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FDA Action Update, December 2025: Approval, Designations, and Clinical Hold
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Key Takeaways
- STK-001 received FDA breakthrough designation for Dravet syndrome, aiming to restore NaV1.1 protein levels and reduce seizures and comorbidities.
- Clene received FDA guidance for CNM-Au8 in ALS, focusing on biomarker data to support accelerated approval.
Catch up on any of the neurology news headlines you may have missed over the course of November 2024, compiled all into one place by the NeurologyLive® team.
The FDA was busy in December 2024, making a number of decisions on potential new therapeutic agents including granting approvals, a clearance, placing a clinical hold, and issuing a complete response letter.
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 over the course of the last month, we’ve compiled all the updates into one place. The coverage includes the latest FDA approvals, new designations, submissions and resubmissions, and clinical trial initiations and holds.
Click the read more buttons for more details and information about each update.
STK-001 Gains FDA Breakthrough Designation as Potential Disease-Modifying Treatment for Dravet Syndrome
Early in the month, on December 4, the FDA granted breakthrough therapy designation to Stoke Therapeutics investigational antisense agent STK-001 for the treatment of genetically confirmed Dravet syndrome (DS), a rare epilepsy disorder. The company remains in discussions with the agency for plans on a phase 3 registrational study, which are expected to be released by the end of this year.1
Also known as zorevunersen, the agent is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. To date, there have been more than 600 doses of the medication administered to patients, with some currently on the drug for more than 3 years.
"The FDA’s Breakthrough Therapy designation for zorevunersen is supported by promising clinical data that suggest that zorevunersen has the potential to demonstrate substantial improvement over current treatments for Dravet syndrome," Shamim Ruff, chief regulatory affairs officer at Stoke, said in a statement.1 "By helping the body restore naturally occurring NaV1.1 protein levels, zorevunersen is designed to treat the underlying cause of the disease. We thank the FDA for their support and look forward to continuing to work together closely to efficiently advance zorevunersen into a registrational Phase 3 study."
Clene Receives FDA Guidance on Accelerated Approval Pathway for CNM-Au8 in ALS, Plans Further Biomarker Analysis
A month after Clene’s recent meeting with the FDA and presentation of new data, on December 10, the agency provided written guidance to the company regarding a potential accelerated approval pathway for its investigational product CNM-Au8 in amyotrophic lateral sclerosis (ALS). Clene announced its intention to follow the FDA’s recommendations for CNM-Au8, expressing confidence in its ability to address the agency’s requests.2
Earlier this year, the company was initially advised that the data presented in its briefing package for the ALS agent was insufficient to support a new drug application (NDA) submission under the accelerated approval pathway. With the FDA’s recommendation, Clene will need to investigate whether additional data from the ongoing compassionate use expanded access programs (EAPs) can be leveraged to substantiate the effect of CNM-Au8 on neurofilament light chain (NfL) decline.
“We are incredibly grateful for the FDA’s willingness to consider how the available data from our expanded access programs may be able to support the existing clinical study data to allow for the review of an application for approval of CNM-Au8 for ALS via an accelerated regulatory pathway, and for the valuable feedback we have received to date,” Rob Etherington, president and CEO at Clene, said in a statement.2 “Together with the survival and supportive biomarker data generated thus far, the drug’s benign safety profile, and the emerging EAP NfL data, we look forward to continued discussions with the Agency. Clene plans to include the additional data in an NDA submission under the accelerated approval pathway in mid-2025. We remain dedicated to the ALS community and honored to help critically ill patients and their families.”
FDA Reaches Alignment on Key Elements of Accelerated Approval Pathway for AMT-130 in Huntington Disease
On the same day, on December 10, following uniQure’s recent regenerative medicine advanced therapy (RMAT) Type B meeting with the FDA, the agency reached agreement with the company on key elements of an accelerated approval pathway for its investigational gene therapy AMT-130 for patients living with Huntington disease (HD).3
The FDA concurred that data from the ongoing phase 1/2 clinical trials (NCT0543017; NCT04120493) of AMT-130, utilizing a natural history external control as a comparator, could serve as the primary basis for a biologics license application submission under the accelerated approval pathway. Thereby, eliminating the requirement for an additional presubmission study. Furthermore, the agency agreed that the Composite Unified Huntington’s Disease Rating Scale (cUHDRS) could be utilized as an intermediate clinical end point, with reductions in neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) to provide supportive evidence of therapeutic efficacy for the accelerated approval submission.
“We are very pleased to reach agreement with the FDA on core components of an Accelerated Approval pathway for AMT-130,” Walid Abi-Saab, MD, chief medical officer of uniQure, said in a statement.3 “Our alignment reflects the strength of our data and collaborative discussions with the staff and senior management at FDA’s Center for Biologics Evaluation and Research (CBER). This is an important milestone for the Huntington’s disease community as it puts us on the most rapid and efficient pathway to deliver a potentially life-changing therapy to people living with this devastating neurodegenerative disorder. We have initiated BLA readiness activities and look forward to further engaging with the FDA in the first half of 2025 to discuss our statistical analysis plan and the technical CMC requirements.”
FDA Grants Tolebrutinib Breakthrough Therapy for Nonrelapsing Secondary Progressive Multiple Sclerosis
A few days later, on December 13, the FDA granted breakthrough therapy designation to Sanofi’s tolebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, for patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The company noted that regulatory submissions for tolebrutinib are being finalized for the United States and prepared for Europe, with confirmation to follow once a submission has been accepted.4
This is designation was based on findings from the HERCULES phase 3 study (NCT04411641), which showed that treatment with tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP), the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026) in patients with nrSPMS.2,3 Additional results of the secondary end points revealed that the number of patients who experienced confirmed disability improvement increased by nearly 2-fold, 10%, for those treated with tolebrutinib compared with 5% those in the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).
"We think that tolebrutinib compares favorably in terms of being able to effectively target BTK in the CNS based on the combination of potency and brain penetration," Erik Wallström, MD, PhD, global head of neurology development at Sanofi, told NeurologyLive® in a recent interview. "Clinicians should be aware that this compound class, including tolebrutinib, has the problem with drug-induced liver injury, particularly during the early months of treatment, requiring intense monitoring."
FDA Places Clinical Hold on Phase 2 Study of PGN-EDO51 in Duchenne Muscular Dystrophy
A few more days later, on December 16, the FDA placed a clinical hold on PepGen’s investigational new drug application for its phase 2 CONNECT2-EDO51 study, assessing PGN-EDO51 in patients with Duchenne muscular dystrophy (DMD), and will issue an official clinical hold letter within 30 days. The company noted that CONNECT2, a 25-week multinational, double-blind, placebo-controlled trial with multiple ascending doses, is currently open in the United Kingdom.5
Earlier this year in July, PepGen reported data from the first dose cohort (5 mg/kg) of its ongoing phase 2 CONNECT1-EDO51 study (NCT06079736) evaluating PGN-EDO51 in patients DMD amendable to an exon 51 skipping therapy. In the trial, PGN-EDO51 showed higher levels of exon skipping and had a comparable, or higher, change from baseline in total dystrophin production and muscle-adjusted dystrophin production compared with reports from prior studies with other oligonucleotide therapies at similar PMO dose levels in patients with DMD.6
“We intend to work closely with the FDA to address their questions on our application to initiate CONNECT2 as expeditiously as possible,” Paul Streck, MD, MBA, head of R&D at PepGen, said in a statement.5 “Our open-label CONNECT1-EDO51 multiple ascending dose study of PGN-EDO51 in boys and young men living with DMD continues as planned in Canada. We have completed enrollment of the 10 mg/kg dose cohort; all four patients in this cohort have received at least one dose.”
FDA Approves Tirzepatide as First Treatment for Obstructive Sleep Apnea and Obesity
At the end of the month, on December 20, the FDA approved tirzepatide (Zepbound; Eli Lilly and Company) as the first and only prescription treatment for adults with moderate-to-severe obstructive sleep apnea (OSA) and obesity, to be used in combination with a reduced-calorie diet and increased physical activity.7
In November 2023, the FDA initially approved tirzepatide for the treatment of adults with obesity or overweight who also experience weight-related medical problems based on positive findings from the SURMOUNT-1 (NCT04184622) and SURMOUNT-2 (NCT04657003) trials.2,3 It became the first and only dual-activating glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist for obesity, tackling an underlying cause of excess weight. Now, the agency has approved the treatment for moderate-to-severe OSA and obesity based on positive data from the phase 3 SURMOUNT-OSA trial (NCT05412004).7
“Too often, OSA is brushed off as ‘just snoring’ – but it’s far more than that. It is important to understand OSA symptoms and know that treatments are available, including new options like [tirzepatide],” Julie Flygare, JD, president and chief executive officer at Project Sleep, said in a statement.7 “We hope this will spark more meaningful conversations between patients and health care providers and ultimately lead to better health outcomes.”
REFERENCES
1. Stoke Therapeutics Receives FDA Breakthrough Therapy Designation for Zorevunersen for the Treatment of Dravet Syndrome. News release. Stoke Therapeutics. December 4, 2024. Accessed December 5, 2024. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-receives-fda-breakthrough-therapy-designation/
2. FDA Provides Roadmap for Accelerated Approval Pathway Through Submission of Additional CNM-Au8® Biomarker Data in ALS. News Release. Clene. Published December 10, 2024. Accessed December 11, 2024. https://invest.clene.com/news-releases/news-release-details/fda-provides-roadmap-accelerated-approval-pathway-through
3. uniQure Announces Alignment with FDA on Key Elements of Accelerated Approval Pathway for AMT-130 in Huntington’s Disease. News Release. Published December 10, 2024. Accessed December 11, 2024. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-alignment-fda-key-elements-accelerated
4.Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis. News Release. Sanofi. Published December 13, 2024. Accessed December 13, 2024. https://www.sanofi.com/assets/dotcom/pressreleases/2024/2024-12-13-06-00-00-2996609-en.pdf
5. PepGen Announces Clinical Hold in the U.S. on IND Application to Initiate CONNECT2-EDO51 Phase 2 Study of PGN-EDO51 for Duchenne Muscular Dystrophy. News Release. PepGen. Published December 16, 2024. Accessed December 17, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-clinical-hold-us-ind-application-initiate
6. PepGen Announces Positive Data from Low-Dose Cohort of PGN-EDO51 in Ongoing CONNECT1-EDO51 Phase 2 Clinical Trial for Treatment of Duchenne Muscular Dystrophy. News Release. PepGen. Published July 30, 2024. Accessed December 17, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-positive-data-low-dose-cohort-pgn-edo51-ongoing
7. FDA Approves First Medication for Obstructive Sleep Apnea. News Release. FDA. Published December 20, 2024. Accessed December 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea
