Category: The Pipeline Blog

Author: Stacy Pitcairn

Editor: Meghan Diefenbacher

What is Myasthenia gravis?

Generalized myasthenia gravis is a rare autoimmune neuromuscular disease characterized by weakness in voluntary muscles, including those used for movement, breathing, and swallowing.¹ For most people, the first symptoms involve weakness of eye muscles such as ptosis (drooping of the eyelid) and diplopia (double vision).¹  Myasthenia gravis has a global prevalence estimated to be between 50 and 250 cases per million people, though the true number is likely higher due to underdiagnosis and inconsistent reporting.² Although it can affect anyone, it is more common in women younger than 40 and men older than 60.¹ This intriguing distribution in prevalence hints at complex interactions between hormones, genetics, and age‑related immune changes. Although several hypotheses exist, the exact trigger remains unknown, making it challenging to develop targeted treatments. Currently, there’s no way to prevent or cure myasthenia gravis. Since it is a chronic condition, the majority of patients need life-long treatment, leading to high disease burden for patients and caregivers.³ Current approaches to treat myasthenia gravis seek to minimize symptoms and slow progression, but this is often not achieved with the current standard of care.

In April of 2025, the United States Food and Drug Administration (FDA) approved a novel first-in-class medication for this condition. IMAAVY (nipocalimab-aahu) was developed by Janssen Biotech, Inc. for the treatment of generalized myasthenia gravis in adult and pediatric patients 12 years of age and older.⁴  But how does it work?

The neuromuscular junction: a key component for muscle contraction

Voluntary muscle movements are possible because of the connection between the nervous system and the muscles. Nerves are able to modulate skeletal muscle tissue through a specialized connection called the neuromuscular junction. The neuromuscular junction facilitates the transfer of electrical signals from the somatic nervous system to the muscle, initiating the process of muscle contraction.⁵

To communicate, nerves release a molecule called acetylcholine that binds to receptors in the muscle. When acetylcholine binds to receptors in the muscle, it triggers the muscle fiber to contract.

Figure 1: Schematics of the Neuromuscular Junction. Left: Healthy neuromuscular junction. Acetylcholine is released from a motor neuron and binds to acetylcholine receptors on the muscle. When bound, the muscle can contract, and the body can move. Right: Neuromuscular junction affected by myasthenia gravis (MG). Acetylcholine is released from a motor neuron, but antibodies from the immune system block the receptor on the muscle. Acetylcholine cannot bind to the receptor, so the muscle does not contract. Created in BioRender. Pitcairn, S. (2026) https://BioRender.com/ s6kw9cr

What causes Myasthenia gravis?

Generalized myasthenia gravis is an autoimmune disease, which occurs when the body’s immune system mistakenly attacks itself. Antibodies are proteins made by your immune system that identify and neutralize foreign invaders like bacteria and viruses. In autoimmune diseases, these antibodies attack the body’s healthy proteins. In myasthenia gravis, it is thought that these antibodies attack critical parts of the neuromuscular junction.⁶ Harmful antibodies block acetylcholine receptors at the neuromuscular junction, preventing muscle contraction⁶. This is what leads to weakness in the voluntary muscles.

IMAAVY: A New Drug

IMAAVY, a novel medication, was developed to combat this. This medication specifically targets the harmful antibodies that block muscle receptors and prevent them from working properly.⁷ Specifically, immunoglobulin G (IgG) antibodies such as anti-Acetylcholine Receptor (AchR) and anti-muscle-specific tyrosine kinase (MuSK) are proteins that cause nerves and muscles to communicate less effectively.⁷ Another relevant protein is called neonatal fragment crystallizable receptor (FcRn). This protein keeps harmful antibodies circulating in your body longer, where they can continue to interfere with nerve signals.⁷

IMAAVY binds and blocks FcRn. By binding the receptors that keep harmful antibodies circulating, it reduces harmful antibodies like anti-AChR and anti-MuSK.⁷

Clinical Trial Overview

The FDA approved IMAAVY based on evidence from a pivotal Phase 3 clinical trial called VIVACITY-MG.^4,8 The trial included 196 adult patients with generalized myasthenia gravis whose blood had antibodies against the AChR and MuSK.^4,9 This study was conducted at 82 sites in 17 countries across America, Europe, and Asia.^8,9 

Patients were randomized to receive either placebo injections or an injection of IMAAVY (30 mg/kg loading dose) followed by a maintenance dose (15mg/kg) two weeks later.^8,9 The maintenance dose continued every 2 weeks thereafter for 24 weeks.^8,9

The primary efficacy endpoint was the comparison of the average change from baseline in the Myasthenia Gravis–Activities of Daily Living (MG‑ADL) total score at Weeks 22, 23, and 24 between patients treated with IMAAVY in addition to standard of care and those who received placebo with standard of care.^8,9 MG‑ADL is a patient‑reported scale that assesses the impact of myasthenia gravis on daily function.^7,9 Scores range from 0 to 24 and reflect functional ability (e.g., speech, chewing, swallowing, breathing). A low MG-ADL score indicates MG symptoms are less severe⁷. In MG research, a ≥2‑point decrease in MG‑ADL is considered a clinically meaningful improvement.¹⁰ IMAAVY demonstrated statistically significant improvement on this measure: patients taking IMAAVY + standard of care experienced a 4.7-point mean improvement in total MG-ADL score to weeks 22, 23, and 24 while patients taking placebo + standard of care saw a 3.3-point mean improvement (p =0.002).⁹ Additionally, IMAAVY was well tolerated during Vivacity-MG3, with most adverse events characterized as mild or moderate.⁹

Conclusion

Overall, the results of this trial add to an evolving treatment landscape for generalized myasthenia gravis. Due to IMAAVY’s distinct molecular features, mode of action, clinical efficacy, and schedule of administration, it represents a new treatment option for patients.¹¹ IMAAVY joins other novel treatment modalities, such as B cell depletion and complement inhibition, as ongoing mechanistic targets for myasthenia gravis. As of 2025, the field has many directions to explore. Some stated goals include facilitating rapid diagnosis via improvements in laboratory medicine, developing effective strategies for neuromuscular protection, improving understanding of pathophysiology and treatment response in older individuals, and exploring the role of therapies aimed at delivering a durable response (such as chimeric antigen receptor T cells)¹². Even as the treatment landscape continues to advance, the results achieved with IMAAVY mark a meaningful step forward in the care of individuals with generalized myasthenia gravis.

References

1. Mayo Clinic Staff. Myasthenia Gravis: Symptoms and Causes. 2025. https://www.mayoclinic.org/diseases-conditions/myasthenia-gravis/symptoms-causes/syc-20352036

2. Salari N, Fatahi B, Bartina Y, et al. Global prevalence of myasthenia gravis and the effectiveness of common drugs in its treatment: a systematic review and meta-analysis. J Transl Med. 2021;19(1):516. doi:10.1186/s12967-021-03185-7

3. Lehnerer S, Herdick M, Mevius A, et al. The economic burden of Myasthenia gravis from the patient´s perspective and reflected in German claims data. Sci Rep. 2025;15(1):6687. doi:10.1038/s41598-025-91372-7

4. U.S. Food and Drug Administration. Drug Trials Snapshot: IMAAVY. April 29, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-imaavy

5. Khalil B, Marwaha K, Bollu PC. Physiology, Neuromuscular Junction. StatPearls [Internet]. February 17, 2025. https://www.ncbi.nlm.nih.gov/books/NBK470413/

6. National Institute of Neurological Disorders and Stroke. Myasthenia Gravis. National Institute of Neurological Disorders and Stroke. 20250522. https://www.ninds.nih.gov/health-information/disorders/myasthenia-gravis

7. Janssen Pharmaceuticals. About IMAAVY for Generalized Myasthenia Gravis. IMAAVY: How It Works and Treatment Information. December 9, 2025. https://www.imaavy.com/generalized-myasthenia-gravis/about-imaavy/

8. Janssen Research & Development L. A Study of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis. Janssen Research & Development, LLC; 2025. https://clinicaltrials.gov/study/NCT04951622

9. Antozzi C, Vu T, Ramchandren S, et al. Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2025;24(2):105-116. doi:10.1016/S1474-4422(24)00498-8

10. Muppidi S, Wolfe GI, Conaway M, Burns TM. MG-ADL: still a relevant outcome measure. Muscle Nerve. 2011;44(5):727-731. doi:10.1002/mus.22140

11. Antozzi C, Fitzgibbon M. An evaluation of nipocalimab for the treatment of generalized myasthenia gravis. Expert Opin Biol Ther. 2025;25(10):1047-1058. doi:10.1080/14712598.2025.2561935

12. Binks SNM, Morse IM, Ashraghi M, Vincent A, Waters P, Leite MI. Myasthenia gravis in 2025: five new things and four hopes for the future. J Neurol. 2025;272(3):226. doi:10.1007/s00415-025-12922-7

AI Statement

Microsoft Copilot was used to generate Research Information Systems (.RIS) entries from online sources (e.g. Mayo Clinic) for import into the citation manager Zotero (version 7.0.27). AI software was not used for any other tasks related to this article.

Writer: Meghan Diefenbacher

Editor: Kaitlin Kinney

HIV-1 Global Public Health Burden

Human immunodeficiency virus (HIV-1) remains a significant global public health burden. Since the HIV-1 pandemic began in the 1980s, it has claimed over 44.1 million lives, and, currently, 39.4 million adults and 1.8 million children are living with HIV-1.¹ Although antiretroviral therapy (ART) currently allows people with HIV-1 to live relatively normal lives by suppressing viral loads to low or undetectable levels, effective ART is lifelong and requires daily treatment with oral medications which can cause significant side effects and impose costly financial burdens on patients.² For example, the average monthly costs of ART range from several hundred to several thousand dollars per month in the United States³, and the all-cause lifetime costs of HIV infections is estimated to be over one million dollars.⁴ Therefore, new treatment regimens and modalities with similar efficacy to daily oral ART that are long-acting and, therefore, require less frequent dosing to maintain viral suppression are urgently needed.²

Recent Development of Lenacapavir as a LA-ART HIV-1 PrEP and Treatment Option

In recent years, the development of long-acting (LA) ART has been a game changer in terms of increasing patient adherence to treatment regimens and preventing new HIV-1 infections.² Lenacapavir (LEN), a first-in-class twice-yearly subcutaneous (SC) injection developed by Gilead, was approved by the FDA in 2022 as a treatment for patients with multidrug resistant HIV-1 (Sunlenca®)⁵ and most recently in June 2025 as a pre-exposure prophylaxis treatment (PrEP) (Yeztugo®) for adults and adolescents at risk of acquiring HIV.⁶ The development of LA-ART like LEN has the potential to increase ART effectiveness, adherence, and accessibility, stemming the tide of the HIV-1 pandemic by decreasing transmission and virus burden in patients while we await the development of a viable vaccine or cure for HIV-1.

Overview of Article

In this article we will discuss the following:

• Why has HIV-1 proven so difficult to eradicate?

• How does ART work to suppress viral replication?

• How does LA-ART such as LEN function and improve upon existing ART?

• How do recent clinical trials demonstrate LEN’s efficacy and viability as a LA-ART treatment and PrEP option?

Why has HIV-1 proven so difficult to eradicate?

Once a person becomes infected with HIV-1, the virus remains in their body throughout their entire lifetime and requires daily oral ART to prevent virus replication and transmission.

HIV-1 Transmission

HIV-1 transmission occurs when a person comes in contact with the body fluids, such as blood, semen, and vaginal secretions, from an HIV-1 infected person.⁷ This can occur through several methods including sexual contact, exposure to contaminated needles or blood in the context of a healthcare setting or via recreational drug use, or direct transmission from mother to child during pregnancy and childbirth.⁷

Stages of HIV Infection

Once in the body, HIV-1 primarily targets and replicates in a type of immune cell called a CD4+ T lymphocyte which plays a critical role in helping other immune cells respond to infection.⁸ During this primary stage of infection, virus levels rapidly rise and cause a decline in the levels of CD4+ T lymphocytes.^8–11

What makes HIV-1 so challenging to eliminate is that in a subset of CD4+ T lymphocytes that survive the initial infection, HIV-1 establishes a latent infection.^8–11 During latency, HIV-1 is maintained in an inactive state where no viral replication occurs within the infected CD4+ T lymphocyte.^10,12 The proportion of latently infected CD4+ T lymphocytes is very low (0.0001%)¹³ and can be spread throughout many different reservoirs (i.e. tissues in the body that harbor latently infected cells) such as the lymph nodes, gut associated lymphoid tissue (GALT), liver, spleen, brain, genital tract, and lungs,^12,14 making it difficult to detect and eliminate all the HIV-1 latently infected cells.

If an HIV-1 infection remains untreated, CD4+ T lymphocytes levels continue to decline over time, and can lead to the onset of a dangerous condition called acquired immunodeficiency syndrome (AIDS) once CD4+ T lymphocyte counts go below a specific threshold (~200 cells/µL).^9,11 During AIDS, HIV patients are incapable of mounting an effective  immune response due to the loss of CD4+ T lymphocytes which results in them becoming highly susceptible to potentially deadly opportunistic infections.¹⁵

Requirement for Lifetime ART

To prevent progression of the disease to AIDS, patients with HIV-1 can undergo oral ART to reduce HIV-1 levels in the blood to levels below the limit of detection and correspondingly increase the level of CD4+ T lymphocytes.¹⁰ However, ART is unable to eliminate the latent HIV-1 reservoir, requiring patients with HIV-1 to take oral ART for the remainder of their lives.¹⁰

The development of oral ART has been transformative for HIV-1 patients by turning what was once a deadly disease into a lifelong, but manageable condition. How does oral ART function to limit virus replication, what challenges remain in ensuring that ART remains effective and accessible to all patients, and how do novel LA-ART like Lenacapavir improve upon ART effectiveness and accessibility as both treatment and PrEP?

How does oral ART limit HIV-1 replication?

Oral ART treatment regimens typically consist of  combinations of 2-3 small molecule inhibitors designed to target specific HIV-1 proteins that play essential roles in its replication cycle.¹⁶

HIV-1 Virus Particle Structure

The HIV-1 virus particle consists of two major components- an inner nucleoprotein core and an outer lipid membrane that surrounds the core (Figure 1).¹⁷ The inner nucleoprotein core contains the genetic material of the virus (two identical copies of positive-sense, single-stranded RNA) stabilized by the nucleocapsid protein, and enzymes necessary for virus replication (RT, IN) which are all contained within a shell made up of the capsid protein (Figure 1).¹⁷ The inner nucleoprotein core is enclosed within a lipid membrane studded with viral envelope (Env) glycoproteins anchored into the membrane via the matrix layer underneath (Figure 1).¹⁷

HIV-1 Replication Cycle

How HIV-1 Enters CD4+ T Lymphocytes

HIV-1 specifically targets and invades CD4+ T Lymphocytes via specific interactions between the Env protein and the CD4 receptor and CXCR4/CCR5 co-receptors expressed on the cellular surface (Figure 2).^17,18 Once an HIV-1 virus particle binds to the receptors on the cell surface, the viral and cellular membrane fuse, releasing the inner nucleoprotein core into the cytoplasm of the cell (Figure 2).¹⁷

Reverse Transcription and Integration into Host DNA

Once in the cell, the inner nucleocapsid core then traffics to and enters the cell nucleus (Figure 2). During this translocation, the enzyme reverse transcriptase converts the viral genomic RNA into double-stranded DNA (Figure 2).¹⁷ The core then disassembles within the nucleus, releasing the viral DNA and core-associated enzymes (Figure 2).¹⁷ One of the enzymes- integrase- then catalyzes the integration of the viral DNA into the host DNA (Figure 2).¹⁷

Assembly and Release of Virus Particles

The viral DNA, now called a provirus, directs the transcription of viral mRNAs which are then translated into the viral proteins required for HIV-1 particle formation (Figure 2).¹⁷ The viral genomic RNA copies and proteins are trafficked to the cell membrane where they are assembled into new viral particles (Figure 2).¹⁷ The viral particles are then released from the cell and undergo maturation into fully infectious virus particles through the actions of the viral protease which cleaves the viral protein precursors into their final forms (Figure 2).¹⁷

ART Drug Classes and their Targets

Inhibitors used for oral ART are divided into distinct categories based on the specific viral protein/replication stage that they target.^16,17,19 Current inhibitor classes (Figure 2):

• Binding inhibitors: prevent the interaction of HIV-1 with the CD4 receptor and CCR5/CXCR4 co- receptors

• Fusion Inhibitors: prevent the fusion of HIV-1 membrane with the cellular membrane

• Reverse transcription inhibitors (NRTIs, NNRTIs): prevent reverse transcriptase from converting the HIV-1 genomic RNA into double-stranded DNA

• Integrase inhibitors (INSTIs): prevent integrase from catalyzing the insertion of the HIV-1 DNA into the host DNA

• Capsid inhibitors (CAIs): interfere with capsid assembly/disassembly and prevent interaction with host factors

• Protease inhibitors (PIs): inhibit the activity of the HIV-1 protease, preventing virus particle maturation

Oral ART in HIV Prevention (PrEP)

Reducing the incidence of newly-acquired HIV infections is a key component of the strategy to end the HIV-1 pandemic.²⁰ Uninfected individuals at a high risk of acquiring HIV-1 can use oral ART as a PrEP option to prevent HIV-1 transmission.²⁰ Typically, PrEP regimens consist of one or two inhibitors of the same functional class that inhibit early stages of HIV-1 replication. In the US, two daily oral ART regimens (Truvada®- containing the NRTIs tenofovir disoproxil fumarate & emtricitabine (TDF/FTC) and Descovy®- containing the NRTIs tenofovir alafenamide & emtricitabine (TAF/FTC)) are currently FDA approved.²¹ When taken as directed, oral ART regimens are 99% effective at reducing the sexual transmission of HIV-1.²⁰

Oral ART for HIV-1 Treatment

Oral ART regimens for HIV-1 treatment tend to be more complex than oral ART regimens for PrEP, typically consisting of combinations of at least 2-3 drugs representing different inhibitor classes.^16,19 The complex drug cocktail serves to maximize treatment efficacy and minimize treatment failure by decreasing the likelihood of cross-resistance between inhibitors in case the virus acquires resistance to one of the inhibitors in the regimen.^16,19 For instance, to maintain viral suppression in HIV-infected individuals, current oral ART typically includes one or two inhibitors of the NRTI class combined with an inhibitor of the INSTI or NNRTI class (Figure 2).^16,22 Due to their superior efficacy, lower rates of antiviral resistance, fewer drug-drug interactions, and better safety profile, many oral ART regimens include inhibitors of the INSTI class.^16,22,23 Oral ART regimens containing inhibitors of the INSTI class are effective at maintaining viral suppression in patients with efficacies of 89.5% and 94.5% after one and seven years respectively.²⁴

Challenges with Oral ART Adherence and Resistance

High adherence rates are necessary to maintain the efficacy of oral ART regimens used for PrEP and HIV-1 treatment. A systematic review of clinical trials evaluating the efficacy of oral PrEP found that PrEP exhibited the greatest efficacy in preventing HIV-1 infection if the adherence rates were high (>70%) while clinical trials with low PrEP adherence rates did not see a similar protective effect.²⁵ However, PrEP adherence rates remain low with one systemic review of PrEP discontinuation in clinical trials finding that about 41% of patients discontinued PrEP within 6 months.²⁶ For HIV-1 treatment, it is predicted that adherence rates of 75-82% (variation based on the inhibitor class) are required to maintain viral suppression.²⁷ A meta-analysis evaluating oral ART treatment adherence in observational studies found that only approximately 62% of patients exhibited high levels of adherence (90%) to their treatment regimens.²⁸ Maintaining high levels of adherence to oral ART for PrEP or treatment remains a persistent challenge due to factors such co-morbidities associated with drug treatment, access to and affordability of the medications, and stigma associated with HIV.²²

An additional concern with existing oral ART for PrEP and HIV-1 treatment is the emergence of drug-resistant strains of HIV which can potentially be exacerbated through low adherence rates to the therapies. Drug-resistant mutations that confer resistance to one or more of the existing ART inhibitor classes are present within circulating HIV strains and can result in treatment failure.^29,30

How does LEN improve upon existing oral ART?

To increase adherence rates to ART regimens and retain their efficacy in the face of antiviral resistance, it is essential to develop therapies that are long-acting and exhibit novel mechanisms of action to prevent cross-resistance with contemporary therapies. LEN addresses both concerns with its novel mechanism of action targeting the HIV-1 capsid protein, and its formulation which allows for twice-a-year dosing.

LEN Exhibits a Unique Mechanism of Action via its Inhibition of Capsid Protein Function

Currently, LEN is the only FDA-approved ART therapy that specifically targets the HIV-1 capsid protein.³¹ The HIV-1 capsid is more than just an inert structure that houses the genetic material of HIV-1, it plays an essential role in multiple stages of the HIV replication cycle. The HIV-1 capsid is made up of individual subunits which are arranged in groups of five (pentamers) or six (hexamers) that come together to form a cone-like structure (Figure 3).^32,33 During the earlier stages of infection, the capsid serves to protect the HIV-1 RNA while it is being reverse transcribed into DNA, and it interacts with host proteins to co-opt host pathways involved in nuclear trafficking and entry so that the HIV-1 DNA can be integrated into the host DNA (Figure 2).^32,33 The HIV-1 capsid also plays important roles at later stages of the replication cycle including virus particle assembly (Figure 2).^32,33 LEN binds to the interface between capsid subunits (Figure 3) and leads to the formation of a hyper-stabilized capsid with defects in its ability to properly disassemble/assemble at the appropriate stages of the replication cycle and to interact with the host factors required for nuclear import (Figure 2).³⁴ LEN’s ability to inhibit capsid function at multiple stages of the HIV-1 replication cycle makes it  an incredibly potent inhibitor with extremely small concentrations (picomolar ~10^-12) inhibiting HIV-1 replication in cellular assays.³⁴

LEN’s SC Formulation Allows for Less Frequent Twice-a-Year Dosing

The second major advantage of LEN is its formulation and stability which allows for twice-a-year dosing. LEN is administered via a SC injection and exhibits a two-phase absorption profile in the body.^2,35,36 After LEN is injected into the body, it forms a depot at the injection site where there is an initial fast release of the drug followed by a slow but sustained release.^2,35,36 A phase one study in uninfected volunteers found that the concentration of LEN in the body was over six-fold above the minimum concentration required to inhibit HIV replication after 26 weeks (~6.5 months), supporting the viability of a twice-year dosing regimen.³⁷ This represented a significant improvement over other approved LA-ART therapies such as intramuscularly (IM) injected cabotegravir-rilpivirine/ cabotegravir (Cabenuva®/Apretude®) and the dapivirine vaginal ring which require monthly or bi-monthly dosing.² LEN’s novel mechanism of action as well as its lower frequency dosage requirements has contributed to its success as both a LA-ART treatment regimen and PrEP option.

LEN as a viable option for inclusion in current ART treatment regimens

LEN’s novel mechanism of action and efficacy has opened the possibility for its inclusion in ART treatment regimens as an additional option available for patients to optimize the efficacy of their therapy and reduce treatment failure.

CALIBRATE Clinical Trial

The CALIBRATE phase 2 trial evaluated the safety and efficacy of LEN in combination with other available ART regimens in people living with HIV (PLWH).³⁸ There were three treatment groups containing LEN. In the first two groups, LEN was given as an oral loading dose combined with the oral ART regimen Descovy® (TAF/FTC) which was followed by either SC administration of LEN every 26 weeks in combination with TAF (a NRTI) (Group 1) or bictegravir (BIC) (an INSTI with a high genetic barrier to resistance) (Group 2). The third group was given daily oral LEN and Descovy®.³⁸ These groups were compared to a single group treated with the oral ART regimen Biktarvy® (BIC/TAF/FTC).³⁸ In the groups that included LEN in the ART regimen, the percentage of participants with viral suppression at week 54 was between ~85-90% which was comparable to the percentage obtained (~92%) in the group treated with Biktarvy®.^38,39 This result indicated that the addition of LEN to existing oral ART regimens does not compromise protection against virus replication and leads to similar levels of protection relative to currently available oral ART regimens.

CAPELLA Clinical Trial

Concurrent with the CALIBRATE clinical trial, the CAPELLA trial evaluated the safety and efficacy of LEN in combination with optimized background regimens of oral ART in participants with multi-drug resistant (MDR) HIV-1.⁴⁰ In these participants, the emergence of MDR-HIV-1 can lead to treatment failure if the virus is resistant to one or more inhibitors in the oral ART regimen.⁴¹ Therefore, it is essential to identify new inhibitors to supplement or replace the failing treatment that have a unique mechanism of action to minimize cross-resistance to the existing inhibitors in the regimen.⁴¹ In cohort one, participants initially received either an oral loading dose of LEN or a placebo in addition to their failing treatment, while in cohort 2, the participants received an oral loading dose of LEN in addition to an optimized background regimen. Subsequently, all groups were given SC injections of LEN every 26 weeks combined with an optimized background regimen.⁴⁰ In the group treated with LEN on top of their failing oral ART regimen, a greater percentage of the participants exhibited at least a 0.5 log₁₀ decrease in HIV RNA copies from baseline (88%) compared to 17% in the placebo group.^40,42 This indicated that LEN more effectively reduced initial virus replication levels relative to the failing treatment. Additionally, all cohorts exhibited high percentages of viral suppression (~81-83%).^40,42 Together these results indicated that ART regimens containing LEN are effective at suppressing virus replication in participants with MDR-HIV-1.

Together the success of the CALIBRATE & CAPELLA clinical trials paved the way for the approval of LEN (Sunlenca®) for treatment of HIV-1 patients by the FDA in 2022.⁴³

Ongoing Clinical Trials Including LEN Treatment Regimens

In addition to the CALIBRATE and CAPELLA clinical trials there are ongoing clinical trials evaluating LEN’s efficacy as a HIV-1 treatment in combination with other ART regimens. Most recently, Gilead announced positive results for one of the preliminary endpoints in the phase 2/3 ARTISTRY-1 clinical trial.⁴⁴ This study enrolled virologically suppressed PLWH and divided them into two groups: participants who switched from their current oral, multi-tablet ART regimen to a single oral tablet with a fixed dose of BIC/LEN, and participants who remained on their current oral, multi-tablet ART regimen.^44,45 At 48 weeks, viral suppression levels in the BIC/LEN group were comparable to the group taking the oral, multi-tablet regimens.^44,45 The finding that a single BIC/LEN tablet was as efficacious as the complex, multi-tablet, oral ART regimen is encouraging as it would decrease the daily pill burden and have the potential to increase adherence to oral ART.⁴⁴ The safety and efficacy of single tablet BIC/LEN is being further evaluated in the ARTISTRY-2 clinical trial where it will be directly compared to Biktarvy® (BIC/FTC/TAF) which is also a fixed-combination, single-tablet oral ART regimen.⁴⁶ Additional clinical trials evaluating the safety and efficacy of LEN with other oral ART treatment regimens and broadly-neutralizing antibodies are still at early stages, but if successful, could provide additional treatment options for PLWH to maintain viral suppression.³¹

The results of the CALIBRATE, CAPELLA, and ARTISTRY-1 clinical trials support the inclusion of LEN (oral and SC) in ART regimens to increase their efficacy, minimize cross-resistance to existing therapies, and increase treatment adherence by reducing pill burden.

LEN shows promise as a highly efficacious PrEP regimen to prevent the spread of HIV-1 infections

One of the most exciting applications of LEN is its use as a highly efficacious PrEP that requires significantly fewer doses to maintain efficacy.

PURPOSE-1/2 Clinical Trials

The PURPOSE-1 phase 3 clinical trial evaluated the efficacy of SC-LEN as a PrEP option for South African and Ugandan adolescent girls and young women at risk for HIV-1 infection.⁴⁷ The participants received SC injections of LEN every 26 weeks or the oral ART regimens Descovy® (FTC/TAF) or Truvada® (FTC/TDF) daily.⁴⁷ The researchers measured the HIV-1 incidence rate using the metric of “per 100 person-years” which is the ratio of the total number of new HIV-1 cases observed during the study divided by the sum of the lengths of time each participant was observed for the study multiplied by the population standard (100).⁴⁸ This metric accounts for differences in the total lengths of time that each participant was able to be observed during the course of the study.⁴⁸ Notably, there were no participants that acquired HIV-1 in the LEN group (out of 2134 total) while the HIV-1 incidence rates in the Descovy® and Truvada® treated groups were 2.02 per 100 person years and 1.69 per 100 person years compared to a background HIV-1 incidence of 2.41 per 100 person years.^47,49 The PURPOSE-2 phase 3 clinical trial further evaluated the efficacy of SC-administered LEN as a PrEP regimen in cisgender men, transgender women and men, and gender non-binary individuals.⁵⁰ It compared the HIV-1 incidence rate in participants receiving SC-injections of LEN every 26 weeks or the oral ART regimen Descovy® (FTC/TAF).⁵⁰ Similar to the results of the PURPOSE-1 clinical trial, the LEN group exhibited lower HIV-1 incidence rates (0.1 per 100 person years) relative to the Descovy® treated group (0.93 per 100 person years) and the background HIV-1 incidence (2.37 per 100 person years).⁵¹ The encouraging results from the PURPOSE-1 and PURPOSE-2 clinical trials paved the way for the FDA to approve twice-yearly, SC-injected LEN as a PrEP option (Yeztugo®) in 2025.⁵²

Ongoing Clinical Trials for LEN PrEP

Currently, the PURPOSE3-5 clinical trials are investigating the safety and efficacy of LEN as a PrEP option in other patient populations such as cis-gender women in the US, injection drug users, and other populations more heavily burdened with HIV-1.³¹ Additionally, the PURPOSE-365 clinical trial is evaluating whether decreasing the number of doses of LEN from twice-yearly SC-injections to once-yearly IM-injections still provides effective protection against acquiring HIV-1.⁵³ By maintaining efficacy as a PrEP option while decreasing dosage frequency to twice per year, LEN presents an exciting opportunity to increase PrEP uptake and adherence to decrease the total number of new HIV-1 infections acquired.

Preventing new infections as a small step toward the ultimate goal of eradicating HIV-1

By 2025, global health agencies such as the World Health Organization (WHO), The Global Fund, and UNAIDS aim for 95% of PLWH to be diagnosed, 95% of PLWH to be on ART, and 95% of PLWH and taking ART to have suppressed viral loads as a preliminary milestone in the ultimate goal of ending the HIV pandemic by 2030.⁵⁴ As of 2024, only 87% of PLWH received a diagnosis, 89% of PLWH who were diagnosed were on ART, and 94% of PLWH on ART had suppressed viral loads.⁵⁴ Considering all of the PLWH, only 87% knew their status, 77% were on ART, and 73% had suppressed viral loads.⁵⁴ The success of LA-ART like LEN as a treatment and PrEP option for PLWH is encouraging due to its efficacy and lower frequency dosing requirements which has the potential to increase ART adherence and, thereby, help PLWH maintain viral suppression and decrease the incidence of new HIV infections. Challenges remain in terms of the accessibility and cost of LEN (estimates of $25,000 per year for Yeztugo® and $39,000 per year for Sunlenca® in the US)⁵⁵ which may preclude its worldwide adoption in resource limited settings such as the Africa region where approximately two-thirds of PLWH reside.⁵⁴ New LA-ART regimens are being continually developed with novel mechanisms of action and formulations/administration methods (nano-formulations, implants, vaginal rings, microarray patches etc.) that make dosing more convenient and less frequent for PLWH.² By making ART more efficacious, convenient, and accessible for PLWH, we can increase our likelihood of achieving the 95/95/95 goal of HIV diagnosis, treatment, and viral suppression and move a step closer towards ending the HIV-1 pandemic.

References

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32. Rossi E, Meuser ME, Cunanan CJ, Cocklin S. Structure, Function, and Interactions of the HIV-1 Capsid Protein. Life. 2021;11(2):100. doi:10.3390/life11020100

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36. Subramanian R, Tang J, Zheng J, et al. Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent. Mol Pharm. 2023;20(12):6213-6225. doi:10.1021/acs.molpharmaceut.3c00626

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38. Gilead Sciences. A Phase 2 Randomized, Open Label, Active Controlled Study Evaluating the Safety and Efficacy of Long-Acting Capsid Inhibitor GS-6207 in Combination With Other Antiretroviral Agents in People Living With HIV. clinicaltrials.gov; 2024. Accessed November 22, 2025. https://clinicaltrials.gov/study/NCT04143594

39. Gupta SK, Berhe M, Crofoot G, et al. Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial. Lancet HIV. 2023;10(1):e15-e23. doi:10.1016/S2352-3018(22)00291-0

40. Gilead Sciences. A Phase 2/3 Study to Evaluate the Safety and Efficacy of Long-Acting Capsid Inhibitor GS-6207 in Combination With an Optimized Background Regimen in Heavily Treatment Experienced People Living With HIV-1 Infection With Multidrug Resistance. clinicaltrials.gov; 2025. Accessed November 22, 2025. https://clinicaltrials.gov/study/NCT04150068

41. Temereanca A, Ruta S. Strategies to overcome HIV drug resistance-current and future perspectives. Front Microbiol. 2023;14. doi:10.3389/fmicb.2023.1133407

42. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542

43. Sunlenca lenacapavir Receives FDA Approval as a First in Class Twice Yearly Treatment Option for People Living With Multi Drug Resistant HIV. Accessed November 22, 2025. https://www.gilead.com/news/news-details/2022/sunlenca-lenacapavir-receives-fda-approval-as-a-first-in-class-twice-yearly-treatment-option-for-people-living-with-multi-drug-resistant-hiv

44. Gilead’s Investigational Single Tablet Regimen of Bictegravir and Lenacapavir for HIV 1 Treatment Meets Primary Endpoint in Phase 3 ARTISTRY 1 Trial. Accessed November 22, 2025. https://www.gilead.com/news/news-details/2025/gileads-investigational-single-tablet-regimen-of-bictegravir-and-lenacapavir-for-hiv-1-treatment-meets-primary-endpoint-in-phase-3-artistry-1-trial

45. Gilead Sciences. An Operationally Seamless Phase 2/3 Randomized, Open-Label, Multicenter, Active-Controlled Study to Evaluate the Safety and Efficacy of Bictegravir/Lenacapavir Versus Stable Baseline Regimen in Virologically Suppressed People With HIV-1 on Stable Complex Treatment Regimens. clinicaltrials.gov; 2025. Accessed November 22, 2025. https://clinicaltrials.gov/study/NCT05502341

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Author: Pari Dhayagude

Editor: Grace Stroman

Alzheimer’s disease (AD) remains one of the most challenging neurodegenerative disorders to diagnose in its early stages.¹ Before the 2000s, a postmortem autopsy was the only definitive method for diagnosing AD. Since then, progress has been made with magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) assays, but all are costly and invasive, which limits access for many patients.^2,3 Cognitive tests, such as the Alzheimer’s Disease Assessment Scale – Cognitive Test (ADAS-Cog), help monitor cognitive symptoms in patients already diagnosed with AD but do not reliably detect changes during mild cognitive impairment (MCI), the precursor to AD.^4,5 However, in 2025, the FDA approved the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test developed by Fujirebio Diagnostics, as the first blood-based diagnostic aid for patients with cognitive impairment undergoing AD assessment.⁶ Using a simple blood draw, this test measures the ratio of two key proteins, phosphorylated tau 217 (pTau217) and β-amyloid 1-42 (Aβ1-42), providing a less invasive, more accessible, and affordable method for early detection and diagnosis.⁷ Although the test is currently approved to support clinical evaluation rather than serve as a standalone diagnosis, it represents a significant step forward in early AD diagnosis.

Overview of Alzheimer’s Disease

Alzheimer’s disease is the leading cause of dementia, accounting for approximately 60-80% of cases.⁸ Driven by the aging U.S. population, the number of new AD cases per year is expected to double by 2060.⁹ AD is characterized by progressive cognitive decline that affects memory, reasoning, language, and daily activity.¹⁰ The disease progresses through stages, from preclinical AD to MCI and eventually to moderate and severe dementia over several years.¹¹ Individuals with AD often experience comorbidities such as depression, anxiety, cardiovascular disease, and diabetes, complicating both diagnosis and disease management.^12,13 Because of the nature of disease progression and the presence of symptoms, pathological changes in the brain begin almost a decade before noticeable cognitive decline.¹⁴ 

AD Pathology

AD pathology is characterized by two abnormal protein aggregates: extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein.¹⁵ The amyloid cascade hypothesis suggests that the accumulation of Aβ peptides triggers downstream tau hyperphosphorylation at multiple sites, leading to the formation of helical filaments and neurofibrillary tangles throughout the brain.¹⁶ These pathological changes result in synaptic loss, neuroinflammation, and progressive neurodegeneration, primarily affecting the hippocampus and entorhinal cortex before spreading to cortical regions.¹⁷ 

Current Diagnostic Methods

Clinical Assessment

AD is first evaluated through a comprehensive assessment that includes patient history, a physical examination, and a battery of neuropsychological tests, including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA).^18,19 While clinical assessments help quantify cognitive deficits and track disease progression, they are limited in their ability to distinguish AD from other types of dementia.

Neuroimaging

Neuroimaging modalities such as MRI and PET improve AD diagnosis by allowing for visualization of pathologies in living patients, something that was not possible a few decades ago. Structural MRIs can characterize patterns of brain atrophy, particularly in the medial temporal lobe, and PET imaging using different radiotracers can detect both Aβ plaque deposition and neurofibrillary tangle distribution.^20,21,22 However, these methods are costly, require specialized facilities, and, for PET, expose patients to radiation, limiting widespread accessibility.²³

CSF Analysis

CSF biomarkers have high accuracy in detecting AD pathology, with core biomarkers including decreased Aβ1-42, increased total tau, and increased phosphorylated tau.²⁴ While these tests have a high sensitivity and specificity, the lumbar puncture itself is an invasive procedure with several risks and side effects, including infection, bleeding, pain, and adverse reaction to anesthesia, with additional challenges in elderly patients with spinal abnormalities or those taking anticoagulants.²⁵ 

How The Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio Works

The Lumipulse G pTau217/β-Amyloid 1-42 is a blood-based diagnostic test developed by Fujirebio Diagnostics that uses chemiluminescent enzyme immunoassay (CLEIA) technology to measure two key biomarkers: phosphorylated tau at threonine 217 (pTau217), which reflects tau pathology, and β-amyloid 1-42 (Aβ1-42), which inversely correlates with amyloid plaque burden in the brain.^26,27 The monoclonal antibodies can detect these proteins at low concentrations present in plasma, with results available within 30 minutes per sample.²⁶ This diagnostic test is advantageous because it captures changes in both Aβ and tau pathologies simultaneously and presents them in a ratio that is easy to interpret. In individuals with AD, pTau217 levels are elevated due to active tau phosphorylation, while Aβ1-42 levels are reduced because the peptide is sequestered into brain plaques.²⁸ A positive value suggests the presence of AD pathology, while a negative value suggests the absence of AD pathology.²⁹ It is important to note that this test has only been FDA-approved for diagnosing AD in conjunction with a clinical evaluation.

Clinical Validation

The Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test demonstrated robust performance in clinical validation studies. The study submitted to the FDA contained data from a multi-center clinical study of 499 individual plasma samples from cognitively impaired adults to assess the diagnostic performance of the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test.⁶ Plasma samples were tested using the Lumipulse G assay and compared with either amyloid PET imaging or an FDA-cleared CSF biomarker test as reference standards. The test demonstrated a positive predictive value (PPV) of 91.7%, meaning that 91.7% of individuals with positive Lumipulse results had confirmed amyloid pathology by PET or CSF analysis.⁶ The negative predictive value (NPV) was 97.3%, meaning that the vast majority of individuals with negative results were confirmed to lack amyloid pathology.⁶ Less than 20% of the samples had an indeterminate result.

Additional large-scale studies have validated this assay, including validation of both pTau217 and Aβ1-42 separately. pTau217 is one of the most accurate plasma biomarkers for detecting AD pathology. Palmqvist et al. (2020) evaluated plasma pTau217 across three independent cohorts totaling over 1,500 participants, finding that it distinguished AD from other neurodegenerative disorders with similar accuracy to PET and CSF-based measures, and it performed significantly better than other plasma and MRI-based biomarkers.³⁰ Another study found that pTau217 levels start to rise about 20 years before expected symptom onset in autosomal-dominant AD and correlate strongly with CSF pTau217 and PET signal, further establishing pTau217 as a marker of AD-related tau pathology.³¹ Other studies have validated that decreased plasma Aβ reflects amyloid sequestration into brain plaques.³² Because pTau217 increases as Aβ1-42 decreases in AD, the ratio helps show greater separation between the two, improving accuracy and reducing indeterminate results compared to single analyte approaches.²⁹

Limitations and Concluding Remarks

While the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test has significant advantages, it is also important to acknowledge limitations. It is FDA-approved, but only for an aid to diagnosis rather than a standalone diagnostic tool.⁶ Additionally, about 20% of results fall into an indeterminate zone requiring confirmatory PET or CSF testing, and tests may be affected by comorbidities such as chronic kidney disease.^6,33 This test also cannot reliably distinguish AD from all taupathies or identify mixed pathologies, often common in elderly patients, and it requires the LUMIPULSE G platform, which may not be available in all clinical settings.³⁴ Nonetheless, the FDA approval of this test offers a minimally invasive, cost-friendly, accessible pathway to detect AD pathology that was previously only possible through PET imaging or a lumbar puncture. 

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22. Ossenkoppele R, Schonhaut DR, Schöll M, et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain. 2016;139(5):1551-1567. doi:https://doi.org/10.1093/brain/aww027

23. Rabinovici GD, Gatsonis C, Apgar C, et al. Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA. 2019;321(13):1286. doi:https://doi.org/10.1001/jama.2019.2000

24. Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. The Lancet Neurology. 2003;2(10):605-613. doi:https://doi.org/10.1016/s1474-4422(03)00530-1

25. Duits FH, Martinez-Lage P, Paquet C, et al. Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lumbar puncture feasibility study. Alzheimer’s & Dementia. 2015;12(2):154-163. doi:https://doi.org/10.1016/j.jalz.2015.08.003

26. Lumipulse® G pTau 217/β-Amyloid 1-42 Plasma Ratio | Fujirebio. Fujirebio.com. Published 2025. https://www.fujirebio.com/en-us/products-solutions/lumipulser-g-ptau-217bamyloid-142-plasma-ratio

27. Janelidze S, Teunissen CE, Zetterberg H, et al. Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease. JAMA Neurology. 2021;78(11):1375-1382. doi:https://doi.org/10.1001/jamaneurol.2021.3180

28. Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. The Lancet Neurology. 2020;19(5):422-433. doi:https://doi.org/10.1016/s1474-4422(20)30071-5

29. Hansson O, Blennow K, Zetterberg H, Dage J. Blood biomarkers for Alzheimer’s disease in clinical practice and trials. Nature Aging. 2023;3(5):506-519. doi:https://doi.org/10.1038/s43587-023-00403-3

30. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020;324(8):772-781. doi:https://doi.org/10.1001/jama.2020.12134

31. Barthélemy NR, Horie K, Sato C, Bateman RJ. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. Journal of Experimental Medicine. 2020;217(11). doi:https://doi.org/10.1084/jem.20200861

32. Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018;554(7691):249-254. doi:https://doi.org/10.1038/nature25456

33. Mielke MM, Dage JL, Frank RD, et al. Performance of plasma phosphorylated tau 181 and 217 in the community. Nature Medicine. 2022;28(7):1398-1405. doi:https://doi.org/10.1038/s41591-022-01822-2
34. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. The Lancet Neurology. 2022;21(1):66-77. doi:https://doi.org/10.1016/S1474-4422(21)00361-6

Author: Sarah Sizer, Ph.D.

Editor: Jessica Sprinkles

This article will discuss Jascayd (nerandomilast), a phosphodiesterase 4B inhibitor developed by the pharmaceutical company Boehringer Ingelheim. In October 2025, the Food and Drug Administration (FDA) approved Jascayd for the treatment of idiopathic pulmonary fibrosis (IPF).¹ The FDA approval was based on data from a phase 3 clinical trial demonstrating that 52 weeks of Jascayd significantly slowed disease progression compared to placebo.² In this article, I provide an overview of IPF pathogenesis and outline the current FDA-approved drugs to treat IPF. I also describe Jascayd’s mechanism of action and summarize the results of the FIBRONEER-IPF phase 3 clinical trial. 

Overview of Idiopathic Pulmonary Fibrosis (IPF)

IPF is a rare and terminal lung disease characterized by the progressive scarring and stiffening of the lung tissue. IPF affects between 0.33 and 4.51 per 10,000 people globally³, and is most prevalent among men, older adults, and cigarette smokers.^4–6 IPF begins with a subclinical period in which the initial changes to lung physiology precede symptom onset. The most common symptoms include dyspnea (shortness of breath), velcro-like crackles during inspiration, hacking cough, exercise intolerance, and hypoxia, which worsen over time. IPF progression varies and can be rapid, slow, or contain intermittent periods of relative stability interposed with periods of acute decline.⁷ Mortality typically occurs 3.2 to 5 years after diagnosis and primarily results from respiratory failure (38.7%), but can also result from comorbid diseases like heart failure, bronchogenic carcinoma, ischemic heart disease, infection, and pulmonary embolism (Figure 1).¹²

There are significant challenges associated with diagnosing IPF because it causes non-specific symptoms that mimic those of other fibrotic interstitial lung diseases.^8,9 Since there are currently no clinical biomarkers to screen for IPF, medical professionals must rely on the process of elimination to exclude the possibility of other interstitial lung diseases before diagnosis. Misdiagnoses and delays in treatment last between 1 and 3 years and correlate with worse clinical outcomes.^10,11

Pulmonologists use a combination of diagnostic tools and imaging to assess lung function in individuals presenting with IPF symptoms. Spirometry is a non-invasive clinical examination that measures breathing output using metrics such as the forced expiratory volume (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. FEV1 is the volume of air forcefully exhaled after 1 second, while the FVC is the total volume of air forcefully exhaled following a deep breath. The FEV1, FVC, and FEV1/FVC ratio help clinicians diagnose lung diseases and monitor changes in lung function over time. For example, the FEV1/FVC ratio is higher in early-stage IPF patients (FEV1/FVC>0.8) than in healthy individuals (FEV1/FVC=0.7) due to significant reductions in the FVC.^13,14 The percent change in FVC over 1 year is often the primary endpoint in clinical trials for interstitial lung diseases because it positively correlates with mortality risk.¹⁵ Although spirometry is a quick and useful measure of lung function, IPF diagnosis also requires a high-resolution CT scan or a surgical biopsy to visualize usual interstitial pneumonia (UIP). UIP is a pattern of lung fibrosis characterized by honeycomb cysts in the interstitium that indicate advanced-stage disease.⁸ Once patients receive an official IPF diagnosis, they are treated with pulmonary rehabilitation, supplemental oxygen, and FDA-approved therapies to slow disease progression.¹⁶

Lung Physiology and IPF Pathogenesis

Gas exchange is an essential physiological process that adds oxygen and removes carbon dioxide from the bloodstream and occurs in the alveoli. The alveoli is a network of air sacs lined with Type 1 (AEC1) and Type 2 (AEC2) alveolar epithelial cells. Both cell types serve distinct roles in maintaining alveolar homeostasis. AEC1s are large, flat cells that cover approximately 96% of the alveolar surface area and serve as the primary locus of gas exchange.^17,18 AEC2s are cube-shaped stem cells that cover only 4% of the alveolar surface area, yet serve two critical functions. First, AEC2s can proliferate and produce new AEC1 or AEC2 cells to replenish the alveolar cell population after environmental damage. Second, AEC2s have microvilli on their apical membranes to maximize surfactant secretion, a process necessary to reduce surface tension and preserve alveolar integrity. The basolateral membrane of alveolar epithelial cells is adjacent to the alveolar interstitium, a thin layer of extracellular matrix that allows the alveolar epithelial cells to interface with the pulmonary capillary system to facilitate gas exchange. During gas exchange, oxygen diffuses from the alveoli into the bloodstream, while carbon dioxide diffuses from the bloodstream to the alveoli. Oxygenated blood then travels throughout the body, delivering oxygen to sustain organ function, while carbon dioxide is exhaled as a waste product (Figure 2).

While the etiology of IPF is unclear, environmental (i.e., smoking, pollution) and genetic factors influence disease onset and progression.^19–21 Persistent damage to the alveolar epithelial cells leads to senescence of AEC2s, rendering these cells incapable of proliferating and replenishing apoptotic AEC1s.²² Alveolar epithelial cell damage triggers an immune response and recruits macrophages, neutrophils, and mast cells to the alveolar interstitium.²³ These immune cells secrete a variety of proinflammatory cytokines, including transforming growth factor beta (TGFβ1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and interleukin-8 (IL-8), creating a positive feedback loop that further amplifies the immune response.^24–26 In particular, pathological TGFβ1 release from macrophages, neutrophils, mast cells, and AEC2s serves as a critical mediator of lung fibrosis.^27–30 TGFβ1 activates fibroblasts, causing them to proliferate and differentiate into myofibroblasts, specialized cells involved in wound repair that deposit collagen and other components of the extracellular matrix (ECM).³¹ The excess collagen thickens and stiffens the alveolar interstitium, impeding gas exchange and making breathing for people with IPF progressively difficult.³²

IPF Treatment Landscape

On October 15th, 2014, Esbriet (pirfenidone) and Ofev (nintedanib) became the first FDA-approved drugs for the treatment of IPF.^33,34 Pirfenidone and nintedanib are antifibrotic drugs that inhibit fibroblast proliferation through distinct mechanisms. Pirfenidone inhibits TGFβ1 signaling by downregulating TGFβ1 mRNA and protein expression, whereas nintedanib blocks downstream signaling from PDGF, FGF, and VEGF receptors.^35–37 The FDA approvals were based on data from their respective phase 3 clinical trials, which showed that both drugs significantly reduced the rate of FVC decline; however, neither drug improved mortality compared to placebo.^38,39 Patients taking pirfenidone and nintedanib reported similar adverse events, including elevated liver enzymes, gastrointestinal upset, and skin-related issues. While “pirfenidone and nintedanib…have markedly moved the field forward,” their undesirable side effects cause approximately 35-50% of IPF patients to stop taking these antifibrotic therapies.^40,41 The high discontinuation rate and lack of improvements to mortality necessitate the development of new treatments for IPF.⁴² Since the FDA approvals of pirfenidone and nintedanib, the phase 3 clinical trials for multiple promising drug candidates (ziritaxestat, pinpentraxin, and pamrevlumab) were discontinued due to lack of efficacy, despite their promising phase 2 clinical trial results.^43–45

On October 7^th, 2025, nerandomilast became the third FDA-approved drug to treat IPF after 10 years of failed clinical trials.^1,46 Nerandomilast slows fibrosis by upregulating cyclic AMP (cAMP), a second messenger that inhibits inflammatory and fibrotic signaling pathways. Nerandomilast upregulates cAMP by inhibiting phosphodiesterase 4B (PDE4B), the enzyme that converts cAMP to 5’-AMP. Increased cellular cAMP levels dampen the immune response and reduce fibroblast proliferation within the alveolar interstitium. Although the complete mechanism remains unclear, one way nerandomilast reduces fibroblast proliferation is by downregulating TGFβ1 signaling.⁴⁷ The FDA approval for nerandomilast was a result of a double-blind, randomized, placebo-controlled phase 3 clinical trial. The FIBRONEER-IPF clinical trial compared the effects of nerandomilast (9 mg or 18 mg twice daily) as a monotherapy or in combination with background antifibrotic therapy (pirfenidone or nintedanib) versus placebo on lung function over 52 weeks.⁴⁵ The primary endpoint was the change in FVC, and the key secondary endpoint was the first acute exacerbation, hospitalizations for respiratory causes, or death during the trial. Nerandomilast dose-dependently improved the FVC in IPF patients, regardless of background antifibrotic therapy, but did not significantly alter the secondary endpoints compared with placebo. Like pirfenidone and nintedanib, gastrointestinal upset was the most frequent adverse event and had the highest incidence among patients taking nintedanib as a background therapy. However, nerandomilast did not significantly alter liver enzymes, suggesting this drug may be more tolerable for some individuals. Regardless of its shortcomings, the development of nerandomilast provides people with IPF with options to develop a more effective treatment plan that slows disease progression and improves their quality of life.

References

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2. Richeldi L, Azuma A, Cottin V, et al. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2025;392(22):2193-2202. doi:10.1056/NEJMoa2414108

3. Maher TM, Bendstrup E, Dron L, et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res. 2021;22(1):197. doi:10.1186/s12931-021-01791-z

4. Jo HE, Glaspole I, Grainge C, et al. Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry. Eur Respir J. 2017;49(2):1601592. doi:10.1183/13993003.01592-2016

5. Zaman T, Moua T, Vittinghoff E, Ryu JH, Collard HR, Lee JS. Differences in Clinical Characteristics and Outcomes Between Men and Women With Idiopathic Pulmonary Fibrosis. Chest. 2020;158(1):245-251. doi:10.1016/j.chest.2020.02.009

6. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155(1):242-248. doi:10.1164/ajrccm.155.1.9001319

7. Ley B, Collard HR, King TE. Clinical Course and Prediction of Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. doi:10.1164/rccm.201006-0894CI

8. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. Longo DL, ed. N Engl J Med. 2018;378(19):1811-1823. doi:10.1056/NEJMra1705751

9. Idiopathic Pulmonary Fibrosis. American Academy of Family Physicians Accessed November 22, 2025. https://www.aafp.org/home.html

10. Lamas DJ, Kawut SM, Bagiella E, Philip N, Arcasoy SM, Lederer DJ. Delayed Access and Survival in Idiopathic Pulmonary Fibrosis: A Cohort Study. Am J Respir Crit Care Med. 2011;184(7):842-847. doi:10.1164/rccm.201104-0668OC

11. Cosgrove GP, Bianchi P, Danese S, Lederer DJ. Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey. BMC Pulm Med. 2018;18(1):9. doi:10.1186/s12890-017-0560-x

12. Panos RJ, Mortenson RL, Niccoli SA, King TE. Clinical deterioration in patients with idiopathic pulmonary fibrosis: Causes and assessment. Am J Med. 1990;88(4):396-404. doi:10.1016/0002-9343(90)90495-Y

13. Cortes-Telles A, Forkert L, O’Donnell DE, Morán-Mendoza O. Idiopathic Pulmonary Fibrosis: New Insights to Functional Characteristics at Diagnosis. Can Respir J. 2014;21(3). doi:10.1155/2014/825606

14. Alyami SM, Moran-Mendoza O. Increased expiratory flows identify early interstitial lung disease. Ann Thorac Med. 2023;18(3):152-155. doi:10.4103/atm.atm_38_23

15. Du Bois RM, Weycker D, Albera C, et al. Forced Vital Capacity in Patients with Idiopathic Pulmonary Fibrosis: Test Properties and Minimal Clinically Important Difference. Am J Respir Crit Care Med. 2011;184(12):1382-1389. doi:10.1164/rccm.201105-0840OC

16. Nolan CM, Polgar O, Schofield SJ, et al. Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis and COPD: A Propensity-Matched Real-World Study. Chest. 2022;161(3):728-737. doi:10.1016/j.chest.2021.10.021

17. Weibel ER. On the Tricks Alveolar Epithelial Cells Play to Make a Good Lung. Am J Respir Crit Care Med. 2015;191(5):504-513. doi:10.1164/rccm.201409-1663OE

18. Wang J, Li K, Hao D, et al. Pulmonary fibrosis: pathogenesis and therapeutic strategies. MedComm. 2024;5(10):e744. doi:10.1002/mco2.744

19. Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013;45(6):613-620. doi:10.1038/ng.2609

20. Sack C, Vedal S, Sheppard L, et al. Air pollution and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA) air–lung study. Eur Respir J. 2017;50(6):1700559. doi:10.1183/13993003.00559-2017

21. Seibold MA, Wise AL, Speer MC, et al. A Common MUC5B Promoter Polymorphism and Pulmonary Fibrosis. N Engl J Med. 2011;364(16):1503-1512. doi:10.1056/NEJMoa1013660

22. Yao C, Guan X, Carraro G, et al. Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis. Am J Respir Crit Care Med. 2021;203(6):707-717. doi:10.1164/rccm.202004-1274OC

23. Hunt LW, Colby TV, Weiler DA, Sur S, Butterfield JH. Immunofluorescent Staining for Mast Cells in Idiopathic Pulmonary Fibrosis: Quantification and Evidence for Extracellular Release of Mast Cell Tryptase. Mayo Clin Proc. 1992;67(10):941-948. doi:10.1016/S0025-6196(12)60924-0

24. Bargagli E, Prasse A, Olivieri C, Muller-Quernheim J, Rottoli P. Macrophage-derived biomarkers of idiopathic pulmonary fibrosis. Pulm Med. 2011;2011:717130. doi:10.1155/2011/717130

25. Martinet Y, Rom WN, Grotendorst GR, Martin GR, Crystal RG. Exaggerated Spontaneous Release of Platelet-Derived Growth Factor by Alveolar Macrophages from Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 1987;317(4):202-209. doi:10.1056/NEJM198707233170404

26. Inoue Y, King TE, Tinkle SS, Dockstader K, Newman LS. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol. 1996;149(6):2037-2054.

27. Khalil N, O’Connor RN, Unruh HW, et al. Increased Production and Immunohistochemical Localization of Transforming Growth Factor- α in Idiopathic Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 1991;5(2):155-162. doi:10.1165/ajrcmb/5.2.155

28. Wu X, Yang Y. Neutrophil extracellular traps (NETs) and fibrotic diseases. Int Immunopharmacol. 2024;133:112085. doi:10.1016/j.intimp.2024.112085

29. Shimbori C, Upagupta C, Bellaye PS, et al. Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis. Thorax. 2019;74(5):455-465. doi:10.1136/thoraxjnl-2018-211516

30. Liu S, Wang Q, Min J, et al. The CCL20–integrin α5β1 interaction enhances TGF-β/Smad signaling to promote fibroblast activation in pulmonary fibrosis. Nat Commun. 2025;16(1):9183. doi:10.1038/s41467-025-64211-6

31. Huang Y, Guzy R, Ma SF, et al. Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis. BMJ Open Respir Res. 2023;10(1):e001391. doi:10.1136/bmjresp-2022-001391

32. O’Leary EM, Tian Y, Nigdelioglu R, et al. TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation. Am J Respir Cell Mol Biol. 2020;63(5):601-612. doi:10.1165/rcmb.2020-0143OC

33. (OFEV) Nintedanib Capsules.; 2014. Accessed November 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205832Orig1s000TOC.cfm

34. Esbriet (Pirfenidone) Capsules.; 2014. Accessed November 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022535Orig1s000toc.cfm

35. Pourgholamhossein F, Rasooli R, Pournamdari M, et al. Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression. Food Chem Toxicol. 2018;112:39-46. doi:10.1016/j.fct.2017.12.034

36. Hirano A, Kanehiro A, Ono K, et al. Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge. Am J Respir Cell Mol Biol. 2006;35(3):366-377. doi:10.1165/rcmb.2005-0452OC

37. Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015;45(5):1434-1445. doi:10.1183/09031936.00174914

38. Richeldi L, Du Bois RM, Raghu G, et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. N Engl J Med. 2014;370(22):2071-2082. doi:10.1056/NEJMoa1402584

39. King TE, Bradford WZ, Castro-Bernardini S, et al. A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2014;370(22):2083-2092. doi:10.1056/NEJMoa1402582

40. Majewski S, Gorska K, Lewandowska KB, et al. Real-World Treatment Persistence and Predictive Factors for Discontinuation of Antifibrotic Therapies in Patients With Idiopathic Pulmonary Fibrosis: A Post-hoc Analysis of Two Multicenter Observational Cohort Studies in Poland. Am J Respir Crit Care Med. 2025;211(Abstracts):A2082-A2082. doi:10.1164/ajrccm.2025.211.Abstracts.A2082

41. Ogura T, Inoue Y, Azuma A, et al. Real-World Safety and Tolerability of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Interim Report of a Post-Marketing Surveillance in Japan. Adv Ther. 2023;40(4):1474-1493. doi:10.1007/s12325-022-02411-y

42. Kalina D, Wygrecka M. Nerandomilast – A Multifrontal Therapeutic Approach to Lung Fibrosis. Am J Respir Cell Mol Biol. 2025;73(5):646-647. doi:10.1165/rcmb.2025-0140ED

43. Richeldi L, Schiffman C, Behr J, et al. Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial. Am J Respir Crit Care Med. 2024;209(9):1132-1140. doi:10.1164/rccm.202401-0116OC

44. FibroGen Announces Topline Results from Phase 3 ZEPHYRUS-1 Study of Pamrevlumab for the Treatment of Idiopathic Pulmonary Fibrosis. FibroGen Accessed December 5, 2025. https://investor.fibrogen.com/news-releases/news-release-details/fibrogen-announces-topline-results-phase-3-zephyrus-1-study

45. Galapagos and Gilead Discontinue ISABELA Phase 3 Trials in IPF. GILEAD; 2021. Accessed December 5, 2025. https://www.gilead.com/news/news-details/2021/galapagos-and-gilead-discontinue-isabela-phase-3-trials-in-ipf

46. Klein H. Overcoming Failures: Lessons From IPF Clinical Trials in the Past Year. American Journal of Managed Care; 2024. Accessed November 25, 2025. https://www.ajmc.com/view/overcoming-failures-lessons-from-ipf-clinical-trials-in-the-past-year

47. Wang Y, Sun D, Dilixiati N, Wang D, Song Y, Ye Q. Nerandomilast, a PDE4B inhibitor, alleviates silica‐induced lung inflammation and fibrosis by inhibition of NLRP3 inflammasome and TGF‐β/Smad signalling. Br J Pharmacol. Published online November 19, 2025:bph.70240. doi:10.1111/bph.70240

Author: Tiffany Ko

Editor: Karen Wang

Overview of hypermobile Ehlers-Danlos Syndrome

Hypermobile Ehlers-Danlos syndrome (hEDS) is one of the thirteen subtypes of Ehlers-Danlos syndrome (EDS), which are typically characterized by varying degrees of hypermobile joints, hyperextensible skin, and fragile tissues prone to bruising and delayed wound healing.¹ These thirteen subtypes are heterogeneous in their clinical symptoms and genetic causes.¹ For example, classical EDS (cEDS) is marked by atrophic scarring and genetic mutations in type V collagen genes, while vascular EDS (vEDS) is marked by arterial rupture occurring at a young age and a mutation in the type III collagen gene COL3A1¹. EDS has long been described as a heritable connective tissue disorder, and with the recent advances in next-generation sequencing technology, genetic causes and markers for all subtypes of EDS have been discovered- except for hEDS.¹ Scientists postulate that this may be due to genetic heterogeneity in the hEDS patient population.¹

Diagnostic criteria

hEDS primarily manifests as joint hypermobility and corresponding acute and chronic pain.² Other common, yet variable, clinical manifestations of hEDS include hyperextensible and/or fragile skin, chronic fatigue, and cardiovascular issues.²

Since there is no identified genetic marker for hEDS as of yet, diagnostic criteria are primarily based on clinical presentation.³ The current diagnostic criteria for EDS were revised in 2017, and hEDS has been defined using the following three criteria^1,3:

1. Generalized joint hypermobility, accounting for age and sex (aging often correlates with lower flexibility, and females tend to be more flexible).

2. Two of the following three features:

• Five characteristics of connective tissue disorders (such as velvety or soft skin, mildly hyperextensible skin, bilateral piezogenic papules on the heels, recurrent abdominal hernias, arachnodactyly, or mitral valve prolapse)

• Family history (at least one first-degree relative meeting hEDS diagnostic criteria)

• Musculoskeletal complications due to joint laxity (e.g., chronic pain, recurrent dislocations, joint instability)

3. Exclusion of alternative diagnoses, such as other heritable connective tissue diseases

In addition to the lack of a known genetic cause for hEDS, there are currently no biomarkers for diagnosis of hEDS.^2,3 This leads to a significant limitation in the diagnostic process, since providers are often not familiar with the hEDS clinical diagnostic criteria compared to the straightforward genetic diagnostic tests available for the other subtypes of EDS.

Common comorbidities

Comorbidities can include a wide range of cardiovascular, neurological, immunological, gastrointestinal, genitourinal, endocrine, and dental conditions.⁴ The most common neurological comorbidities are migraines, scoliosis, Raynaud’s phenomenon (numbing of extremities), tinnitus, and herniated disks.⁴ Autonomic disorders are also common: 52.7% of hEDS patients also are diagnosed with postural orthostatic tachycardia syndrome (POTS), and 27% are diagnosed with general dysautonomia.⁴ Gastrointestinal disorders, such as irritable bowel syndrome, gastroesophageal reflux disease, and constipation, are common comorbidities as well.⁴

Impact of hEDS

For all subtypes of EDS, the minimum prevalence is reportedly 1 in every 5,000 people⁵, and within EDS, hEDS is estimated to comprise 80-90% of all cases.² More recently, a large-scale general population survey used joint hypermobility and chronic widespread pain as a proxy for hEDS and estimated that 3.4% of the survey population were affected.⁶ hEDS is considered the most common systemic heritable connective tissue disorder and has been estimated to affect 255 million people globally.²

A recent survey reports that nearly half of hEDS patients spend an average of 5 hours or more per week coordinating their medical care and see 6-7 medical specialists per year on average.⁴ hEDS patients also averaged a 22-year delay in receiving an hEDS diagnosis from symptom onset.⁴ These data suggest a high burden of seeking medical care and difficulty in receiving diagnosis.

Management

There is no cure for hEDS, and management of hEDS consists of treatment of acute and chronic musculoskeletal symptoms, as well as treatment and prevention of acute and chronic complications.² For many patients with hEDS, this often includes physical therapy, exercise, massage, chiropractic treatment, and pain medications.^2,4 Physical therapy, in particular, is considered a primary  pillar of management in hEDS.² The most common pain medications among hEDS patients for management of pain were NSAIDs, acetaminophen, and opioids, which range in their self-reported efficacy.⁴ hEDS patients also often try alternative medicine modalities: 70% of hEDS patients have tried massage, 55% have tried chiropractic treatments, and 44% have tried acupuncture.

Studies on molecular etiology of hEDS

As the only subtype of EDS with no known genetic marker or cause, hEDS diagnosis relies solely on clinical presentation of symptoms.¹ To address this, the Ehlers-Danlos Society is funding and leading a series of research studies to uncover the molecular etiology of hEDS with the overarching future goal to develop diagnostic tests and specific treatments for hEDS patients.⁷ From these studies, recent publications and preprints have emerged describing preclinical investigations into genes potentially involved in hEDS⁸, proteomics of hEDS patients⁹, and genetic variants found in hEDS patients.¹⁰

Recently, whole-exome sequencing on a cohort of 200 hEDS patients led to the discovery of rare and low-frequency variants of kallikrein (KLK) genes in one-third of the cohort.⁸ Kallikreins are enzymes, specifically serine proteases, that play a wide variety of physiological roles, including remodeling of the extracellular matrix, inflammation, and cardiovascular regulation.¹¹ Notably, the investigators reported that they did not identify polymorphisms in MTHFR, a gene that has previously been proposed as a genetic cause for hEDS.¹² However, a specific missense KLK15 variant, predicted to have high pathogenicity, was identified in two separate patient families and correlated with the hEDS phenotype in both families.⁸ KLK15 is found across many human tissues and was found to interact with extracellular matrix proteins.⁸ The effects of this KLK15 variant were further interrogated by the development of a mouse model carrying the KLK15 variant.⁸ This mouse model showed reduced tendon collagen fibril diameters, as well as increased elasticity and decreased strength in tendons.⁸ Furthermore, the mouse model had a high occurrence of mitral valve prolapse (a cardiac phenotype) and decreases in regulatory cytokines, which have been highly reported in hEDS patients as well.⁸ These findings generally suggest that KLK variants may contribute to hEDS pathology.

A preprint on a genome-wide association study meta-analysis has also identified two genomic loci linked to hEDS.¹⁰ The investigators suggest that variants in the candidate genes ACKR3 and SLC39A13 may contribute to hEDS pathogenesis.¹⁰ ACKR3 is an atypical scavenger receptor for chemokines that is functionally known to bind to opioid peptides and chemokines and prevent them from activating their proper targets, thereby affecting neurological pain and immune signaling.¹³ Furthermore, the investigators noted that high ACKR3 gene activity is predicted in both nervous-system cell types as well as stromal cells in hEDS patients.¹⁰ SLC39A13 is a zinc ion transporter that is highly involved in development of connective tissue¹⁴, and a specific rare homozygous mutation can cause spondylocheiro-dysplastic EDS.¹⁵ It is possible that variants in SLC39A13 may affect the function of this zinc ion transporter and affect connective tissue development in hEDS. Genetic correlations between hEDS and common comorbidities were discovered as well, including chronic pain, fibromyalgia, irritable bowel syndrome, gastroesophageal reflux disease, migraines, and major depressive disorder.¹⁰ The authors reconcile this work with the previously discussed KLK findings by raising the possibility that hEDS is a complex and polygenic disease composed of many variants that increase hEDS risk.¹⁰

A recent proteomic study on hEDS patients and age- and sex-matched controls similarly suggests that hEDS is heterogeneous and may broadly affect rheumatic and immune systems beyond connective tissue.⁹ Of 35 differentially expressed serum proteins, almost half were implicated in dysfunction of the innate immune system, which the authors suggest could be linked to common comorbidities of hEDS such as mast-cell activation syndrome or other autoimmune diseases.⁹ Furthermore, cytokine profiles suggested chronic inflammation and dysregulation of the immune system.⁹ This proteomic study also identified alterations in kallikrein-related pathways in hEDS patients, which aligns with the previously discussed study on KLK variants.

Overall, herculean efforts have been made to study large cohorts of hEDS patients using cutting-edge genetic and proteomic tools. Although a single genetic cause or biomarker has not been identified through these studies, the conclusions from these studies support the hypothesis that hEDS is a complex and potentially polygenic condition. Furthermore, these studies have provided evidence for biological underpinnings of common comorbidities and chronic symptoms. As research continues, investigators and patients alike hope for the development of clearer and biomarker-based diagnostic criteria and treatments informed by the molecular etiology of hEDS.

References

1.         Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017/03/01;175(1)doi:10.1002/ajmg.c.31552

2.         Tinkle B, Castori M, Berglund B, et al. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017/03/01;175(1)doi:10.1002/ajmg.c.31538

3.         Forghani I, See J, McGonigle WC, Forghani I, See J, McGonigle WC. Hypermobile Ehlers–Danlos Syndrome: Diagnostic Challenges and the Role of Genetic Testing. Genes 2025, Vol 16, Page 530. 2025-04-29;16(5)doi:10.3390/genes16050530

4.         Daylor V, Griggs M, Weintraub A, et al. Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs. Journal of Clinical Medicine 2025, Vol 14, Page 5636. 2025-08-09;14(16)doi:10.3390/jcm14165636

5.         Peter M. Royce BS, ed. Connective Tissue and Its Heritable Disorders. 2nd ed. Wiley-Liss, Inc.; 2002.

6.         Mulvey MR, Macfarlane GJ, Beasley M, et al. Modest association of joint hypermobility with disabling and limiting musculoskeletal pain: results from a large-scale general population-based survey. Arthritis Care Res (Hoboken). Aug 2013;65(8):1325-33. doi:10.1002/acr.21979

7.         hEDS & HSD Research: The Search for Causes and Diagnostic Tests. The Ehlers-Danlos Society. Accessed November 7, 2025. https://www.ehlers-danlos.com/heds-hsd-research/#1694081509342-b520a782-2bf7

8.         Gensemer C, Petrucci T, Beck T, et al. KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome. iScience. 2025/09/19;28(9)doi:10.1016/j.isci.2025.113343

9.         Griggs M, Daylor V, Petrucci T, et al. Proteomic discoveries in hypermobile Ehlers–Danlos syndrome reveal insights into disease pathophysiology. ImmunoHorizons. 2025/09/17;9(10)doi:10.1093/immhor/vlaf044

10.      Petrucci-Nelson T, Guilhaumou S, Berrandou TE, et al. Complex Genetics and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome: Insights from Genome-Wide Association Study Meta-analysis. medRxiv. 2025-09-21;doi:10.1101/2025.09.19.25336146

11.      Kalinska M, Meyer-Hoffert U, Kantyka T, Potempa J. Kallikreins – The melting pot of activity and function. Biochimie. 2016/03/01;122doi:10.1016/j.biochi.2015.09.023

12.      Courseault J, Umar M, Bordnick P, et al. Prevalence of MTHFR Polymorphisms in Patients With Hypermobile Ehlers‐Danlos Syndrome and Hypermobile Spectrum Disorders in a US Hypermobility Clinic. ACR Open Rheumatology. 2024/07/01;6(7)doi:10.1002/acr2.11667

13.      Meyrath M, Szpakowska M, Zeiner J, et al. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nature Communications 2020 11:1. 2020-06-19;11(1)doi:10.1038/s41467-020-16664-0

14.      Fukada T, Civic N, Furuichi T, et al. The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways. PLOS ONE. Nov 5, 2008;3(11)doi:10.1371/journal.pone.0003642

15.      C G, NH E, B A, et al. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome–an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13 – PubMed. American journal of human genetics. 2008 Jun;82(6)doi:10.1016/j.ajhg.2008.05.001

Author: Stacy Pitcairn

Editor: Kaitlin Kinney

Overview

As individuals age, many experience the onset of presbyopia. Presbyopia is a term that refers to the gradual loss of the eye’s ability to change its focus. Patients often report increasing difficulty concentrating on nearby objects. Other symptoms consist of eye strain, exhaustion, headache, and a tendency to hold reading materials at arm’s length.^1–3 Presbyopia is part of the aging process and is not considered a disease, but treatments such as eyeglasses, contact lenses, and surgery help to minimize its effect on an individual’s quality of life and daily functioning.^2,3

In July of 2025, the Food and Drug Administration (FDA) approved a new eye drop medication to treat presbyopia called Vizz (aceclidine ophthalmic solution).⁴ This medication was developed by LENZ Therapeutics, Inc. and seems to be a promising new treatment option, based on available data. Aceclidine is the second pharmacological agent approved for presbyopia in the U.S. following Abbvie’s Vuity, a pilocarpine hydrochloride ophthalmic solution that was approved in 2021.⁵

Understanding Presbyopia

Presbyopia is very common. Globally, about 1.8 billion people had presbyopia in 2015 and this number is expected to increase.^1,2 Research indicates that presbyopia generally manifests symptomatically between the ages of 40 and 45. Studies show that more than 80% of individuals aged 40 develop presbyopia.⁶ By age 60, there is nearly universal prevalence.⁷ Additionally, the worldwide prevalence of presbyopia is escalating as a result of an aging population and growing life expectancy.

Although there are various explanations about the underlying physiological process that leads to presbyopia, the most widely accepted explanation is increased stiffness of a part of the eye called the crystalline lens.¹ The crystalline lens functions to transmit and focus light onto the retina, similar to the lens on a camera.⁸ With age, the lens becomes increasingly rigid due to protein aggregation.¹ These changes reduce the lens’s capacity to bend and thicken and reduce the ability to focus on near objects⁹.

Figure 1. Diagram of normal vision compared with presbyopia. The top image shows normal vision. The flexible lens allows an image to be focused onto the retina and viewed clearly. The bottom image shows the effect of presbyopia. Since the lens is less flexible and more rigid, light cannot be properly focused. This causes the point of focus fall behind the retina, causing close-up objects to be blurry. Created in BioRender. Pitcairn, S. (2025) https://BioRender.com/eujsyc6.

How does aceclidine work?

Aceclidine is a cholinergic muscarinic receptor agonist, meaning that it binds to and activates muscarinic acetylcholine receptors in the nervous system.¹⁰ By activating these receptors, aceclidine makes the pupil smaller. This creates a “pinhole effect” that increases depth of focus and improves near vision.⁴

The CLARITY Clinical Trials

FDA approval was based on data from the CLARITY trials, which were randomized, double-blinded, controlled phase 3 clinical trials.^4,11 CLARITY 1 and CLARITY 2 were 6-week efficacy trials while CLARITY 3 was a 6-month safety trial¹¹. CLARITY 1 and 2 met all primary outcomes for improvement of near vision^4,11. The primary outcome for improvement of vision was the percentage of subjects who achieve a 3-line or greater improvement from baseline with no loss in Best Corrected Distance Visual Acuity (BCDVA) ≥ 5 letters. This was measured using the ETDRS chart at 4 meters.

Over these three trials, the safety and efficacy of Vizz were evaluated in 683 participants who were given a daily dose of Vizz for a 46 day period. Vizz demonstrated its ability to improve near vision within 30 minutes and last 8-10 hours. Vizz was also well tolerated, with no serious treatment-related adverse effects observed over the 30,000 treatment days across all 3 CLARITY trials^4,10,11. The most common side effects consisted of eye irritation, dim vision, and headache.^4,11 More serious events were eye redness (ocular hyperemia) and redness of the conjunctiva (conjunctival hyperemia)¹⁰. The FDA prescribing information also mentions the rare possibility of retinal tear/detachment with miotic (pupil constricting) pharmacological agents.¹⁰

Overall, the results from the placebo-controlled CLARITY studies appear promising. However, studies that directly compare Vizz versus pilocarpine (Vuity) or other medications are not yet available.⁴ Additionally, uncertainties remain regarding long-term safety, durability of effect, and adherence with chronic use.⁴ Studies assessing these factors will ultimately inform the clinical benefit and application of Vizz.

Aceclidine vs. Current Treatments

Eyeglasses and contact lenses remain a simple, safe way to correct vision problems caused by presbyopia.^1–3 Currently, corneal surgical procedures such as monovision techniques, corneal inlays, or multifocal LASIK also remain in use to correct presbyopia, but are associated with potential risks⁴. With the promising findings outlined above, Vizz provides a strong non-invasive treatment option for patients who want to reduce reliance on eyeglasses and contacts.

Key Takeaways & Looking Ahead

• Presbyopia is a common condition that refers to the eye losing the ability to change its focus with age.

• In July of 2025, the Food and Drug Administration (FDA) approved Vizz aceclidine ophthalmic solution, a new eye drop medication to treat presbyopia developed by LENZ Therapeutics, Inc.

• CLARITY clinical trials (randomized, double-blinded, controlled phase 3) demonstrated efficacy and safety.

• Further research is required to establish direct randomized comparisons with similar medications, as well as to evaluate long-term safety, durability of effect, adherence during chronic use, and other clinically relevant outcomes.

• Current treatments such as eyeglasses and surgery remain effective treatment options while Vizz continues to be assessed.

References

1.         Singh P, Zeppieri M, Tripathy K. Presbyopia. In: StatPearls [Internet]. 2025 Jan-. StatPearls Publishing; 2025. https://www.ncbi.nlm.nih.gov/books/NBK560568/

2.         Cleveland Clinic. Presbyopia: Symptoms, Causes & Treatment. November 3, 2025. https://my.clevelandclinic.org/health/diseases/8577-presbyopia

3.         Mayo Clinic Staff. Presbyopia: Diagnosis & Treatment. November 15, 2025. https://www.mayoclinic.org/diseases-conditions/presbyopia/diagnosis-treatment/drc-20363329

4.         Aslam HG, Fatima M, Sajid H, Irshad NUN, Imran SB. FDA approval of aceclidine (Vizz): a new chapter in nonsurgical presbyopia management. Ann Med Surg (Lond). 2025;87(11):6923-6925. doi:10.1097/MS9.0000000000004008

5.         AbbVie. U.S. Food and Drug Administration Approves VUITY^TM (pilocarpine HCI ophthalmic solution 1.25%), the First and Only Eye Drop to Treat Presbyopia (Age-Related Blurry Near Vision).https://news.abbvie.com/2021-10-29-U-S-Food-and-Drug-Administration-Approves-VUITY-TM-pilocarpine-HCI-ophthalmic-solution-1-25-,-the-First-and-Only-Eye-Drop-to-Treat-Presbyopia-Age-Related-Blurry-Near-Vision. October 29, 2021.

6.         Global estimates on the number of people blind or visually impaired by Uncorrected Refractive Error: a meta-analysis from 2000 to 2020. Eye (Lond). 2024;38(11):2083-2101. doi:10.1038/s41433-024-03106-0

7.         Fricke TR, Tahhan N, Resnikoff S, et al. Global Prevalence of Presbyopia and Vision Impairment from Uncorrected Presbyopia: Systematic Review, Meta-analysis, and Modelling. Ophthalmology. 2018;125(10):1492-1499. doi:10.1016/j.ophtha.2018.04.013

8.         Hejtmancik JF, Shiels A. Overview of the Lens. Prog Mol Biol Transl Sci. 2015;134:119-127. doi:10.1016/bs.pmbts.2015.04.006

9.         Motlagh M, Geetha R. Physiology, Accommodation. In: StatPearls [Internet]. 2025 Jan-. StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK542189/

10.       U.S. Food and Drug Administration. VIZZ (Aceclidine Ophthalmic Solution) Prescribing Information. U.S. Food and Drug Administration; 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218585s000lbl.pdf

11.       LENZ Therapeutics. LENZ Therapeutics Announces Positive Topline Data from Phase 3 CLARITY Presbyopia Trials. November 15, 2025. https://ir.lenz-tx.com/news-events/press-releases/detail/11/lenz-therapeutics-announces-positive-topline-data-from-phase-3-clarity-presbyopia-trials

AI Statement

Microsoft Copilot was used to generate Research Information Systems (.RIS) entries from online sources (e.g. Mayo Clinic) for import into the citation manager Zotero (version 7.0.27). AI software was not used for any other tasks related to this article.

Author – Kaitlin Kinney
Editor – Grace Stroman

For adults living with Becker muscular dystrophy (BMD), treatment options have been limited. While Duchenne muscular dystrophy (DMD) has seen multiple therapies approved in recent years, including gene therapies,¹ exon-skipping drugs,^2-5 and novel anti-inflammatory agents,^6,7 BMD has largely been managed with supportive care alone. However, that landscape may be changing.

A new investigational therapy called sevasemten (EDG-5506) is showing promise in clinical trials. Developed by Edgewise Therapeutics, this oral medication takes a novel approach: instead of trying to replace dystrophin, it aims to protect muscle from the damage caused by its absence.⁸ Early results from the CANYON trial, the largest interventional study conducted in BMD, suggest that this strategy might work.

Understanding Becker Muscular Dystrophy

BMD is a genetic disorder caused by mutations in the dystrophin gene, the same gene affected in DMD. However, while Duchenne patients produce little to no functional dystrophin protein, individuals with BMD produce a shortened or reduced amount of partially functional dystrophin. This crucial difference results in a generally milder, more variable disease course.

BMD typically manifests in late childhood or adolescence with progressive muscle weakness, particularly affecting the legs and pelvis. Many individuals with BMD are mobile into adulthood, though the degree of weakness and rate of progression varies considerably. Cardiac complications and respiratory involvement can also occur but are generally less severe than in Duchenne.

Despite the relatively milder phenotype, adults with BMD face significant challenges. Progressive weakness impacts mobility, independence, and quality of life. The current standard of care focuses on symptom management including physical therapy, orthopedic interventions, and cardiac monitoring. No disease-modifying therapies have been approved specifically for BMD. This represents a substantial unmet need for individuals with BMD.

What Happens in Dystrophic Muscle?

To understand how sevasemten might help, it is useful to look at what happens inside dystrophic muscle over time.

In healthy muscle, dystrophin acts like a shock absorber, stabilizing the muscle cell membrane during contraction. In BMD, mutations in the dystrophin gene result in reduced or abnormal dystrophin protein. This makes muscle fibers more vulnerable to mechanical stress. Each contraction causes tiny tears in the membrane, triggering a cascade of damage: calcium influx, inflammation, and eventually, muscle cell death and fibrosis.^9,10

Figure 1: Progression of Muscle Damage in Dystrophic Muscle. In dystrophic muscle, repeated contraction-induced injuries impair the muscle’s ability to repair itself. Over time, damaged muscle is replaced by fat and scar tissue, leading to progressive loss of function. Created in BioRender. Kinney, K. (2025) https://BioRender.com/sxob41j

This cycle of muscle injury and failed repair is a hallmark of dystrophinopathies such as BMD. This ongoing damage leads to the release of intracellular components into the bloodstream, which is why biomarkers like creatine kinase (CK) and troponin I type 2 (TNNI2) are elevated.¹¹ CK, an enzyme normally found in skeletal muscle, heart muscle, and the brain, serves as a key indicator of muscle stress, inflammation, or injury following tissue damage.¹¹

By reducing the force of muscle contractions, sevasemten aims to interrupt this cycle. 

What is Sevasemten?

Sevasemten is a first-in-class, orally administered inhibitor of fast skeletal myosin. Fast skeletal myosin is a motor protein that drives rapid, high-force contractions in skeletal muscle. In dystrophin-deficient fibers, these strong contractions amplify mechanical stress on fragile membranes, accelerating damage.^12,13 By selectively inhibiting fast skeletal myosin, sevasemten reduces peak contraction force without impairing overall muscle function.^14,15 This mechanism is designed to reduce contraction-induced muscle damage, a key contributor to disease progression in Becker muscular dystrophy and other dystrophinopathies.^14,15

Unlike therapies that aim to replace or repair dystrophin, sevasemten takes a “muscle protection” approach by modulating the force of muscle contractions. By reducing mechanical stress on dystrophin-deficient muscle fibers, this strategy may help preserve muscle tissue, maintain strength, and slow disease progression over time. While it does not correct the underlying genetic mutation, sevasemten offers a promising avenue for mitigating the downstream effects of dystrophin deficiency.

The CANYON Trial: A Milestone for BMD

The CANYON study was a randomized, double-blind, placebo-controlled Phase 2 trial. It is the largest interventional trial ever conducted in Becker muscular dystrophy. The study enrolled 40 adults and 29 adolescents with BMD who were randomly assigned to receive either sevasemten or placebo for 12 months, followed by a 4-week observation period.⁸

The trial’s primary endpoint was creatine kinase (CK), a biomarker of muscle damage. Patients on sevasemten showed a 28% average reduction in CK compared to placebo over months 6–12 (p = 0.02).⁸ This sustained reduction in CK suggests that sevasemten successfully reduced ongoing muscle damage.

Additionally, after just one month of treatment, patients exhibited significant reductions in multiple muscle injury biomarkers, with the most responsive being TNNI2, fast skeletal regulatory light chain, and Calpain-3 (p < 0.0001).⁸ These rapid changes support the drug’s mechanism of action and suggest early engagement with its target.

In addition to biomarker improvements, the trial assessed functional outcomes. Participants on sevasemten showed favorable trends on timed tests like the 10-meter walk/run and 4-stair climb. On the North Star Ambulatory Assessment (NSAA), a validated scale for measuring motor function in neuromuscular disorders,¹⁶ sevasemten-treated adults had a 1.1 point advantage over placebo (p = 0.16).⁸ While not statistically significant, the directional trend is encouraging and supports further investigation. 

Importantly, throughout the 12-month treatment period, sevasemten was generally well-tolerated, with a safety profile that supports continued development.⁸ 

Long-Term Data from the ARCH Study

Complementing the CANYON results are findings from ARCH, a 2-year open-label study that provided longer-term data on sevasemten. This single-center study followed 12 ambulatory adult males with BMD who received continuous sevasemten treatment for 24 months.¹⁷

The ARCH study demonstrated that sevasemten’s benefits were sustained over time. Participants maintained higher NSAA scores compared to external natural history controls, with advantages of +2.3 points at one year, +3.2 at 18 months, and +3.1 at two years.¹⁷ These results suggest that sevasemten may slow functional decline in BMD, though randomized comparisons are still needed.

Like CANYON, the ARCH study confirmed that sevasemten was well-tolerated over an extended treatment period, with rapid and sustained decreases in biomarkers of muscle damage and stabilization of functional assessments with trends toward improvement.¹⁷

What This Means for the BMD Community 

The CANYON trial represents a significant milestone for individuals with Becker muscular dystrophy. It is the first interventional study in BMD to meet its primary endpoint, validating both the muscle protection approach and sevasemten as a potential therapy.

While functional outcomes didn’t reach statistical significance, the consistency of trends across multiple measures, and the longer-term data from ARCH, are promising. Together, these findings suggest that sevasemten could offer meaningful clinical benefit.

Edgewise Therapeutics is now working with the FDA and European Medicines Agency (EMA) to explore regulatory pathways for approval.⁸ The timeline to potential approval remains uncertain, but regulatory discussions represent an important next step toward making this therapy available to individuals with BMD.

Looking Ahead: The GRAND CANYON Trial

Building on the positive results from the CANYON study, the GRAND CANYON trial, a larger Phase 3 study, is now underway. This multicenter, randomized, double-blind, placebo-controlled trial is evaluating sevasemten in adults with BMD, using change in the NSAA over 18 months as the primary endpoint.¹⁸ Results are expected by the end of 2025 and will be critical for regulatory submissions.

The BMD community is watching these trials closely, as they set important precedents. CANYON demonstrated that rigorous clinical trials in BMD are feasible and that biomarkers like CK can serve as meaningful endpoints. These insights will inform and strengthen future drug development efforts in this underserved population.

For adults living with BMD and their families, sevasemten offers a promising new therapeutic approach. While future data from the Phase 3 trial will be essential, the CANYON results represent a significant step forward in advancing treatment options for individuals with BMD.

Key Takeaways

• Sevasemten (EDG-5506) is a first-in-class oral therapy that reduces contraction-induced muscle damage in Becker muscular dystrophy.
• The CANYON trial met its primary endpoint, showing significant reductions in muscle damage biomarkers.⁸
• Functional outcomes showed encouraging trends, and the ARCH study suggests benefits may be sustained over two years.^8,17
• Sevasemten was well-tolerated in both studies.^8,17
• A Phase 3 trial (GRAND CANYON) is ongoing, with results expected in late 2025.¹⁸

This post is dedicated to my brother CJ, who lives with Becker muscular dystrophy. His resilience and determination inspires this work and reminds us why advancing treatments for BMD matters so deeply.

References

1. US Food and Drug Administration. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. June 20, 2024. Accessed October 26, 2025. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy
   
2. Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen treatment for Duchenne muscular dystrophy: exon skipping and dystrophin production. Neurology. 2018;90(24):e2146-e2154.
   
3. Frank DE, Schnell FJ, Akana C, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020;94(21):e2270-e2282.
   
4. Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of viltolarsen in boys with Duchenne muscular dystrophy amenable to exon 53 skipping: a Phase 2 randomized clinical trial. JAMA Neurol. 2020;77(8):982-991.
   
5. Novak JS, Spathis R, Dang UJ, et al. Interrogation of dystrophin and dystroglycan complex protein turnover after exon skipping therapy. J Neuromuscul Dis. 2021;8(6):1015-1035.
   
6. Guglieri M, Clemens PR, Perlman SJ, et al. Efficacy and safety of vamorolone in Duchenne muscular dystrophy: a 30-month nonrandomized controlled open-label extension trial. JAMA Netw Open. 2022;5(1):e2144178.
   
7. Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024;23(4):393-403.
   
8. Edgewise Therapeutics. Edgewise Therapeutics announces positive topline results from the CANYON Phase 2 trial of sevasemten in individuals with Becker muscular dystrophy (Becker). Press release. December 16, 2024. Accessed October 26, 2025. https://www.biospace.com/press-releases/edgewise-therapeutics-announces-positive-topline-results-from-the-canyon-phase-2-trial-of-sevasemten-in-individuals-with-becker-muscular-dystrophy-becker
   
9. Duan D, Goemans N, Takeda S, et al. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi:10.1038/s41572-021-00248-3
   
10. Farini A, Sitzia C, Villa C, et al. Defective dystrophic thymus determines degenerative changes in skeletal muscle. Nat Commun. 2021;12:2953. doi:10.1038/s41467-021-22305-x
    
11. Baird MF, Graham SM, Baker JS, Bickerstaff GF. Creatine-kinase- and exercise-related muscle damage: implications for muscle performance and recovery. J Nutr Metab. 2012;2012:960363. doi:10.1155/2012/960363
    
12. Hill C, Brunello E, Fusi L, et al. Myosin-based regulation of twitch and tetanic contractions in mammalian skeletal muscle. eLife. 2021;10:e68211. doi:10.7554/eLife.68211.
    
13. Song T, McNamara JW, Ma W, et al. Fast skeletal myosin-binding protein-C regulates fast skeletal muscle contraction. Proc Natl Acad Sci U S A. 2021;118(17):e2003596118. doi:10.1073/pnas.2003596118.
    
14. Donovan J, Silverman JA, Barthel B, et al. A Phase 1, Double-Blind, Placebo-Controlled Trial of Sevasemten (EDG-5506), a Selective Modulator of Fast Skeletal Muscle Contraction, in Healthy Volunteers and Adults With Becker Muscular Dystrophy. Muscle Nerve. 2025. doi:10.1002/mus.28444.
    
15. Roberts TC, Wood MJA, Davies KE. Therapeutic approaches for Duchenne muscular dystrophy. Nat Rev Drug Discov. 2023;22(5):365–384. doi:10.1038/s41573-023-00775-6
    
16. Bello, L., Campadello, P., Barp, A. et al. Functional changes in Becker muscular dystrophy: implications for clinical trials in dystrophinopathies. Sci Rep 2016; 6, 32439. https://doi.org/10.1038/srep32439
    
17. Edgewise Therapeutics Announces Positive Two-Year Topline Results from the ARCH Open Label Trial of Sevasemten (EDG-5506) in Adults with Becker Muscular Dystrophy (Becker). News release. Edgewise Therapeutics. April 15, 2024. Accessed October 26, 2025. https://www.businesswire.com/news/home/20240415221564/en/Edgewise-Therapeutics-Announces-Positive-Two-Year-Topline-Results-from-the-ARCH-Open-Label-Trial-of-Sevasemten-EDG-5506-in-Adults-with-Becker-Muscular-Dystrophy-Becker
    
18. Edgewise Therapeutics. Phase 2 study of EDG-5506 in Becker muscular dystrophy (GRAND CANYON). ClinicalTrials.gov identifier: NCT05291091. Accessed October 26, 2025. https://clinicaltrials.ucsd.edu/trial/NCT05291091

Author- Pari Dhayagude
Editor- Sarah Sizer, PhD

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting over 1 million people in the United States and over 10 million people worldwide.¹ PD is a progressive neurological condition defined by motor symptoms such as tremor, rigidity, bradykinesia, and postural instability.² In February 2025, the Food and Drug Administration (FDA) approved Medtronic’s software update for the first adaptive deep brain stimulation (DBS) device for PD, marking a significant advancement in neuromodulation therapy.³ Unlike conventional DBS systems that deliver constant stimulation, adaptive DBS continuously monitors brain signals and adjusts stimulation in real time based on the patient’s fluctuating symptoms.⁴ This individualized approach allows for improved symptom management with fewer side effects for patients with advanced PD.

Overview of Parkinson’s Disease

Parkinson’s disease is a chronic, progressive neurodegenerative disorder that is defined by loss of dopaminergic neurons in the substantia nigra, a subcortical structure in the midbrain involved in movement control, and accumulation of α-synuclein protein aggregates. It primarily affects the motor system but is still considered a multisystem disorder.⁵ The disease affects males more than females, with a 1.5-2:1 ratio, and typically manifests after age 60. Approximately 4% of cases occur before age 50, which is known as young-onset PD. While the cause for sex differences is still being studied, research suggests that sex-specific variations in striatal dopamine signaling, including differences in dopamine D1 and D2 receptor expression patterns and dopamine metabolism, may contribute to the lower PD risk for women.⁶ The striatum, another subcortical brain region involved in coordinating movement, receives dopaminergic input from the substantia nigra, functionally connecting both regions for motor regulation. 

The main motor symptoms include resting tremors, bradykinesia (slowness of movement), rigidity, and postural instability. Symptoms start off asymmetrically, appearing on one side of the body, and get worse over time.⁷ Non-motor symptoms include cognitive impairment, mood disorders, sleep disturbances, autonomic dysfunction, and sensory abnormalities.⁸ Depression affects 35-50% of patients, while anxiety disorders occur in 40% of cases.⁹ Cognitive impairment is also common, with 20-30% of patients showing mild cognitive impairment at diagnosis. Cognitive impairment often progresses to dementia in up to 80% of patients who survive 20 years after diagnosis.¹⁰ Other common non-motor symptoms include rapid eye movement (REM) sleep behavior disorder, loss of smell, hypotension, constipation, and bladder problems.^11,12 Many of these manifestations occur several years before the onset of motor symptoms.

Clinicians measure PD progression using the Hoehn and Yahr scale, which primarily measures motor function and ranges from stage 1 (unilateral symptoms) to stage 5 (bedridden) (Figure 1).¹³ Motor fluctuations develop over time, with patients experiencing “on” periods of symptom control and “off” periods of worsening disability. These fluctuations become harder to manage with medications and affect 50% of patients by 5 years and nearly 100% by 10 years since diagnosis.¹⁴ Because of the variation in symptoms and progression rates among patients, personalized treatments that adapt to changing symptoms in real time are essential.

Pathophysiology

PD is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in striatal dopamine deficiency and the disruption of basal ganglia circuits.¹⁵ Both the substantia nigra and the striatum are key components of the basal ganglia. Alongside this neural damage, α-synuclein protein aggregates build up, forming Lewy bodies (Figure 2).¹⁶ Approximately 50-70% of dopaminergic neurons have already been lost by the time motor symptoms show, indicating the gradual and often asymptomatic progression of the disease.¹⁷ Beyond the dopaminergic degeneration in PD, early pathology involves noradrenergic neuronal loss in the locus coeruleus, a nucleus in the pons of the brainstem critical for synthesizing norepinephrine. This neurodegeneration occurs before substantia nigra degeneration and may play a role in disease progression.²⁰ Reduced norepinephrine levels are involved in several non-motor symptoms of PD, including mood disturbances, cognitive decline, REM sleep behavior disorder, and autonomic dysfunction.²⁰ 

The basal ganglia-thalamocortical circuits control movement through two main pathways: one that facilitates movement (direct), and one that inhibits movement (indirect).¹⁸ In PD, dopamine depletion causes the direct pathway to become less active and the indirect pathway to become overactive, resulting in increased inhibition of thalamic and cortical motor areas. This imbalance leads to the motor symptoms associated with PD. Additionally, abnormal oscillatory activity in the beta frequency band (13-35 Hz), normally associated with maintaining the current motor set and inhibiting unnecessary movement, has been observed in the basal ganglia-cortical network and is associated with motor symptom severity, especially bradykinesia and rigidity.^19,34  Understanding these abnormal neural patterns has guided treatments such as deep brain stimulation, which aims to change and correct the changes to network activity.

Current Available Treatments and Limitations

Pharmacological Therapy

Levodopa, a dopamine precursor, is the primary line of treatment used for symptom management in PD. Once taken, neurons in the brain convert levodopa to dopamine, raising depleted dopamine levels and relieving motor symptoms.²¹ Despite its efficacy, chronic levodopa use is linked to side effects including wearing-off episodes and levodopa-induced dyskinesias (involuntary erratic movements), impacting up to 80% of patients within 5-10 years of beginning treatment.²² Patients often take other medications such as dopamine receptor agonists, monoamine oxidase (MAO) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors simultaneously to extend the therapeutic effects of levodopa. MAO inhibitors block the breakdown of dopamine and other neurotransmitters, which increases their levels, while COMT inhibitors block the breakdown of levodopa, which increases levodopa levels. MAO inhibitors may also be used as early monotherapy.³⁵ However, these medications have additional side effects, including impulse control disorders, daytime sleepiness, and hallucinations. As the disease advances, the therapeutic window narrows, complicating medication titration and often diminishing the overall efficacy of available treatment options.²³

Conventional Deep Brain Stimulation

Since its FDA approval in 1997, conventional DBS has become a well-validated treatment for advanced PD patients whose motor symptoms cannot be controlled with medications. DBS involves a surgery to implant electrodes in target brain regions, usually the subthalamic nucleus or globus pallidus internus (Figure 3). These brain regions are targeted because they are the key output nodes that become overactive with dopamine loss in PD. The electrodes are connected to a pulse generator that delivers continuous electrical stimulation.²⁴ While conventional DBS can reduce motor symptoms by 50-60%, it has significant limitations. The fixed parameters of the pulse generator cannot adapt to fluctuating symptoms throughout the day, leading to overstimulation during the “on” periods and understimulation during the “off” periods. Overstimulation causes dyskinesias, while understimulation results in loss of symptom control.²⁴ Additionally, optimization of the programming requires frequent clinic visits and relies on subjective symptom reporting, increasing patient burden.

Adaptive Deep Brain Stimulation: Mechanism of Action

Adaptive DBS (aDBS) uses closed-loop control systems that continuously monitor neural biomarkers and adjust stimulation parameters in real time. This system uses embedded sensors to record local field potentials (LFPs) from the same electrodes used for stimulation. LFPs are low-frequency extracellular voltage fluctuations that reflect the summed synaptic and dendritic currents of local neuronal populations, which enables detecting pathological oscillatory activity patterns associated with specific PD symptoms.²⁵

Neural Biomarkers and Sensing

The key improvement of aDBS compared to conventional DBS is its ability to identify and track neural biomarkers of PD symptoms. Beta band oscillations (13-30 Hz) in the subthalamic nucleus serve as the primary biomarker, with elevated beta power correlating with bradykinesia and rigidity severity.²⁵ High beta activity is associated with “off” states and increased symptoms, while successful treatment reduces beta oscillations to normal levels or “on” states. The aDBS system continuously monitors these oscillations and other frequency bands, providing a better understanding of the patient’s neurological state in real time.

Closed-Loop Algorithm

In aDBS, the adaptive algorithm reads the neural signals and compares them to threshold values that were personalized to the patient during the initial programming.²⁷ When activity exceeds the threshold, stimulation increases to suppress symptoms. Alternatively, when activity normalizes, the machine decreases stimulation to minimize side effects. These adjustments occur on the order of milliseconds, significantly faster than the response to medication adjustments or manual DBS programming.²⁷ The system can also incorporate feedback from multiple biomarkers and stimulation parameters, allowing for further customization of treatment based on individual symptom profiles.

Clinical Evidence and FDA Approval

The FDA approval of aDBS in February 2025 was based on results from the ADAPT-PD (Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease) clinical trial.²⁸ This multi-center trial sponsored by Medtronic Neuro enrolled patients with advanced PD who had been previously implanted with DBS systems capable of both adaptive or conventional sensing. The study aimed to evaluate whether adaptive stimulation based on beta oscillations could provide better symptom control compared to conventional continuous DBS. The ADAPT-PD trial used a single-blind, randomized crossover experimental design where each patient served as their own control.²⁹ The primary endpoint was the proportion of time participants experienced “on” states without significant dyskinesia. Clinicians assessed this endpoint in 30-minute intervals using the PD Home Diary over a one-month evaluation period.²⁹ The sensors used in the trial collected over 250,000 hours of brain signal data across a variety of daily activities, including sleep, medication, and physical exercise.³¹ 

In February 2025, preliminary positive results led to FDA approval of Medtronic’s Percept™ RC neurostimulator with BrainSense™, making it the world’s first commercially available adaptive DBS system.^{30, 31} The device can sense brain signals and deliver targeted stimulation through the same electrodes. The approval specifically covers use in patients with PD experiencing motor fluctuations despite current medical therapy.³¹ This approval represents a treatment shift from open-loop to closed-loop neuromodulation, providing personalized treatment therapy that adapts to each patient’s changing neurological state throughout the day.

Implementation and Future Directions

Implementing aDBS in practice requires the clinician to have expertise in both surgical technique for device implantation as well as device programming. Clinicians begin by identifying each patient’s optimal neural biomarkers by testing different frequency bands and brain states and seeing what signals best track their symptoms. From there, individualized thresholds and control parameters are set to offer the most symptom relief while keeping side effects to a minimum. This process is more complex than conventional DBS programming, but the long-term benefits include fewer programming sessions and more stable symptom control, lessening patient burden.

Ongoing research is working to incorporate additional biomarkers outside of just beta oscillations into aDBS technology, including gamma band activity for dyskinesia detection and theta-alpha activity for cognitive states.³² Additionally, machine learning algorithms may allow for more accurate stimulation therapeutic strategies by identifying complex patterns in neural data that predict symptom fluctuations. Pairing these brain signals with data from wearable sensors tracking movement, sleep, and other physiological measures could provide additional inputs for the adaptive algorithm, making a more comprehensive closed-loop system for disease management.³³

Conclusion

The FDA approval of aDBS marks a shift in PD treatment by allowing for the first personalized neuromodulation therapy. It monitors brain activity continuously and adjusts stimulation in real time, addressing fundamental limitations of both pharmacological therapy and conventional DBS. Although challenges remain, including the need for specialized programming and long-term data, the technology represents a significant step toward personalized, targeted medicine in treating neurodegenerative disorders. Adaptive DBS may serve as a model for developing closed-loop therapies for other neurological conditions down the line.

Publication Licenses for Figures:

Figure 1: Created in BioRender. Dhayagude, P. (2025) https://BioRender.com/qkcpplv 

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

Figure 3: Created in BioRender. Dhayagude, P. (2025) https://BioRender.com/zqwrtvi

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9. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord. 2008;23(2):183-313. doi:10.1002/mds.21803

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12. Cersosimo MG, Benarroch EE. Autonomic involvement in Parkinson’s disease: pathology, pathophysiology, clinical features and possible peripheral biomarkers. J Neurol Sci. 2012;313(1-2):57-63. doi:10.1016/j.jns.2011.09.030

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14. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology. 2009;72(21 Suppl 4):S1-S136. doi:10.1212/WNL.0b013e3181a1d44c

15. Dickson DW. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med. 2012;2(8):a009258. Published 2012 Aug 1. doi:10.1101/cshperspect.a009258

16. Calabresi P, Mechelli A, Natale G, Volpicelli-Daley L, Di Lazzaro G, Ghiglieri V. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023;14(3):176. Published 2023 Mar 1. doi:10.1038/s41419-023-05672-9

17. Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol. 2010;67(6):715-725. doi:10.1002/ana.21995

18. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007;64(1):20-24. doi:10.1001/archneur.64.1.20

19. Hammond C, Bergman H, Brown P. Pathological synchronization in Parkinson’s disease: networks, models and treatments. Trends Neurosci. 2007;30(7):357-364. doi:10.1016/j.tins.2007.05.004

20. Espay AJ, LeWitt PA, Kaufmann H. Norepinephrine deficiency in Parkinson’s disease: the case for noradrenergic enhancement. Mov Disord. 2014;29(14):1710-1719. doi:10.1002/mds.26048

21. Katzenschlager R, Lees AJ. Treatment of Parkinson’s disease: levodopa as the first choice. J Neurol. 2002;249 Suppl 2:II19-II24. doi:10.1007/s00415-002-1204-42

22. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30(1):80-89. doi:10.1002/mds.26125

23. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-1683. doi:10.1001/jama.2014.3654

24. Hariz M, Blomstedt P. Deep brain stimulation for Parkinson’s disease. J Intern Med. 2022;292(5):764-778. doi:10.1111/joim.13541

25. Bouthour W, Mégevand P, Donoghue J, Lüscher C, Birbaumer N, Krack P. Biomarkers for closed-loop deep brain stimulation in Parkinson disease and beyond [published correction appears in Nat Rev Neurol. 2019 Jun;15(6):363. doi: 10.1038/s41582-019-0189-x.]. Nat Rev Neurol. 2019;15(6):343-352. doi:10.1038/s41582-019-0166-4

26. Neumann WJ, Degen K, Schneider GH, et al. Subthalamic synchronized oscillatory activity correlates with motor impairment in patients with Parkinson’s disease. Mov Disord. 2016;31(11):1748-1751. doi:10.1002/mds.26759

27. Little S, Beudel M, Zrinzo L, et al. Bilateral adaptive deep brain stimulation is effective in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2016;87(7):717-721. doi:10.1136/jnnp-2015-310972

28. Stanslaski S, Summers RLS, Tonder L, et al. Sensing data and methodology from the Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease (ADAPT-PD) clinical trial. NPJ Parkinsons Dis. 2024;10(1):174. Published 2024 Sep 17. doi:10.1038/s41531-024-00772-5

29. Study Details, Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease. Clinicaltrials.gov. Published 2025. Accessed July 9, 2025. https://clinicaltrials.gov/study/NCT04547712

30. Medtronic earns U.S. FDA approval for the world’s first Adaptive deep brain stimulation system for people with Parkinson’s. Medtronic News. Published Feb 24, 2025. Accessed July 9, 2025. https://news.medtronic.com/2025-02-24-Medtronic-earns-U-S-FDA-approval-for-the-worlds-first-Adaptive-deep-brain-stimulation-system-for-people-with-Parkinsons

31. U.S. Food and Drug Administration. Premarket Approval (PMA) P960009/S478 Decision Summary: Percept PC Adaptive DBS System. Published February 20, 2025. Accessed July 10, 2025. https://www.accessdata.fda.gov/cdrh_docs/pdf/P960009S478B.pdf.

32. Swann NC, de Hemptinne C, Thompson MC, et al. Adaptive deep brain stimulation for Parkinson’s disease using motor cortex sensing. J Neural Eng. 2018;15(4):046006. doi:10.1088/1741-2552/aabc9b

33. Malekmohammadi M, Herron J, Velisar A, et al. Kinematic Adaptive Deep Brain Stimulation for Resting Tremor in Parkinson’s Disease. Mov Disord. 2016;31(3):426-428. doi:10.1002/mds.26482

34. Engel AK, Fries P. Beta-band oscillations–signalling the status quo?. Curr Opin Neurobiol. 2010;20(2):156-165. doi:10.1016/j.conb.2010.02.015

35. Parkinson’s Foundation. MAO-B Inhibitors. www.parkinson.org. Published 2025. Accessed July 28, 2025. https://www.parkinson.org/living-with-parkinsons/treatment/prescription-medications/mao-b-inhibitors

Author: Colin McArdle
Editor: Morgan McCullough

Approximately every 40 seconds, someone will suffer from a stroke.¹ As one of the top burdensome neurological disorders and the second leading cause of global deaths, roughly 94 million people worldwide are living with the effects of stroke in 2025.² A stroke, or the loss of blood circulation to the brain, can be categorized into two subtypes: an ischemic or hemorrhagic stroke. An ischemic stroke involves the occlusion of blood flow within the arteries that circulate around the brain. A hemorrhagic stroke, on the other hand, results from the rupturing of an artery.³ In simpler terms, an ischemic stroke stems from a blockage while a hemorrhagic stroke stems from a rupture (Figure 1). Approximately 87% of strokes are classified as ischemic,³ making it the predominant subtype and the focus of this discussion.

To function properly in the brain, neurons heavily rely on the circulating supply of oxygen from the blood. When oxygen is lacking due to a clogged cerebral artery, neurons die rapidly within minutes,⁴ resulting in permanent brain tissue atrophy (a reduction in brain volume), severe behavioral disabilities, or death. The resulting behavioral disabilities furthermore depend on where the ischemic stroke occurred along the brain. For example, a stroke that occurs in the occipital cortex, the area in the back of the brain that is responsible for processing visual information, may result in impairments in visual perception and localization.⁵ A stroke that occurs in Broca’s area, a specific region on the left side of the brain that is responsible for speech production, can result in Broca’s aphasia, or an impairment to produce sounds and words.⁶ The effects of an ischemic stroke however are not limited to these specific disabilities, as other motor, cognitive, and psychiatric symptoms can arise depending on the location of the clot.

Several risk factors of ischemic stroke have already been identified which include smoking, high fat diets, high blood pressure, and alcohol use.⁷ Although modifying these lifestyle choices does reduce the probability of future stroke onset, they unfortunately are not a foolproof avenue to completely prevent stroke-related damage. Therefore, researchers and clinicians are actively developing novel therapeutics to rapidly mitigate permanent brain damage following the onset of an ischemic stroke. 

Ischemic Stroke Progression: From Vascular Occlusion to Neuronal Injury

The resulting brain atrophy from an ischemic stroke arises from a cascade of events that begin with the initial occlusion of a cerebral artery.⁸ The cessation of cerebral blood flow during an ischemic stroke can arise from two types of blockages: a thrombus and an embolus.⁹ A thrombus is defined as a blood clot that remains where it was initially formed. In the context of ischemic stroke, a thrombus forms and resides in a cerebral artery. An embolus, on the other hand, is a separated fragment of a blood clot that was originally formed in a different part of the body. During an ischemic stroke, a piece of a thrombus located in the heart or lungs can break away (embolus) and travel through the bloodstream to block circulation in a cerebral artery.⁹

The formation of either a thrombus or embolus arises primarily from atherosclerosis, or the formation of fibrofatty plaques along the arterial wall.¹⁰ These plaques, or aggregates, are made up of a combination of fats, lipids, and cholesterol that slowly build up in the endothelial layer of cerebral arteries. Over time, the accumulation of fibrofatty plaques diminish oxygen circulation and partially obstruct blood flow throughout the brain. If the plaque is large enough, it can often tear through the endothelium and enter the bloodstream, causing a cascade of events that result in blood clot formation and hemostasis, or a complete cessation of blood flow.¹⁰

How does this work exactly? Hemostasis is carried out through two phases: primary hemostasis, which involves platelet activation, and secondary hemostasis, which involves coagulation.¹¹ Primary hemostasis occurs immediately following the damage to the endothelial layer. Endothelial cells begin to secrete a protein known as von Willebrand factor (vWF) which binds to exposed collagen fibers that reside in the subendothelial matrix.¹² vWF secretion attracts nearby platelets, or small cell fragments that circulate in the blood, which express glycoprotein Ib (GPIb) receptors that recognize and bind to vWF. Once bound, platelets undergo a process of activation where their morphology transitions from a regular, discoid shape to an irregular shape with filapodial, or finger-like, extensions that cover the exposed area in the endothelium. Activated platelets also undergo two biochemical changes to attract surrounding inactive platelets. The first change is that the initially active platelets will secrete factors such as adenosine diphosphate (ADP), platelet-derived growth factor (PDGF), and vWF which aid in the activation and the recruitment of additional platelets. The second change is that activation will result in the expression of glycoprotein IIb/IIIa (GPIIb/IIIa) receptors on platelets which recognize a circulating protein called fibrinogen. Fibrinogen serves as a bridge to connect two active platelets, causing further aggregation and the formation of a platelet plug around the exposed endothelium.¹²

Secondary hemostasis involves coagulation, or the release of blood clotting factors, which aids in strengthening the platelet plug that formed prior.¹³ The first step in this cascade is the activation of an enzyme known as prothrombinase which resides on the extracellular surface of the activated platelet membrane. Prothrombinase is responsible for catalyzing and activating the blood clotting factor thrombin from its inactive precursor, prothrombin. Thrombin is also an enzyme which further converts fibrinogen into fibrin. Fibrin are insoluble protein monomers that can polymerize into a larger mesh-like structure that covers and secures the platelet plug, forming a stable blood clot to shut off blood flow (Figure 2).¹³

In order to effectively mitigate the aversive cascade of events that result in brain atrophy during an ischemic stroke, a new therapeutic was furthermore designed to target and dismantle the formation of blood clots in the brain – tenecteplase. 

Breaking Down Clots: How Tenecteplase Mitigates Ischemia

Prior to the development of therapeutics that directly target pre-existing blot clots, early pharmaceuticals, such as anticoagulants, antihypertensives, and antiplatelet agents, were commonly prescribed to decrease the risk of ischemia in later-life.¹⁴ While these therapeutics help to decrease stroke probability, their primary limitation is that they lack the specificity and function to break down blood clots if they may occur. In 1996, the FDA-approved therapeutic alteplase (tPA) revolutionized stroke prevention and care by providing clinicians with the ability to directly target blood clots after the onset of a stroke. As the first of its kind at the time, tPA is classified as a thrombolytic, or a drug that directly targets and dissolves pre-existing thrombi.¹⁵ Although tPA has accelerated the advancement in ischemic stroke care, it does however have one primary limitation: it is only effective if administered within a 4.5-hour period, AFTER the onset of the stroke.¹⁵ Therefore, this limited time window can disproportionately affect patients who lack quick and easy access to this care.

The latest FDA-approved thrombolytic, tenecteplase (TNK), works in a similar manner to tPA by breaking down pre-existing blood clots once the patient is experiencing an ischemic stroke.¹⁶ Tenecteplase dissolves clot formation by first binding to the polymerized fibrin mesh that surrounds the platelet plug.¹⁷ Tenecteplase’s enzymatic activity then catalyzes the conversion of plasminogen into plasmin. Plasmin is a proteolytic enzyme, meaning its function is to cleave and break down other proteins in the blood. What exactly does plasmin target? Fibrin. Plasmin therefore acts similarly to a pair of scissors that cut the fibrin mesh and allow the blood clot to dissolve and resume normal blood flow throughout the brain (Figure 3).¹⁷

Compared to alteplase (tPA), the standard thrombolytic that is used for ischemic stroke care, tenecteplase offers a few key advantages that make it unique. One, tenecteplase has a longer half-life, approximately 22 minutes, as opposed to alteplase which has a half-life of approximately 3.5 seconds.¹⁸ Tenecteplase’s sustained duration of treatment leads to its second advantage over alteplase such that it is easier and faster to administer in patients. In the clinics, alteplase is first administered as a single bolus, or a rapid and concentrated dose, followed by a one-hour intravenous (IV) infusion that is a slower route to fully incorporate the dose into the body. Because of the longer half-life, a dosage of tenecteplase is only administered through a single bolus over approximately 5-10 seconds, without the hour-long IV infusion.¹⁸ The simpler route of tenecteplase administration also allows clinicians to transport patients faster to secondary stroke care centers, thus saving time and mitigating further adverse effects of the ischemic stroke.

The third and final advantage of using tenecteplase is that it displays a higher specificity towards fibrin. Previous pharmacokinetic research furthermore has shown that tenecteplase has a binding affinity towards fibrin that is approximately 80-fold higher than alteplase.¹⁸ From a biological perspective, tenecteplase can be presumed as the superior thrombolytic based off its longer half-life, easy administration, and high target specificity. However, it is still necessary to evaluate tenecteplase from a clinical perspective to fully determine its potential therapeutic benefits towards alleviating behavioral impairments following an ischemic stroke. 

Comparing the Clinical Effects of Tenecteplase to the Standard Ischemic Stroke Care

The approval of tenecteplase by the Food and Drug Administration (FDA) was supported by the phase 3, randomized, noninferiority clinical trial titled “Alteplase Compared to Tenecteplase in Patients with Acute Ischemic Stroke” (AcT) which completed in April 2023 (Identifier: NCT03889249).¹⁹ Unlike a traditional clinical trial that determines the superiority of a drug over placebo, a noninferiority clinical trial tests whether a new therapeutic is just as good, if not better, than the standard care. These new therapeutics typically are a more ‘updated’ version of the standard care and often come with several advantages which could include lowered cost, simpler administration, or fewer side effects.²⁰ Furthermore, with the biological advantages of tenecteplase that were discussed previously, longer half-life, easier administration, and higher specificity, the goal of the AcT trial was to determine if tenecteplase could yield the same, positive clinical outcomes as alteplase but with some additional biological perks. 

Approximately 1600 patients enrolled in this study with the following criteria: 1) each participant experienced an ischemic stroke within 4.5 hours, and 2) a neurological deficit was diagnosed as a result of said stroke.¹⁹ Within that 4.5 hour time-window, patients were then randomized to receive either alteplase (90 mg total: 10% administered as a bolus, followed by the remaining 90% administered through a 60-minute infusion) or tenecteplase (25 mg total: single bolus over 10-20 seconds). The primary outcome was measured as the proportion of patients who achieve no disabilities 90-120 days following their respective dose. This was further measured through the modified Rankin Scale (mRS), where scores ranging from 0 to 6 indicate the severity of neurological disabilities following an ischemic stroke. Scores between 0 and 1 indicate no functional disabilities or symptoms. A score between 2 and 4 indicates moderate disabilities. A score of 5 denotes severe disabilities, while a 6 indicates death. Moreover, the patients who received an mRS score between 0 and 1 were included in the percentage of patients who displayed no disabilities following the 90–120-day trial period.¹⁹

The primary endpoint was met following the conclusion of the AcT trial.¹⁹ Approximately 36.9% of patients that received tenecteplase scored between 0 and 1 on the mRS, while this score was reported in 34.8% of patients who received alteplase. Post-hoc statistical analyses further showed that results met the prespecified noninferiority threshold, indicating that tenecteplase was noninferior to alteplase in ischemic stroke recovery. Safety analyses also showed a comparable percentage of treatment emergent adverse events (TEAEs) between groups, indicating that tenecteplase does not increase safety risks compared to the standard care. Furthermore, the AcT trial demonstrates that tenecteplase is a suitable alternative in the treatment of ischemic stroke with several key advantages when compared to alteplase.¹⁹

Beyond the AcT Trial: Examining the Treatment Efficacy of Telectenase Under Different Lenses

With the positive results of the AcT trial, follow-up clinical studies have supported the noninferiority of tenecteplase in treating ischemic strokes. For example, the ORIGINAL (Identifier: NCT04915729), TASTE (Identifier: ACTRN12613000243718), and TRACE-II (Identifier: NCT04797013) trials all used a similar experimental design as AcT, which compared the treatment effects of tenecteplase versus alteplase in patients who experienced an ischemic stroke within 4.5 hours of treatment.^21-23 The percentage of patients who scored 0-1 on the mRS was further used as the primary outcome measure in all three trials. Similar to the results of AcT, statistical analyses in ORIGINAL, TASTE, and TRACE-II all indicated that tenecteplase was noninferior in treating ischemic strokes within a 4.5-hour time window as compared to alteplase.^21-23

While tenecteplase shows positive treatment benefits when administered shortly after stroke onset, additional clinical trials aimed to determine if tenecteplase could prevent stroke-related disabilities if administered beyond a 4.5-hour time window. Unfortunately, this question is currently inconclusive as studies have shown both positive and negative results. For example, the TRACE-III trial (Identifier: NCT05141305) showed that 33% of patients who received tenecteplase 4.5 to 24 hours after stroke received a 0 to 1 mRS score during the 90 day follow-up visit. Compared to the 24.2% of participants who scored 0 to 1 after receiving a non-thrombolytic drug, the TRACE-III trial highlights that tenecteplase can significantly mitigate future stroke-related disabilities when administered in a later time window.²⁴ On the contrary, the TIMELESS clinical trial (Identifier: NCT03785678) indicated that a dose of tenecteplase given in the same time window did not significantly improve behavioral outcomes when compared to placebo.²⁵

Despite these results, tenecteplase still represents a promising alternative to the standard ischemic stroke care. While its therapeutic benefit when administered within a short time frame has been supported over multiple clinical trials, future studies are needed to confirm if tenecteplase is suitable in preventing behavioral disabilities when given in an extended time window after stroke onset. Due to its key advantages over alteplase that include an extended half-life, easier administration, and greater target specificity, tenecteplase offers clinicians and healthcare providers an avenue to ensure superior efficiency in mitigating the debilitating effects of ischemic stroke.

References

1.      Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association. Circulation. 2023;147(8):e93-e621.

2.      Feigin VL, Brainin M, Norrving B, et al. World Stroke Organization: Global Stroke Fact Sheet 2025. Int J Stroke. 2025;20(2):132-144.

3.      Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of Ischemic and Hemorrhagic Stroke: Incidence, Prevalence, Mortality, and Risk Factors. Neurol Clin. 2008;26(4):871-895.

4.      Ferriero DM. Protecting Neurons. Epilepsia. 2005;46(s7):45-51.

5.      Lawlor M, Perry R, Hunt BJ, Plant GT. Strokes and vision: The management of ischemic arterial disease affecting the retina and occipital lobe. Surv Ophthalmol. 2015;60(4):296-309.

6.      Ochfeld E, Newhart M, Molitoris J, et al. Ischemia in broca area is associated with broca aphasia more reliably in acute than in chronic stroke. Stroke. 2010;41(2):325-330.

7.      Sacco RL. Risk factors, outcomes, and stroke subtypes for ischemic stroke. Neurology. 1997;49(5_suppl_4):S39-S44.

8.      Endres M, Dirnagl U, Moskowitz MA. Chapter 2 The ischemic cascade and mediators of ischemic injury. In: Handbook of Clinical Neurology. Vol 92. Elsevier; 2008:31-41.

9.      Chernysh IN, Nagaswami C, Kosolapova S, et al. The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli. Sci Rep. 2020;10(1):5112.

10.    Libby P, Buring JE, Badimon L, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5(1):56.

11.    Hiller E. Basic principles of hemostasis. In: Modern Hematology: Biology and Clinical Management. Springer; 2007:327-345.

12.    Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Platelets at work in primary hemostasis. Blood Rev. 2011;25(4):155-167.

13.    Revel-Vilk S, Rand ML, Israels SJ. Primary and secondary hemostasis, regulators of coagulation, and fibrinolysis: Understanding the basics. SickKids Handbook of Pediatric Thrombosis and Hemostasis 2nd ed, Basel: Karger. 2017:8-16.

14.    Bansal S, Sangha KS, Khatri P. Drug Treatment of Acute Ischemic Stroke. Am J Cardiovasc Drugs. 2013;13(1):57-69.

15.    Grotta JC. Fifty Years of Acute Ischemic Stroke Treatment: A Personal History. Cerebrovasc Dis. 2021;50(6):666-680.

16.    Loscalzo J. An overview of thrombolytic agents. Chest. 1990;97(4):117S-123S.

17.    Davydov L, Cheng JW. Tenecteplase: a review. Clin Ther. 2001;23(7):982-997.

18.    Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet. 2002;41:1229-1245.

19.    Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400(10347):161-169.

20.    Althunian TA, de Boer A, Groenwold RH, Klungel OH. Defining the noninferiority margin and analysing noninferiority: an overview. Br J Clin Pharmacol. 2017;83(8):1636-1642.

21.    Wang Y, Li S, Pan Y, et al. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial. Lancet. 2023;401(10377):645-654.

22.    Parsons MW, Yogendrakumar V, Churilov L, et al. Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4· 5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial. Lancet Neurol. 2024;23(8):775-786.

23.    Meng X, Li S, Dai H, et al. Tenecteplase vs alteplase for patients with acute ischemic stroke: the original randomized clinical trial. JAMA. 2024;332(17):1437-1445.

24.    Xiong Y, Campbell BCV, Schwamm LH, et al. Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy. N Engl J Med. 2024;391(3):203-212.

25.    Albers GW, Jumaa M, Purdon B, et al. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. N Engl J Med. 2024;390(8):701-711.

Author: Maya Bluitt
Editor: Kéita Yokoyama

The U.S. Food and Drug Administration recently approved a first-in-class medication for the treatment of classic congenital adrenal hyperplasia (CAH).¹ Crenessity (crinecerfont), developed by Neurocrine Biosciences, acts to control adrenal androgens and revolutionizes treatment for adults and children over age 4 living with classic CAH. 

Classic congenital adrenal hyperplasia (CAH)

CAH is a group of rare autosomal recessive disorders affecting the adrenal glands, an organ that produces hormones such as cortisol, aldosterone, and androgens. Classic CAH is the most common form, accounting for approximately 95% of all CAH cases.^2,3 It is primarily characterized by a deficiency of cortisol, a hormone involved in the body’s responses to stress or illness, and an overproduction of androgens, a class of sex hormones required for the development of sexual characteristics and reproductive function.^2,3,4 Aldosterone, a hormone that regulates blood pressure by controlling the concentration of salts in bodily fluids, is additionally deficient in approximately 75% of cases.^2,6

Classic CAH is caused by a mutation in the gene CYP21A2, which encodes the enzyme 21-hydroxylase (21OH).^2,7,14 This enzyme is critical for the adrenal glands to produce cortisol. When 21-hydroxylase is deficient, as it is in classic CAH, cortisol is not properly synthesized, leading to decreased cortisol levels and an accumulation of cortisol precursors (e.g., 17-hydroxyprogesterone (17OHP), which is often used as a biomarker for diagnosing classic CAH).^7,8 In an attempt to regain homeostasis, the adrenal glands are chronically overstimulated; as they are unable to make cortisol, the cortisol precursors are diverted toward the androgen synthesis pathway, ultimately resulting in the overproduction of the androgens androstenedione, testosterone, and dihydrotestosterone. 

The mechanisms that drive these changes are complex and involve the hypothalamic-pituitary-adrenal (HPA) axis.^3,6,9 The HPA axis coordinates bodily responses during basal and stress states. First, the hypothalamus secretes corticotropin-releasing factor (CRF) in response to stress or circadian signals. Then, CRF (in concert with arginine vasopressin, a blood pressure-regulating hormone) stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland, which subsequently drives cortisol production from the adrenal glands. Under normal conditions, adequate cortisol levels in the body act as a negative feedback signal to the HPA axis to suppress any further CRF and ACTH release. In classic CAH, however, cortisol levels are not sufficient to inhibit the HPA axis, leading to increased secretion of CRF and ACTH.^6,10,11 Elevated ACTH levels then drive the adrenal glands to produce excess androgens.

The severity of classic CAH depends on the specific gene mutation type and subsequent extent of 21-hydroxylase deficiency.⁷ Symptoms of classic CAH may reflect low levels of cortisol and aldosterone (e.g., low appetite, nausea, dizziness, fatigue).^3,4 Individuals with classic CAH are also at high risk to experience adrenal crisis, a life-threatening episode of severe cortisol deficiency. Excess androgen production can result in atypical genital development in females, and in both sexes, it can disrupt pubertal development in children and lead to fertility problems in adulthood. Those affected with CAH also experience accelerated growth during childhood, resulting in reduced height in adulthood.¹²

Conventional clinical management of classic CAH

Preventing virilization (the development of male secondary sex characteristics; e.g., facial and body hair) and/or adrenal crisis are primary treatment concerns for children with classic CAH.^2,5 In addition to this, the standard of care for both children and adults has traditionally sought to decrease androgen levels and replace cortisol and aldosterone.^{3,4,6,7,11,12} This is typically achieved by administering glucocorticoids (e.g., hydrocortisone, prednisone, dexamethasone) to replace cortisol and reduce ACTH (and thus androgens) and/or mineralocorticoids (e.g., fludrocortisone) to replace aldosterone.^3,6,11

However, several concerns exist for these treatment regimens. First, the optimal dose size and timing falls within a narrow window, making classic CAH easy to overtreat or undertreat.⁶ Indeed, the amount of glucocorticoids taken in replacement therapy typically surpasses the levels of what is generally found in the body.^3,7 Moreover, dose timing is often nonphysiologic (e.g., evening dosing to suppress peak ACTH secretion, which occurs overnight).⁷ While high-dose glucocorticoid regimens are effective at reducing excess androgen, their prolonged use is associated with adverse effects like growth suppression in children and osteoporosis, as well as metabolic-related symptoms like weight gain/obesity, hypertension, and increased cardiovascular risk.^6,7,11

A revolutionary treatment approach for classic CAH

Crinecerfront is the first new treatment developed for classic CAH in 70 years.¹³ It is a corticotropin-releasing factor type 1 receptor (CRF1) antagonist that is suspected to lead to the reduction in androstenedione (one of the androgen types that is overproduced in classic CAH).^13,15 It is the first CRF1 antagonist successfully used in the clinic for treatment of a genetic disorder.⁶ CRF1 antagonism decreases secretion of ACTH from the pituitary gland, which leads to decreased androgen production downstream.¹¹ This approach thus allows for glucocorticoid treatment to be administered at physiological doses so that their negative side effects can be minimized. 

Clinical trials demonstrated promising efficacy of crinecerfont in mitigating excess androgen production in classic CAH. In a phase 2 study in adolescents aged 14-17 years, 14 days of oral crinecerfont (in addition to participants’ existing glucocorticoid treatment regimens) produced notable reductions in adrenal androgens and androgen precursors (median percent reduction from baseline: ACTH, 57%; 17OHP, 69%, androstenedione, 58%).¹⁰ Another phase 2 study in adults aged 18-50 years found similar decreases (ACTH, 66%; 17OHP, 64%; androstenedione, 64%) following 14 days of crinecerfont treatment.¹¹ Both studies also report significant reductions in testosterone levels in female patients and a decreased ratio of androstenedione to testosterone in males, making crinecerfont the first non-glucocorticoid treatment to affect these hormones over 14 days of treatment. 

A phase 3, randomized, double-blind study further demonstrated that crinecerfont allows for the reduction of glucocorticoid doses while maintaining androstenedione levels (≤120% of baseline). In this trial, 24 weeks of crinecerfont led to a 27% reduction in the daily glucocorticoid dose required for adults compared to a 10% reduction in the placebo group.¹⁴ This reduction resulted in a physiologically appropriate dose of glucocorticoid treatment in 63% of patients treated with crinecerfont compared to 18% of patients in the placebo group. Adverse events were similar between the crinecerfont and placebo groups, with fatigue (25% in both experimental groups) and headache (16% in crinecerfont and 15% in placebo) being the most common. Crinecerfont also appears to be sufficient in lowering the glucocorticoid dose required for children. A separate phase 3 study in children aged 2-17 years observed an 18% decrease in daily glucocorticoid dose following 28 weeks of crinecerfont treatment compared to a 5.6% increase with placebo.¹⁵ However, more research is needed to determine if crinecerfont is able to mitigate the effects of long-term high-dose glucocorticoid exposure. 

The future of CRF1 antagonists

Beyond their use for classic CAH, CRF1 antagonists have been posited as potential effective therapeutics for a number of conditions, such as anxiety disorders, depression, insomnia, irritable bowel syndrome, narcotic withdrawal, and premature labor.^9,17,18 Increasing evidence for the role of CRF in brain stress systems have made them particularly compelling targets for psychiatric conditions. Despite this, most clinical trials have failed to demonstrate CRF1 antagonists as effective treatments for anxiety and depression, due to a combination of pharmacokinetic challenges, biological complexity, and patient heterogeneity.^16,18 

The interest in using CRF1 antagonism in treating psychiatric conditions also underscores an important limitation of its therapeutic potential – CRF has vast functions outside of its role in the HPA axis. It acts as a neuromodulator within the central nervous system and has peripheral proinflammatory and anti-reproductive effects.⁹ The potential effects of CRF1 antagonism will thus likely affect multiple organs and systems. However, the development of novel CRF1 antagonists with increased selectivity, such as CRF1-preferring peptide antagonists, may allow for increased therapeutic precision.¹⁷ Encouragingly, agents like crinecerfont demonstrate the feasibility of harnessing CRF pathways to offer substantial clinical benefit with an acceptable safety profile. As our understanding of CRF signaling deepens, these compounds may help usher in a new era of mechanism-based treatments for endocrine and stress-related disorders.

References 

1. U.S. Food and Drug Administration. FDA Approves New Treatment for Congenital Adrenal Hyperplasia. December 13, 2024. Accessed April 8, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-congenital-adrenal-hyperplasia

2. White PC, Bachega TASS. Congenital Adrenal Hyperplasia Due to 21 Hydroxylase Deficiency: From Birth to Adulthood. Semin Reprod Med. 2012;30:400-409. doi:10.1055/s-0032-1324724

3. Bancos I, Kim H, Cheng H, et al. Glucocorticoid therapy in classic congenital adrenal hyperplasia: traditional and new treatment paradigms. Expert Rev Endocrinol Metab. 2025;20(1):33-49. doi:10.1080/17446651.2025.2450423

4. Dinparastisaleh R. Congenital Adrenal Hyperplasia. November 9, 2021. Accessed April 7, 2025. https://www.hopkinsmedicine.org/health/conditions-and-diseases/congenital-adrenal-hyperplasia

5. Gomes LG, Bachega TASS, Mendonca BB. Classic congenital adrenal hyperplasia and its impact on reproduction. Fertil Steril. 2019;111(1):7-12. doi:10.1016/j.fertnstert.2018.11.037

6. Chrousos GP. Crinecerfont in a First Clinical Application of a CRH Antagonist: Further Potential Uses Are Still an Open Chapter! J Clin Endocrinol Metab. 2024;109(4):e1365-e1366. doi:10.1210/clinem/dgad513

7. Dreves B, Reznik Y, Tabarin A. Congenital adrenal hyperplasia: New biomarkers and adult treatments. Ann Endocrinol (Paris). 2023;84(4):472-480. doi:10.1016/j.ando.2023.01.008

8. Cleto AS, Schirlo JM, Machozeki J, Martins CM. Efficacy and safety of crinecerfont for the treatment of congenital adrenal hyperplasia. Eur J Intern Med. Published online March 25, 2025. doi:10.1016/j.ejim.2025.03.021

9. Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol Metab. 2002;13(10):436-444. doi:10.1016/s1043-2760(02)00670-7

10. Newfield RS, Sarafoglou K, Fechner PY, et al. Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2023;108(11):2871-2878. doi:10.1210/clinem/dgad270

11. Auchus RJ, Sarafoglou K, Fechner PY, et al. Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2022;107(3):801-812. doi:10.1210/clinem/dgab749

12. Turcu AF, Auchus RJ. Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia. Endocrinol Metab Clin North Am. 2015;44(2):275-296. doi:10.1016/j.ecl.2015.02.002

13. PR Newswire. Neurocrine Biosciences Announces FDA Approval of CRENESSITY^TM (crinecerfont), a First-in-Class Treatment for Children and Adults With Classic Congenital Adrenal Hyperplasia. December 13, 2024. Accessed April 7, 2025. https://www.prnewswire.com/news-releases/neurocrine-biosciences-announces-fda-approval-of-crenessity-crinecerfont-a-first-in-class-treatment-for-children-and-adults-with-classic-congenital-adrenal-hyperplasia-302331772.html

14. Auchus RJ, Hamidi O, Pivonello R, et al. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. 2024;391(6):504-514. doi:10.1056/NEJMoa2404656

15. Sarafoglou K, Kim MS, Lodish M, et al. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med. 2024;391(6):493-503. doi:10.1056/NEJMoa2404655

16. Shaham Y, de Wit H. Lost in Translation: CRF1 Receptor Antagonists and Addiction Treatment. Neuropsychopharmacology. 2016;41(12):2795-2797. doi:10.1038/npp.2016.94

17. Zorrilla EP, Koob GF. Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today. 2010;15(9-10):371-383. doi:10.1016/j.drudis.2010.02.011

18. Spierling SR, Zorrilla EP. Don’t stress about CRF: assessing the translational failures of CRF1 antagonists. Psychopharmacology (Berl). 2017;234:1467-1481. doi:10.1007/s00213-017-4556-2