FDA Action Update, March 2024: Approvals, AdComm, and Draft Guidance

The FDA was busy in March 2024, making a number of decisions on potential new therapeutic agents including granting approvals, issuing a revised draft guidance, issuing complete response letters, and scheduling an ADComm meeting.

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 Approves Single-Dose SelfJect Injector Delivery Device for Inflammatory and Autoimmune Conditions

At the start of the month, on March 1, the FDA approved a new single-dose, pre-filled delivery device, named SeflJect, to be used for Acthar Gel (repository corticotropin injection; Mallinckrodt), a treatment indicated for a various number of chronic and acute inflammatory and autoimmune conditions, including multiple sclerosis (MS). SelfJect is intended to provide an appropriate subcutaneous dose of the therapy and may help improve patients' control of administration.¹

SelfJect, which may allow for fewer steps during the self-administration of Arthar Gel, is expected to launch in the US in the second half of 2024. Acthar Gel, which has been prescribed by more than 9200 health care professionals, is indicated for a number of different conditions, including for acute exacerbations of MS, infantile spasms, symptomatic sarcoidosis, and acute and chronic allergic and inflammatory processes involving the eye and its adnexa.

"We're excited to bring this innovation to US patients with chronic and acute inflammatory and autoimmune conditions," Peter Richardson, MRCP, executive vice president and chief scientific officer at Mallinckrodt, said in a statement.¹ "This approval reflects Mallinckrodt's longstanding commitment to clinical research and therapeutic modernization efforts providing a new delivery device for patients, caregivers, and medical professionals managing these challenging conditions."

FDA Issues Complete Response Letter for Vanda Pharmaceuticals' Tasimelteon for Insomnia

A few days later, on March 6, the FDA rejected Vanda Pharmaceuticals' supplemental new drug application (sNDA) for tasimelteon (Hetlioz) in the treatment of insomnia.²

In July 2023, the FDA assigned a PDUF date of March 4, 2024, to make a decision on tasimelteon for insomnia, characterized by difficulties with sleep initiation. A month prior, on February 4, 2024, the FDA identified deficiencies regarding labeling and post-marketing requirements. As a result of these deficiencies, the FDA issued a Complete Response Letter (CRL) stating the submission of tasimelteon could not be approved in the treatment's current form.

The FDA previously approved tasimeleton on January 31, 2014, for non-24-hour sleep-wake disorder in blind individuals.³ Tasimeleton is also approved for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome.⁴

FDA AdComm to Review Investigational Alzheimer Agent Donanemab and Phase 3 Results

A couple of days later, on March 8, Eli Lilly announced that the FDA’s Peripheral and Central Nervous System Drugs Committee will convene for a meeting to deliberate over its antiamyloid therapy donanemab, and the supportive phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511). The date of the advisory meeting has yet to be set by the FDA, and, as a result, the timing of expected FDA action for the treatment will be delayed beyond the first quarter of 2024.⁵

Donanemab, a humanized IgG1 monoclonal antibody designed for the treatment of symptomatic Alzheimer disease (AD), looks to be the third approved antiamyloid therapy for the neurodegenerative disorder, following the conditional approval of aducanumab (Aduhelm; Biogen) in 2021, and lecanemab (Leqembi; Eisai) in 2023. In its announcement, Eli Lilly noted that the agency would like to review topics related to the safety and efficacy of the therapy, including the safety results in donanemab-treated patients and the efficacy implications of the unique trial design of TRAILBLAZER-ALZ 2.

"We are confident in donanemab's potential to offer very meaningful benefits to people with early symptomatic Alzheimer's disease," Anna White, executive vice president at Eli Lilly, and president of Lilly Neuroscience, said in a statement.⁵ "It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process, but we look forward to the opportunity to further present the TRAILBLAZER-ALZ 2 results and put donanemab's strong efficacy in the context of safety. We will work with the FDA and the stakeholders in the community to make that presentation and answer all questions."

FDA Issues Revised Draft Guidance for Drug Development in Early Alzheimer Disease

A few more days later, on March 11, the FDA issued a revised draft guidance for industry leaders titled “Early Alzheimer's Disease: Developing Drugs for Treatment.” Once the guidance is finalized, the agency noted the information will help to provide recommendations for drug companies in development of treatments for patients in the early stages of Alzheimer disease (AD) that occur before the onset of overt dementia.^7,8

This newly proposed draft guidance is a revision of the prior draft issued on February 16, 2018.⁹ The FDA noted in the statement that participants can submit either electronic or written comments on the draft until May 13, 2024, to ensure the agency considers the comment before the initiation of the final version.

“The FDA is committed to reducing the burden of AD,” Teresa Buracchio, MD, director of the Center for Drug Evaluation and Research’s Office of Neuroscience, said in a statement.⁷ “This guidance document provides the agency’s current thinking about diagnostic criteria and clinical staging and the selection of appropriate outcome measures, including the use of surrogate endpoints, for the early stages of AD.”

FDA Issues Complete Response Letter for Long-Acting Form of Glatiramer Acetate for Relapsing Multiple Sclerosis

On the same day, March 11, the FDA issued a complete response letter (CRL) for Viatris and Mapi Pharma’s investigational agent GA Depot, a long-acting, once-monthly glatiramer acetate (GA Depot) solution as a potential treatment for patients with relapsing forms of multiple sclerosis (MS). The companies are reviewing the content of the CRL and will be determining the next steps to advance this treatment for patients with MS.¹⁰

The agency originally accepted the new drug application (NDA), which comprised of data from a phase 3, multinational, double-blind, placebo-controlled study (NCT04121221) of GA Depot in November 2023. In the trial, treatment with GA Depot led to statistically significant reduction of annualized relapse rate (ARR) relative to placebo (P = .0066) over a 52-week period. Findings from the study were strengthened by MRI end points as well.¹¹

In the study, 1016 patients with relapsing-remitting MS and active secondary progressive MS aged 18-55 were randomly assigned to 40 mg of GA Depot or placebo, via intramuscular injection, once every 4 weeks for a total of 13 doses. At 52 weeks, patients on the therapy demonstrated 28.5% reduction in cumulative new enhancing T1 lesions (P = .0083) and a 17.3% reduction of cumulative number of new or newly enlarging hyperintense T2 lesions (P = .0305). Additionally, treatment with the therapy resulted in consistently and statistically significant (P = .0193) reductions in mean Expanded Disability Status Scale (EDSS) scores.

FDA Approves Italfarmaco's Givinostat for Duchenne Muscular Dystrophy

About more than a week later, on March 21, the FDA approved Italfarmaco SpA's givinostat (Duvyzat), a proprietary histone deacetylase (HDAC) inhibitor, as a treatment for patients with Duchenne muscular dystrophy (DMD).^13,14 The treatment is designed to inhibit HDACs, enzymes that prevent gene translation by changing the 3-dimensional folding of DNA in the cell. The decision makes it the first nonsteroidal drug approved to treat patients with all genetic variants of DMD.

The supporting data for the approval of givinostat comes from the phase 3 EPIDYS trial (NCT02851797). EPIDYS, a randomized, double-blind, placebo-controlled, multicenter study, included 179 ambulant male individuals who were randomly assigned 2:1 to either oral givinostat or placebo for an 18-month treatment period. Of these, 120 boys formed the target population. Published recently in The Lancet Neurology, results showed a slower decline in givinostat-treated patients on the primary end point of climbing 4 stairs in comparison with placebo (difference, 1.78 seconds; P = .0345).¹⁵

“We are pleased that the FDA approved givinostat for individuals with Duchenne age 6 and older. This adds to the list of approved treatments for families facing this devastating disease and is an important step forward in accelerating transformative treatments for everyone independent of their genetic mutation," Debra Miller, the founder and chief executive officer of CureDuchenne, told NeurologyLive®.

FDA Approves Alexion's Ravulizumab-cwvz for Neuromyelitis Optica Spectrum Disorder

At the end of the month, on March 25, the FDA approved ravulizumab-cwvz (Ultomiris; Alexion), a terminal compliment C5 inhibitor, for the treatment of patients with anti-aquaporin (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). With the decision, ravulizumab-cwvz becomes the fourth approved therapy for this patient population, following behind eculizumab (Soliris; Alexion), inebilizumab (Uplizna; Horizon Therapeutics), and satralizumab (Enspryng; Genentech).¹⁶

In September 2023, the FDA issued a complete response letter to the company for the supplemental biologics license application (sBLA) of ravulizumab-cwvz for NMOSD. In its response, the agency requested modifications to enhance the Risk Evaluation and Mitigation Strategy program and did not need any additional analysis or reanalysis of the phase 3 CHAMPION-NMOSD study (NCT04201262), the supporting trial for ravulizumab-cwvz’s sBLA.

"Complement inhibition is a very powerful treatment for prevention of NMOSD relapses. Now that ravulizumab-cwvz is approved, it makes it easier for patients to take a once every 2 months infusion rather than once every 2 weeks. The safety issues regarding infections with encapsulated organisms are essentially the same as eculizumab and other complement inhibitors. I am hopeful an improved [Risk Evaluation and Mitigation Strategy] program will help to address those concerns," Michael Levy, MD, PhD, associate professor of neurology at Harvard Medical School and also serves as the chairman for the medical advisor board at The Sumaira Foundation, told NeurologyLive®.

REFERENCES
1. Mallinckrodt announces US FDA approval of supplemental new drug application for Acthar Gel (repository corticotropin injection) single-dose pre-filled SelfJect injector. News release. Mallinckrodt. March 1, 2024. Accessed April 3, 2024. https://www.prnewswire.com/news-releases/mallinckrodt-announces-us-fda-approval-of-supplemental-new-drug-application-for-acthar-gel-repository-corticotropin-injection-single-dose-pre-filled-selfject-injector-302077212.html
2. Vanda Pharmaceuticals Announces FDA Update for Supplemental NDA for HETLIOZ® in the Treatment of Insomnia. Vanda Pharmaceuticals. March 6, 2024. Accessed April 3, 2024. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://vandapharmaceuticalsinc.gcs-web.com/node/15816/pdf.
3. FDA Approves Hetlioz. Drugs.com. January 2014. Accessed April 3, 2024.https://www.drugs.com/newdrugs/fda-approves-hetlioz-first-non-24-hour-sleep-wake-disorder-blind-individuals-4005.html.
4. FDA Approves Hetlioz (Tasimelteon) For the Treatment of Nighttime Sleep Disturbances In Smith-Magenis Syndrome. Drugs.com. December 2020. Accessed April 3, 2024. https://www.drugs.com/newdrugs/fda-approves-hetlioz-tasimelteon-nighttime-sleep-disturbances-smith-magenis-syndrome-5398.html.
5. US Food and Drug Administration to convene advisory committee meeting to discuss the TRAILBLAZER-ALZ 2 study of donanemab. News release. Eli Lilly. March 8, 2024. Accessed April 3, 2024. Eli Lilly. https://investor.lilly.com/news-releases/news-release-details/us-food-and-drug-administration-convene-advisory-committee
6. FDA issues guidance regarding drug development for early Alzheimer’s disease. News Release. U.S. Food and Drug Administration. Published March 11, 2024. Accessed April 3, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-guidance-regarding-drug-development-early-alzheimers-disease
7. FDA issues guidance regarding drug development for early Alzheimer’s disease. News Release. U.S. Food and Drug Administration. Published March 11, 2024. Accessed April 3, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-guidance-regarding-drug-development-early-alzheimers-disease
8. U.S. Food and Drug Administration Early Alzheimer’s Disease: Developing Drugs for Treatment. Guidance Document. Published March 11, 2024. Accessed April 3, 2024.
9. U.S. Food and Drug Administration. Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry.; 2018.
10. Viatris and Mapi Pharma Statement Regarding New Drug Application for GA Depot. News Release. Viatris. Published March 11, 2024. Accessed April 3, 2024. https://newsroom.viatris.com/press-releases?item=123816
11. Miller AE, Popper L, Berger JR, et al. Results of a Phase III, Multinational, Double Blind, Placebo-Controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P087.
12. FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy. FDA. News release. March 21, 2024. Accessed April 3, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-nonsteroidal-treatment-duchenne-muscular-dystrophy
13. FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy. FDA. News release. March 21, 2024. Accessed April 3, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-nonsteroidal-treatment-duchenne-muscular-dystrophy
14. Italfarmaco group announces new PDUFA date for givinostat DMD NDA. News release. November 29, 2023. Accessed April 3, 2024. https://finance.yahoo.com/news/italfarmaco-group-announces-pdufa-date-100000954.html
15. Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024;23(4):393-403. doi:10.1016/S1474-4422(24)00036-X
16. ULTOMIRIS® (ravulizumab-cwvz) approved in the US for the treatment of adults with neuromyelitis optica spectrum disorder (NMOSD). News Release. Alexion Pharma. Published March 25, 2024. Accessed April 3, 2024.