FDA Action Update, November 2024: Approvals, Clearance, and Clinical Hold

The FDA was busy in November 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.

FDA Places Clinical Hold on Epilepsy Agent RAP-219 for Diabetic Peripheral Neuropathic Pain

Early in the month, on November 7, the FDA placed a clinical hold on Rapport Therapeutics’ submitted investigational new drug (IND) application for the initiation of a phase 2a proof-of-concept trial assessing RAP-219, an investigational therapy for epilepsy, as a potential treatment of patients with diabetic peripheral neuropathic pain (DPNP).¹

The agency has requested the company to provide additional information and amendments specific to the protocol design of the trial. Rapport noted in the announcement that it believes in its ability to resolve this request and will offer an update on the expected timing of the phase 2a trial initiation once obtainable. This clinical hold is specific to the IND for DPNP and did not impact the company’s other studies assessing RAP-219, such as in the ongoing phase 2a trial for focal epilepsy or planned proof-of-concept trial for bipolar disorder.

"We are pleased with the progress we’re making with RAP-219, particularly as we continue the execution of our phase 2a proof-of-concept trial in focal epilepsy,” Abraham N. Ceesay, chief executive officer of Rapport, said in a statement.¹ “The continued learnings from our ongoing clinical activities, including the MAD-2 and PET trials as well as our pharmaceutical development efforts, have only strengthened our confidence in the pipeline-in-a-product potential of RAP-219 as a potentially transformational treatment for focal epilepsy, peripheral neuropathic pain, and bipolar disorder.”

FDA Grants Accelerated Approval to PTC Therapeutics’ Gene Therapy for AADC Deficiency

About a week later, on November 13, the FDA granted PTC Therapeutics’ gene therapy eladocagene exuparvovec-tneq an accelerated approval indicated for the treatment of patients aged 18 years and older with aromatic L-amino acid decarboxylase (AADC) deficiency, including the full spectrum of disease severity.1 Marketed under Kebilidi, it becomes the first-ever gene therapy that is directly administered to the brain approved in the United States.²

AADC deficiency is a fatal, rare genetic disorder that typically causes severe disability and suffering from the first months of life, leading to decreased muscle tone, movement disorders, and disruption of the autonomic nervous system. The company reported that launch preparations are progressing smoothly, with centers of excellence designated and surgeons already trained to administer the gene therapy.

"PTC has once again pioneered a new approach to treating highly morbid neurologic diseases," Matthew B. Klein, MD, chief executive officer at PTC Therapeutics, said in a statement.² "I am proud of our team's unwavering commitment to achieve this important regulatory milestone. We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."

FDA Clears Icobrain Aria, First AI Tool for Safer ARIA Detection in Alzheimer Treatment

A day later, on November 14, the FDA cleared icobrain aria (icometrix), the first artificial-intelligence (AI) software approved to detect, measure, and grade amyloid-related imaging abnormalities (ARIA), a potential serious adverse effect of new anti-amyloid treatments for Alzheimer disease (AD).³

This software, trained using thousands of brain MRI scans, generates a quantitative summary report with includes a severity rating score that is integrated into the hospital workflow. For ARIA-edema (ARIA-E), the number of ARIA-E sites, their locations, and the longest axis of the largest site are measured and combined into an area severity score, graded according to clinical guidelines. For ARIA-hemorrhages (ARIA-H), the number of new microhemorrhages and areas of superficial siderosis are individually counted and localized, with an ARIA-H severity score reported, graded per clinical guidelines.⁴

"Amyloid-lowering treatments represent an important advance in the treatment of Alzheimer's disease but they are associated with a risk of brain swelling and hemorrhage called ARIA," Stephen Salloway, MD, professor of neurology and psychiatry at the Warren Alpert Medical School of Brown University, said in a statement.³ "New standardized tools are needed, such as icobrain aria, to assist radiologists and treating clinicians in detecting and managing ARIA to optimize patient safety."

FDA Approves Expanded Age Indication for Nerivio Migraine Device in Pediatric Patients

On the same day, on November 14, the FDA approved an expanded age indication for Theranica's Nerivio remote electrical neuromodulation (REN) wearable to treat patients aged 8 years and older with acute migraine. With this expanded indication, the needle-free alternative treatment becomes the first cleared nondrug therapy for acute migraine treatment in pediatric patients and the only prescribed preventive migraine treatment in this patient age group.⁵

This decision comes following a recently published study (NCT06138756) led by Klaus Werner, MD, PhD, a pediatric neurologist at Duke Health, which showed that treatment with the REN device was safe and effective for treating acute migraine in pediatric patients aged between 6 years and 11 years.^6,7 Published in the Annals of the Child Neurology Society, the study featured 293 patients with a median age of 11 years who used the REN device to treat at least 1 migraine attack. Of them, 18.4% reported at least 1 attack with aura, and the remaining 81.6% never reported aura. Notably, two-thirds (67.4%) of REN treatments were not followed by another REN treatment in 24 hours, indicating no retreatment and implying no recurrence in 24 hours.

“This device, Nerivio, is a truly unique and novel treatment for migraine, especially now for children 8 years of age and above, recently approved by the FDA for both acute and preventative treatment,” Klaus Werner, MD, PhD, pediatric neurologist at Duke Health and associate professor of pediatrics at Duke University, recently told NeurologyLive® in an interview. “I was very encouraged by the study findings and the experiences of my patients, many of whom I see every week. That encouragement led me to speak out and reach a broader community to share what is really happening—especially for those aged 8 years and older. It’s a very unique, new finding.”

FDA Issues CRL for Govorestat Application As Treatment for Classic Galactosemia

At the end of the month, on November 27, the FDA issued a complete response letter (CRL) to Applied Therapeutics investigational agent govorestat, a central nervous system penetrant Aldose Reductase inhibitor (ARI), which had been submitted as a potential new treatment for patients with classic galactosemia. As of now, there are no approved therapies specifically indicated for this rare genetic metabolic disease.⁸

The CRL indicates that the agency is unable to approve the NDA in its current form, citing deficiencies in the clinical application. Applied Therapeutics noted that it is "reviewing the feedback and plans to immediately request a meeting to discuss requirements for a potential resubmission of the NDA or appeal of the decision along with appropriate next steps."

“We are disappointed by the FDA’s decision today. Our strong commitment to the Galactosemia community is rooted in our belief that govorestat has the potential to change the lives of patients with Galactosemia, which we believe is evidenced by the breadth of efficacy and safety data demonstrating its ability to stop the decline on progressive clinical outcomes, including cognition and behavior,” Shoshana Shendelman, PhD, founder and CEO of Applied Therapeutics, said in a statement.⁸ “Galactosemia is a progressive and debilitating disease without any existing treatment options and there remains a high unmet medical need for this community. As we move forward, we plan to work with the FDA to address the concerns in the CRL and determine an expeditious path to bring this much needed treatment to patients. We are grateful to the patients, families, and healthcare providers who participated in the govorestat clinical studies.”

REFERENCES
1. Rapport Therapeutics Reports Third Quarter Financials and Provides Business Update. News Release. Rapport Therapeutics. Published November 7, 2024. Accessed December 4, 2024. https:/https://investors.rapportrx.com/news-releases/news-release-details/rapport-therapeutics-reports-third-quarter-financials-and
2. PTC Therapeutics Announces FDA Approval of AADC Deficiency Gene Therapy. News Release. PTC Therapeutics. Published November 13, 2024. Accessed December 4, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-approval-aadc-deficiency-gene
3. FDA authorizes the first AI-driven MRI solution for safer Alzheimer's treatment. News release. Icometrix. November 14, 2024. Accessed December 4, 2024. https://www.prnewswire.com/news-releases/fda-authorizes-the-first-ai-driven-mri-solution-for-safer-alzheimers-treatment-302305479.html
4. icobrain aria. Icometrix. Accessed December 4, 2024. https://icometrix.com/services/icobrain-aria
5. FDA Expands the Age Indication for Nerivio® as the First-and-Only REN Wearable for Migraine Treatment for Children Aged Eight and Above. News Release. Theranica. Published November 14, 2024. Accessed November 14, 2024.
6. New Study Evaluates Use of the Nerivio® REN Wearable for Treatment of Migraine in Children Under the Age of 12. News release. Theranica. July 25, 2024. Accessed November 12, 2024. https://www.prnewswire.com/news-releases/new-study-evaluates-use-of-the-nerivio-ren-wearable-for-treatment-of-migraine-in-children-under-the-age-of-12-302206102.html
7. Werner K, Gerson T, Stark-Inbar A, et al. Acute treatment of migraine in children aged 6-11: real-world analysis of remote electrical neuromodulation (REN). Annals of Child Neurology Soc. 2024;2(2):135-145. doi:10.1002/cns3/20073
8. Applied Therapeutics Receives Complete Response Letter from U.S. FDA Regarding New Drug Application for Govorestat for Classic Galactosemia. News release. Applied Therapeutics. November 27, 2024. Accessed December 4, 2024. https://www.globenewswire.com/news-release/2024/11/27/2988438/0/en/Applied-Therapeutics-Receives-Complete-Response-Letter-from-U-S-FDA-Regarding-New-Drug-Application-for-Govorestat-for-Classic-Galactosemia.html