Nancy Reau, MD, is Professor of Internal Medicine, Richard B. Capps Chair of Hepatology, Associate Director of Solid Organ Transplantation, and Section Chief of Hepatology at Rush University Medical Center.

This Year in Medicine episode of Liver Lineup focused on breakthrough in cholestatic liver disease

Liver Lineup: Breakthroughs in Cholestatic Liver Disease in 2025

As the calendar turns to 2026, cholestatic liver disease is among the most active and rapidly evolving areas in 

, hosts Nancy Reau, MD, and Kimberly Brown, MD, break down the most consequential updates of the year across 

primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC)

, and autoimmune hepatitis (AIH), highlighting data that may reshape both near-term management and longer-term treatment strategies.

A major theme was the persistent underutilization of second-line therapy in PBC. Despite well-established criteria for inadequate biochemical response to ursodeoxycholic acid, real-world data continue to demonstrate many eligible patients are not escalated to additional treatment.

Reau emphasizes newer FDA-approved PPAR agonists have expanded options for patients, removing prior safety barriers that limited use of older agents in advanced disease. As treatment goals evolve toward deeper biochemical response, the hosts say closing this implementation gap remains a critical educational priority.

Additionally, interim results from extension studies for elafibranor and seladelpar indicate sustained alkaline phosphatase and bilirubin response over several years, suggesting improvements rather than late loss of efficacy. While liver stiffness measurements showed stability rather than dramatic regression, other fibrosis-related biomarkers highlight potential antifibrotic benefits with longer follow-up. Brown noted that in chronic liver disease, stabilization itself may meaningfully translate into improved long-term outcomes.

Across multiple studies, PPAR agonists showed sustained reductions in pruritus and fatigue, 2 of the most burdensome symptoms in PBC. Of note, improvements in fatigue appeared independent of pruritus relief or biochemical response, reinforcing the concept that symptom burden does not always mirror disease severity. The discussion raised the possibility that symptom-driven treatment strategies may eventually play a larger role, even if they are not yet reflected in guidelines.

Beyond PBC, Reau and Brown note that emerging therapies for PSC have generated cautious optimism. Phase 2 data for elafribanor demonstrated rapid and sustained reductions in alkaline phosphatase, alongside improvements in itch and fibrosis-related markers.

Although PSC’s heterogeneity complicates the interpretation of surrogate endpoints, Reau highlights the significance of seeing consistent biochemical signals in a disease long defined by therapeutic nihilism. Additional early-stage data targeting inflammatory chemokine pathways with nebokitug further underscored growing interest in mechanism-driven approaches for PSC, even if clinical applicability remains distant.

The conversation then transitioned to autoimmune hepatitis, where treatment options have remained largely unchanged for decades. A novel immunomodulatory agent, zetomipzomib, demonstrated steroid-free biochemical remission in a subset of patients with refractory disease.

Both hosts emphasize the unmet need among patients who cannot be adequately controlled with steroids and antimetabolites and suffer the long-term consequences of chronic corticosteroid exposure.

Collectively, advances in 2025 reflect a cholestasis landscape in transition: durable second-line therapies in PBC, early momentum in PSC, and the first glimmers of innovation in AIH. As Reau and Brown underscore, the challenge now lies not only in advancing the pipeline, but in translating progress into routine clinical practice.

Editors’ note: Relevant Disclosures for 

 include AbbVie, Gilead, Salix, Arbutus, and VIR. Relevant disclosures for 

 include Mallinckrodt Pharmaceuticals, Gilead, Salix, Intercept, Ipsen, and Madrigal.

Cuoto C, Cancado G, Ferraz ML, et al. TREATMENT OUTCOMES AND UNDERUTILIZATION OF SECOND-LINE THERAPIES FOR PRIMARY BILIARY CHOLANGITIS IN LATIN AMERICA: A CALL TO BRIDGE THE GAP. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Levy C, Akarca U, Alvares-da-Silva MR, et al. Long-term treatment with elafibranor leads to biochemical and symptomatic improvements for at least 3 years in patients with primary biliary cholangitis. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Pratt D, Lawitz EJ, Bowlus CL, et al. Seladelpar Is Associated With a Sustained Reduction in Cholestatic Markers and a Consistent Safety Profile in Patients With Primary Biliary Cholangitis Treated up to 48 Months in the Ongoing, Open-Label ASSURE Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Bowlus CL, Levy C, Abouda G, et al. Long-term data of elafibranor in primary sclerosing cholangitis: Interim safety and efficacy data from the ongoing open-label extension of the ELMWOOD phase II trial. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Bowlus CL, Barclay S, Joshi D, et al. Safety and activity of nebokitug over 48 weeks in patients with primary sclerosing cholangitis: Open-label extension results from the SPRING Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Kremer A, Jones D, Levy C, et al. Changes in fatigue and pruritus in patients with primary biliary cholangitis treated with elafibranor are largely independent from improvements in serum biomarkers. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Lammert C, Anand N, Bade D, et al. Zetomipzomib, a First-in-Class Selective Immunoproteasome Inhibitor, Demonstrates Steroid Sparing Biochemical Remission in Patients with Relapsed or Insufficiently Responding Autoimmune Hepatitis in a Randomized, Double-blind, Placebo-controlled, Phase 2a Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Podcasts

This episode spotlights how advancements in 2025, including data from AASLD 2025, set the stage for future standards of care in cholestatic liver disease. 

News

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Cholangitis

cholangitis page, resources on the topics of medical news and expert insight into cholangitis can be found. Content includes articles, interviews, videos, podcasts, and breaking news on research, treatment, and drug development in PBC, PSC, and more!

Hepatology

Liver Lineup: Updates & Unfiltered Insights

Introducing Liver Lineup: Updates & Unfiltered Insights — an exciting new podcast delivering timely, candid perspectives on the most pressing topics in the fast-moving world of hepatology. Created by Nancy Reau, MD, and Kimberly Brown, MD, and hosted by HCPLive, this series dives into the cutting edge of liver disease research, clinical care, and real-world practice.

podcasts page features a feed of medical news and interview podcast series, including DocTalk, Lungcast, Derm Discussions, and Heart Trials.

This Year In Medicine

Tim Smith joined the MJH Life Sciences team in 2022 and is currently an associate editor for HCPLive. He is also the executive producer of two podcasts: Skin of Color Savvy and The Medical Sisterhood. Previously, he was the producer of the Lungcast podcast. He graduated from UC Berkeley and worked in multimedia journalism as a staff writer prior to joining MJH. You can contact him at tsmith@mjhlifesciences.com.

A generalized set of patient-reported outcomes measures known as the Patient-Reported Outcomes Measurement Information System (PROMIS) has been validated for evaluating the impacts of 

PROMIS was evaluated in a recent analysis for which the corresponding author was John S. Barbieri, MD, MBA, from the Department of Dermatology at Brigham and Women’s Hospital. Barbieri et al noted the potential integration of this set of patient-reported outcome measures (PROMs) into the dermatologic clinic setting. Nonetheless, prior to this study, the measurement properties of these PROMs among individuals with various chronic skin diseases had not yet been established.

“...[There] have been limited studies on the validity of these measures among patients with chronic skin diseases,” the investigative team wrote.

 “...[We] aimed to investigate the measurement properties of PROMIS measures among a cohort of US adults with a range of chronic skin diseases.”

Barbieri and colleagues set out to evaluate multiple psychometric properties of the PROMIS short-form instruments, including the measures' construct validity, structural validity, internal consistency, and responsiveness, for domains of anxiety, social satisfaction, depression, and social isolation. Additionally, the investigative team assessed the construct validity and responsiveness of single-item measures evaluating both pain and pruritus intensity among patients with various skin diseases.

Those taking part were recruited through Prolific, an online research recruitment platform, for this cohort analysis. Those deemed eligible were adults in the age range of 18 years or older, residents of the US, and those who reported having at least a single chronic dermatologic condition. Such skin diseases included:

Additionally, patients involved in Barbieri and coauthors' analysis might have a condition such as the following autoimmune connective tissue disorders:

They could also have reported a blistering diseases including the following:

Pemphigus vulgaris and bullous pemphigoid

Those involved as participants in Barbieri et al's study self-identified their ancestral, racial, or ethnic background via a questionnaire. The survey included a separate item used to determine whether subjects of the study identified as Hispanic or Latino/a/x. Those involved would then fill out a baseline survey that included PROMIS instruments and additional relevant outcome measures between February 5 and February 7, 2025. The investigative team also carried out a follow-up evaluation approximately 3 months later. The team's survey was available from April 30 - May 29. Data collection encompassed PROMIS measures, Skindex-29, the Dermatology Life Quality Index, a patient global assessment at baseline, and a follow-up anchor inquiry looking at any perceived shifts in participants' skin condition status.

The investigators highlighted structural validity, internal consistency, construct validity, and responsiveness for the PROMIS short-form measures. Both construct validity and responsiveness were specifically evaluated for the single-item pain and itch intensity measures. In their final analytic sample, the team included 549 adults with chronic skin diseases, with 52.3% being listed as women and 47.7% as men. There was a median age of 36 years among the subjects. Acne was noted by 44.8% of participants, atopic dermatitis by 45.1%, and psoriasis by 20.6%.

In Barbieri and colleagues' psychometric assessment, their findings suggested  anxiety, social satisfaction, depression, and social isolation PROMIS short forms met the study's criteria for adequate structural validity.

 They noted comparative fit index and/or Tucker-Lewis index values exceeding .95 and standardized root mean residual values below .08. The PROMIS instruments also demonstrated strong internal consistency, which the investigators noted was reflected by Cronbach α values greater than .90.

The construct validity was shown by the investigators to have been supported across all measures through known-groups comparisons as well as convergent validity analyses.

 These included Pearson correlation coefficients of .30 or higher between measures which evaluated related constructs. In looking at responsiveness, Barbieri and coauthors' standardized response mean analyses suggested the single-item pain measure (SRM, .41) as well as intensity of pruritus measures (SRM range, .32–.44) showed responsiveness comparable to the Skindex-29 symptoms domain (SRM, .47).

In a similar conclusion, the investigative team highlighted social isolation (SRM, .27) and social satisfaction (SRM, −.20) PROMIS measures were shown to be similarly responsive to those observed for the Skindex-29 functioning domain (SRM, .25).

 Conversely, Barbieri et al found responsiveness for the measures of anxiety (SRM, .11) and depression (SRM, .16) was below that of the Skindex-29 emotions domain, which had an SRM of .43.

“Our study demonstrates the good measurement properties of a novel profile of PROMIS instruments for capturing the physical, emotional, and social effects of chronic skin diseases,” they concluded.

 “Further research is needed to confirm the generalizability of our findings.”

Nock MR, Ershadi S, Sánchez-Feliciano A, et al. Measurement Properties of PROMIS Measures Relevant to Chronic Skin Diseases. JAMA Dermatol. Published online December 23, 2025. 

Terwee CB. The Value of Item Banks, CAT, and PROMIS for Dermatology. J Invest Dermatol. 2020 May;140(5):1089-1091. 

Esaa F, Prezzano J, Ryan Wolf J, et al. The utility of PROMIS domain measures in dermatologic care. Arch Dermatol Res. 2021 Jan;313(1):17-24. 

Articles

The Patient-Reported Outcomes Measurement Information System (PROMIS) has been validated for assessing chronic skin diseases, demonstrating strong psychometric properties. The study, led by John S. Barbieri, evaluated PROMIS short-form instruments for anxiety, social satisfaction, depression, and social isolation, showing adequate structural validity and internal consistency. The research involved 549 adults with various chronic skin conditions, revealing that PROMIS measures are comparable to existing tools like Skindex-29. However, further research is needed to confirm the generalizability of these findings across broader populations.

Investigators explored the measurement properties of the Patient-Reported Outcomes Measurement Information System (PROMIS) among patients with chronic skin disease.

Plaque Psoriasis

The HCPLive plaque psoriasis page is a resource for medical news and expert insights on psoriasis. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments for psoriatic disease, and more.

PROMIS Outcome Measures Effective for Evaluating Chronic Skin Disease

Ryan Livingston joined the MJH Life Sciences team in March of 2025, shortly after graduating from TCNJ with a bachelor’s degree in English. He enjoys creative writing, reading, and scuba diving. He can be reached at rlivingston@mjhlifesciences.com.

Image Credit: US Food and Drug Administration

Announced by Outlook Therapeutics on December 31, 2025, the 

 has issued a Complete Response Letter (CRL) to ONS-5010 for the treatment of 

wet age-related macular degeneration (AMD)

In the CRL, the FDA determined that the additional mechanistic and natural history data provided in the resubmission failed to alter the previous review conclusion, which stated that confirmatory evidence of efficacy must be submitted to support the application. According to the release, the FDA has not yet indicated what type of confirmatory evidence would be acceptable.

"We are disappointed and disagree with this decision, but we remain fully committed to taking all necessary steps to receive approval in the United States," Bob Jahr, chief executive officer of Outlook Therapeutics, said in a statement. "We continue to believe strongly in the clinical need and commercial potential of the first on-label bevacizumab product for patients in the United States that is specifically formulated, manufactured, and packaged for intravitreal use."

ONS-5010 is an ophthalmic formulation of bevacizumab for the treatment of wet AMD. Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to all isoforms of human vascular endothelial growth factor (VEGF) with high affinity, neutralizing VEGF’s biologic activity through a steric blocking of its binding to its receptors on endothelial cells. This reduces endothelial cell proliferation, vascular leakage, and new blood vessel formation in the retina.

ONS-5010 has previously received regulatory approval in the European Union and the United Kingdom in 2024 for the first authorized use of an ophthalmic formulation of bevacizumab for the treatment of wet AMD.

ONS-5010 has had a long regulatory road in the US, having received a Complete Response Letter from the FDA in August of 2023 after their first Biologics License Application (BLA). At the time, despite the pivotal NORSE TWO trial achieving its safety and efficacy endpoints, the FDA concluded it was unable to approve the BLA on account of several Chemistry Manufacturing and Controls (CMC) issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.

On April 8, 2025, Outlook Therapeutics announced the FDA’s acceptance of a new BLA, which allows ONS-5010 – under the brand name LYTENAVA – 12 years of regulatory exclusivity after regulatory approval. This resubmission was based on the NORSE EIGHT trial results, as well as the additional CMC data requested by the FDA.

On August 28, 2025, however, the FDA issued another CRL, citing a lack of substantial evidence of effectiveness. Outlook Therapeutics conducted a Type A meeting, after which a third BLA was submitted on November 3, 2025. The submission contains the same data from NORSE TWO and NORSE EIGHT, as well as a response to the CRL crafted from the official minutes of the Type A meeting.

NORSE EIGHT was a randomized, controlled, parallel group, masked, non-inferiority study investigating the difference in best-corrected visual acuity (BCVA) and retinal thickness between ONS-5010 and ranibizumab. After analysis, investigators announced on January 16, 2025, that ONS-5010 demonstrated noninferiority to ranibizumab at week 12.

ONS-5010 did not, however, meet its primary non-inferiority endpoint by week 8, as suggested in the special protocol assessment with the FDA. Investigators did note the consistent BCVA improvement across all time points, the generally good tolerability, and the safety and efficacy results compared to NORSE ONE, NORSE TWO, and NORSE THREE.

According to the press release, Outlook Therapeutics continues to explore all available pathways for approval while expanding into additional markets in Europe, where it has already received several regulatory approvals.

"Our goal has always been to provide wet AMD patients and their physicians with a safe, consistent, FDA-approved alternative to compounded Avastin manufactured in the United States, and that goal has not changed," Jahr said.

Outlook Therapeutics. Outlook Therapeutics Provides Regulatory Update on US Food and Drug Administration Review of ONS-5010/LYTENAVA (bevacizumab-vikg) for the Treatment of Wet AMD. December 31, 2025. Accessed December 31, 2025.

 https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-provides-regulatory-update-us-food-and-0

Outlook Therapeutics. Outlook Therapeutics Announces Acceptance of Biologics License Application by US FDA for ONS-5010 as a Treatment for Wet AMD. November 13, 2025. Accessed December 24, 2025. 

https://ir.oncobiologics.com/news-releases/news-release-details/outlook-therapeutics-announces-acceptance-biologics-license

Outlook Therapeutics. Outlook Therapeutics Announces Acceptance of Biologics License Application by U.S. FDA for ONS-5010 as a Treatment for Wet AMD. April 8, 2025. Accessed December 24, 2025. 

https://ir.oncobiologics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-acceptance-biologics-license-0

Campbell P. FDA Issues CRL for Ophthalmic Bevacizumab in Wet AMD. 

. August 30, 2023. Accessed December 24, 2025. 

https://www.hcplive.com/view/fda-issues-crl-for-ophthalmic-bevacizumab-in-wet-amd

Outlook Therapeutics. Outlook Therapeutics Re-Submits Biologics License Application for ONS-5010. November 3, 2025. Accessed December 24, 2025. 

https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-re-submits-biologics-license-application

Harp M. Outlook Therapeutics completes analysis of 12-week safety and efficacy results of NORSE EIGHT. 

 January 16, 2025. Accessed December 24, 2025. 

https://www.ophthalmologytimes.com/view/outlook-therapeutics-completes-analysis-of-12-week-safety-and-efficacy-results-of-norse-eight

The FDA issued a Complete Response Letter to Outlook Therapeutics for ONS-5010, a bevacizumab formulation for wet AMD, citing insufficient confirmatory evidence of efficacy. Despite previous regulatory approvals in Europe, the US approval process has faced challenges, including Chemistry Manufacturing and Controls issues and unmet efficacy endpoints. The NORSE EIGHT trial showed non-inferiority to ranibizumab at week 12 but not at week 8. Outlook Therapeutics remains committed to pursuing US approval and expanding in European markets, emphasizing the clinical need for an FDA-approved alternative to compounded Avastin.

The CRL notes that additional mechanistic and natural history data have not altered the previous review conclusions.

FDA News

Ophthalmology

Ophthalmology page, resources on the topics of medical news and expert insight into ophthalmic disease can be found. Content includes articles, interviews, videos, podcasts, and breaking news on eye disease research, treatment, and drug development.

Age-Related Macular Degeneration

age-related macular degeneration condition center page is a comprehensive resource for clinical news and insights on retina disease. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for patients with AMD.

FDA Issues Complete Response Letter for ONS-5010 for Wet AMD

Announced by Axsome Therapeutics, Inc., on December 31, 2025, the 

 has accepted – and granted Priority Review to – the supplemental New Drug Application (sNDA) for AXS-05 for the treatment of agitation in 

“Up to 76% of people with Alzheimer’s disease experience agitation, representing a significant unmet medical need for patients and their caregivers, and currently there is a dearth of approved treatments,” Herriot Tabuteau, MD, chief executive officer of Axsome Therapeutics, said in a statement. “We look forward to continuing to work with the FDA for the remainder of the review.”

AXS-05 is a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor under development for Alzheimer’s disease and smoking cessation. The medication utilizes a proprietary dextromethorphan and bupropion formulation and dose, along with Axsome’s metabolic inhibition technology, to modulate component delivery. It has already received FDA approval for major depressive disorder in adults.

The sNDA was submitted following positive results from a series of phase 3 clinical trials, including ACCORD/ACCORD-2 and ADVANCE-2. ACCORD was a double-blind, multi-center, randomized-controlled trial consisting of a 9-week open-label period followed by a 26-week double-blind period. A total of 178 participants with a mean Cohen Mansfield Agitation Inventory (CMAI) baseline total score of 70.9 were enrolled in the open-label phase and were treated with AXS-05. During this phase, AXS-05 treatment was associated with improvements from baseline in CMAI scores at all timepoints from Week 1 (6.7 points; 

A total of 108 responders, defined as those with ≥30% improvement from baseline in CMAI total score and with Patient Global Impression of Change (PGI-C) score improvements ≤3 lasting ≥4 consecutive weeks, were then randomly assigned in a 1:1 ratio to either AXS-05 (n = 53) or placebo (n = 55). During the second phase, AXS-05 delayed time to relapse of agitation symptoms compared to placebo (HR, 0.276; 

 = .014), representing a 3.6-fold lower risk. It also displayed improved relapse prevention (7.5%) compared to placebo (25.9%; 

ADVANCE-2 was a multi-center, double-blind, placebo-controlled, randomized study investigating AXS-05's safety and efficacy compared to placebo. Investigators enrolled patients with a diagnosis of probable Alzheimer’s disease based on the 2011 National Institute on Aging-Alzheimer Association (NIA-AA) criteria and a diagnosis of clinically significant agitation resulting from probable Alzheimer’s disease according to the International Psychogeriatric Association (IPA) provisional definition of agitation. Patients who had dementia of a non-Alzheimer’s type were excluded.

Ultimately, a total of 408 patients were enrolled and randomly assigned in a 1:1 ratio to either AXS-05 or placebo for ≤5 weeks, both in the form of tablets taken twice daily. During the trial, AXS-05 failed to demonstrate statistical significance in changing the CMAI total score from baseline to Week 5 (AXS-05, 13.8 points; placebo, 12.6 points). However, the results from this endpoint did numerically favor AXS-05.

AXS-05 was safe and well-tolerated in both studies, and it was not associated with an increased risk of falls, cognitive decline, or sedation. Additionally, AXS-05 led to no deaths in the clinical program.

According to the press release, the FDA has established a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2026.

Axsome Therapeutics. Axsome Therapeutics Announces FDA Acceptance and Priority Review of Supplemental New Drug Application for AXS-05 for the Treatment of Alzheimer’s Disease Agitation. December 31, 2025. Accessed December 31, 2025. 

https://www.globenewswire.com/news-release/2025/12/31/3211743/33090/en/Axsome-Therapeutics-Announces-FDA-Acceptance-and-Priority-Review-of-Supplemental-New-Drug-Application-for-AXS-05-for-the-Treatment-of-Alzheimer-s-Disease-Agitation.html?_gl=1*10bx1vl*_up*MQ..*_ga*MTMwMTY4NzU1OC4xNzY3MTk1NDM2*_ga_ERWPGTJ5X8*czE3NjcxOTU0MzUkbzEkZzAkdDE3NjcxOTU0OTgkajYwJGwwJGgw

Cummings J, Grossberg G, Andersson C, et al. Efficacy and Safety of AXS-05 in Agitation Associated with Alzheimer’s Disease: Results from ACCORD, a Phase 3, Double-blind, Placebo-controlled, Relapse Prevention Trial (PL5.004). 

. April 9, 2024. Accessed December 31, 2025. 

https://www.neurology.org/doi/10.1212/WNL-.0000000000205634

Axsome Therapeutics, Inc. A Study to Assess the Efficacy and Safety of AXS-05 in Subjects With Alzheimer’s Disease Agitation (ADVANCE-2). ClinicalTrials.gov Identifier: NCT05557409. Updated November 26, 2025. Accessed December 31, 2025. 

https://clinicaltrials.gov/study/NCT05557409

Axsome Therapeutics. Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS-06 in Alzheimer’s Disease Agitation. 

. December 30, 2024. Accessed December 31, 2025. 

https://www.biospace.com/press-releases/axsome-therapeutics-announces-successful-completion-and-results-of-phase-3-clinical-program-of-axs-05-in-alzheimers-disease-agitation

The FDA has accepted and granted Priority Review to Axsome Therapeutics' supplemental New Drug Application for AXS-05, targeting agitation in Alzheimer's disease. AXS-05, an NMDA receptor antagonist and sigma-1 agonist, showed promising results in phase 3 trials, including ACCORD and ADVANCE-2. While ACCORD demonstrated significant improvements in agitation symptoms, ADVANCE-2 did not achieve statistical significance but favored AXS-05 numerically. The drug was well-tolerated, with no increased risk of falls or cognitive decline. The FDA's target action date for the application is April 30, 2026.

The novel oral NMDA receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor has indicated its efficacy and safety across 3 clinical trials.

Geriatrics

Geriatric medicine condition center page is a comprehensive resource for clinical news and insights on frequent geriatric-related diseases and conditions. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for sleep disorder, dementia, Alzheimer's disease, and more.

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FDA Accepts, Grants Priority Review to AXS-05 sNDA for Alzheimer’s Disease Agitation

Announced by parent company Corcept Therapeutics on December 31, 2025, the 

 has issued a Complete Response Letter (CRL) regarding relacorilant's New Drug Application (NDA) for hypercortisolism.

"We are surprised and disappointed by this outcome," Joseph Belanoff, MD, chief executive officer of Corcept, said in a statement. "Our commitment to patients suffering from the effects of hypercortisolism is unwavering."

The FDA acknowledged that Corcept's pivotal GRACE trial met its primary endpoint and that the company's GRADIENT trial provided confirming evidence. However, the FDA also determined that it was unable to determine a favorable benefit-risk assessment without additional evidence of effectiveness.

Relacorilant is a selective cortisol modulator, designed to bind to glucocorticoid receptors without interacting with other hormone receptors. Corcept is currently investigating relacorilant in several different disorders, including ovarian and prostate cancer.

The NDA submission was based on results from the pivotal GRACE trial and the phase 3 GRADIENT trial, as well as a phase 2 trial in hypercortisolism and a long-term extension. GRACE was a 2-part, phase 3, double-blind, placebo-controlled, randomized-withdrawal study examining the safety, efficacy, and pharmacokinetics of relacorilant in patients with 

 with impaired glucose tolerance and/or uncontrolled 

The first phase of GRACE was an open-label period where patients with hypercortisolism and either hypertension, hyperglycemia, or both received relacorilant for 22 weeks. Investigators excluded patients with non-endogenous hypercortisolism, uncontrolled and clinically significant hypothyroidism or hyperthyroidism, poorly controlled hypertension, poorly controlled diabetes mellitus, or renal insufficiency.

The second phase was a double-blind, randomized, withdrawal period, allowing investigators to measure blood pressure control maintenance. In this phase, patients who met response criteria were randomly assigned in a 1:1 ratio to either continue relacorilant or switch to placebo therapy for 12 weeks.

Ultimately, investigators found that loss of blood pressure control was 83% less likely to occur in the relacorilant arm compared to placebo (odds ratio [OR], 0.17; 

 = .02), along with similar blood pressure trends favoring relacorilant over placebo in 24-hour systolic and diastolic blood pressure.

GRADIENT was a randomized, double-blind, placebo-controlled study assessing the efficacy and safety of relacorilant to treat hypercortisolism in patients with cortisol-secreting adrenal adenoma or hyperplasia associated with diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension. Investigators included patients with a lack of cortisol suppression based on dexamethasone suppression testing, suppressed or low early-morning adrenocorticotropic hormone levels, and a radiologically confirmed adrenal lesion. Patients were excluded if they had severe uncontrolled hypertension, poorly controlled diabetes mellitus, 

, significantly abnormal liver test results, or uncontrolled hypo- or hyperthyroidism.

Patients were randomly assigned in a 1:1 ratio to either oral relacorilant or placebo for 22 weeks. Primary outcomes included change in average 24-hour systolic blood pressure and the number of patients with ≥1 treatment-emergent adverse event. Secondary endpoints included change in average heart rate, average diastolic blood pressure, and area under the concentration-time curve of blood glucose, among others.

Patients receiving relacorilant exhibited substantial and clinically significant improvements in mean systolic blood pressure at 22 weeks compared to baseline, while those receiving placebo saw no significant reduction. Additionally, 5 patients receiving placebo required rescue therapy, compared to 1 receiving relacorilant.

"I am confident we will find a way to get relacorilant to the patients it could help," Belanoff said in the statement. "We will meet with the FDA as soon as possible to discuss the best path forward."

Corcept Therapeutics. Corcept Receives Complete Response Letter for Relacorilant as a Treatment for Patients with Hypercortisolism. 

. December 31, 2025. Accessed December 31, 2025. 

https://www.businesswire.com/news/home/20251231309474/en/Corcept-Receives-Complete-Response-Letter-for-Relacorilant-as-a-Treatment-for-Patients-with-Hypercortisolism

Corcept Therapeutics. A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome (GRACE). ClinicalTrials.gov Identifier: NCT03697109. Updated July 16, 2025. Accessed December 23, 2025. 

https://clinicaltrials.gov/study/NCT03697109

Campbell P. Full GRACE Results Shed Further Light on Effects of Relacorilant in Hypercortisolism. 

. June 7, 2024. Accessed December 23, 2025. 

https://www.hcplive.com/view/full-grace-results-shed-further-light-on-effects-of-relacorilant-in-hypercortisolism

Corcept Therapeutics. A Study of the Efficacy and Safety of Relacorilant in Patients With Cortisol-Secreting Adrenal Adenomas (GRADIENT). ClinicalTrials.gov Identifier: NCT04308590. Updated September 4, 2025. Accessed December 23, 2025. 

https://clinicaltrials.gov/study/NCT04308590

Corcept Therapeutics. Corcept Therapeutics Announces Third Quarter Financial Results, Positive Results from Phase 3 GRADIENT Trial in Patients With Cushing’s Syndrome and Provides Corporate Update. October 30, 2024. Accessed December 23, 2025. 

https://ir.corcept.com/news-releases/news-release-details/corcept-therapeutics-announces-third-quarter-financial-results-3

The FDA issued a Complete Response Letter for relacorilant's NDA for hypercortisolism, despite positive results from pivotal trials. The GRACE and GRADIENT trials demonstrated relacorilant's efficacy in managing hypercortisolism, particularly in patients with concurrent type 2 diabetes and hypertension. However, the FDA requires additional evidence to assess the benefit-risk profile. Relacorilant, a selective cortisol modulator, showed significant improvements in blood pressure control compared to placebo. Corcept Therapeutics remains committed to advancing relacorilant's approval and plans to engage with the FDA to determine the next steps.

The FDA has issued a CRL for selective cortisol modulator relacorilant, citing a need for more evidence of effectiveness.

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