approved by the European Health Authorities in 2012, called Certican.²²

Temsirolimus systemic

Torisel

Temsirolimus, as previously mentioned, is available in a formulation of intravenous injection due to its significantly improved solubility and stability in comparison to sirolimus. Torisel, the only temsirolimus brand name drug that is FDA-approved, was granted to Pfizer in 2007 for the treatment of advanced renal cell carcinoma (RCC).²³ Torisel is one of many available treatment options for stage IV and recurrent renal cell cancer, along with the aforementioned everolimus brand name drug, Afintor. Torisel can be considered a first-line therapeutic for advanced RCC, whereas Afintor is approved for prescription after failure to treat with first-line therapies sunitib and sorafenib.²⁴

Other applications: Rapamycin-eluting stents

Of note, there are also multiple approved medical devices that elute rapamycin (sirolimus, everolimus, ridaforolimus, zotarolimus) called drug-eluting stents.²⁵ These stents are used in patients that have undergone procedures to open clogged arteries (coronary angioplasty) to help prevent their re-narrowing.²⁵ Stent placement can injure the wall of the arteries, promoting excessive smooth muscle cell proliferation and re-narrowing of the blood vessel, called restenosis.²⁶ Rapamycin inhibits this over-proliferation and allows the stent to keep the artery unblocked. The FDA approved a sirolimus-coated stent to Johnson & Johnson in 2003 (CYPHER), which has since been discontinued due to a decision by manufacturer Cordis in 2011 to focus more on other products in the cardiovascular device space.^26,27 The CYPHER stent was a pioneer in this medical device space and other drug-eluting stents and drug-coated balloons have since been developed and approved for treatment of in-stent restenosis.

The future of mTOR inhibitors in the clinic

mTOR signaling is a master regulator of many cellular and metabolic processes and is therefore very promising as a therapeutic area in a number of different diseases. Aside from its already approved indications, there is growing evidence for mTOR inhibition in protection against neurodegenerative, metabolic, and age-related diseases.² Preclinical studies suggest protection against in vivo mouse models of multiple neurodegenerative conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as spinocerebellar ataxia type 3.² The mechanism of action is likely due to the role of mTORC1 in protein synthesis and autophagy. Misfolded proteins are thought to accumulate in these diseases, causing the associated neurodegenerative damage. Suppressing protein synthesis and inducing autophagy through inhibition of mTORC1 may reduce and/or prevent the aggregation of these proteins to help treat the neurodegeneration.

As a key regulator of anabolic metabolism, metabolic conditions like diabetes and obesity are a target area for future uses of mTOR inhibitors. However, mTOR inhibition can have both positive and negative effects on metabolic disease due to its complicated signaling mechanisms.² Preclinical studies have demonstrated improved insulin sensitivity and protection against obesity induced by a high-fat-diet, but alternatively, have also shown increased blood glucose and lipid levels (hyperglycemia, hyperlipidemia) and insulin resistance, which are hallmarks of diabetes.² These effects are thought to, in part, be controlled by the length of treatment time in these models and how that relates to the inhibition of other regulatory components, like mTORC2, but the translation of these findings to human treatment is still being studied.

Lastly, rapamycin is well-known for its impacts on aging and longevity. Inhibition of mTOR signaling has been shown to extend the lifespan in numerous animal models from fruit flies and nematodes to mice.² Not only is the lifespan extended, but studies show that age-associated health decline and disease are improved with rapamycin treatment, including, but not limited to, cancer, cardiac disease and function, immune function, muscle decline, metabolic function, and neurodegeneration.^2,28,29 Over time, cells accumulate damage to DNA, organelles, and proteins, which contributes to cellular arrest and promotes aging.²⁸ This cellular aging may limit cell function across tissues and cause widespread inflammation, driving age-related decline and pathologies.²⁸ The contribution of mTOR to aging is likely diverse, as mTOR controls many biological processes related to cell function. The mechanism of action of mTOR inhibition in aging may involve its role in autophagy, protein and organelle regulation, DNA damage response, and more. However, the associated side effects, including hyperglycemia, hyperlipidemia, and immunosuppression, present a challenge to the use of rapamycin in age-associated interventions.²⁹ These are suggested to be partially mediated by unintended inhibition of mTORC2, which can occur in long-term rapamycin application, so lower, intermittent doses or analogs with mTORC1 specificity are suggested to help reduce these adverse events.²⁹

Rapamycin is an area of active study in the clinic, with ongoing trials in these promising disease areas or their expansion to indications similar to those it is already approved for (i.e. different cancers). The “miracle” drug discovery over 50 years ago continues to make its way into the clinic across a broad spectrum of diseases. Further development of analogs to improve its properties and efficacy has and will continue to benefit patients with a variety of conditions.

References

 1. Powers T. The origin story of rapamycin: systemic bias in biomedical research and cold war politics. Mol Biol Cell. 2022;33(13):pe7. doi:10.1091/mbc.E22-08-0377

2. Li J, Kim SG, Blenis J. Rapamycin: One drug, many effects. Cell Metabolism. 2014;19(3):373-379. doi:10.1016/j.cmet.2014.01.001

3. Mohamed MA, Elkhateeb WA, Daba GM. Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment. Bioresour Bioprocess. 2022;9(1):65. doi:10.1186/s40643-022-00554-y

4. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-976. doi:10.1016/j.cell.2017.02.004

5. U.S. Food & Drug Administration. Drug approval package: Rapamune (sirolimus) oral solution. September 15, 1999. Accessed March 19, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm

6. South Texas Renal Care Group. What happens when your body rejects a transplanted organ? August 1, 2022. Accessed March 19, 2025. https://www.texaskidneycare.com/what-happens-when-your-body-rejects-a-transplanted-organ/

7.     Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018;14(S2):49. doi:10.1186/s13223-018-0278-1

8. Pfizer. Pfizer’s RAPAMUNE® (sirolimus) becomes first FDA-approved treatment for lymphangioleiomyomatosis (LAM), a rare progressive lung disease. May 29, 2015. Accessed March 19, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizer_s_rapamune_sirolimus_becomes_first_fda_approved_treatment_for_lymphangioleiomyomatosis_lam_a_rare_progressive_lung_disease

9. Khaddour K, Sankari A, Shayuk M. Lymphangioleiomyomatosis. In: StatPearls [Internet]. 2023. Accessed March 19, 2025. https://www.ncbi.nlm.nih.gov/books/NBK534231/#:~:text=Lymphangioleiomyomatosis%20(LAM)%20is%20a%20primary,tumors%20with%20visceral%20organ%20involvement.

10. Sherman S. Statement on Pfizer’s decision on the brand drug, Rapamune, in the U.S. Published November 1, 2023. Accessed March 19, 2025. https://www.thelamfoundation.org/statement-on-pfizers-decision-on-the-brand-drug-rapamune-in-the-u-s/

11. U.S. Food & Drug Administration. FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. November 23, 2021. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sirolimus-protein-bound-particles-malignant-perivascular-epithelioid-cell-tumor

12.   Aadi Bioscience, Inc. Fyarro (sirolimus protein-bound particles for injectable suspension (albumin-bound)). Accessed March 19, 2025. https://www.fyarrohcp.com/

13.   Microfluidics. Nanoparticle albumin bound (nab) drug delivery technology. Accessed March 19, 2025. https://www.microfluidics-mpt.com/applications/nanoparticle-albumin-bound-nab-drug-delivery

14.   Nobelpharma America. FDA approves Nobelpharma’s HYFTOR^TM (sirolimus topical gel) 0.2%. April 4, 2022. Accessed March 19, 2025. https://www.prnewswire.com/news-releases/fda-approves-nobelpharmas-hyftor-sirolimus-topical-gel-0-2-301516272.html

15.   Nobelpharma. Hyftor (sirolimus topical gel) 0.2%. Accessed March 19, 2025. https://www.hyftor.com/

16.   Abdel-Magid AF. Rapalogs potential as practical alternatives to rapamycin. ACS Med Chem Lett. 2019;10(6):843-845. doi:10.1021/acsmedchemlett.9b00215

17.   MacKeigan JP, Krueger DA. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. Neuro Oncol. 2015;17(12):1550-1559. doi:10.1093/neuonc/nov152

18.   Boni JP, Hug B, Leister C, Sonnichsen D. Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations. Semin Oncol. 2009;36 Suppl 3:S18-25. doi:10.1053/j.seminoncol.2009.10.009

19.   Novartis. Afinitor (everolimus) tablets. Accessed March 19, 2025. https://www.afinitor-hcp.com/

20.   Drugs.com. Afinitor FDA approval history. Accessed March 19, 2025. https://www.drugs.com/history/afinitor.html

21.   National Kidney Foundation. Novartis receives US FDA approval for Zortress® (everolimus) to prevent organ rejection in adult kidney transplant recipients. April 22, 2010. Accessed March 19, 2025. https://www.kidney.org/press-room/national-kidney-foundation-news-2#:~:text=East%20Hanover%2C%20NJ%20(April%2022,%2Dto%2Dmoderate%20immunologic%20risk.

22.  Novartis. Novartis drug Zortress® is first in over a decade approved by FDA to prevent organ rejection in adult liver transplant patients. February 15, 2013. Accessed March 19, 2025. https://www.novartis.com/us-en/news/media-releases/novartis-drug-zortress-first-over-decade-approved-fda-prevent-organ-rejection-adult-liver-transplant-patients

23.   Pfizer. Torisel (temsirolimus). Accessed March 20, 2025. https://www.pfizermedicalinformation.com/torisel

24.  National Cancer Institute. Renal cell cancer treatment (PDQ). Accessed March 20, 2025. https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq#_385

25.  Saad M. Drug-eluting stents. February 17, 2012. Accessed March 19, 2025. https://www.uspharmacist.com/article/drug-eluting-stents#:~:text=First%2Dgeneration%20DES%20include%20sirolimus,outcomes%20in%20patients%20undergoing%20PCI.

26.  Abizaid A. Sirolimus-eluting coronary stents: a review. Vasc Health Risk Manag. 2007;3(2):191-201. doi:10.2147/vhrm.2007.3.2.191

27.   Johnson & Johnson. Cordis announces discontinuation of nevo^TM sirolimus-eluting coronary stent. June 15, 2011. Accessed March 20, 2025. https://www.jnj.com/media-center/press-releases/cordis-announces-discontinuation-of-nevo-sirolimus-eluting-coronary-stent

28.  Walters HE, Cox LS. mTORC Inhibitors as broad-spectrum therapeutics for age-related diseases. Int J Mol Sci. 2018;19(8):2325. doi:10.3390/ijms1908232529.  

29. Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. 2023;3(6):642-660. doi:10.1038/s43587-023-00416-y

Author: Sarah Sizer, Ph.D.
Editor: Morgan McCullough

This article will describe Livdelzi, a drug developed by Gilead Sciences and recently granted Accelerated Approval by the Food and Drug Administration (FDA) for treating Primary Biliary Cholangitis (PBC). The approval was based on data from a phase 3 clinical trial demonstrating that Livdelzi normalized key indicators of disease progression, including severe itch and liver enzyme levels.

Overview of Primary Biliary Cholangitis

PBC is a rare autoimmune disease characterized by the gradual destruction of the liver by the immune system that affects between 1.91 and 40.20 per 100,000 people globally depending on the region.¹ Like most autoimmune disorders, PBC is more prevalent in women than men (female:male ratio of 4.2:1); however, men experience more severe disease progression and are less responsive to available therapies for PBC.^2,3 The onset of PBC is influenced by a combination of genetic and environmental factors, where individuals with a genetic predisposition to the disease encounter chemicals or pathogens (i.e., smoking, recurrent urinary tract infections, pollution, xenobiotics) that trigger an immune response against the small bile ducts that transport bile from the liver to the small intestine for fat absorption and digestion.^4–6 Injury to the bile ducts impedes bile flow to the small intestine, causing bile acid accumulation and liver inflammation. Persistent damage to the bile ducts promotes the stiffening of liver tissue and eventually end-stage liver disease, yet early diagnosis and treatment can dramatically attenuate disease progression and reduce the incidence of liver transplants (Figure 1).^7–9

While mid to late-stage PBC is associated with jaundice, fatigue, itching, diarrhea, nausea, and weight loss, approximately 60% of people with PBC are asymptomatic at the time of diagnosis and discover they have the disease through routine blood tests.⁹ Patients must meet two out of the three following criteria for a PBC diagnosis:

1. Elevated alkaline phosphatase levels (1.5X the upper limit)
2. Presence of antimitochondrial antibodies 
3. Histological evidence of bile duct destruction

Laboratory tests measure alkaline phosphatase levels and detect the presence of antimitochondrial antibodies in the blood. Because a small subset of patients with PBC do not produce antimitochondrial antibodies (5-10%), there are instances where a liver biopsy is necessary to assess the damage to the bile ducts.¹⁰ Liver biopsies may also determine the stage of PBC or rule out similar conditions like autoimmune hepatitis.

Pathogenesis of Primary Biliary Cholangitis

Biliary epithelial cells line the bile ducts and serve as critical modulators of bile synthesis and homeostasis by transporting bile acids, salts, and other solutes into the ducts for further processing. Biliary epithelial cells secrete bicarbonate and create a ‘bicarbonate umbrella’ around their cell membranes to shield themselves from prolonged contact with bile acids. In PBC patients, biliary epithelial cells become more vulnerable to injury due to the downregulation of the anion exchanger 2 (AE2) transporter (Cl^–/HCO₃^–), a membrane protein responsible for shuttling bicarbonate into the bile ducts.¹¹ Dysregulation of the AE2 transporter weakens the ‘bicarbonate umbrella’, ultimately leading to increased biliary epithelial cell alkalinity and irregularly acidic bile, cell stress, and apoptosis. 

As the biliary epithelial cells undergo apoptosis, their plasma membranes fragment into portions of the cell membrane and cytoplasm called apoptotic blebs that contain a modified version of a mitochondrial protein called the pyruvate dehydrogenase complex E2 subunit, or PDC-E2.¹² Whether modifications to PDC-E2 result from cell stress or molecular mimicry from environmental exposure is unclear; however, these alterations render immune cells unable to recognize PDC-E2 and promote a targeted response against biliary epithelial cells.⁵ Specifically, macrophages and dendritic cells present fragments of the protein to CD4⁺ T helper cells to determine whether PDC-E2 is foreign. Once CD4⁺ T helper cells classify PDC-E2 as an antigen, they release pro-inflammatory cytokines to activate multiple immune cell types, including B cells, T killer cells, hepatic stellate cells, and portal fibroblasts. B cells become plasma cells and produce antimitochondrial antibodies targeting PDC-E2, while activating CD8⁺ T killer cells and natural killer cells induces apoptosis and premature senescence of biliary epithelial cells. Hyperactivation of these pro-inflammatory and apoptotic pathways create a positive feedback loop driving the release of PDC-E2, recruitment of more immune cells, and further apoptosis and senescence. Portal fibroblasts and hepatic stellate cells respond to sustained inflammation by depositing collagen, which stiffens (fibrosis) the liver tissue and causes irreversible scarring called cirrhosis (Figure 2). 

Current and Emerging Therapies for Primary Biliary Cholangitis

Prior to 2024, there were two FDA approved medications for PBC. While these drugs significantly reduce the progression of the disease, they both have limitations that necessitate the development of novel therapeutics for PBC. Last year, the FDA approved two medications from the same drug class for PBC (Iqirvo and Livdelzi) through their accelerated approval process. This section will discuss the two medications that were FDA-approved prior to 2024 (Ursodiol and Ocaliva) and one of the newest FDA-approved drugs for PBC, Livdelzi (Figure 3).¹³

Ursodiol (ursodeoxycholic acid) remains the first-line therapy for PBC. The pharmaceutical company Allergan initially developed Ursodiol in 1987 to treat gallstones. After clinicians discovered Ursodiol simultaneously reduces alkaline phosphatase levels, it was repurposed to treat PBC and became FDA-approved for this indication in 1997. Ursodiol is a naturally occurring secondary bile acid that incorporates itself into the bile pool and alters its composition, replacing toxic bile acids and reducing inflammation.^15,16 Ursodiol protects the bile ducts by upregulating scaffolding proteins to stabilize the biliary epithelial cell barrier and promoting bicarbonate secretion to regenerate the ‘bicarbonate umbrella.’ Through these mechanisms, Ursodiol restores liver homeostasis and dampens the autoimmune response in people with PBC; however, up to 40% of individuals with PBC have an incomplete biochemical response to Ursodiol.¹⁷ Although Ursodiol is safe and can be prescribed during pregnancy, it can lead to an array of side effects, including vomiting, diarrhea, constipation, hives, weight gain, and hair loss.¹⁸ While Ursodiol improves the quality of life of many people with PBC, the inconsistent therapeutic effectiveness and side effect profile make it unsuccessful in treating everyone.¹⁷

Ocaliva (obeticholic acid) was FDA-approved in 2016 as a second-line therapy for PBC in patients who do not experience complete normalization of their alkaline phosphatase levels or who cannot tolerate Ursodiol.^19,20 Ocaliva is a synthetic bile acid that activates a nuclear transcription factor called the farnesoid X receptor (FXR). Activation of FXR downregulates the transcription of enzymes critical for bile acid synthesis and increases bile flow to the small intestine. Improved clearance prevents the buildup of bile in the liver and attenuates the autoimmune response. However, Ocaliva is not a first-line therapy for PBC because it can worsen symptoms and present safety concerns. In a double-blind phase 3 clinical trial, Ocaliva caused a higher incidence of itching than placebo.²¹ Itching is a severe and irritating symptom of PBC that primarily occurs on the feet at nighttime and can significantly diminish the patient’s quality of life. Additionally, the FDA issued a black box warning for Ocaliva in 2018, indicating that it can cause severe liver injury in patients with advanced cirrhosis.²² The safety profile of Ocaliva suggests that it is a viable therapy for an even smaller subset of patients with PBC compared to Ursodiol.

Livdelzi (seladelpar) became the most recent FDA-approved drug for PBC in August 2024 and can be prescribed in combination with Ursodiol or as a monotherapy.¹³ Livdelzi activates the nuclear transcription factor called the peroxisome proliferator-activated receptor (PPAR-δ) to regulate the transcription of genes involved in bile acid synthesis. Since liver cells like hepatocytes, biliary epithelial cells, hepatic stellate cells, and Kupffer cells widely express PPAR-δ, the complete mechanism of Livdelzi is unclear. Preclinical and clinical studies suggest that Livdelzi activates a signaling pathway that decreases the expression of CYP7A1, an enzyme necessary for bile synthesis in hepatocytes. Downregulation of CYP7A1 decreases bile acid production and enhances bile flow to the small intestine.^23–25 However, the FDA approval process for Livdelzi did not come without complications. In a separate phase 2 clinical trial for Livdelzi and the treatment of metabolic dysfunction-associated steatohepatitis (MASH), some patients experienced abnormal liver biopsy results that prompted a hold on the development of Livdelzi across all indications and the early termination of Livdelzi clinical trials.²⁶ An independent committee of hepatologists and pathologists reviewed the MASH clinical trial data and unanimously concluded that there was “no chemical, biochemical, or histological evidence that the observed changes were directly attributed to [Livdelzi].”²⁷ Consequently, the phase 3 clinical trial for PBC resumed and found that Livdelzi normalizes alkaline phosphatase levels and reduces the severity of itching in a greater percentage of participants than placebo.²⁸ While Iqirvo (elafibranor) was FDA-approved in June 2024 and acts through a similar mechanism as Livdelzi, it did not significantly improve itching in phase 3 clinical trials.²⁹ Regardless of their shortcomings, the development of Livdelzi and Iqirvo are exciting advancements in the field of liver diseases. The creation of these drugs provides options for people with PBC to find a treatment plan that is suitable for them that will slow the progression of the disease and increase their quality of life.

References

1. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review. J Hepatol. 2012;56(5):1181-1188. doi:10.1016/j.jhep.2011.10.025

2. Lleo A, Jepsen P, Morenghi E, et al. Evolving Trends in Female to Male Incidence and Male Mortality of Primary Biliary Cholangitis. Sci Rep. 2016;6(1):25906. doi:10.1038/srep25906

3. Adejumo AC, Akhtar DH, Dennis BB, et al. Gender and Racial Differences in Hospitalizations for Primary Biliary Cholangitis in the USA. Dig Dis Sci. 2021;66(5):1461-1476. doi:10.1007/s10620-020-06402-3

4. Begovich AB, Klitz W, Moonsamy PV, Van De Water J, Peltz G, Gershwin ME. Genes within the HLA class II region confer both predisposition and resistance to primary biliary cirrhosis. Tissue Antigens. 1994;43(2):71-77. doi:10.1111/j.1399-0039.1994.tb02303.x

5. Probert PM, Leitch AC, Dunn MP, et al. Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. J Hepatol. 2018;69(5):1123-1135. doi:10.1016/j.jhep.2018.06.027

6. Varyani FK, West J, Card TR. An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterol. 2011;11(1):95. doi:10.1186/1471-230X-11-95

7. Murillo Perez CF, Hirschfield GM, Corpechot C, et al. Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response. Aliment Pharmacol Ther. 2019;50(10):1127-1136. doi:10.1111/apt.15533

8. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The Effect of Ursodeoxycholic Acid Therapy on Liver Fibrosis Progression in Primary Biliary Cirrhosis. Hepatology. 2000;32(6):1196-1199. doi:10.1053/jhep.2000.20240

9. Poupon R, Lindor K, Cauch-Dudek K, Dickson E, Poupon R, Heathcote E. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113(3):884-890. doi:10.1016/S0016-5085(97)70183-5

10. Prince MI. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut. 2004;53(6):865-870. doi:10.1136/gut.2003.023937

11. Al-Handola R, Chinnappan J, Hussain M, Mahgoub A, Bachuwa G. Antimitochondrial Antibody-Negative Primary Biliary Cholangitis: A Retrospective Diagnosis. Cureus. Published online March 17, 2023. doi:10.7759/cureus.36309

12. Prieto J, Qian C, García N, Díez J, Medina JF. Abnormal expression of anion exchanger genes in primary biliary cirrhosis. Gastroenterology. 1993;105(2):572-578. doi:10.1016/0016-5085(93)90735-U

13. Lleo A, Selmi C, Invernizzi P, et al. Apotopes and the biliary specificity of primary biliary cirrhosis†. Hepatology. 2009;49(3):871-879. doi:10.1002/hep.22736

14. Drug Trials Snapshots: LIVDELZI. FDA; 2024. Updated October 31, 2024. Accessed March 20, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-livdelzi

15. Poupon RE, Chrétien Y, Poupon R, Paumgartner G. Serum bile acids in primary biliary cirrhosis: Effect of ursodeoxycholic acid therapy. Hepatology. 1993;17(4):599-604. doi:10.1002/hep.1840170412

16. Crosignani A, Podda M, Battezzati PM, et al. Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acid administration. Hepatol Baltim Md. 1991;14(6):1000-1007.

17. Lammers WJ, Van Buuren HR, Hirschfield GM, et al. Levels of Alkaline Phosphatase and Bilirubin Are Surrogate End Points of Outcomes of Patients With Primary Biliary Cirrhosis: An International Follow-up Study. Gastroenterology. 2014;147(6):1338-1349.e5. doi:10.1053/j.gastro.2014.08.029

18. Williamson C, Geenes V. Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol. 2014;124(1):120-133. doi:10.1097/AOG.0000000000000346

19. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid. Gastroenterology. 2015;148(4):751-761.e8. doi:10.1053/j.gastro.2014.12.005

20. Gao Y, Li L, Li B, Zhan Y. Response Rate and Impact on Lipid Profiles of Obeticholic Acid Treatment for Patients with Primary Biliary Cholangitis: A Meta-Analysis. Granito A, ed. Can J Gastroenterol Hepatol. 2021;2021:1-7. doi:10.1155/2021/8829510

21. Nevens F, Andreone P, Mazzella G, et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med. 2016;375(7):631-643. doi:10.1056/NEJMoa1509840

22. FDA Adds Boxed Warning to Highlight Correct Dosing of Ocaliva (Obeticholic Acid) for Patients with a Rare Chronic Liver Disease. Published February 1, 2018. Accessed March 20, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-highlight-correct-dosing-ocaliva-obeticholic-acid-patients-rare-chronic-liver

23. Vrins CLJ, Van Der Velde AE, Van Den Oever K, et al. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux. J Lipid Res. 2009;50(10):2046-2054. doi:10.1194/jlr.M800579-JLR200

24. Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol. 2017;2(10):716-726. doi:10.1016/S2468-1253(17)30246-7

25. Kouno T, Liu X, Zhao H, Kisseleva T, Cable EE, Schnabl B. Selective PPARδ agonist seladelpar suppresses bile acid synthesis by reducing hepatocyte CYP7A1 via the fibroblast growth factor 21 signaling pathway. J Biol Chem. 2022;298(7):102056. doi:10.1016/j.jbc.2022.102056

26. Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology. 2023;78(2):397-415. doi:10.1097/HEP.0000000000000395

27. Biotech Bay. FDA Lifts All Clinical Holds on Seladelpar. July 23, 2020. Accessed March 30, 2025. https://www.biospace.com/fda-lifts-all-clinical-holds-on-seladelpar

28. Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med. 2024;390(9):783-794. doi:10.1056/NEJMoa2312100

29. Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. N Engl J Med. 2024;390(9):795-805. doi:10.1056/NEJMoa2306185

Publication Licenses for Figures: 

Figure 1: Created in BioRender. Sizer, S. (2025) https://BioRender.com/g8cg9x6 

Figure 2: Created in BioRender. Sizer, S. (2025) https://BioRender.com/1bhek0z

Author: Ashley Aguillard
Editor: Michaela Price

This article will cover a well-known class of drugs for type 2 diabetes (T2D), GLP-1 receptor agonists. Multiple drugs within this class have been approved for T2D management since the mid-2000s. Here, we review the pathophysiology and treatment of T2D, the many mechanisms of action of the GLP-1 receptor agonists, and their efficacy as T2D and obesity treatments.

Type 2 Diabetes Prevalence and Etiology 

T2D is a common metabolic disorder characterized by major dysregulations in glucose homeostasis. In 2020, it was estimated that nearly 462 million people worldwide suffer from the disorder.¹  It also continues to be one of the most common comorbidities of obesity with nearly half of new T2D cases being reported in patients with obesity.² T2D can cause serious complications, including neuropathy, retinopathy, nephropathy (kidney damage), and cardiovascular disease. If left untreated, these complications can progress to blindness and may necessitate limb amputations.³ 

Systemic glucose levels are tightly regulated by hormone signaling. Under normal physiological conditions, the fed state leads to increased circulating glucose, which stimulates the secretion of insulin from pancreatic β-cells. Insulin binds to receptors on insulin-sensitive tissues to trigger the uptake of glucose into the cell. In the fasted state, when glucose levels drop, glucagon is secreted by pancreatic ɑ-cells to trigger the release of stored glucose from the liver to maintain normal blood glucose levels. During T2D development, chronic overnutrition interferes with insulin signaling leading to decreases in insulin sensitivity. Initially, the body compensates for this by enhancing insulin secretion leading to abnormally high concentrations of insulin in the blood, a condition called hyperinsulinemia. If interventions are not started, the increased demand for insulin can overload pancreatic β-cells leading to pancreatic β-cell failure, decreased insulin secretion, and uncontrolled glycemia (Figure 1).^4,5 

Current Treatment Options for T2D

Oftentimes, the first form of treatment for patients with T2D is lifestyle intervention. Patients are usually advised to decrease sugar consumption, lower their intake of processed foods, and add more fruits, vegetables, and legumes to their diet.^5,6 Increasing physical activity is also recommended as it has been shown to improve glycemic control.^5,6 Along with lifestyle changes, oral medications, such as metformin, may be prescribed. Metformin is a safe and highly effective drug treatment for T2D and is the most commonly prescribed drug to treat the disorder.⁶ Although metformin is usually an effective treatment for regulating glucose levels, many patients with T2D have an elevated risk of cardiac events that does not improve in response to metformin.⁶ Alternatively, some patients may be prescribed sulfonylureas or thiazolidiniones to improve insulin secretion, but both of these treatment options are associated with an elevated risk of heart failure making them unsuitable for use in patients with cardiovascular disease.^6,7 Sulfonylurea treatment is also associated with hypoglycemia.⁷ If these treatments do not improve glycemia or if patients stop producing insulin, doctors may prescribe insulin in combination with other drugs to be injected directly by patients.⁶ 

GLP-1 Agonists and the Mechanism of Action

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone that plays an integral role in initiating the physiological response to feeding.⁸ L cells in the gastrointestinal tract sense the presence of nutrients in the gut lumen during feeding and secrete GLP-1 to act on multiple tissues, including the pancreas, intestines, and brain.^9,10 GLP-1 receptor agonists (GLP-1RAs) are a class of drugs designed to mimic endogenous GLP-1 and bind to its receptors to promote glucose homeostasis in patients with T2D.¹¹ Importantly, structural modifications to GLP-1RAs can prolong their half-life to 5-7 days compared to the 1-5 minute long half-life of endogenous GLP-1.^11-13 GLP-1 receptors are expressed in multiple tissues, therefore, GLP-1RAs have multiple mechanisms of action (Figure 2). 

In the pancreas, GLP-1RAs are well known to promote insulin secretion.⁴ Receptor binding activates adenylate cyclase causing intracellular accumulation of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) and triggers insulin secretion.¹⁴ At the same time, GLP-1RAs can also inhibit glucagon secretion from pancreatic ɑ-cells.¹⁵ GLP-1RAs also improve β-cell proliferation and inhibit β-cell apoptosis to promote cellular survival by preventing oxidative stress and lipotoxicity.^14,16 

In the brain, GLP-1RAs bind to receptors in the hypothalamus to promote satiety and reduce food intake.^10,17 GLP-1 receptor stimulation in the arcuate nucleus also improves glycemic control independent of feeding behavior.¹⁸ Exendin-4, a GLP-1 analogue, also elicits protection against neuroinflammation, which is linked to a decrease in stroke risk.¹⁹ This effect likely contributes to the decreased risk of stroke in T2D patients receiving treatment with certain GLP-1RAs.^19,20 

In the gastrointestinal tract, GLP-1RAs can activate the autonomic nervous system that regulates gastrointestinal motility to slow the movement of food from the stomach to the intestines, a process called gastric emptying.^4,21 There is also evidence to suggest GLP-1RAs can reduce motility in the small intestine.²¹ These effects can lower nutrient absorption and prevent overnutrition directly related to T2D development and weight gain. While the specific mechanism causing the effects on the gastrointestinal tract are not fully elucidated, studies suggest GLP-1 and its analogues likely exert effects on the vagus nerve and inhibit cholinergic neurotransmission in the gastrointestinal system to prevent movement of the intestine.^22,23 

In the liver, GLP-1RAs can also decrease hepatic gluconeogenesis and enhance glucose uptake, which can improve circulating glucose levels.^24,25 Treatment can also reduce lipid storage to protect against the development of fatty liver disease by inhibiting fatty acid synthesis and promoting fatty acid oxidation.^26,27

Drug Efficacy and Side Effects in Clinical Trials

The first GLP-1RA that received FDA approval was put on the market in 2005 under the name exenatide. This drug is a synthetic version of the human GLP-1 analogue exendin-4, a hormone discovered in the saliva of Gila monsters.^28,29 Although highly effective,³⁰ patients must administer injections of exenatide multiple times a day leading to low patient compliance.³¹ 

Over the past 20 years, new GLP-1RAs with extended half-lives have proven to be highly effective treatments for T2D and even weight loss. Though most GLP-1RAs are approved only for T2D, semaglutide and liraglutide are also approved for weight loss likely driven by GLP-1RA’s actions on satiety and gastric emptying.³² A meta-analysis of over 76 clinical trials that investigated the efficacy of 15 different types of GLP-1RAs revealed that all 15 of the drugs were highly effective at treating T2D. Patients consistently had improved glycemic levels and multiple drugs, such as tirzepatide alone or semaglutide in combination with cagrilinitide, were highly effective at promoting weight management.³³ Similar findings were observed in a meta-analysis of 40 trials which concluded that GLP-1RAs were highly effective at lowering circulating glucose levels without causing hypoglycemia. Semaglutide and liraglutide alone are also more effective than metformin at lowering the risk of developing T2D in patients with prediabetes and pre-obesity.⁶ The use of GLP-1RAs is also associated with a lower risk of adverse cardiac events, such as myocardial infarction and stroke.²⁰ This observation emphasizes their potential to promote systemic metabolic health beyond glucose homeostasis and makes GLP-1RAs a more suitable treatment option for T2D patients with a higher risk of cardiovascular disease compared to metformin. 

Unfortunately, many studies also reported concerns about adverse gastrointestinal events, likely related to GLP-1’s role in gastric emptying.³³ Although decreases in gastric emptying via GLP-1RAs help prevent overnutrition by decreasing nutrient absorption, there is concern that patients could be at risk of nutrient deficiencies driven by malabsorption from delayed gastric emptying.³⁴ This finding emphasizes the importance of nutrient-dense diets while taking these medications. Recent findings also revealed concerns with the loss of skeletal muscle mass when taking GLP-1RAs with some studies reporting up to 50% of weight loss being due to decreases in muscle mass.^35,36 Although some studies report smaller reductions in muscle mass, many scientists argue that these findings should not be ignored due to the high metabolic rate of skeletal muscle which plays an important role in maintaining significant weight loss.³⁶ Along these lines, maintaining weight loss is a common issue after halting GLP-1RA treatment, which raises concerns about the longevity of the treatment efficacy, especially considering the high financial cost to the patient.^37,38 A recent preclinical study investigated a combination therapy with semaglutide and bimagrumab. Bimagrumab is a drug that promotes muscle hypertrophy. By combining the two drugs, researchers were hoping to preserve muscle mass during weight loss. The findings of this study revealed that the combination therapy was highly effective at preserving muscle mass in mice, though, whether these findings will translate to humans has yet to be determined.³⁹ Although GLP-1RAs continue to be promising therapies for T2D, their long-term efficacy for weight loss after halting treatment should be further improved.  

References

1. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 Diabetes – Global Burden of Disease and Forecasted Trends. J Epidemiol Glob Health. 2020;10(1):107-111. doi:10.2991/jegh.k.191028.001
2. Petito LC, McCab M, Allen NB, O’Brien MJ, Carnethon MR. Obesity contributes to up to half of new diabetes cases annually in the United States. AHA. Published February 12, 2021. Accessed March 3, 2025. https://newsroom.heart.org/news/obesity-contributes-to-up-to-half-of-new-diabetes-cases-annually-in-the-united-states
3. Farmaki P, Damaskos C, Garmpis N, Garmpi A, Savvanis S, Diamantis E. Complications of the Type 2 Diabetes Mellitus. Curr Cardiol Rev. 2020;16(4):249-251. doi:10.2174/1573403X1604201229115531
4. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333-1346. doi:10.1016/S0140-6736(05)61032-X
5. Lu X, Xie Q, Pan X, et al. Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. Signal Transduct Target Ther. 2024;9(1):262. doi:10.1038/s41392-024-01951-9
6. Uusitupa M, Khan TA, Viguiliouk E, et al. Prevention of Type 2 Diabetes by Lifestyle Changes: A Systematic Review and Meta-Analysis. Nutrients. 2019;11(11):2611. doi:10.3390/nu11112611
7. Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2023;381:e074068. doi:10.1136/bmj-2022-074068
8. Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010
9. Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138(1):159-166. doi:10.1677/joe.0.1380159
10. Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. J Clin Invest. 2014;124(10):4223-4226. doi:10.1172/JCI78371
11. Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):234. doi:10.1038/s41392-024-01931-z
12. Hui H, Farilla L, Merkel P, Perfetti R. The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. Eur J Endocrinol. 2002;146(6):863-869. doi:10.1530/eje.0.1460863
13. Lee S, Lee DY. Glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes. Ann Pediatr Endocrinol Metab. 2017;22(1):15-26. doi:10.6065/apem.2017.22.1.15
14. Doyle ME, Egan JM. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther. 2007;113(3):546-93. doi: 10.1016/j.pharmthera.2006.11.007. PMID: 17306374; PMCID: PMC1934514.
15. de Heer J, Rasmussen C, Coy DH, Holst JJ. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia. 2008;51(12):2263-2270. doi:10.1007/s00125-008-1149-y
16. Buteau J. GLP-1 receptor signaling: effects on pancreatic beta-cell proliferation and survival. Diabetes Metab. 2008;34(Suppl 2):S73-S77. doi:10.1016/S1262-3636(08)73398-6
17. Secher A, Jelsing J, Baquero AF, Hecksher-Sørensen J, Cowley MA, Dalbøge LS, Hansen G, Grove KL, Pyke C, Raun K, Schäffer L, Tang-Christensen M, Verma S, Witgen BM, Vrang N, Bjerre Knudsen L. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124(10):4473-88. doi: 10.1172/JCI75276. PMID: 25202980; PMCID: PMC4215190.
18. Sandoval DA, Bagnol D, Woods SC, D’Alessio DA, Seeley RJ. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57(8):2046-2054. doi:10.2337/db07-1824
19. Yang X, Qiang Q, Li N, Feng P, Wei W, Hölscher C. Neuroprotective Mechanisms of Glucagon-Like Peptide-1-Based Therapies in Ischemic Stroke: An Update Based on Preclinical Research. Front Neurol. 2022;13:844697.  doi:10.3389/fneur.2022.844697
20. Hu EH, Tsai ML, Lin Y, Chou TS, Chen TH. A Review and Meta-Analysis of the Safety and Efficacy of Using Glucagon-like Peptide-1 Receptor Agonists. Medicina (Kaunas). 2024;60(3):357. doi:10.3390/medicina60030357
21. Hellström PM, Näslund E, Edholm T, et al. GLP-1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome. Neurogastroenterol Motil. 2008;20(6):649-659. doi:10.1111/j.1365-2982.2007.01079.x
22. Schirra J, Nicolaus M, Woerle HJ, Struckmeier C, Katschinski M, Göke B. GLP-1 regulates gastroduodenal motility involving cholinergic pathways. Neurogastroenterol Motil. 2009;21(6):609-e22. doi:10.1111/j.1365-2982.2008.01246.x
23. Amato A, Cinci L, Rotondo A, et al. Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol Motil. 2010;22(6):664-e203. doi:10.1111/j.1365-2982.2010.01476.x
24. Panjwani N, Mulvihill EE, Longuet C, et al. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology. 2013;154(1):127-139. doi:10.1210/en.2012-1937
25. Jin T, Weng J. Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives. Am J Physiol Endocrinol Metab. 2016;311(3):E620-E627. doi:10.1152/ajpendo.00069.2016
26. Gupta NA, Mells J, Dunham RM, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010;51(5):1584-1592. doi:10.1002/hep.23569
27. Targher G, Mantovani A, Byrne CD. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol. 2023;8(2):179-191. doi:10.1016/S2468-1253(22)00338-7
28. Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes. 1993;42(11):1678-1682. doi:10.2337/diab.42.11.1678
29. Raufman JP, Singh L, Singh G, Eng J. Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin-4. J Biol Chem. 1992;267(30):21432-21437.
30. Edwards CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab. 2001;281(1):E155-E161. doi:10.1152/ajpendo.2001.281.1.E155
31. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34(Suppl 2):S279-S284. doi:10.2337/dc11-s231
32. Jensterle M, Rizzo M, Haluzík M, Janež A. Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review. Adv Ther. 2022;39(6):2452-2467. doi:10.1007/s12325-022-02153-x
33. Yao H, Zhang A, Li D, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024;384:e076410. doi:10.1136/bmj-2023-076410
34. Almandoz JP, Wadden TA, Tewksbury C, et al. Nutritional considerations with antiobesity medications. Obesity (Silver Spring). 2024;32(9):1613-1631. doi:10.1002/oby.24067
35. Old VJ, Davies MJ, Papamargaritis D, Choudhary P, Watson EL. The Effects of Glucagon-Like Peptide-1 Receptor Agonists on Mitochondrial Function Within Skeletal Muscle: A Systematic Review. J Cachexia Sarcopenia Muscle. 2025;16(1):e13677. doi:10.1002/jcsm.13677
36. Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab (Seoul). 2019;34(3):247-262. doi:10.3803/EnM.2019.34.3.247
37. Abdullah Bin Ahmed I. A Comprehensive Review on Weight Gain following Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists for Obesity. J Obes. 2024;2024:8056440. doi:10.1155/2024/8056440
38. Waldrop SW, Johnson VR, Stanford FC. Inequalities in the provision of GLP-1 receptor agonists for the treatment of obesity. Nat Med. 2024;30(1):22-25. doi:10.1038/s41591-023-02669-x
39. Nunn E, Jaiswal N, Gavin M, et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024;80:101880. doi:10.1016/j.molmet.2024.101880

Publication Licenses

Figure 1: Created in BioRender. Aguillard, A. (2025) https://BioRender.com/8bj6eub

Figure 2: Created in BioRender. Aguillard, A. (2025) https://BioRender.com/3fd60ud

Author: Joseph Krzeski 
Editor: Ashley Aguillard 

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that causes early life mortality. Within the past decade, the Food and Drug Administration (FDA) has approved three novel therapeutics for SMA – Spinraza, Evrysdi, and Zolgensma. While challenges remain, these innovative therapies offer significant clinical improvements for individuals with SMA, marking a major advancement in the treatment of this devastating condition. 

Overview of Spinal Muscular Atrophy

SMA is an autosomal recessive disorder that leads to progressive muscle degeneration and atrophy. Affecting ~1:10,000 births, SMA exhibits a heterogenous clinical spectrum. The disorder is categorized into five main types (Type 0 – Type 4) based on symptom severity and age of onset. SMA Type 0 is a rare and severe form that is fatal around birth. SMA Type 1 – Type 3 are the most prevalent forms, with Type 1 representing ~60% of all diagnoses. Life expectancy for SMA Type 1 is ~10 months, while life expectancy for Type 2 is ~20 years. Individuals with SMA Type 3 have a typical life expectancy, but experience pronounced muscle degeneration that impairs motor function. SMA Type 4 is a rare adult-onset form, marked by some muscle weakness and a typical life expectancy (Table 1).^1,2

The genetic cause of SMA is connected to a single gene, Survival of Motor Neuron 1 (SMN1). The loss of functional SMN1 causes the degeneration of motor neurons, which are essential for controlling voluntary muscles involved in movement, breathing, and swallowing. As these motor neurons degenerate, significant muscle atrophy occurs and leads to early-life mortality. The severity of SMA symptoms, ranging from the fatal early onset in SMA Type 1 to the progressive muscle degeneration seen in SMA Type 3, is influenced by the presence of a second gene, Survival of Motor Neuron 2 (SMN2). Although SMN2 is nearly identical to SMN1, it contains a coding variant in exon 7, a critical component of the SMN2 gene. This variant causes exon 7 to be preferentially skipped during SMN2 mRNA splicing, which results in the production of only about 10% of functional SMN2 protein (Figure 1). While SMN2 protein can partially compensate for the lack of SMN1 protein, the degree of compensation varies with the number of SMN2 gene copies. Generally, individuals with SMA Type 3 have more copies of the SMN2 gene, which guards against more severe symptoms, while individuals with SMA Type 1 have fewer SMN2 gene copies, which contributes to a more severe manifestation (Table 1).^1,2  

Current Therapeutic Landscape 

Historically, clinical care for SMA focused on symptom management, including physical and respiratory therapy, alongside palliative care. In 2016, the FDA approved the first disease-modifying therapy for SMA, Spinraza. Since then, two additional therapies, Evrysdi and Zolgensma, also received FDA approval. Two of these treatments—Spinraza and Evrysdi—enhance the production of functional SMN2 protein to compensate for the lack of SMN1 protein. The third therapy, Zolgensma, restores functional SMN1 to motor neurons.  

Spinraza (nusinersen) 

Background: Developed by Ionis Pharmaceuticals and Biogen, Spinraza was approved by the FDA in 2016 as the first disease-modifying treatment for SMA.³ Spinraza is an antisense oligonucleotide (ASO), or a short, engineered sequence of nucleic acids that can bind RNA. It is administered directly into the spinal canal, through an intrathecal injection.⁵ Spinraza requires an initial series of four loading doses. The first three loading doses are spaced 14 days apart while the fourth loading dose occurs 30 days after the third dose. Following the loading doses, Spinraza is administered once every four months as maintenance.⁴

Mechanism of Action: Spinraza was designed to bind to a specific region of SMN2 pre-mRNA, called the intronic splicing silencer N1 (ISS-N1). By binding to this region, Spinraza prevents splicing factors from excluding exon 7, thereby promoting the inclusion of exon 7 in mature SMN2 mRNA. This results in the production of more functional SMN2 protein, which compensates for the lack of functional SMN1 protein and mitigates symptom progression (Figure 2).^1,5  

Clinical Trial: The safety and efficacy of Spinraza in both early-onset and late-onset SMA was evaluated in the ENDEAR and CHERISH phase 3 clinical trials, respectively.⁴ Both studies were double-blinded with sham-treated control groups. In the ENDEAR trial, which focused on early-onset SMA (i.e., SMA Type 1 patients <7 months old), 51% of Spinraza-treated individuals showed improvements on the Hammersmith Infant Neurological Examination 2 (HINE-2), a scale that measures infant motor milestones such as head control, rolling, independent sitting, and standing. Additionally, there was a 47% reduction in mortality and permanent ventilation risk compared to those who did not receive treatment.⁶ The CHERISH trial, which examined later-onset SMA (i.e., SMA Type 2 and 3 patients 2-9 years old), found that 56.8% of Spinraza-treated individuals had clinical improvements on the Hammersmith Functional Motor Scale-Expanded (HFMSE), a scale that examines motor control in older individuals with SMA.⁷  

Evrysdi (risdiplam) 

Background: Evrysdi, developed collaboratively by Genentech, PTC Therapeutics, and the Spinal Muscular Atrophy Foundation, was approved by the FDA in 2020.⁸ Like Spinraza, Evrysdi increases the production of functional SMN2 protein. Evrysdi is a small molecule therapeutic that is administered daily as an oral solution in infants or as an oral tablet in older children and adults.⁹ 

Mechanism of Action: While Evrysdi also enhances the inclusion of exon 7 in SMN2, its mechanism of action differs from Spinraza. Evrysdi binds to two regions of SMN2 pre-mRNA, the 5′ splice site (just after exon 7) and the exonic splicing enhancer 2 (ESE2) region within exon 7. This binding stabilizes the interaction of splicing factors on exon 7, ultimately promoting its inclusion and the production of functional SMN2 protein (Figure 3).¹⁰  

Clinical Trial: The safety and efficacy of Evrysdi was tested in three phase 3 clinical trials: RAINBOWFISH, FIREFISH, and SUNFISH.⁹ The RAINBOWFISH trial, an open-label, single-arm study, focused on presymptomatic newborns with confirmed SMA diagnoses. After one year of treatment, 96% of infants treated with Evrysdi were able to sit independently for at least five seconds.¹¹ The FIREFISH trial investigated Evrysdi in infants aged 2 to 7 months with SMA Type 1 and was an open-label study. After two years of treatment, 84% of the patients were alive and showed improvements in motor function (i.e., ability to sit unsupported for at least 5 seconds) compared to the natural progression of SMA.^12,13 The SUNFISH trial, a placebo-controlled study, tested Evrysdi in individuals aged 9 years or older with SMA Type 2 or Type 3. There were significant improvements in motor function, as measured by the Motor Function Measure-32 (MFM-32) and Revised Upper Limb Module (RULM), in individuals treated with Evrysdi compared to the placebo group.^14,15 Collectively, these trials demonstrate that Evrysdi improves motor function and survival outcomes in a broad range of individuals with SMA. 

Zolgensma (onasemnogene abeparvovec) 

Background: Zolgensma, developed by Novartis Gene Therapies (previously AveXis), was approved by the FDA in 2019.¹⁶ Unlike Spinraza and Evrysdi, Zolgensma reinstates the functional SMN1 gene directly in neurons. Administered as a single intravenous injection, Zolgensma’s effects are enduring, presumably lasting an entire lifetime.¹⁷ 

Mechanism of Action: Zolgensma utilizes adeno-associated virus (AAV)-mediated gene transfer to directly deliver the functional SMN1 gene into neurons. AAVs are small, non-pathogenic viruses that can be engineered to carry therapeutic genes. In Zolgensma, the SMN1 gene is packaged into a specific AAV, called AAV9, that allows it to enter neurons. Once inside a neuron, the AAV particle releases the SMN1 gene for expression. AAV9 cannot replicate, which ensures a safe delivery in neurons (Figure 4).¹⁸ 

Clinical Trial: The safety and efficacy of Zolgensma for SMA Type 1 was evaluated in the STR1VE clinical trial, a phase 3 open-label, single-arm study.¹⁷ The primary outcome measures included survival at 14 months of age and the ability to sit independently for more than 30 seconds at 18 months of age. The STR1VE trial found that 91% of individuals with SMA Type 1 treated with Zolgensma were alive at 14 months, and 59% were able to sit independently for over 30 seconds.¹⁹ These results demonstrate that Zolgensma significantly improves survival and motor milestones in infants with SMA Type 1.  

The Road Ahead 

Spinraza, Evrysdi, and Zolgensma have all leveraged cutting-edge science to develop disease-modifying therapies for SMA and demonstrated clear benefits that improve motor function and/or reduce the risk of early mortality and permanent ventilation. However, some challenges persist. Spinraza requires intrathecal injections every four months. While these injections are routine procedures, they require a specialized medical team and are associated with side effects such as intense headaches and nausea.²⁰ Adherence to Spinraza has been lower than anticipated, potentially due to difficulties associated with these injections.^21,22 Evrysdi must be taken orally by individuals with SMA, which can be challenging for those who have difficulties swallowing. Zolgensma is an AAV-mediated therapy and may not be suitable for all patients. Because AAVs are naturally-occurring viruses, previous exposures can result in the development of neutralizing AAV antibodies. As a result, Zolgensma is not typically administered to individuals with detectable AAV antibodies, as these antibodies could trigger immune responses. While prior screening for AAV antibodies prevents this issue, it results in the exclusion of individuals from receiving Zolgensma.¹⁸ Overcoming these challenges will broaden the number of individuals that can be treated. Despite these obstacles, Spinraza, Evrysdi, and Zolgensma have significantly improved the quality of life for individuals with SMA and ushered in new medical standards. 

Early intervention is optimal to prevent SMA symptom progression.²³ As a result, the ideal time to treat individuals with SMA is prior to motor neuron degeneration and symptom onset, as it becomes challenging to regenerate neurons and muscles once atrophy has occurred. Since 2018, all newborns in America are screened for SMA, and prenatal testing is available for parents with known SMN1 mutations.²⁴ Early screening evokes the possibility of treating SMA individuals in utero and/or immediately after birth. In fact, Evrysdi was recently administered to a pregnant woman carrying a fetus diagnosed with SMA (likely SMA Type 1). After birth, the infant continued Evrysdi treatment and, at two years old, has shown no symptoms.²⁵ While this is only a single case and not conclusive, it heralds a new frontier for treating SMA. Prenatal treatment carries risks and opportunities that will likely vary on a case-by-case basis. Specialized medical teams will need to review each case independently to weigh the risks and benefits of prenatal treatment. Whether Spinraza or Zolgensma can also be administered safely and effectively in utero remains undetermined and will require special considerations for each therapeutic modality. 

References:

1.    Mercuri E, Sumner CJ, Muntoni F, Darras BT, Finkel RS. Spinal muscular atrophy. Nat Rev Dis Primers. 2022;8(1):52. doi:10.1038/s41572-022-00380-8 

2.    Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. doi:10.3389/fmolb.2016.00007 

3.    FDA approves first drug for spinal muscular atrophy | FDA. Accessed March 20, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-spinal-muscular-atrophy 

4.    Later-Onset SMA (Types 2 & 3)| SPINRAZA® (nusinersen). Accessed March 20, 2025. https://www.spinraza.com/en_us/home/why-spinraza/later-onset-studies.html 

5.    Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016;44(14):6549-6563. doi:10.1093/nar/gkw533 

6.    Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/NEJMoa1702752 

7.    Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-635. doi:10.1056/NEJMoa1710504 

8.    FDA Approves Oral Treatment for Spinal Muscular Atrophy | FDA. Published August 7, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy 

9.    Learn About Evrysdi Clinical Trials Treating SMA | Evrysdi® (risdiplam). Accessed March 20, 2025. https://www.evrysdi.com/about-evrysdi/clinical-trials.html 

10.   Ratni H, Scalco RS, Stephan AH. Risdiplam, the first approved small molecule splicing modifier drug as a blueprint for future transformative medicines. ACS Med Chem Lett. 2021;12(6):874-877. doi:10.1021/acsmedchemlett.0c00659 

11.   Finkel RS, Al-Muhaizea M, Farrar MA, et al. RAINBOWFISH: A Study of Risdiplam in Newborns with Presymptomatic Spinal Muscular Atrophy (SMA) (4281). Neurology. 2021;96(15_supplement). doi:10.1212/WNL.96.15_supplement.4281 

12.   Baranello G, Darras BT, Day JW, et al. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. 2021;384(10):915-923. doi:10.1056/NEJMoa2009965 

13.   Masson R, Mazurkiewicz-Bełdzińska M, Rose K, et al. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022;21(12):1110-1119. doi:10.1016/S1474-4422(22)00339-8 

14.   Mercuri E, Deconinck N, Mazzone ES, et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022;21(1):42-52. doi:10.1016/S1474-4422(21)00367-7 

15.   Mercuri E, Baranello G, Boespflug-Tanguy O, et al. Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment. Eur J Neurol. 2023;30(7):1945-1956. doi:10.1111/ene.15499 

16.   FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality | FDA. Published May 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease 

17.   Symptomatic trials | ZOLGENSMA® (onasemnogene abeparvovec-xioi). Accessed March 20, 2025. https://www.zolgensma-hcp.com/clinical-trials/symptomatic 

18.   Wang J-H, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther. 2024;9(1):78. doi:10.1038/s41392-024-01780-w 

19.   Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284-293. doi:10.1016/S1474-4422(21)00001-6 

20.   Wurster CD, Winter B, Wollinsky K, et al. Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients. J Neurol. 2019;266(1):183-194. doi:10.1007/s00415-018-9124-0 

21.   Fox D, To TM, Seetasith A, Patel AM, Iannaccone ST. Adherence and Persistence to Nusinersen for Spinal Muscular Atrophy: A US Claims-Based Analysis. Adv Ther. 2023;40(3):903-919. doi:10.1007/s12325-022-02376-y 

22.   Elman L, Youn B, Proud CM, et al. Real-world Adherence to Nusinersen in Adults with Spinal Muscular Atrophy in the US: A Multi-site Chart Review Study. J Neuromuscul Dis. 2022;9(5):655-660. doi:10.3233/JND-210768 

23.   Goedeker NL, Rogers A, Fisher M, et al. Outcomes of early-treated infants with spinal muscular atrophy: A multicenter, retrospective cohort study. Muscle Nerve. 2024;70(6):1247-1256. doi:10.1002/mus.28267 

24.   Newborn Screening for SMA – Cure SMA. Accessed March 20, 2025. https://www.curesma.org/newborn-screening-for-sma/ 

25.   Finkel RS, Hughes SH, Parker J, et al. Risdiplam for prenatal therapy of spinal muscular atrophy. N Engl J Med. February 19, 2025. doi:10.1056/NEJMc2300802  

Author: Caryssa Drinkuth
Editor: Keita Yokoyama

Today, we will be covering Bristol-Myers Squibb’s Cobenfy (xanomeline and trospium chloride). On September 26, 2024, the Food and Drug Administration (FDA) approved Cobenfy for the treatment of schizophrenia in adults, designating Cobenfy as the first antipsychotic drug to utilize a novel mechanism of action for the treatment of schizophrenia in over 50 years.^1,2 In this post, we will provide an overview of schizophrenia and the available options for its treatment, discuss the mechanism of action and clinical trials for Cobenfy, and conclude with the clinical impact of Cobenfy’s approval.

Overview of Schizophrenia

Schizophrenia spectrum disorder is a complex, chronic mental health disorder that affects 24 million people worldwide  and approximately 2.5 million adults in the United States between the ages of 18 to 65.^3,4 Individuals with schizophrenia disorder typically report an onset of symptoms between the ages of 20 to 30 years old, and they often exhibit an array of psychotic symptoms including delusions, paranoia, visual or auditory hallucinations, disorganized behavior, and cognitive impairment.⁵ Symptoms of schizophrenia disorder are often classified as “positive”  in that the patient presents aberrant excess or distortion in normal cognitive function (e.g. hallucinations) or “negative” in that patients exhibit the absence or lack of normal cognitive function (e.g. social withdrawal, blunted affect, apathy).⁶ In particular, negative symptoms are associated with both greater risk of morbidity and worse treatment outcomes due to their impairment of social functioning and difficulty to assess in clinical settings.^5,6 The complex combination of positive and negative symptoms, as well as the early onset of the disease, makes schizophrenia particularly damaging to the lives of patients affected by this disorder. 

While the pathophysiology of schizophrenia disorder is still unclear, abnormal activity at the dopamine D₂ receptor is the most widely studied candidate. Specifically, alterations in neurotransmission in the ventral tegmental area (VTA), a key brain region involved in dopamine release, are thought to contribute to much of the dysregulation of dopamine signaling seen in schizophrenia.^{5, 13} Neurons originating in the VTA project to, and release dopamine in, the prefrontal cortex (PFC) to form the mesocortical pathway. The mesocortical pathway is involved in the regulation of emotional and cognitive processes.²² Reduced dopamine release through the mesocortical pathway is thought to produce negative symptoms and cognitive deficits by dysregulating emotional and cognitive processes.⁵ The VTA also sends inputs to brain regions involved in reward, fear, and anxiety, such as the nucleus accumbens (NAc) and amygdala, forming the mesolimbic pathway. Increased dopamine release through the mesolimbic pathway is thought to contribute to positive symptoms of schizophrenia by dysregulating reward and emotional processes.⁵

Available Treatments

Prior to the approval of Cobenfy in September 2024, all FDA-approved antipsychotic treatments for schizophrenia were aimed at blocking activity at the dopamine D₂  receptor.⁷ Pharmacological treatments are considered the first-line treatment for schizophrenia and can be classified as either first- or second-generation antipsychotics. Non-pharmacological treatments such as psychotherapy also play an important role in the treatment of schizophrenia disorder.

First-Generation Antipsychotics (FGAs): The earliest of the FGAs is chlorpromazine, which was approved for the treatment of schizophrenia in 1953.⁷ Chlorpromazine is thought to exert its antipsychotic effects via postsynaptic blockade of the dopamine D₂ receptor in the mesolimbic pathway.⁸ While blocking dopamine activity in the mesolimbic pathway reduced positive symptoms of schizophrenia, chlorpromazine and other FGAs also block D₂ receptors within the nigrostriatal pathway. This led to broader ‘extrapyramidal’ side effects, such as dystonia, restlessness and pacing, and Parkinson’s disease-like symptoms like tremor, rigidity, and bradykinesia.⁸ Additionally, blockade of D₂ receptors within the mesocortical pathway may worsen the negative and cognitive symptoms of schizophrenia,⁷ leading to treatment-resistant schizophrenia. Only 10% to 30% of patients experience symptomatic improvement after multiple trials of FGAs, while nearly 30% to 60% of these patients experience harmful side effects in response to FGA treatment.⁵ 

Second-Generation Antipsychotics (SGAs): To overcome FGAs’ burdensome extrapyramidal side effects and poor ability to ameliorate negative symptoms, SGAs such as clozapine were developed. Clozapine was first synthesized in Europe in 1956,⁹ though it would not be FDA-approved for treatment-resistant schizophrenia in the United States until 1989.¹⁰ Like chlorpromazine, clozapine acts as an antagonist at the D₂ receptor. However, clozapine preferentially antagonizes the dopamine D₄ receptor while also acting as a partial agonist at the serotonin 5-HT1A receptor.⁹ As a result, clozapine mitigates many of the extrapyramidal side effects of FGAs while also aiding negative symptoms of schizophrenia. Specifically, treatment with clozapine has been demonstrated to reduce suicidal behavior and improve cognitive function in patients with treatment-resistant schizophrenia.⁹ Thanks to these features, clozapine is now the most effective pharmacotherapy for patients with treatment-resistant schizophrenia. Schizophrenic episodes were reduced by 30%, a massive improvement from the 4% efficacy rate seen for chlorpromazine.⁵

Unfortunately, clozapine also has a problematic safety profile. Patients taking high doses of clozapine may have increased risk of developing agranulocytosis, a complication causing low neutrophil count in the blood that may increase risk of fatal infection.¹¹ High doses of clozapine may also induce life-threatening toxicity manifesting in coma, seizures, hypotension, and tachycardia.^{8, 11,19} Despite being one of the only FDA-approved treatments for treatment-resistant schizophrenia, clozapine is only prescribed to approximately 4% of patients with schizophrenia in the United States.²⁰ This underutilization reflects major barriers that restrict the effective use of clozapine, including patients’ fear of serious side effects, lack of training amongst healthcare providers, and the burdensome requirement for continuous blood monitoring throughout clozapine treatment.²¹

Non-Pharmacological Therapies: Cognitive behavioral therapy (CBT) is frequently used in conjunction with FGAs or SGAs to treat symptoms of schizophrenia. CBT for patients with schizophrenia disorder aims to promote effective coping strategies, address and ameliorate comorbid disorders, such as substance use, anxiety, and depression, and improve adherence to FGA or SGA treatment.¹² CBT has demonstrated efficacy for reducing positive symptoms of schizophrenia, though negative symptoms remain difficult to address through CBT alone.¹²

In addition to CBT, addressing social determinants of health (SDoH) may improve the health outcomes of people with schizophrenia. SDoH, such as housing instability, discrimination, and poverty, are associated with greater incidence of schizophrenia disorder and worse health outcomes²⁶ by impacting social connections, access to health care, and increasing risk of comorbid mental disorders. While improving SDoH by improving access to resources and fostering social support may improve the outcomes of people with schizophrenia, the effectiveness of interventions related to SDoH remains poorly studied.²⁶ While individual-level interventions may improve health outcomes, properly addressing SDoH associated with schizophrenia will likely require dismantling large systemic inequities that exist regarding access to mental health care. Due to the challenging and extensive nature of addressing SDoH related to schizophrenia disorder, pharmacological approaches are often favored as primary therapies for the treatment of schizophrenia, with non-pharmacological approaches being considered as adjunctive therapies.

Mechanism of Action

Taken twice daily, Cobenfy is an oral prescription medication composed of xanomeline and trospium chloride.¹³ Unlike FGAs and SGAs, xanomeline does not directly target dopamine receptors. Instead, it acts as a preferential agonist at M1 and M4 muscarinic acetylcholine receptors.¹³ Xanomeline’s activity at the M1 and M4 receptors has been demonstrated to relieve psychosis and improve cognition in individuals with schizophrenia.¹³ Muscarinic acetylcholine receptors are a family of metabotropic G-protein coupled receptors (GPCRs) that may produce either inhibitory or excitatory neuronal responses to the binding of an agonist. Specifically, the M1 receptor produces excitatory responses by coupling with the G_q subtype G protein, while the M4 receptor produces inhibitory responses by coupling with the G_i/o subtype G protein.¹³ Additionally, the M4 receptor is located presynaptically and may act as an autoreceptor to inhibit release of acetylcholine, a key neurotransmitter that modulates communication between neurons.²³

Preclinical studies suggest that xanomeline’s agonism with M1 and M4 receptors impart downstream effects on dopamine release, leading to its antipsychotic effects. One possible way that this could happen is for postsynaptic M1 receptors to excite GABAergic interneurons that synapse onto pyramidal neurons, resulting in increased GABA inhibition of excitatory signals that would otherwise travel from the glutamatergic pyramidal neurons onto dopamine neurons of the ventral tegmental area (VTA). This is critical since the VTA is a key region involved in dopamine transmission and the dysregulation of dopamine signaling in schizophrenia.^{5, 13} Another mechanism may involve xanomeline activating presynaptic M4 receptors within the VTA. This would blunt the stimulatory effects of acetylcholine on dopamine neurons to reduce downstream dopamine transmission.¹⁴ 

Muscarinic receptor agonism is not without side effects. In addition to the M1 and M4 receptors, which are predominantly localized to the brain, xanomeline may also act as an agonist at M2 and M3 muscarinic receptors, which are found throughout the gastrointestinal tract, bladder, and lungs.^{13, 14}  Use of xanomeline alone may produce peripheral side effects, including nausea and vomiting.¹⁴ To combat this, Cobenfy also contains trospium chloride, a pan-muscarinic antagonist with high affinity for the M2 and M3 muscarinic receptors.²⁷ Trospium chloride does not readily cross the blood-brain barrier,²⁷ allowing it to preferentially bind to M2 and M3 muscarinic receptors to block peripheral side effects and improve tolerability.¹³

Clinical Trials

The safety and efficacy of Cobenfy was tested in three separate inpatient, five-week, double-blind, placebo-controlled, randomized control trials. These studies (EMERGENT-1, EMERGENT-2, and EMERGENT-3) enrolled a total of 608 participants aged 18-65 with a confirmed diagnosis of schizophrenia as based on Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria.¹³ Cobenfy’s efficacy was determined by changes between baseline and week 5 scores on a Positive and Negative Symptom Scale (PANSS), a test that numerically ranks severity of positive and negative schizophrenia symptoms on a scale of 30-120, with higher scores reflecting greater severity.¹³ Participants with a PANSS score of 80 or higher at baseline were determined to be eligible for the clinical trial. All participants discontinued their existing antipsychotic treatments for at least 2 weeks prior to the start of the trial and were given either placebo or flexible dosing of twice-daily Cobenfy over the 5 week trial. Participants were also monitored for adverse symptoms, including weight gain, gastrointestinal distress, and drowsiness.¹³ 

Pooled analyses of the three EMERGENT trials demonstrated that participants who received Cobenfy showed significant improvement in both positive and negative symptoms of schizophrenia. Participants in the EMERGENT-2  and EMERGENT-3 trials had statistically significant reductions of 9.6 and 8.4 points on the PANSS, respectively.¹³ Furthermore, over 75% of participants displayed a 30% or greater improvement in PANSS score.¹³ Importantly, changes in weight gain, metabolic parameters, or extrapyramidal symptoms did not appear to differ between treatment groups, highlighting the improved safety profile of Cobenfy compared to other antipsychotic medications.^{13, 15}

It should be noted that some adverse effects of Cobenfy were reported. These include gastrointestinal-related events, hypertension, and tachycardia, though the severity of these events were rated as mild to moderate.^{13, 15} Cobenfy may also pose risks of liver damage and is not recommended for patients with mild hepatic impairment.^{1, 15} Despite these risks, Cobenfy appears to have relatively high tolerability, safety, and efficacy for the treatment of positive and negative symptoms of schizophrenia compared to other FDA-approved antipsychotic medications. Altogether, the FDA approved Cobenfy for the treatment of schizophrenia based on meaningful reductions in the severity of positive and negative schizophrenia symptoms over a 5 week trial.¹ 

Clinical Significance

Addressing Unmet Needs: The FDA’s approval of Cobenfy marks a turning point in the treatment and management of schizophrenia disorder. To date, Cobenfy is the only FDA-approved treatment for schizophrenia that does not directly act on dopamine receptors, which offers a distinct advantage that mitigates adverse extrapyramidal side effects and confers increased safety and tolerability.¹⁵ Cobenfy’s novel mechanism of action may also prove to be promising for patients with schizophrenia disorder who cannot rely on other antipsychotics due to issues with tolerability or reducing negative symptoms.¹³ 

Prescribing and Costs: How Cobenfy will change the landscape of antipsychotic prescribing practices remains to be seen. There are at least 20 other FDA-approved treatments for schizophrenia disorder,¹⁶ many of which have been long-established by clinicians as first-line antipsychotics. Additionally, concerns about cost may serve as a barrier to the prescription of Cobenfy. Bristol Myers’ listed price of a year’s supply of Cobenfy is $22,500, and it remains unclear to what extent this cost will be covered by insurers.¹⁷ Cobenfy was granted new chemical entity exclusivity until September of 2029,²⁵ which means that cheaper generic alternatives may potentially become available after this date.

Due to the availability of cheaper alternatives, patients may be required to trial multiple antipsychotics before being approved for treatment with Cobenfy.¹⁷ Unfortunately, this means many patients may endure ineffective treatments or intolerable adverse effects before receiving approval for Cobenfy prescription. Currently, Cobenfy is intended for use as a second- or third-line treatment in patients that partially respond to FGAs or SGAs. However, Cobenfy is actively undergoing development as an adjunctive therapy in combination with FGAs/SGAs and may become the first approved adjunctive treatment for schizophrenia if positive results emerge from ongoing clinical trials.²⁴ Questions remain for whether clinicians and payors decide to embrace Cobenfy after these additional studies, as well as whether Cobenfy may replace FGAs/SGAs as first-line treatments.

Future of Muscarinic Agonists: Given the success of Cobenfy, multiple biopharmaceutical companies have begun to work on muscarinic drugs for treatment-resistant schizophrenia that may rival Cobenfy, such as Cerevel Therapeutics’ emraclidine. Bristol Myers Squibb has also begun testing Cobenfy as a treatment for psychosis and cognitive decline in patients with Alzheimer’s disease.¹⁸ M1 muscarinic receptor agonists such as Cobenfy are also actively being investigated for managing symptoms of bipolar disorder, Parkinson’s disease, and opioid use disorder.¹⁸

References

1. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. Press Release. September 26, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia
2. Duerr HA. FDA Approves Cobenfy, A First In-Class Agent for Schizophrenia. Psychiatric Times. September 26, 2024. Accessed February 16, 2025. https://www.psychiatrictimes.com/view/fda-approves-cobenfy-for-schizophrenia
3. Schizophrenia. World Health Organization (WHO). January 10, 2022. Accessed February 16, 2025. https://www.who.int/news-room/fact-sheets/detail/schizophrenia
4. Ringeisen H, Edlund, MJ, Guyer H, Geiger P, Stambaugh LF, Dever JA, Liao D, Carr CM, Peytchev, A, Reed W, McDaniel K, Smith TK. Mental and Substance Use Disorders Prevalence Study: Findings report; 2023. RTI International.
5. Patel, KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: Overview and treatment options. P & T. 2014;39(9):638–645.
6. Correll, CU, Schooler, NR. Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment. Neuropsychiatric Disease and Treatment. 2020;16:519–534. https://doi.org/10.2147/NDT.S225643
7. Stępnicki P, Kondej M, Kaczor AA. Current Concepts and Treatments of Schizophrenia. Molecules (Basel, Switzerland). 2018;23(8):2087. https://doi.org/10.3390/molecules23082087
8. Mann SK, Marwaha R. Chlorpromazine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Updated May 16, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553079/
9. Haidary HA, Padhy RK. Clozapine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Updated November 10, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535399/
10. Richmond, LM. FDA Panel Votes Overwhelmingly to Abolish Clozapine REMS. Psychiatric News. 2024;59(12), appi.pn.2024.12.12.41. https://doi.org/10.1176/appi.pn.2024.12.12.41
11. Mijovic A, MacCabe JH. Clozapine-induced agranulocytosis. Annals of Hematology. 2020;99(11):2477–2482. https://doi.org/10.1007/s00277-020-04215-y
12. Morrison AK. Cognitive behavior therapy for people with schizophrenia. Psychiatry (Edgmont, Pa.). 2009;6(12):32–39.
13. Smith CM, Augustine MS, Dorrough J, Szabo ST, Shadaram S, Hoffman EOG, Muzyk A. Xanomeline-trospium (Cobenfy^TM) for Schizophrenia: A Review of the Literature. Clinical Psychopharmacology and Neuroscience. 2025;23(1):2–14. https://doi.org/10.9758/cpn.24.1253
14. Paul SM., Yohn SE, Popiolek M, Miller AC, Felder CC. Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. American Journal of Psychiatry. 2022;179(9):611–627. https://doi.org/10.1176/appi.ajp.21101083
15. Hasan AH, Abid, MA. Cobenfy (Xanomeline-Trospium Chloride): A New Frontier in Schizophrenia Management. Cureus. 2024;16(10):e71131. https://doi.org/10.7759/cureus.71131
16. Christian R, Saavedra L, Gaynes BN, et al. Future Research Needs for First- and Second-Generation Antipsychotics for Children and Young Adults [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Feb. (Future Research Needs Papers, No. 13.) Appendix A, Tables of FDA-Approved Indications for First- and Second-Generation Antipsychotics. Available from: https://www.ncbi.nlm.nih.gov/books/NBK84656/
17. Bell J, Pagliarulo N. Approval in hand, Bristol Myers sets out to sell first-of-its-kind schizophrenia drug. BioPharma Dive. September 26, 2024. Retrieved February 19, 2025. https://www.biopharmadive.com/news/karxt-fda-approval-schizophrenia-cobenfy-bristol-myers-karuna/727959/
18. Kwon D. New schizophrenia drug could treat Alzheimer’s disease. Nature. November 21, 2024. https://www.nature.com/articles/d41586-024-03707-5#:~:text=Given%20the%20role%20of%20M1,might%20also%20slow%20its%20progression.
19. Yu ZX, Pi Y, Chen MK, Dong DJ, Gu Q. Clozapine-Induced Severe Toxicity: Exploring the Pharmacokinetic Profile of Clozapine and Its Significance in Hemodynamic Instability – A Case Report. International Medical Case Reports Journal. 2024;17:111–120. https://doi.org/10.2147/IMCRJ.S444685
20. Improving Access to Clozapine for Patients with Treatment-Resistant Schizophrenia. Johns Hopkins Medicine. February 9, 2024. Retrieved March 10, 2025. https://www.hopkinsmedicine.org/news/articles/2024/02/improving-access-to-clozapine-for-patients-with-treatment-resistant-schizophrenia
21. Farooq S, Choudry A, Cohen D, Naeem F, Ayub M. Barriers to using clozapine in treatment-resistant schizophrenia: Systematic review. BJPsych Bulletin. 2019;43(1):8–16. https://doi.org/10.1192/bjb.2018.67
22. Gorelova N, Mulholland PJ, Chandler LJ, Seamans JK. The glutamatergic component of the mesocortical pathway emanating from different subregions of the ventral midbrain. Cerebral Cortex. 2012;22(2):327–336. https://doi.org/10.1093/cercor/bhr107
23. Picciotto MR, Higley, MJ, Mineur YS. Acetylcholine as a neuromodulator: Cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116–129. https://doi.org/10.1016/j.neuron.2012.08.036
24. GlobalData Healthcare.  A schizophrenia win for BMS’ Cobenfy, but challenges lie ahead. Clinical Trials Arena. October 1, 2024. https://www.clinicaltrialsarena.com/analyst-comment/cobenfy-bms-schizophrenia-win/?cf-view
25. Generic Cobenfy Availability. Drugs.com. Accessed January 8, 2025. https://www.drugs.com/availability/generic-cobenfy.html#:~:text=Related%20exclusivities,Related%20treatment%20guides
26. Jester DL, Thomas ML, Sturm ET, Harvey PD, Keshavan M, Davis BJ, Saxena S, Tampi R, Leutwyler H, Compton MT, Palmer BW, Jeste DV. Review of Major Social Determinants of Health in Schizophrenia-Spectrum Psychotic Disorders: I. Clinical Outcomes. Schizophrenia Bulletin. 2023;49(4):837–850. https://doi.org/10.1093/schbul/sbad023
27. Rovner ES. Trospium Chloride in the Management of Overactive Bladder: Drugs. 2004;64(21):2433-2446. doi:10.2165/00003495-200464210-00005

Publication Licenses

Figure 1: Created in BioRender. Drinkuth, C. (2025) https://BioRender.com/svdpijq

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Author Name: Kéita Yokoyama
Editor Name: Michaela Price

The Food and Drug Administration of the United States has approved a new non-opioid treatment for moderate to severe acute pain.^1,2 The new drug, Journavx (suzetrigine), is a novel sodium channel blocker that is administered orally as a tablet.^1,2 The approval was based on data from a phase 3 clinical trial that showed that Suzetrigine was effective in reducing pain intensity in patients with moderate to severe acute pain.^1,3,4,5 

The all-American problem of chronic pain management

The opioid crisis

Opioid-related deaths in the United States have reached epidemic proportions, with over 727,000 deaths reported between 1999 and 2022.^6,7,8 This public health emergency has been driven primarily by the illegal distribution of synthetic opioids, such as fentanyl, mixed with stimulants like ketamine.^6,7,9  The opioid crisis is rooted in the misuse of prescription opioids that were initially intended to manage chronic pain conditions. According to science news outlet Nature News, socioeconomic factors, such as homelessness, unemployment, and social isolation, “can make individuals more vulnerable to drug addiction and less likely to recover.”⁶ 

In response to the opioid crisis, the United States Congress included the Non-Opioids Prevent Addiction in the Nation (NOPAIN) and Mainstreaming Addiction Treatment (MAT) Acts as part of its omnibus bill for the 2023 federal budget.^10,11 The NOPAIN Act provides funding for the research and development of non-opioid analgesics (pain-relieving medicine). The new law also mandates Medicare reimbursement for non-opioid analgesics that have demonstrated the ability to reduce intra- or post-operative pain and opioid use. Furthermore, the MAT Act removes the requirement for practitioners to obtain a Notice of Intent, a special form of regulatory consent to prescribe controlled substances that practically discourages the prescription of addiction-treating drugs, before prescribing buprenorphine for opioid use disorder.¹¹

The United States Department of Health and Human Services has taken steps to address the opioid crisis through its Overdose Prevention Framework.^12,13 The framework aims, among other things, to reduce opioid overdose deaths by implementing strategies to reduce opioid prescriptions and by expanding access and improving options for evidence-based treatments. The FDA is taking part in this framework by working to develop new mechanisms for controlling opioid access, working to prosecute their illegal distribution, expanding access to overdose withdrawal medications, and – crucially for suzetrigine – supporting the development of alternative, non-addictive technologies for pain management.

The race for new paradigms

In light of the latest wave of the opioid crisis, as well as the growing recognition of interdisciplinary approaches to chronic disease management following the COVID-19 pandemic, the medical community has been exploring new paradigms for pain management. A core reckoning has been the recognition that pain is a symptom, not a disease, and that chronic pain is a complex condition that can be caused by a variety of factors.¹⁴ Given that pain may be caused by injury, infection, psychology, socioeconomic status, neurodegenerative diseases, autoimmune conditions, or a complex constellation of any of these factors, the treatment of pain is recommended to be multimodal and tailored to the individual patient.^14,15,16

Pain can be categorized in a variety of manners. First, pain may be considered to be nociceptive (i.e. caused by noxious stimulus such as thermal, mechanical, or chemical damage to tissues), neuropathic (i.e. caused by damage or dysfunction to the nervous system), psychogenic (i.e. pain due to a psychotic disorder), or nociplastic (i.e. chronic pain from changes in neural signal processing despite a lack of tissue damage).¹⁶ Notably, nociceptive pain can be further categorized by the source of the pain, such as somatic (e.g. skin, mucous membranes, muscles, or other connective tissues), visceral (e.g. internal organs), or radicular pain (i.e. based on pinched or irritated nerves). Furthermore, pain may be considered acute (≤ 3 months) or chronic (>3 months), and the source of the pain may implicate different parts of the sensory nervous system (i.e. peripheral or central). By understanding how to identify and categorize pain, clinicians can better tailor treatment to the individual patient.^14,16

Opioids impact the central nervous system and are relatively nonspecific in their effects. To avoid over-prescribing them for pain management as a blanket solution, clinicians are encouraged to consider other options for pain management. Excluding opioids, the first-line option for pain management is typically considered to be over-the-counter oral medications, such as ibuprofen or acetaminophen, and topical agents such as menthol.^14,16 Clinicians who do not see their patients improving after being treated with those drugs may consider other classes of medications, such as steroids, muscle relaxants, GABA receptor agonists (e.g. gabapentin or pregabalin), capsaicin, and even antidepressants.^14,16 In certain cases, more specialized approaches to pain management may also be used, such as nerve block injections, nerve ablation, pain-relieving injection pumps, and biofeedback-based medical devices (e.g. TENS units or implanted electrodes). Finally, nontraditional or otherwise alternative approaches, such as mental health hygiene-focused approaches, nutritional supplements, cannabinoid-based therapies, physical therapy, and bodywork (e.g. massage or acupuncture) may also be considered.^14,16,17 However, every one of these approaches are either focused on masking pain systemically, only provide intermittent pain relief, or are expensive and invasive. Therefore, there is a critical need for a pain management technique that is noninvasive, cost-effective, repeatable, and specific to the source of the pain.

One promising avenue for pain management is the development of sodium channel blockers that target specific voltage-gated sodium channels.¹⁸ These channels are expressed in the peripheral and central nervous systems and play a key role in the transmission of pain signals.^18,19,20 By selectively inhibiting these channels, it is possible to reduce pain sensation with minimal impact on other physiological functions. The development of these drugs, particularly those that only select voltage-gated sodium channels in the peripheral nervous system, has been a focus of research in recent years. Researchers initially focused on the NaV1.7 sodium channel, which is expressed in peripheral sensory neurons and plays a key role in the transmission of pain signals.²¹ NaV1.7 was particularly promising due to its unusually straightforward mechanism. When the protein that forms the channel had a gain-of-function mutation, people with those mutations exhibited hypersensitivity to pain; patients with loss-of-function mutations, on the other hand, were insensitive to pain.^22,23,24 Furthermore, people who exhibited null mutations (i.e. people without any NaV1.7 channels at all) did not have any other physiological effects aside from losing their sense of smell.^23,24 Putting those three findings together, researchers initially believed that drugs that target NaV1.7 could modulate pain in the peripheral nervous system without significant off-target effects.^21,24 However, the development of NaV1.7-specific inhibitors turned out to be mired with challenges, as drugs turned out to not be very selective to NaV1.7 versus other similar targets.^5,18,21 As a result, researchers have shifted their focus to other voltage-gated sodium channels that work in concert with NaV1.7.

Introducing the blockbuster drug

Mechanism of action: how does suzetrigine work?

Sequential actions through NaV1.7 and NaV1.8 channels help to propagate electrical signals from peripheral sensory neurons, making NaV1.8 a viable target for managing pain.

In light of the difficulty of targeting NaV1.7, researchers began focusing on a similar, nearby protein involved in action potential propagation: NaV1.8.^5,18 Like NaV1.7, NaV1.8 is expressed throughout the sensory peripheral nervous system, including in dorsal root ganglia, and is responsible for propagating pain signals from the periphery to the central nervous system.^5,18,24 Thus, drugs that inhibit the function of NaV1.8 play a key role in stopping nociceptive signals from being transmitted into the central nervous system. Vertex Pharmaceuticals developed suzetrigine, a potent and selective inhibitor of NaV1.8, which obstructs pain signals from propagating through the peripheral nervous system.^5,20,25 Suzetrigine is over 31,000 times more selective for NaV1.8 than for other voltage-gated sodium channels, allowing the drug to modulate pain signals without affecting other physiological functions.^2,18,26,27

Suzetrigine is administered orally in 50 mg tablets, making it a convenient and accessible option for patients with moderate to severe acute pain.^20,25,28 The drug is gradually absorbed into the bloodstream as it reaches maximum blood concentration in approximately 3 hours when taken on an empty stomach.² The drug’s active metabolite, M6-SUZ, takes a longer time to reach maximum blood concentration (approximately 8-10 hours).² The absorption of suzetrigine is only marginally affected by food, with high- or moderate-fat meals delaying the time to reach maximum blood concentration by only 2 hours.² The drug’s maximum blood concentration and area under the curve (AUC) of the drug concentration profile are not affected by changes in meal composition.² Thanks to the pharmacodynamic consistency imparted by M6-SUZ, suzetrigine can be taken once a day regardless of whether patients take it on an empty stomach. This is a dramatic change from current practice; unlike opioids, which must be taken several times a day, suzetrigine does not require patients to regularly ingest pills multiple times throughout the day. While it remains to be shown empirically, one could imagine that this change in dosing regimens may even facilitate behavioral changes that preclude drug-dependent behaviors and habit formation. 

Clinical trials: the evidence

Suzetrigine was evaluated in a phase 3 clinical trial with moderate to severe acute pain following abdominoplasty (“tummy-tucking”; 1,118 patients) or bunionectomy (removing a painful bone spur in the big toe; 1,073 patients).^2,25,26 The trial was double-blind and placebo- and active-controlled, with participants randomized to receive suzetrigine, hydrocodone bitartrate-acetaminophen (active comparator), or a sugar pill (placebo).^2,25,26 The trial was primarily evaluated based on how participants rated the intensity of their pain on a scale of 0 to 10. In this study, suzetrigine demonstrated a reduction in pain intensity that was statistically significant compared to placebo and comparable to the active comparator.^2,25,26 The drug was well-tolerated, with the most common adverse events being nausea, dizziness, and headache.^2,26 The safety profile of suzetrigine was consistent with that of other sodium channel blockers, with no new safety signals identified.^2,26

Suzetrigine received a priority review designation from the FDA. This status speeds up the timeline for clinical trial review and staff feedback for drugs that offer significant improvements in the treatment of serious conditions.^1,25,27 The drug was also granted a breakthrough therapy designation, which is intended to expedite the development and review of first-in-class drugs for serious conditions.^1,25,27 The FDA approved suzetrigine for the treatment of moderate to severe acute pain in adults, making it the first non-opioid treatment for this indication in decades.^1,25 While the drug is currently expected to cost about $15.50 per pill wholesale, this cost is expected to decrease as suzetrigine’s five-year new chemical exclusivity expires in 2030 and its patent ultimately expires in 2040.^1,3,25,28

What’s next for pain management?

The future of suzetrigine

Suzetrigine is expected to be evaluated for two other indications. The drug’s use in the first upcoming indication, painful lumbosacral radiculopathy (leg pain), showed mean changes in pain scores that were significantly, but not meaningfully, different between placebo (-1.98) and treatment groups (-2.02, p < 0.0001).^21,29 Vertex appears to take the stance that the comparable decreases in pain levels for the placebo group are due to variability across study sites and that the presence of fewer adverse events in the treatment group justifies its ongoing phase 3 trial.²⁹ The drug’s use in the second upcoming indication, painful diabetic peripheral neuropathy, concluded its phase 2 clinical trial in December 2023; Vertex completed its review of the trial results with the FDA in the first quarter of 2024.³⁰ The phase 3 trial is ongoing, with additional controls in place to ensure the drug’s efficacy and safety. Furthermore, Vertex is planning to initiate a phase 1 trial for a spray-dried dispersion formulation of suzetrigine in March 2025.²¹

Other upcoming NaV1.8 inhibitors

Vertex Pharmaceuticals is also considering two additional drug candidates for the treatment of pain. VX-993, another NaV1.8 inhibitor, is being developed in both oral and intravenous formulations.^27,29 The oral formulation is expected to enter phase 2 clinical trials for the treatment of acute pain and peripheral neuropathic pain later in 2025, while the intravenous formulation is expected to enter phase 1 clinical trials later in 2025. VX-150, a NaV1.7 inhibitor, was investigated as a single-drug regimen for moderate to severe pain but was halted after phase 2 trials.³² However, Vertex is now evaluating VX-150 as a part of a combination therapy alongside suzetrigine for the treatment of acute pain.^32,33

It should be noted, though, that Vertex is not the only company working on NaV1.8 inhibitors. SiteOne Therapeutics is developing STC-004, a NaV1.8 inhibitor that has completed phase 1 clinical trials.³⁴ SiteOne Therapeutics, which is ironically collaborating with Vertex for NaV1.7 inhibitors, has also received $100 million in Series C funding to support the development of STC-004.^34,35 Latigo Biotherapeutics is developing LTG-001, a NaV1.8 inhibitor that is being evaluated for the treatment of pain following wisdom tooth extraction. LTG-001 has shown faster uptake than suzetrigine, suggesting that it may be a promising alternative to existing treatments.⁴ Additionally, NaV1.7 inhibitors are making a comeback, with researchers exploring new ways to target this channel for the treatment of pain.

A potential newcomer: NaV1.9 inhibitors

Finally, the future of pain management may lie in the development of NaV1.9 inhibitors.^36,37 AlphaNavi, a subsidiary of Sumitomo, is developing ANP-230, a novel NaV1.9 inhibitor that has shown promise in preclinical studies.³⁸ ANP-230 is being evaluated for the treatment of acute pain and is expected to enter phase 1 clinical trials later this year.

Regardless of its success in additional indications and combination therapies, suzetrigine represents a significant advancement in the field of pain management. By targeting specific voltage-gated sodium channels in the peripheral nervous system, suzetrigine offers a novel approach to pain management that is both effective and well-tolerated. As the first non-opioid treatment for moderate to severe acute pain in decades, suzetrigine has the potential to revolutionize the way pain is treated and managed. However, its true impact may be modulated by the success of other NaV1.8 inhibitors and the development of new drugs targeting other voltage-gated sodium channels.

References

1. FDA Approves Novel Non-Opioid Treatment for Moderate to Severe Acute Pain. Press release. Food and Drug Administration (FDA). Published January 30, 2025. Accessed February 21, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-non-opioid-treatment-moderate-severe-acute-pain
2. Hang Kong AY, Tan HS, Habib AS. VX-548 in the treatment of acute pain. Pain Management. 2024;14(9):477–486. doi: https://doi.org/10.1080/17581869.2024.2421749
3. BusinessWire. Vertex Announces FDA Approval of JOURNAVX™ (suzetrigine), a First-in-Class Treatment for Adults With Moderate-to-Severe Acute Pain. Published January 30, 2025. Accessed February 21, 2025. https://www.businesswire.com/news/home/20250109747971/en/
4. Dolgin E. US drug agency approves potent painkiller — the first non-opioid in decades. Nature News. Published January 31, 2025. Accessed February 21, 2025. https://www.nature.com/articles/d41586-025-00274-1
5. Kingwell K. NaV1.8 inhibitor poised to provide opioid-free pain relief. Nat Rev Drug Discovery. 2024;24:3-5. doi: https://doi.org/10.1038/d41573-024-00203-3
6. Emiliano-Rodriguez M. The psychiatrist at the centre of the opioid crisis. Nature. 2020;580:178-181. doi: https://doi.org/10.1038/d41586-020-00921-9
7. NIDA. Drug Overdose Deaths: Facts and Figures. National Institute on Drug Abuse website. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates. August 21, 2024. Accessed February 21, 2025.
8. Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. 2025. Updated February 12, 2025. Accessed February 21, 2025. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
9. Becerra X. Renewal of determination that a public health emergency exists. Published December 20, 2024. Accessed February 21, 2025. https://aspr.hhs.gov/legal/PHE/Pages/Opioid-Renewal-20Dec2024.aspx
10. Consolidated Appropriations Act of 2023, 42 U.SC § 1833(t) et seq. (2023). https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf#page=1463
11. Substance Abuse and Mental Health Services Administration. Waiver Elimination (MAT Act). Published November 6, 2024. Accessed February 21, 2025. https://www.samhsa.gov/substance-use/treatment/statutes-regulations-guidelines/mat-act
12. Food and Drug Administration Overdose Prevention Framework. Food and Drug Administration (FDA). Published December 26, 2024. Accessed February 21, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/food-and-drug-administration-overdose-prevention-framework
13. Guidance Document: Development of Non-Opioid Analgesics for Acute Pain; Draft Guidance for Industry. Food and Drug Administration (FDA). Published February 26, 2022. Accessed February 21, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-non-opioid-analgesics-acute-pain-draft-guidance-industry
14. Loeser JD, Treede RD. The Kyoto protocol of IASP Basic Pain Terminology. Pain. 2008;137(3):473–7. doi:10.1016/j.pain.2008.04.025
15. Nguyen KT, Beauchamp DW, O’Hara RB. A Pathophysiological Approach for Selecting Medications to Treat Nociceptive and Neuropathic Pain in Service members. Mil Med. 2024;189(9-10):e1879–e1889. doi: https://doi.org/10.1093/milmed/usad506
16. Peperzak K. Clinical overview: acute pain management in adults. In: ClinicalKey. Elsevier; 2021. Updated April 19, 2024. Accessed February 21, 2025. http://www.clinicalkey.com
17. National Center for Complementary and Integrative Health. Chronic Pain and Complementary Health Approaches. Published January 2023. Accessed February 21, 2025. https://www.nccih.nih.gov/health/chronic-pain-and-complementary-health-approaches-usefulness-and-safety
18. Hameed S. NaV1.7 and NaV1.8: Role in the pathophysiology of pain. Mol Pain. 2019;15. doi: https://doi.org/10.1177/1744806919858801
19. Xue Y et al. Pain behavior in SCN9A (Nav1.7) and SCN10A (Nav1.8) mutant rodent models. Neurosci Lett. 2021;135844. doi: https://doi.org/10.1016/j.neulet.2021.135844
20. Osteen JD et al. Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain. Pain Ther. Published January 8, 2025. Accessed February 21, 2025. doi:10.1007/s40122-024-00697-0
21. Kingwell K. NaV1.7 withholds its pain potential. Nat Rev Drug Discovery. 2019;18:321-323. doi: https://doi.org/10.1038/d41573-019-00007-1
22. Minett MS et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel NaV1.7. Nat Comm. 2015;6:8967. doi: https://doi.org/10.1038/ncomms9967
23. Deuis JR et al. NaV1.7: a pain-sensing channel. Sci Rep. 2017;7:40883. doi: https://doi.org/10.1038/srep40883
24. Goodwin G, McMahon SB. The physiological function of different voltage-gated sodium channels in pain. Nat Rev Neurosci. 2021;22:263–274. https://doi.org/10.1038/s41583-021-00444-w
25. BusinessWire. Vertex Announces Advancements of Suzetrigine (VX-548) in Acute and Neuropathic Pain. Published April 18, 2024. Accessed February 21, 2025. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-advancements-suzetrigine-vx-548-acute-and
26. Jones J et al. Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. New Eng J Med. 2023;389:292-405. doi: https://doi.org/10.1056/NEJMoa2209870
27. Giara K. Suzetrigine’s Approval Signals a Shift in Non-Opioid Pain Management. MedCentral. Published January 21, 2025. Accessed February 21, 2025. https://www.medcentral.com/pain/suzetrigine-pending-approval-signals-a-shift-in-non-opioid-pain-management
28. Durant SJ et al., inventors; Vertex Pharmaceuticals Inc., assignee. Substituted tetrahydrofurans as modulators of sodium channels. US Patent 11,919,887. September 14, 2023.
29. BusinessWire. Vertex Announces Results From Phase 2 Study of Suzetrigine for the Treatment of Painful Lumbosacral Radiculopathy. Published December 19, 2024. Accessed February 21, 2025. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-results-phase-2-study-suzetrigine-treatment
30. Evaluation of Efficacy and Safety of Suzetrigine for Pain Associated With Diabetic Peripheral Neuropathy. ClinicalTrials.gov identifier: NCT06628908. Published October 8, 2024. Updated February 17, 2025. Accessed February 21, 2025. https://clinicaltrials.gov/study/NCT06628908
31. A Study of Suzetrigine (SUZ) Spray-dried Dispersion (SSD) in Healthy Adult Panelists. ClinicalTrials.gov identifier: NCT06834009. Published February 19, 2025. Accessed February 21, 2025. https://clinicaltrials.gov/study/NCT06834009
32. A Study to Evaluate Efficacy and Safety of VX-150 in Subjects With Acute Pain Following Bunionectomy. ClinicalTrials.gov identifier: NCT03206749. Published July 2, 2017. Updated February 3, 2021. Accessed February 21, 2025. https://clinicaltrials.gov/study/NCT03206749
33. Vaelli P et al. State-Dependent Inhibition of Nav1.8 Sodium Channels by VX-150 and VX-548. Mol Pharmacol. 2024;106(6):298-308. Published November 18, 2024. Accessed February 21, 2025. doi: https://doi.org/10.1124/molpharm.124.000944
34. SiteOne Therapeutics. SiteOne Therapeutics Announces Positive Phase 1 Clinical Data for STC-004, a Novel NaV1.8 Inhibitor in Development for the Non-Opioid Treatment of Pain. Published February 4, 2025. Accessed February 21, 2025. https://siteonetherapeutics.com/siteone-therapeutics-announces-positive-phase-1-clinical-data-for-stc-004-a-novel-nav1-8-inhibitor-in-development-for-the-non-opioid-treatment-of-pain/
35. SiteOne Therapeutics. SiteOne Therapeutics Announces Collaboration and License Agreement with Vertex Pharmaceuticals to Advance NaV1.7 Inhibitors for the Treatment for Pain. Published January 19, 2022. Accessed February 21, 2025. https://siteonetherapeutics.com/2022-1-19-siteone-therapeutics-announces-collaboration-and-license-agreement-with-vertex-pharmaceuticals-to-advance-nav17-inhibitors-for-the-treatment-for-pain/
36. Dib-Haji SD, Black JA, Waxman SG. NaV1.9: a sodium channel linked to human pain. Nat Rev Neurosci. 2015;16:511-519. doi: https://doi.org/10.1038/nrn3977
37. Kühn H, et al. Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling. Sci Rep. 2020;10:2326. doi: https://doi.org/10.1038/s41598-020-59092-2
38. Kamei T et al. Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230. Biochem Biophys Res Commun. 2024;150126. doi: https://doi.org/10.1016/j.bbrc.2024.150126

AI statement

Portions of this article were written and edited with the assistance of GitHub Copilot, the inline auto-complete tool integrated into the text-editing software Microsoft Visual Studio Code (VS Code). GitHub Copilot was called using GPT 3.5-Turbo as the backend LLM. After an outline was manually completed, each section of placeholder text was replaced with complete sentences and citations from top to bottom. Primarily, text was written manually. However, as the full text was being written, certain sentences or clauses were suggested by GitHub Copilot. Additional information on the use of AI in this article can be found in the AI statement.

Author: Morgan McCullough

Editors: Kylie VanDerMolen and Michaela Price, PhD

 

This article will describe the first vaccine, Arexvy, approved for prevention of lower respiratory tract disease arising from respiratory syncytial virus (RSV) infection. Approved by the Food and Drug Administration (FDA) in May of 2023, Arexvy is a product of GlaxoSmithKline (GSK). Here, I describe the burden of RSV, the history of RSV vaccine development, the clinical trial leading to Arexvy’s approval, and updates to the therapeutic landscape since May 2023, including additional vaccines now approved for use in pregnant women to prevent severe RSV disease in infant children.

What is RSV?

 RSV is a virus that circulates seasonally in temperate climates. In most adults, RSV infection is quite mild. However, those who suffer from pre-existing conditions, such as heart disease or weakened immune systems, are more likely to develop lower respiratory tract disease (LRTD) during RSV infection.¹ LRTD refers to bronchiolitis (airway swelling) and pneumonia (inflammation and edema of the alveoli) that may develop as complications from severe RSV infection. 

Who is most at risk?

Because heart disease and weakened immune systems are more common in individuals aged 65 and older, RSV infection is more likely to lead to LRTD in this population.^1,2 Among this high-risk group, there are 60,000-120,000 hospitalizations and 6,000-10,000 annual deaths from LRTD-associated RSV in the United States.³ Immunity derived from natural RSV infection wanes over time, meaning that re-infection may occur year after year, which presents a persistent risk of developing RSV-related LRTD in susceptible populations. 

Although older adults are at a high risk for developing severe RSV, the most vulnerable population for severe RSV is infants. Because RSV is so widespread, it is likely the first pathogen that infants encounter. Risk of LRTD from RSV is highest in newborns, with the risk of severe RSV infection decreasing as infants age.⁴ Most individuals are infected with RSV from a young age. In children 6 months and older and healthy adults, RSV infection is usually mild. However, RSV may cause serious disease in infants and young children with limited prior RSV exposure, with 75,000-150,000 hospitalizations⁵ and about 500 deaths⁶ caused by RSV infection per year in the United States, making RSV the leading cause of LRTD in infants. Further, RSV infection early in life is associated with subsequent development of asthma in children.⁷

For these reasons, scientists have spent decades chasing down a strategy to develop an RSV vaccine. Finally, in May of 2023, GSK was granted approval for their novel RSV vaccine, Arexvy, following presentation of evidence that Arexvy was safe and effective in preventing LRTD and severe LRTD in adults aged 60 and older.³ Subsequent updates to the therapeutic landscape have resulted in the ability for infants to gain immunity to RSV via their mothers.

The scientific obstacles to developing an RSV vaccine

Soon after RSV was discovered, a vaccine formulation was developed to induce immunity to the virus beginning in 1965. The vaccine formulation, termed “Lot 100”, was built on the technology of successful influenza and polio vaccines, where formalin was used to inactivate the virus before delivery with an adjuvant to excite the immune system.¹² For reasons that remain unclear, the Lot 100 vaccine induced worse outcomes of natural RSV infection in children receiving the vaccine, with the youngest cohort of children experiencing a 16-fold increased hospitalization rate and two deaths.⁸ While the exact reasons that Lot 100 resulted in worse RSV outcomes are not entirely clear, this failure likely set back the development of the RSV vaccine for many years and proved that the development of immunity to RSV through vaccination would need to be more targeted than other inactivated vaccines.

A major obstacle to the development of an effective RSV vaccine was understanding which part of the virus the vaccine should target. When a virus infects cells in the human body, it takes over the host cells’ machinery to make more copies of itself before spreading to new cells. Early experimental RSV vaccines were unable to generate robust protection from RSV infection because they targeted a piece of the virus that only emerges after RSV initially infects cells.⁹ 

In 2013, RSV researchers discovered a new target for RSV vaccines to improve their effectiveness in infection prevention. This protein, termed the prefusion F protein, is expressed by the virus before it infects host cells; thus, targeting this protein allows the immune system to recognize and attack RSV prior to infection.¹⁰ Discovery of the prefusion F protein set the stage for vaccine developers to use their already-robust vaccine pipelines to develop an RSV vaccine.

How Arexvy induces “memory” to RSV

Arexvy includes a stabilized form of the prefusion F protein (RSVPreF3), along with GSK’s adjuvant AS01_E, which is included to promote an immune response to the prefusion F protein.¹¹ AS01_E contains 3-O-desacyl-4’-monophosphoryl lipid A (MPL), which is a lipopolysaccharide that has been detoxified, as well as Quillaja saponaria Molina, fraction 21 (QS-21), which is a triterpene glycoside purified from Quillaja saponaria Molina tree bark. Both of these components activate the immune system.¹² 

Following vaccination, the RSVPreF3 protein is taken up by cells of the immune system, which are stimulated by the AS01_E adjuvant. This stimulation tells the cells of the immune system to initiate the process of developing memory to the viral RSVPreF3 protein, so that the immune system may recognize the RSV prefusion F protein and mount an efficient, effective response when natural infection occurs. Specifically, “memory” comes from the RSV-neutralizing antibodies that develop following vaccination. These antibodies then circulate throughout the body, where they may detect RSV and neutralize it before it causes (severe) infection. Thus, vaccination will allow the immune system to develop memory as it would during a natural infection, but without the illness or complications associated with natural infection.¹² The mechanism of immune memory development is depicted in Figure 1.

Clinical trials leading to Arexvy approval

The phase III clinical trial leading to the FDA approval of Arexvy included 25,000 participants: half of which received Arexvy and half of which received a placebo. Among these participants, Arexvy reduced incidence of RSV-associated LRTD by 82.6% and reduced the incidence of severe RSV-associated LRTD by 94.1%. In this trial, 10 patients who received Arexvy and 4 patients who received placebo developed atrial fibrillation (irregular heartbeat). Further trials for Arexvy included 2,500 participants who were 60 years or older, which is a key patient population considering their susceptibility to RSV-related LRTD. Some participants were also vaccinated for the FDA-approved influenza vaccine at the time of RSV vaccination, and among these participants, two developed acute disseminated encephalomyelitis (a rare autoimmune disease where the brain and spinal cord become inflamed), leading to one death. In a separate study, one participant suffered from Guillain-Barre syndrome (autoimmune inflammation of the nerves) following Arexvy treatment. More common side effects included injection site pain, fatigue, muscle pain, headache, and joint stiffness/pain.³

Because RSV vaccines have the potential to provide “significant improvements in the […] prevention of serious conditions when compared to standard applications”, Arexvy was granted priority review. This process allows new drugs to finish the FDA review process in 6 months, as opposed to the 10 months necessary for standard review.¹³ The FDA approved Arexvy with the stipulation that GSK conducts postmarketing studies to understand the indicators for elevated risk of Guillain-Barre syndrome and acute disseminated encephalomyelitis. These postmarketing studies have resulted in an FDA mandate to require the inclusion of warnings regarding the development of Guillain-Barre syndrome in the prescribing information for Arexvy.¹⁴

RSV vaccines: updates since approval

Although immunity developed from natural RSV infection wanes over time, Arexvy is not currently administered annually, as it is too soon to understand how long immunity following vaccination lasts. Following approval of Arexvy in early May 2023, another RSV vaccine from Pfizer, Abrysvo, was approved weeks later at the end of May 2023 for use in adults 60 years of age or older.¹⁵ In May of 2024, Moderna was granted FDA approval for their RSV vaccine, mRESVIA, for the prevention of LRTD resulting from RSV in those 60 years of age and older.¹⁶ mRESVIA utilizes a similar mRNA platform as Moderna’s vaccines to protect against COVID-19. Indications for initial approval of RSV vaccines have been updated in subsequent years to better target those at risk for severe LRTD. These updates are outlined in Table 1. The CDC does not provide recommendations regarding choices in prescribing one vaccine over another, and which vaccine an individual receives could result from eligibility, personal preference, availability, and physician recommendations.

Abrysvo for prevention of RSV in infants

While initial RSV vaccine approvals focused on protection for elderly individuals, these approvals did not allow for the protection of those most vulnerable to severe RSV: infants. This is unsurprising, as the establishment of safety and efficacy in a population that has been exposed to RSV previously was desired prior to testing in more vulnerable populations. 

Due to failed clinical trials in infants, modern strategies for inducing protective immunity to RSV in infants has shifted from vaccinating infants to vaccinating pregnant individuals, who have likely encountered RSV before. Protection of infants via maternal vaccination occurs through transplacental antibody transfer. In August of 2023, Abrysvo was approved for use in pregnant individuals in the 32-36 week gestational age range to prevent LRTD resulting from RSV in infants following birth (Table 1).¹⁹ Immunity granted to infants via this route is estimated to last through the first four months of life, which is when risk of LRTD from RSV is highest. Among infants born to individuals vaccinated between 32-36 weeks of gestational age, newborn protection from LRTD from RSV was most robust, with Abrysvo reducing the risk of severe LRTD by 91.1% within the first 90 days (3 months) of birth and 76.5% within the first 180 days (6 months) of birth in clinical trials.¹⁹

What’s next?

Over 60 years following RSV’s initial discovery, approval of Arexvy represented a major step forward in preventing severe disease in vulnerable populations. As postmarketing monitoring studies on Arexvy and other RSV vaccines continue, prescribing information and recommendations may be updated to better serve populations affected by severe RSV infection. Early observational studies on the effectiveness of Arexvy and Abrysvo RSV vaccines are favorable, with both decreasing the incidence of infection, emergency department and urgent care visits, and hospitalizations among individuals 60 years of age and older²², indicating that these preventative therapies represent a major advancement in protecting those most vulnerable to severe RSV infection.

References:

1. Melgar M, Britton A, Roper LE, Talbot HK, Long SS, Kotton CN, Havers FP. Use of Respiratory Syncytial Virus Vaccines in Older Adults: Recommendations of the Advisory Committee on Immunization Practices — United States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(29);793-801. doi:10.15585/mmwr.mm7229a4
2. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory Syncytial Virus Infection in Elderly and High-Risk Adults. New England Journal of Medicine. 2005;352(17):1749-1759. doi:10.1056/NEJMoa043951
3. FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine. FDA. Published May 3, 2023. Accessed February 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-respiratory-syncytial-virus-rsv-vaccine
4. Fleming-Dutra K. RSV Epidemiology and Disease Burden in Infants from Birth through 6 Months of Age. Presented at: Published May 18, 2023. Accessed February 9, 2025. https://www.fda.gov/media/168259/download
5. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;282(15):1440-1446. doi:10.1001/jama.282.15.1440
6. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ. Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979-1997. J Infect Dis. 2001;183(1):16-22. doi:10.1086/317655
7. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Björkstén B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: A prospective cohort study with matched controls. Pediatrics. 1995;95(4):500-505.
8. Blanco JCG, Boukhvalova MS, Shirey KA, Prince GA, Vogel SN. New insights for development of a safe and protective RSV vaccine. Hum Vaccin. 2010;6(6):482-492. doi:10.4161/hv.6.6.11562
9. Park A. Why It Took So Long to Get an RSV Vaccine. TIME. Published May 3, 2023. Accessed February 25, 2025. https://time.com/6275289/rsv-vaccine-history/
10. McLellan JS, Chen M, Leung S, et al. Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody. Science. 2013;340(6136):1113-1117. doi:10.1126/science.1234914
11. GlaxoSmithKline. Package-Insert-AREXVY. Accessed February 9, 2025. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert-AREXVY.pdf
12. Roman F, Burny W, Ceregido MA, et al. Adjuvant system AS01: From mode of action to effective vaccines. Expert Review of Vaccines. 2024;23(1):715-729. doi:10.1080/14760584.2024.2382725
13. Priority Review. FDA. Published January 4, 2018. Accessed February 25, 2025. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review
14. FDA Requires Guillain-Barré Syndrome (GBS) Warning in the Prescribing Information for RSV Vaccines Abrysvo and Arexvy. FDA. Published January 7, 2025. Accessed February 25, 2025. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-requires-guillain-barre-syndrome-gbs-warning-prescribing-information-rsv-vaccines-abrysvo-and
15. FDA Roundup: June 2, 2023. FDA. Published June 2, 2023. Accessed February 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-roundup-june-2-2023
16. FDA Roundup: May 31, 2024. FDA. Published May 31, 2024. Accessed February 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-roundup-may-31-2024
17. US FDA approves expanded age indication for GSK’s Arexvy, the first respiratory syncytial virus (RSV) vaccine for adults aged 50-59 at increased risk. GSK. Published June 7, 2024. Accessed February 25, 2025. https://www.gsk.com/en-gb/media/press-releases/us-fda-approves-expanded-age-indication-for-gsk-s-arexvy-the-first-rsv-vaccine-for-adults-aged-50-59-at-increased-risk/
18. U.S. FDA Approves Pfizer’s RSV Vaccine ABRYSVO® for Adults Aged 18 to 59 at Increased Risk for Disease. October 22, 2024. Accessed February 25, 2025. https://www.businesswire.com/news/home/20241018199265/en/U.S.-FDA-Approves-Pfizer%E2%80%99s-RSV-Vaccine-ABRYSVO%C2%AE-for-Adults-Aged-18-to-59-at-Increased-Risk-for-Disease
19. FDA Approves First Vaccine for Pregnant Individuals to Prevent RSV in Infants. FDA. Published August 21, 2023. Accessed February 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-vaccine-pregnant-individuals-prevent-rsv-infants
20. CDC. Vaccines for Older Adults. Respiratory Syncytial Virus Infection (RSV). Published August 30,2024. Accessed February 25, 2025. https://www.cdc.gov/rsv/vaccines/older-adults.html
21. CDC. Immunizations to Protect Infants. Respiratory Syncytial Virus Infection (RSV). Published August 30, 2024. Accessed February 25, 2025. https://www.cdc.gov/rsv/vaccines/protect-infants.html
22. Surie D. Effectiveness of adult respiratory syncytial virus (RSV) vaccines, 2023–2024. Presented at: Published June 26, 2024. Accessed February 9, 2025. https://www.cdc.gov/acip/downloads/slides-2024-06-26-28/07-RSV-Adult-Surie-508.pdf

Publication Licenses for Figures:

Figure 1: Created in BioRender. Mccullough, M. (2025) https://BioRender.com/v25c042

Table 1: Created in BioRender. Mccullough, M. (2025) https://BioRender.com/d38l930