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FDA Action Update, June 2022: Approvals, Extended Reviews, and Clinical Holds

Catch up on any of the neurology news headlines you may have missed over the course of the last month, compiled all into one place by the NeurologyLive® team.

Several FDA actions took place throughout June 2022 (and late May), including several approvals, as well as mulitple extensions to ongoing reviews and clinical holds for ongoing trials of investigational therapies.

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 detail and information about each update.

FDA Approves Risdiplam to Treat Presymptomatic Babies Under 2 Months With SMA

On May 31, 2022, the FDA greenlit an expanded indication for risdiplam (Evrysdi; Genentech) to include the treatment of presymptomatic babies under 2 months old with spinal muscular atrophy (SMA), making it the first approved treatment administered at home for this patient group, and now approved for children and adults of all ages.1

The decision to expand the indication was made after reviewing interim efficacy and safety data from the RAINBOWFISH study (NCT03779334), which showed that, following 12 months of treatment with risdiplam, a majority of presymptomatic babies met key milestones of healthy babies.

Principal investigator Richard Finkel, MD, director, Experimental Neuroscience Program, St. Jude Children’s Research Hospital, said in a statement, "The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones. With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed."

FDA Review of FT218 in Narcolepsy Pushed Back to 2023

Also on May 31, 2022, a securities filing from Avadel Pharmaceuticals announced that the FDA issued a proposed final label and medication guide for the company’s investigational treatment for excessive daytime sleepiness and cataplexy in adults with narcolepsy, FT218. A portion of the new drug application (NDA) for the once-nightly sodium oxybate formulation relating to the REMS patent was deemed inappropriate, and pushed the approval deadline to June 17, 2023.2

Avadel further stated that the FDA requested an added certification to the Risk Evaluation and Mitigation Strategy (REMS) patent but confirmed that no additional patent certifications were required. Approval for FT218 can occur sooner, but only if the REMS patent is delisted from the FDA’s Orange Book; or otherwise, if the patent is deemed invalid, not infringed, or otherwise unenforceable by a court; or if a court determines that FDA erred in requesting the certification.

“The Company believes in the potential of FT218 and its importance to the narcolepsy community. The Company is committed to pursuing all options for FT218 to realize its full value,” Avadel noted in the filing.

FDA Extends Review of Amylyx ALS Treatment

On June 3, 2022, Amylyx Pharmaceuticals announced that the FDA had pushed its pending PDUFA date for AMX0035— originally set for June 29, 2022—out 3 months to September 29, 2022.3

The news follows a less than stellar review by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee back in March, which voted (6 no; 4 yes; 0 abstain) that the data from the phase 2/3 CENTAUR trial (NCT03127514) and open-label extension study did not adequately establish AMX0035 as an effective treatment for ALS amyotrophic lateral sclerosis (ALS). The decision to extend the review of Amylyx's investigational treatment stems from additional data analyses that were submitted for review. According to the agency, the additions were significant enough to warrant a major amendment to the application.

"We are confident in the potential of AMX0035 to help people living with ALS and other neurodegenerative diseases, and we continue to work closely with the FDA as they complete their review," said Justin Klee and Joshua Cohen, co-CEOs and cofounders of Amylyx, in a statement.

FDA Clears EksoNR Robotic Exoskeleton for Rehabilitation in Multiple Sclerosis

On June 13, 2022, FDA granted 501(k) clearance to the EksoNR robotic exoskeleton for use with patients with multiple sclerosis (MS), making it the first such device to be approved for rehabilitation efforts in MS.4

"The studies used for the FDA submission demonstrated that the participants demonstrated both improvements and gait speed and balance. People who have MS often have fatigue and endurance impairments. EksoNR can help reduce fatigue and improve endurance and activity tolerance," Michael Glover, PT, NCS, global director of clinical experience, Ekso Bionics, told NeurologyLive®.

He added that the EksoNR also allows for postural support and spasticity management, as well as a carry-over effect to core strength. "Lastly, there are cognition and psychological benefits. The improvements in functional activity and mobility offer hope for disease management," he said.

FDA Approves Vutrisiran to Treat hATTR Amyloidosis

The following day, on June 14, the FDA approved Alnylam’s investigational subcutaneous RNA interface therapy vutrisiran, marketed as Amvuttra, for the treatment of transthyretin-mediated (ATTR) amyloidosis.5

The RNAi therapeutic administered once every 3 months was approved based on positive 9-month results from the phase 3 HELIOS-A study (NCT03759379). Results from the study showed that the treatment met the primary end point of change from baseline in the modified Neuropathy Impairment Score, and statistically significant results on secondary measures such as the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy and timed 10-meter walk test as compared with historical placebo results.

"Today, Amvuttra has the potential to change the standard of care for people living with the polyneuropathy of this devastating disease,” Yvonne Greenstreet, MBChB, chief executive officer, Alnylam Pharmaceuticals, said in a statement. “As the fifth RNAi therapeutic developed by Alnylam to receive regulatory approval in less than four years, we believe Amvuttra represents an important milestone that brings us one step closer to achieving our P5x25 goals aimed at Alnylam’s transition to a leading biotech company."

FDA Advisory Committee Votes Down Pimavanserin's Efficacy in AD Psychosis Ahead of PDUFA

In the June 17, 2022, meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee to review pimavanserin (Nuplazid; Acadia Pharmaceuticals) ahead of the agency’s pending decision on the drug's treatment of Alzheimer disease (AD) psychosis, the committee voted in opposition to the drug's efficacy for the treatment of hallucinations and delusions in patients with AD psychosis.6

Among 12 voting members, 3 voted 'yes' and 9 voted 'no' in answering the question, "Does available evidence support a conclusion that pimavanserin is effective for the treatment of hallucinations and delusions in the AD [psychosis] population?" The vote casts further doubt on Acadia's chances of a positive decision, with its PDUFA date set for August 4, 2022, when the FDA will decide the fate of the brand's resubmitted supplemental NDA.

“We appreciate our ongoing engagement with the FDA and look forward to a productive discussion on the clinical evidence supporting the positive benefit-risk profile for pimavanserin as a treatment for ADP at the upcoming Advisory Committee meeting,” Steve Davis, chief executive officer, Acadia, said in a statement when the AdComm meeting was annnounced.7

AbbVie Submits Supplemental New Drug Application for Atogepant in Chronic Migraine

On June 22, 2022, AbbVie submitted a supplemental NDA to the FDA to expand atogepant’s (Qulipta) indication to include the preventive treatment of chronic migraine.8 If approved, the medication would be the first oral calcitonin gene-related peptide receptor antagonist approved as a preventive treatment for both episodic and chronic migraine.

Results from the PROGRESS trial (NCT03855137), a double-blind, placebo-controlled, parallel-group study assessing 60-mg once daily and 30-mg twice-daily doses of atogepant, were the basis for the submission.

Michael Gold, MD, therapeutic area head, Neuroscience Department, AbbVie, said in a statement, "Having one oral medication to treat both episodic and chronic migraine would be an important advancement for health care providers and patients. This sNDA approval would also diversify AbbVie's migraine portfolio and make it the only company to offer two approved preventive treatments for those living with chronic migraine. No two migraine patients are alike, so having multiple treatment options with unique mechanisms of action is critical."

FDA Places Clinical Hold on Duchenne Muscular Dystrophy Drug SRP-5051 Amid Safety Concerns

On June 24, 2022, Sarepta Therapeutics announced that the FDA placed a clinical hold on testing for its investigational agent SRP-5051, a next-generation peptide conjugated phosphorodiamidate morpholino oligomer (PPMO) to treat patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.9

The decision was made based on data from a patient in part B of the phase 2 MOMENTUM trial (NCT04004065) who suffered a serious adverse event of low magnesium, otherwise known as hypomagnesemia, after treatment with high-dose SRP-5051. The FDA will request information on all cases of hypomagnesemia, including a small number of nonserious grade 2 cases, and to assess the adequacy of the risk mitigation and safety monitoring plan.

"Patient safety is always our top priority. The hypomagnesemia was identified through lab tests conducted as part of the monitoring outlined in the protocol of the MOMENTUM study and is similar to previously observed cases of hypomagnesemia in clinical trials of SRP-5051,” Louise Rodino-Klapac, PhD, executive vice president and chief executive officer, Sarepta Therapeutics said in a statement. "The hypomagnesemia was transient and patients’ magnesium levels returned to normal following additional supplementation."

FDA Pauses Tolebrutinib Trials in MS, Myasthenia Gravis Over Liver Injuries

Finally, on June 30, 2022, the FDA placed a partial clinical hold on Sanofi's phase 3 clinical trials for tolebrutinib, its Bruton tyrosine kinase (BTK) inhibitor being evaluated for the treatment of MS and myasthenia gravis.10

The hold was placed based on reported cases of drug-induced liver injury in patients who received the study drug in the ongoing trials. As such, new enrollment in the studies is paused, and any participant who has been in a study for less than 60 days has been instructed to suspend the study drug. Sanofi had revised its global study protocols in May of this year to both update safety monitoring and enrollment criteria to exclude those with preexisting factors related to hepatic dysfunction. Study sites outside of the US remain in active enrollment.

The company said in a statement, "Sanofi is working closely with the independent data monitoring committee members and investigators around the world to evaluate the effectiveness of safety measures. Sanofi remains confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS."

1. FDA approves Genentech’s Evrysdi (risdiplam) for use in babies under two months with spinal muscular atrophy (SMA). News release. Genentech. May 31, 2022. Accessed July 1, 2022. https://www.biospace.com/article/releases/fda-approves-genentech-s-evrysdi-risdiplam-for-use-in-babies-under-two-months-with-spinal-muscular-atrophy-sma-
2. Securities and Exchange Commission Filing. Avadel Pharmaceuticals. May 24, 2022. Accessed July 1, 2022. https://investors.avadel.com/static-files/a4fde6ad-d060-4b02-a02a-01b9d567ce2c
3. Amylyx Pharmaceuticals Receives Notification of PDUFA Date Extension for AMX0035 for the Treatment of ALS. News release. Amylyx. June 3, 2022. Accessed July 1, 2022. https://finance.yahoo.com/news/amylyx-pharmaceuticals-receives-notification-pdufa-110000354.html
4. Ekso Bionics Receives FDA Clearance to Market its EksoNR™ Robotic Exoskeleton for Use with Multiple Sclerosis Patients. News release. Ekso Bionics Holdings. June 13, 2022. Accessed July 1, 2022. https://www.globenewswire.com/news-release/2022/06/13/2461153/29945/en/Ekso-Bionics-Receives-FDA-Clearance-to-Market-its-EksoNR-Robotic-Exoskeleton-for-Use-with-Multiple-Sclerosis-Patients.html
5. Alnylam announces FDA approval of Amvuttra (Vutrisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. News release. Alnylam. June 13, 2022. Accessed July 1, 2022. https://investors.alnylam.com/press-release?id=26776
6. June 17, 2022, Meeting of the Psychopharmacologic Drugs Advisory Committee Meeting Announcement. FDA website. June 17, 2022. Accessed July 1, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/june-17-2022-meeting-psychopharmacologic-drugs-advisory-committee-meeting-announcement-06172022
7. Acadia Pharmaceuticals Announces FDA Advisory Committee Meeting to Review Resubmission of Supplemental New Drug Application for NUPLAZID® (pimavanserin) for the Treatment of Alzheimer’s Disease Psychosis Scheduled for June 17, 2022. News release. May 2, 2022. Accessed July 1, 2022. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-fda-advisory-committee-meeting-to-review-resubmission-of-supplemental-new-drug-application-for-nuplazid-pimavanserin-for-the-treatment-of-alzheimers-d/
8. AbbVie submits supplemental new drug application to US FDA for atogepant (Qulipta) to support label expansion for the preventive treatment of migraine. News release. AbbVie. June 21, 2022. Accessed July 1, 2022. https://news.abbvie.com/news/press-releases/abbvie-submits-supplemental-new-drug-application-to-us-fda-for-atogepant-qulipta-to-support-label-expansion-for-preventive-treatment-migraine.htm
9. Sarepta Therapeutics provides update on SRP-5051 for the treatment of Duchenne muscular dystrophy. News release. Sarepta. June 23, 2022. Accessed July 1, 2022. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-update-srp-5051-treatment-duchenne
10. Media Update: Patient enrollment of phase III tolebrutinib trials paused in the U.S. News release. Sanofi. June 30, 2022. Accessed July 1, 2022. https://www.sanofi.com/en/media-room/press-releases/2022/2022-06-30-05-30-00-2471767