FDA Action Update, September 2021: Approvals, Submissions, and Access Programs

The FDA made several actions in September 2021, including granting approvals and accepting applications for novel therapies across a variety of neurologic and central nervous system (CNS) diseases, as well as giving the green light for therapeutic expanded access programs.

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.

Click the read more buttons for more detail and information about each update.

Acute Migraine Treatment INP104 Approved

Impel NeuroPharma nasal spray agent, INP104, was approved in early September for the acute treatment of migraine headaches with or without aura in adults. The treatment is marketed as Trudhesa, and is first and only approved therapy that utilizes the Precision Olfactory Delivery technology, a novel delivery system that specifically targets the upper nasal space.¹ Its intranasal administration optimizes dihydroergotamine mesylate (DHE) for fast migraine relief regardless of when in the migraine attack it is administered. The drug delivery system is also designed to deliver a lower dose of DHE compared with other nasally administered, FDA-approved products, in turn reducing the adverse effects that are typically associated with delivery of DHE to the lower nasal space.

The FDA’s decision was based on data from the phase 3 STOP 301 study (NCT03557333), in which INP104 met the primary end point and demonstrated no new safety signals or concerning trends in nasal safety findings during the 52-week study period. The data were included in Impel's new drug application, which was filed in November 2020 and accepted in January of this year.²

Plans Announced for the Submission of NDA for AMX0035 for ALS

Amylyx Pharmaceuticals has announced that it is prepared to submit a new drug application (NDA) to the FDA for its investigational agent AMX0035—a combination of sodium phenylbutyrate and taurursodiol (also known as ursodoxicoltaurine)—for the treatment of amyotrophic lateral sclerosis (ALS).This decision was made based on a recent discussion between the FDA and Amylyx, according to the company. Joshua Cohen, co-CEO, chairman, and cofounder, Amylyx, said in a statement that the company was “thrilled to move toward the US submission” and that they “look forward to continuing to work with the FDA.”³

The ALS Association lauded the news of Amylyx's decision to move forward with the submission of an NDA—marking its ongoing and longstanding support of the combination therapy. In June 2016, the association provided $750,000 in grant funding to Amylyx for a pilot trial of the therapy, following that up with a $1.46 million grant to the Northeast ALS Consortium to aid in funding the phase 2 clinical trial. Then, in September 2020, the organization, along with I AM ALS, submitted more than 50,000 signatures to the FDA in favor of the therapy being approved, and in May 2021, the group brought members of the community to speak directly with the agency officials.⁴

Phase 3b Study of Higher-Dose Nusinersen in SMA Announced

In mid-September, Biogen announced plans to initiate a phase 3b trial, ASCEND, to study the safety and efficacy of higher doses of nusinersen (Spinraza; Biogen) in patients with spinal muscular atrophy (SMA) who have been treated previously with risdiplam (Evrysdi; PTC Therapeutics). The protocol has been submitted to the FDA, with inclusion criteria including being previously treated with the maximum 5-mg risdiplam and falling within a specific Revised Upper Limb Module measurement range, which will then be used to assess efficacy. Safety, Hammersmith Functional Motor Scale Expanded, and caregiver burden are the planned additional clinical outcomes to be evaluated.⁵

The ASCEND trial is anticipated to begin enrolling its first patients in 2021, with the study spanning approximately 2.5 years and including 135 patients with later-onset, nonambulatory SMA between the ages of 5 and 39 years. Participants will be given 2 loading, 50-mg doses of nusinersen 2 weeks apart, and a 28-mg maintenance dose at 4-month intervals for the duration of the study.

Second Expanded Access Program for ALS Therapy CNM-Au8 Launched

Clene Nanomedicine announced the launch of its second FDA expanded access program (CNMAu8.EAP02) with its lead drug candidate, CNM-Au8, an aqueous suspension of catalytically active, clean-surfaced, faceted gold nanocrystals, in patients with ALS. The expanded access program will be in conjunction with the Healey ALS Platform Trial, the first platform trial for the treatment of ALS. The breakthrough trial features CNM-Au8 and several other drug candidates and aims to help develop these therapies by reducing trial time, costs, and increasing patient participation. Additionally, the new program will provide an opportunity to those with ALS to access CNM-Au8 even if they are not eligible to enroll in the trial.⁶

Three participating clinical trials sites in the Healey ALS Platform Trial will be available to patients in the expanded access program and are supported by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH). At the time of the announcement, Holy Cross Hospital in Fort Lauderdale, Florida, and the Hospital for Special Care in New Britain, Connecticut, are the first 2 sites to be included.

Lecanemab Rolling Submission for Alzheimer Disease Initiated

Eisai and Biogen announced this month that they have begun the process of completing a rolling biologics license application (BLA) submission for their investigational Alzheimer disease (AD) treatment, lecanemab. The therapy, previously known as BAN2401, has been submitted to the FDA under the accelerated approval pathway.⁷

Previously, in June 2021, lecanemab was granted a breakthrough therapy designation, and Eisai noted that after all portions of the BLA are submitted to the FDA and the agency accepts the BLA, the Prescription Drug User Fee Act (PDUFA) action date will be set. The application will be supported by data from the phase 2b clinical trial, known as Study 201 (NCT01767311), which demonstrated a reduction in brain amyloid accompanied by a consistent reduction of decline across several clinical and biomarker end points in patients with mild cognitive impairment (MCI) due to AD or Alzheimer dementia.^7,8

Fenfluramine sNDA Submitted for Lennox-Gastaut Syndrome

Zogenix announced that it submitted a supplemental NDA for fenfluramine (Fintepla), an already FDA-approved treatment for Dravet syndrome (DS), to treat seizures associated with Lennox-Gastaut syndrome (LGS).The application was backed by data from the phase 3 Study 1601 (NCT03355209), which met its primary end point, with the treatment demonstrating significant improvement in monthly drop in seizure frequency (MDSF) among a cohort of 263 patients with LGS. Long-term safety and efficacy of fenfluramine in ongoing open-label extension trials were also included in the submission.⁹

"As LGS is a severe, rare form of epilepsy that is not well-controlled by currently available anti-seizure medications, we believe that Fintepla, if approved, would become an important new treatment option that addresses a significant unmet need for this patient population," Gail Farfel, PhD, executive vice president and chief development officer, Zogenix, said in a statement.⁹

Atogepant Approved for Episodic Migraine Prevention

AbbVie’s atogepant (Qulipta) was approved in late September for the preventive treatment of episodic migraine in adult patients, making it the first oral calcitonin gene-related peptide receptor antagonist—known colloquially as gepants—for this specific indication. It joins rimegepant (Nurtec ODT; Biohaven) as the second overall member of the gepant class to receive FDA approval. The decision was made based on data from a clinical program evaluating the efficacy, safety and tolerability of atogepant in almost 2000 patients with episodic migraine, defined as 4 to 14 migraine days per month. One of the studies, the pivotal phase 3 ADVANCE study (NCT02848326), included 873 patients with episodic migraine who were randomized 1:1:1:1 to receive 1 of 3 once-daily doses of oral atogepant or placebo for 12 weeks.^10,11

"Millions of people living with migraine often lose days of productivity each month because attacks can be debilitating. Qulipta can help by reducing monthly migraine days with a once-daily, oral dose that works quickly and continuously," Michael Severino, MD, vice chairman and president, AbbVie, said in a statement.10 "We are proud that AbbVie is now the only pharmaceutical company to offer 3 products across the full spectrum of migraine treatment, which include preventive therapies for chronic and episodic migraine and an acute treatment for migraine attacks."

REFERENCES
1. Impel NeuroPharma announces US FDA approval of Trudhesa (Dihydroergotamine mesylate) nasal spray for the acute treatment of migraine. News release. Impel NeuroPharma. September 3, 2021. Accessed October 5, 2021. https://www.biospace.com/article/releases/impel-neuropharma-announces-u-s-fda-approval-of-trudhesa-dihydroergotamine-mesylate-nasal-spray-for-the-acute-treatment-of-migraine/
2. Impel NeuroPharma announces US Food & Drug Administration acceptance of new drug application for INP104 for the acute treatment of migraine. News release. January 20, 2021. Accessed October 5, 2021. https://www.prnewswire.com/news-releases/impel-neuropharma-announces-us-food--drug-administration-acceptance-of-new-drug-application-for-inp104-for-the-acute-treatment-of-migraine-301211380.html
3. Amylyx Pharmaceuticals Announces Plan to Submit New Drug Application (NDA) for AMX0035 for the Treatment of ALS in the Coming Months. News release. Amylyx Pharmaceuticals. September 15, 2021. Accessed October 5, 2021. https://www.businesswire.com/news/home/20210915005297/en/Amylyx-Pharmaceuticals-Announces-Plan-to-Submit-New-Drug-Application-NDA-for-AMX0035-for-the-Treatment-of-ALS-in-the-Coming-Months
4. ALS Association Applauds Amylyx AMX0035 Announcement, Urges Swift FDA Approval. News release. ALS Association. September 15, 2021. Accessed October 5, 2021. https://www.prnewswire.com/news-releases/als-association-applauds-amylyx-amx0035-announcement-urges-swift-fda-approval-301376985.html
5. Biogen plans to initiate phase 3b study evaluating potential benefit of a higher dose of nusinersen in patients previously treated with Evrysdi (risdiplam). News release. Biogen. September 15, 2021. Accessed October 5, 2021. https://investors.biogen.com/news-releases/news-release-details/biogen-plans-initiate-phase-3b-study-evaluating-potential
6. Clene announces initiation of a second FDA expanded access program with CNM-Au8 for people living with amyotrophic lateral sclerosis. News release. Clene Nanomedicine. September 23, 2021. Accessed October 5, 2021. https://www.globenewswire.com/news-release/2021/09/23/2302037/0/en/Clene-Announces-Initiation-of-a-Second-FDA-Expanded-Access-Program-with-CNM-Au8-for-People-Living-with-Amyotrophic-Lateral-Sclerosis.html
7. Eisai Initiates Rolling Submission to the U.S. FDA for Biologics License Application of Lecanemab (ban2401) For Early Alzheimer’s Disease Under the Accelerated Approval Pathway. Eisai. News release. September 28, 2021. Accessed October 5, 2021. https://eisai.mediaroom.com/2021-09-27-Eisai-Initiates-Rolling-Submission-To-The-U-S-FDA-For-Biologics-License-Application-Of-Lecanemab-BAN2401-For-Early-Alzheimers-Disease-Under-The-Accelerated-Approval-Pathway
8. Swanson CJ, Zhang Y. Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer disease with lecanemab, an anti-Aß protofibril antibody. Alzheimers Res Ther. 2021;13(80). doi:10.1186/s13195-021-00813-8
9. Zogenix submits supplemental new drug application for fintepla (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome. News release. Zogenix. September 28, 2021. Accessed October 5, 2021. https://finance.yahoo.com/news/zogenix-submits-supplemental-drug-application-120000336.html
10.FDA Approves QULIPTA™ (atogepant), the First and Only Oral CGRP Receptor Antagonist Specifically Developed for the Preventive Treatment of Migraine. News release. AbbVie. September 28, 2021. Accessed October 5, 2021. https://news.abbvie.com/news/press-releases/fda-approves-qulipta-atogepant-first-and-only-oral-cgrp-receptor-antagonist-specifically-developed-for-preventive-treatment-migraine.htm?view_id=1531
11. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. NEJM. 2021; 385:695-706. doi:10.1056/NEJMoa2035908