FDA Action Update, September 2025: Complete Response Letters and Extension of Review Time

The FDA was busy in September 2025, making a number of decisions on potential new therapeutic agents, including issuing complete response letters and giving an extension for review time.

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 August, 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 Issues Complete Response Letter for SL1009 for Pyruvate Dehydrogenase Complex Deficiency

At the beginning of the month, on September 8, 2025, the FDA issued Saol Therapeutics a complete response letter (CRL) for its investigational product SL1009 or sodium dichloroacetate oral solution (DCA) for the treatment of pyruvate dehydrogenase complex deficiency (PDCD), a rare mitochondrial metabolic disorder.¹

SL1009, a formulation of DCA, is an oral solution intended to be used in conjunction with a proprietary genetic test that helps determine appropriate dosing. In the CRL, the agency outlined specific issues that Saol must resolve to define the path forward, though none were related to SL1009’s manufacturing. The company noted that meeting these requirements will likely take several years and demand substantial financial investment.

"Families living with PDCD face an urgent and life-threatening unmet need," Dave Penake, chief executive officer at Saol, said in a statement.¹ "We are encouraged by recent FDA actions and commentary that recognize the importance of regulatory flexibility and speed for treating rare diseases. Traditional clinical trials often take many years; time that children with PDCD simply do not have. We remain committed to productive conversations with the Agency to identify a path forward that brings this therapy to patients as swiftly as possible."

FDA Extends Review Time for Sanofi’s BTK Inhibitor Tolebrutinib

Later in the month, on September 22, 2025, the FDA pushed back the review period for tolebrutinib (Sanofi), an investigational, oral, brain-penetrant Bruton tyrosine kinase (BTK) inhibitor under review for the treatment of nonrelapsing secondary progressive multiple sclerosis (nrSPMS), to later this year. The agency noted that additional information constituted a major amendment to the new drug application, leading to a new Prescription Drug User Fee Act decision date of December 28, 2025.²

Sanofi’s application for tolebrutinib included data from the global phase 3 HERCULES study (NCT04411641) in nrSPMS, as well as the phase 3 GEMINI 1 and 2 trials (NCT04410978; NCT04410991) of patients with relapsing MS. If approved, tolebrutinib will become the only marketed BTK available for the treatment of MS as well as the first marketed BTK specific to patients with nrSPMS. Of note, the agent is still being tested in patients with primary progressive MS through the PERSEUS study (NCT04458051), which will have data read out later this year.

According to Sanofi, the company is confident in the treating potential of tolebrutinib and will continue to work closely with the FDA during the review period. Tolebrutinib, a BTK inhibitor meant to address smoldering neuroinflammation, a key driver of disability progression in MS, is the furthest along among BTK inhibitors in the clinical pipeline.

FDA Gives Complete Response Letter for Higher Dose of SMA Therapy Nusinersen

A day later, on September 23, 2025, the FDA handed Biogen a CRL over its submission for a higher, potentially more effective, dose of nusinersen (Spinraza), an approved therapy for children with spinal muscular atrophy (SMA).³

In the letter, the FDA requested an update to the technical information be included in the Chemistry Manufacturing and Controls module of the supplemental new drug application (sNDA) but did not cite any deficiencies in the clinical data presented in the package. The agency gave some potential resolutions for the submission, and Biogen is planning to resubmit the application as soon as information becomes ready.

"While this outcome was unexpected, we remain committed to bringing the high dose regimen to people living with SMA,” Priya Singhal, MD, MPH, head of development at Biogen, said in a statement.³ "We are working diligently to provide the necessary information to the FDA."

FDA Hands Scholar Rock Complete Response Letter for Spinal Muscular Atrophy Agent Apitegromab

On the same day, on September 23, 2025, the FDA issued Scholar Rock a CRL for the biologics license application (BLA) of apitegromab, an investigational monoclonal antibody for the treatment of SMA, following observations from a routine inspection at Novo Nordisk’s facility. Scholar noted that these inspection findings were not specific to the agent and that the CRL did not cite concerns regarding its efficacy, safety, or the third-party drug substance manufacturer.⁴

According to Scholar Rock’s second-quarter 2025 earnings announcement, Novo Nordisk submitted a comprehensive response to the FDA in early August 2025 and continued implementing corrective actions while providing the agency with progress updates. Scholar Rock reported that it plans to resubmit the BLA for apitegromab after the FDA confirms remediation of the manufacturing findings, anticipating that the agency will review the application once those issues are resolved.

"Apitegromab represents a promising advancement in the treatment of SMA, particularly because of its novel mechanism of action. Unlike current therapies that primarily focus on modifying SMN protein expression, Apitegromab is a fully humanized monoclonal antibody targeting myostatin, a negative regulator of muscle growth. Notably, the SAPPHIRE trial demonstrated meaningful improvements in muscle strength and function even in patients who had been receiving long-term treatment with approved SMN-enhancing therapies such as nusinersen and risdiplam," Pooja Mohan Rao, MD, neuromuscular specialist at Georgetown University Hospital, told NeurologyLive^® in a recent interview.

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REFERENCES
1. Saol Therapeutics receives complete response letter from FDA for SL1009 (DCA) for the treatment of pyruvate dehydrogenase complex deficiency (PDCD). News Release. Saol Therapeutics. Published September 8, 2025. Accessed October 9, 2025. https://www.prnewswire.com/news-releases/saol-therapeutics-receives-complete-response-letter-from-fda-for-sl1009-dca-for-the-treatment-of-pyruvate-dehydrogenase-complex-deficiency-pdcd-302548522.html
2. Press release: update on the US regulatory review of tolebrutinib in non-relapsing, secondary progressive multiple sclerosis. News Release. Sanofi. Published September 22, 2025. Accessed October 9, 2025. https://www.globenewswire.com/news-release/2025/09/22/3153624/0/en/Press-Release-Update-on-the-US-regulatory-review-of-tolebrutinib-in-non-relapsing-secondary-progressive-multiple-sclerosis.html
3. Biogen Provides Regulatory Update on High Dose Regimen of Nusinersen. News Release. Biogen. Published September 23, 2025. Accessed October 9, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-provides-regulatory-update-high-dose-regimen-nusinersen
4. FDA issues complete response letter (CRL) for apitegromab as a treatment for patients with spinal muscular atrophy (SMA) solely related to observations identified at Catalent Indiana LLC fill-finish facility. News Release. Scholar Rock. Published September 23, 2025. Accessed October 9, 2025. https://investors.scholarrock.com/news-releases/news-release-details/fda-issues-complete-response-letter-crl-apitegromab-treatment