FDA Action Update, November 2025: Approvals, Clearance, and Boxed Warning

The FDA was busy in November 2025, making a number of decisions on potential new therapeutic agents, including granting approvals and a clearance, issuing a complete response letter, adding a box warning, providing feedback, and reconsidering its stance on a submission.

With all the treatments that have progressed through the pipeline of clinical development, the NeurologyLive^® team has been hard at work covering all the agency movements to make sure you are up to date on the latest news in neurology. To give you a chance to catch up on any of the headlines you may have missed in October, we’ve compiled all the updates into 1 place. The coverage includes the latest FDA approvals, new designations, submissions, resubmissions, and clinical trial initiations and holds.

FDA Approves Doxecitine and Doxribtimine Combination Therapy as First Treatment for Thymidine Kinase 2 Deficiency

At the beginning of the month, on November 3, 2025, the FDA approved UCB’s doxecitine (dC) and doxribtine (dT), a fixed-dose combination therapy, as the first treatment for patients with thymidine kinase 2 deficiency (TK2d), an ultra-rare neuromuscular disorder that causes issues with myopathy, difficulty walking, and breathing, among others. Marketed as Kygevvi, this combination treatment targets the root cause of TK2d, giving patients and families newfound hope for treating the disease.¹

This new therapy, a 1:1 mixture of dC and dT, is designed to support mitochondrial DNA replication by bypassing the deficient TK2 enzyme and leveraging cytosolic kinases. TK2d, a disorder with a worldwide prevalence of about 1.64 cases per million, is primarily induced by mitochondrial depletion, resulting in progressive muscle weakness, respiratory failure, developmental regression, and premature death.

"The approval of doxecitine and doxribtimine represents a pivotal moment for the TK2d community who previously had no FDA-approved treatment options for this rare genetic mitochondrial disease beyond supportive [palliative] care," Donatello Crocetta, chief medical officer at UCB, said in a statement.¹ "We extend heartfelt thanks to the patients, families and friends, advocates, healthcare providers and dedicated clinical trial teams who have partnered with us on this important journey."

FDA Reverses Course on AMT-130, Citing Insufficient External Data for Submission

On the same day, on November 3, 2025, uniQure disclosed that the FDA has reconsidered its stance on AMT-130, the company’s investigational gene therapy for Huntington disease (HD). After meeting with regulators, the company learned that the phase 1/2 program data (NCT0543017; NCT04120493) will not be enough to support an approval filing at this time.²

The announcement came weeks after uniQure announced promising data from its phase 1/2 program, which showed that treatment with high doses of AMT-130 led to statistically significant slowing of disease progression in patients with HD. Based on the available information, it seems the FDA no longer believes the external control used in the trial was sufficient enough to support AMT-130’s BLA submission as a potential disease-modifying treatment for HD.

"We are surprised by the FDA’s feedback at the recent pre-BLA meeting, which is a drastic change from the guidance the FDA provided in November 2024 that data from the ongoing Phase I/II studies, compared to a natural history external control, may serve as the primary basis for a BLA submission under the Accelerated Approval pathway," Matt Kapusta, chief executive officer at uniQure, said in a statement.² "This news is unexpected, and we are truly disappointed for people living with HD, who have no disease-modifying treatment options for this devastating disease."

FDA Feedback Provides Clarity for Phase 3 Trial of Neflamapimod in Dementia With Lewy Bodies

A day later, on November 4, 2025, the FDA shared written feedback aligning on key aspects of CervoMed’s proposed phase 3 trial for neflamapimod, an investigational oral therapy for the treatment of patients with dementia with Lewy bodies (DLB), to support a potential new drug application (NDA) submission.³

Based on the feedback from the agency, the company plans to initiate a single, global, randomized, double-blind, placebo-controlled phase 3 trial investigating the efficacy and safety of neflamapimod in approximately 300 patients with DLB who meet consensus clinical criteria in the second half of 2026. The study will randomize participants 1:1 to receive either oral neflamapimod or placebo for 32 weeks, followed by a neflamapimod-only extension for 48 weeks.

“DLB is a devastating disease with no approved therapies. The fact that CervoMed and FDA have aligned on the clinical trial design and registration path for neflamapimod marks a pivotal moment for our field. It underscores both the strength of CervoMed’s science and the agency’s recognition of the urgent need for innovation and therapeutic progress in DLB," Marwan Sabbagh, MD, FAAN, FANA, behavioral neurologist at Barrow Neurological Institute and nonexecutive director at CervoMed, told NeurologyLive^® in a recent interview. "This first-ever Phase 3 study in DLB, focused on key measures of both cognition and function, brings us meaningfully closer to delivering an effective medicine for the millions of patients and families affected by this profoundly challenging diagnosis,."

FDA Issues Complete Response Letter for Spinocerebellar Ataxia Agent Troriluzole

On the same day, on November 4, 2025, the FDA issued Biohaven a complete response letter (CRL) for its clinical application regarding troriluzole, an investigational agent for patients with spinocerebellar ataxia (SCA). Troriluzole, a novel, third-generation tripeptide prodrug of riluzole, the FDA-approved drug for ALS, was aiming to become the first approved treatment for SCA, a rare neuromuscular disorder that lacks effective options.⁴

According to Biohaven, the reasons behind the CRL were related to issues with the data included in the new drug application (NDA), such as the decision to use real-world data and external controls. Ultimately, the agency felt that this led to potential bias, design flaws, and lack of pre-specification and unmeasured confounding factors. The company is expected to work with the FDA to discuss next steps for the investigational agent in efforts to bring the treatment to the SCA community.

"We are extremely disappointed on behalf of patients by this action from the Office of Neuroscience at FDA," Vlad Coric, MD, chairman and chief executive officer at Biohaven, said in a statement.⁴ "Beyond substantial evidence of safety and efficacy, patients with rare diseases also deserve an efficient, fair and flexible regulatory process that aligns with the urgency of their high unmet medical needs. Such an approach has been mandated by Congress to empower the FDA with maximum regulatory flexibility for rare disease."

FDA Clears Phase 2a Clinical Trial to Test JOTROL in Patients With Parkinson Disease

A day later, on November 5, 2025, the FDA cleared the Jupiter Neurosciences’ investigational new drug (IND) application to initiate a phase 2a clinical trial of JOTROL in patients with Parkinson disease (PD). JOTROL, an investigational treatment, is a patented resveratrol-based therapeutic platform targeting neuroinflammation and mitochondrial dysfunction.⁵

The impending phase 2a trial is designed to evaluate the safety and tolerability of JOTROL in patients with PD, with secondary and exploratory endpoints to assess pharmacokinetics/pharmacodynamics (PK/PD) of the drug. The phase 2a evaluation comes after a phase 1 trial that provided favorable drug absorption results, namely JOTROL’s 9 times greater bioavailability when compared to resveratrol used in earlier clinical trials. According to the company, the findings of that phase 1 study will be cross-referenced in all upcoming JOTROL trials.

“This IND clearance from the FDA is an important step forward for Jupiter and the Parkinson’s community,” said Christer Rosén, Chairman and CEO of Jupiter Neurosciences, said in a statement.⁵ “JOTROL’s unique formulation has demonstrated strong safety and bioavailability data in Phase 1 and preclinical evidence suggests neuroprotective benefits that may translate into disease-modifying potential in Parkinson. We are proud to advance this innovative program and are now one step closer to initiating patient dosing.”

FDA Adds Boxed Warning, Narrows Indication for DMD Gene Therapy

A couple of weeks later, on November 14, 2025, the FDA approved safety-related labeling updates for delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics), a marketed gene therapy for Duchenne muscular dystrophy (DMD), to include a new boxed warning and a restriction limiting its treatment use for ambulatory patients ages 4 and older with the condition. The decision stems after recently reported cases of fatal acute liver failure for patients on the treatment.⁶

The determination is a result of a CBER (Center for Biologics Evaluation and Research) Safety Communication issued by the FDA in June, which reported 2 fatal cases of acute liver failure in nonambulatory pediatric boys treated with the gene therapy. Responding to these events, Sarepta voluntarily paused the distribution of the gene therapy for nonambulatory patients.⁷

In both cases, the patients developed markedly elevated liver enzymes and required hospitalization in 2 months of delandistrogene moxeparvovec-rokl infusion. An additional serious nonfatal case of acute liver injury, involving complications such as mesenteric vein thrombosis, bowel ischemia and necrosis, and portal hypertension, also contributed to the agency's review.

“We want to thank the FDA for their thorough and collaborative review. Completion of the safety labeling change for ELEVIDYS will ensure that families and healthcare professionals have clear information, supported by a Medication Guide, to help understand these updates and guide treatment decisions,” Louise Rodino-Klapac, PhD, president of research & development and technical operations at Sarepta, said in a statement.⁸

FDA Approves New Intrathecal Administration Route for Spinal Muscular Atrophy Gene Therapy

At the end of the month, on November 24, 2025, the FDA approved an intrathecal formulation of Novartis’ onasemnogene abeparvovec-brve, a gene therapy indicated for children, teens, and adults with spinal muscular atrophy (SMA). Marketed as Itvisma, the medication becomes the first intrathecally administered treatment for SMA, giving patients a new optional route of administration.⁹

The gene therapy, approved for a broad SMA population, is designed to address the genetic root cause of SMA by providing a functional copy of the human SMN1 gene to improve motor function through sustained survival motor neuron (SMN) protein expression. An adeno-associated, virus vector-based medication, onasemnogene abeparvovec was originally approved in 2019 as a single intravenous infusion for a broad range of SMA.

"The efficacy and safety of Itvisma have been convincingly demonstrated at recent meetings, so I was relieved and gratified to hear the FDA’s approval," John Day, MD, PhD, professor of neurology and pediatrics, director, Division of Neuromuscular Medicine, Stanford University School of Medicine, and co-director, Stanford’s Neuro IGNITE Center, told NeurologyLive^®. "The approval finally gives people of all ages the option of gene therapy in addition to currently approved oral and antisense treatments. Since no single treatment is likely to be ideal for everyone, availability of Itvisma provides an important new option for the prevalent SMA community."

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REFERENCES
1. U.S. FDA approves KYGEVVI® (doxecitine and doxribtimine), the first and only treatment for adults and children living with thymidine kinase 2 deficiency (TK2d). News release. UCB. November 3, 2025. Accessed December 9, 2025. https://www.prnewswire.com/news-releases/us-fda-approves-kygevvi-doxecitine-and-doxribtimine-the-first-and-only-treatment-for-adults-and-children-living-with-thymidine-kinase-2-deficiency-tk2d-302603083.html
2. uniQure Provides Regulatory Update on AMT-130 for Huntington’s Disease. News release. November 3, 2025. Accessed December 9, 2025. https://www.globenewswire.com/news-release/2025/11/03/3179114/0/en/uniQure-Provides-Regulatory-Update-on-AMT-130-for-Huntington-s-Disease.html
3. CervoMed Announces Alignment with FDA on Registration Path for Neflamapimod in Dementia with Lewy Bodies. News release. CervoMed. November 4, 2025. Accessed December 9, 2025. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-alignment-fda-registration-path-neflamapimod
4. FDA Issues Complete Response Letter for Biohaven's VYGLXIA (troriluzole) New Drug Application for Spinocerebellar Ataxia. News release. Biohaven. November 4, 2025. Accessed December 9, 2025. https://www.prnewswire.com/news-releases/fda-issues-complete-response-letter-for-biohavens-vyglxia-troriluzole-new-drug-application-for-spinocerebellar-ataxia-302604884.html
5. Jupiter Neurosciences Receives FDA Clearance of IND Application to Initiate Phase 2a Clinical Trial of JOTROL™ in Parkinson’s Disease. Jupiter Neurosciences, Inc. News Release. November 5, 2025. Accessed December 9, 2025. https://www.globenewswire.com/news-release/2025/11/05/3181489/0/en/Jupiter-Neurosciences-Receives-FDA-Clearance-of-IND-Application-to-Initiate-Phase-2a-Clinical-Trial-of-JOTROL-in-Parkinson-s-Disease.html
6. FDA Approves New Safety Warning and Revised Indication that Limits Use for Elevidys Following Reports of Fatal Liver Injury. News release. U.S. Food and Drug Administration. November 14, 2025. Accessed December 9, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-safety-warning-and-revised-indication-limits-use-elevidys-following-reports-fatal?utm_medium=email&utm_source=govdelivery
7. FDA Requests Sarepta Therapeutics Suspend Distribution of Elevidys and Places Clinical Trials on Hold for Multiple Gene Therapy Products Following 3 Deaths. News release. FDA. July 18, 2025. Accessed December 9, 2025. https://www.fda.gov/news-events/press-announcements/fda-requests-sarepta-therapeutics-suspend-distribution-elevidys-and-places-clinical-trials-hold
8. Sarepta Announces FDA’s Approval of Updated ELEVIDYS Prescribing Information. News release. Sarepta. November 14, 2025. Accessed December 9, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-announces-fdas-approval-updated-elevidys-prescribing
9. Novartis receives FDA approval for Itvisma®, the only gene replacement therapy for children two years and older, teens, and adults with spinal muscular atrophy (SMA). News release. Novartis. November 24, 2025. Accessed December 9, 2025. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-itvisma-only-gene-replacement-therapy-children-two-years-and-older-teens-and-adults-spinal-muscular-atrophy-sma