Pending FDA Decisions in Neurology to Watch in the First Half of 2024

There are several pending treatment decisions to come in the first half of 2024, ranging from neurological specialties in movement disorders, neuromuscular, headache and migraine, epilepsy, and much more. As there is so much happening constantly in the clinical drug pipeline, keeping up with the latest approvals might be a challenge.

Here are a few critical FDA pending approvals with expected data readouts in 2024 that NeurologyLive® will have its eye on.

Multiple Sclerosis: GA Depot (Viatris and Mapi Pharma)

Aaron Miller, MD, FAAN,

Viatris and Mapi Pharma’s glatiramer acetate depot (GA Depot) is an investigational long-acting intramuscular injection of GA in development for the treatment of patients with relapsing forms of multiple sclerosis (MS). The therapy is composed of extended-release microspheres administered intramuscularly typically every 28 days, extending the treatment cycle compared with other GA products.¹ The FDA accepted Mapi’s new drug application (NDA) in August 2023, using data from a phase 3 study (NCT04121221) which featured 1016 patients randomly assigned to 40 mg of GA Depot or placebo, via intramuscular injection, once every 4 weeks for a total of 13 doses.²

In the trial, treatment with GA Depot resulted in a 30% statistically significant reduction of annualized relapsing rate relative to placebo (P = .0066). In addition to positive findings on the primary end point, treatment with GA Depot resulted in a 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) over a 52-week treatment period. Mean Expanded Disability Status Scale scores were also consistently and statistically significantly (P = .0193) reduced in the GA Depot arm. Findings from the study were strengthened by MRI end points as well.

The study’s principal investigator, Aaron Miller, MD, FAAN, medical director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, said in a statement that the therapy offers administration advantages with significant efficacy. “The monthly administration of GA Depot should offer patients a much more preferable schedule than current regimens of GA, a long-standing pillar in the treatment of MS, and lead to improved patient satisfaction and medication adherence,” he said.³

Duchenne Muscular Dystrophy: Givinostat (Italfarmaco Group)

Craig McDonald, MD

Givinostat (Italfarmaco Group), a proprietary histone deacetylase (HDAC) inhibitor, is currently in development as a treatment for patients with Duchenne muscular dystrophy (DMD). The treatment is designed to inhibit HDACs, which are enzymes that prevent gene translation by changing the 3-dimensional folding of DNA in the cell. With a PDUFA date of March 21, 2024, if approved, the therapy may help to activate muscle repair mechanisms to increase muscle regeneration, reduce inflammation, and reduce fibrosis. In November 2023, the FDA extended the review time of the accepted NDA submission for givinostat, with data from the phase 3 EPIDYS trial (NCT02851797) as the supporting evidence.⁴

The trial 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. 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). A variety of secondary end points such as the North Star Ambulatory Assessment and time to rise (TTR) test were consistent with the functional primary end point. In addition, fat infiltration in the vastus lateralis muscle of the high, considered a characteristic of disease progression in DMD, was assessed using a noninvasive objective imaging method called magnetic resonance spectroscopy. All told, givinostat treatment resulted in delayed fat infiltration by approximately 30% (difference vs placebo, –2.9%; nominal P = .035).

"I believe the EPIDYS study results are clinically meaningful, are consistent with previous findings and further demonstrate that Givinostat can slow down muscle deterioration leading to a reduction in the decline of muscle function," Craig McDonald, MD, professor in the department of pediatrics and physical medicine & rehabilitation at the University of California Davis, said in a statement at the time.⁵

Parkinson Disease: SPN-830 (Supernus)

Regina Katzenschlager, MD

SPN-830 (Supernus) is an investigational continuous apomorphine infusion pump, for the treatment of patients with Parkinson disease (PD) who experience motor fluctuations, or OFF episodes. According to the company, the SPN-830 continuous pump will allow patients to administer the medication less invasively and more conveniently. The NDA for the infusion device was originally submitted by Supernus in September 2020 but was met with a refusal to file letter from the FDA in November 2020, after an insufficiency was cited in the application. Following a Type A meeting between Supernus and the agency in March 2021, the company resubmitted the NDA in December 2021. In November 2023, the agency accepted the resubmission and is expected to reach a decision on whether to approve the therapy by April 5, 2024.⁶

The new drug application (NDA) was supported by findings from the TOLEDO study (NCT02006121), which were published in Lancet Neurology in 2018.⁷ TOLEDO was a randomized, double-blind, multicenter study that included 128 patients with PD at 23 sites, of whom 106 were included in the full analysis. Patients were randomly assigned to 3-mg/hour to 8-mg/hour dose of apomorphine (n = 53) or placebo saline infusion (n = 53) during their waking hours for a 12-week period. In TOLEDO, treatment with SPN-830 was associated with a difference of –1.89 hours per day in OFF time for patients with PD in comparison with placebo, with reductions observed within the first week of treatment with the infusion device. The intervention group also experienced a reduction in OFF time from baseline of –2.47 hours per day (SD, 3.70) compared with–0.58 hours per day (SD, 2.80) for placebo (95% CI, –3.16 to –0.62; P = .0025).

"The results of the TOLEDO study provide level 1 evidence for the first time and confirm what clinicians had observed and reported in uncontrolled studies for several decades: good efficacy and tolerability of apomorphine SC infusion in PD patients whose motor fluctuations have become difficult to manage by adjusting oral treatment," Regina Katzenschlager, MD, of the Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, told in a previous interview with NeurologyLive. "The effect size is similar to the other infusion therapy, intestinal levodopa gel, and the improvement in OFF duration is not achieved at the expense of increased dyskinesia."

Neuromyelitis Optica Spectrum Disorder: Ravulizumab (Alexion)

Sean J. Pittock, MD

Alexion’s ravulizumab (Ultomiris) is a long-acting C5 complement inhibitor in development for the treatment of adults with aquaporin-4-antibody-positve neuromyelitis optica spectrum disorder (NMSOD). In September 2023, the FDA issued a complete response letter (CRL) to the company for the supplemental biologics license application (sBLA) of ravulizumab for NMOSD, requesting modifications to enhance the Risk Evaluation and Mitigation Strategy program.⁸ AstraZeneca is expected to work with the agency to determine the next steps and will not need any additional analysis or reanalysis of the phase 3 CHAMPION-NMOSD study (NCT04201262), the supporting trial for ravulizumab’s sBLA. The potential approval date for the treatment in NMOSD is currently tentative.

CHAMPION-NMOSD was an open-label, multicenter trial that evaluated the efficacy and safety of ravulizumab in patients with anti-AQP4 NMOSD who had at least 1 attack or relapse in the 12 months prior to the screening visit. In the trial, ravulizumab met its primary end point of time to first on-trial relapse, with no relapses observed in 58 patients with anti-aquaporin-4 NMOSD over a 73-week treatment period.9 Previously approved as a medication for myasthenia gravis, the therapy demonstrated statistically significant and clinically meaningful reductions in the risk of relapse compared with those on placebo from the external PREVENT trial (NCT01892345), a phase 3 study that evaluated eculizumab (Soliris; Alexion), an FDA-approved treatment for NMOSD.

"Every NMOSD relapse can have debilitating and irreversible consequences, so reducing relapses is critical,” primary investigator Sean J. Pittock, MD, director, Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, said in a statement.⁹ “Patients on ravulizumab remained relapse free over a median treatment duration of 73 weeks in the trial."

Epilepsy: Diazepam Buccal Film (Aquestive)

Jacqueline A. French, MD

Diazepam buccal film (Libervant; Aquestive) is a buccally administered soluble film formulation of diazepam, a benzodiazepine that treats acute uncontrolled seizures in selected patients with refractory epilepsy who are on stable regimens of antiseizure medications. The therapy is an alternative to Diastat, or diazepam rectal gel, which was the first FDA-approved treatment for patients with seizure clusters and considered the current standard of care rescue therapy. The FDA is expected to have a decision by April 28, 2024, and if approved, could be the first orally administered dosage form available to manage seizure clusters in patients.

After receiving a CRL from the FDA in September 2020, the FDA accepted the resubmitted NDA for the agent for the management of seizure clusters.¹⁰ The NDA was supported by data from a single-dose crossover study (NCT03953820) that included adult patients aged 18 to 65 with epilepsy who were on a stable regimen of at least 1 antiepileptic drug. In total, 28 patients were included in the final analysis, receiving mean doses of 15.4 (±-1.9) mg of diazepam buccal film and 17.1 (±-3.0) mg of the rectal gel. The second study included in the NDA was a phase 3 safety and tolerability trial (NCT03428360) that included patients aged 2 to 65 who received diazepam buccal film doses ranging from 5 mg to 17.5 mg. Results of that analysis showed that 6.9% (n = 5) of the 72-patient cohort reported 7 mild treatment-related adverse events (AEs) over a mean follow-up of 192 days.¹¹

“One of the goals of rescue therapy is to treat seizure clusters, recognized as medical emergencies, before negative consequences may be experienced,” Jacqueline A. French, MD, professor of neurology, Comprehensive Epilepsy Center, NYU Langone Health, and chief medical & innovation officer, Epilepsy Foundation, said in a statement.¹² “These consequences may include injury and seizure progression to status epilepticus. Having a seizure rescue treatment that is generally safe, reliable and ready-to-use is very empowering. We encourage all epilepsy patients to work with their doctors to make sure they have a seizure rescue treatment plan in place.”

Huntington Disease: Valbenazine (Neurocrine)

Eiry W. Roberts, MD

Valbenazine (Ingrezza; Neurocrine), a selective vesicular monoamine transporter 2 inhibitor, is an FDA-approved treatment for chorea associated with Huntington disease (HD) and tardive dyskinesia. A new formulation of valbenazine capsules for oral administration intend to sprinkle on soft foods prior to administration is currently in development, offering a new method to make administration easier. The agency is expected to make a decision on the agent by August 30, 2024.¹³

The sNDA is supported by findings from the double-blind, placebo-controlled, phase 3 KINECT-HD study (NCT04102579) and the ongoing open-label KINECT-HD2 study (NCT04400331). Each study features adults aged 18 to 75 years of age who have been diagnosed with either manifest HD or motor manifest HD who have sufficient chorea symptoms. In KINECT-HD, a total of 128 patients with HD were randomly assigned 1:1 to either valbenazine or placebo for a 12-week treatment period, with the first 8 weeks being dose-adjusted followed by a 4-week maintenance phase.¹⁴ At the conclusion of the trial, the agent met its primary end point, represented by a statistically significant placebo-adjusted reduction in the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score of 3.2 units (P <.00001) from baseline to weeks 10 and 12.11 KINECT-HD2, the open-label study, continued to highlight the therapy’s longterm efficacy and safety. All told, improvements in chorea were observed at the first evaluation (week 2) when participants were taking the lowest dose of 40 mg, with efficacy sustained through week 50 at a maximal dose of 80 mg.¹⁵

"Interim data results from the KINECT-HD2 open-label study suggest one-capsule, once-daily valbenazine improved chorea at the first evaluation at week 2 when participants were taking the initial dose of 40 mg, with efficacy sustained through week 50 at most 80 mg," Eiry W. Roberts, MD, chief medical officer at Neurocrine Biosciences, told NeurologyLive®. "More than half of participants and investigators rated symptoms as 'much improved' or 'very much improved' at week 6, and about 3-quarters of participants and investigators rated symptoms as 'much improved' or 'very much improved' by week 50. The most common treatment-emergent adverse events at the time of the analysis were consistent with those observed in the phase 3 KINECT-HD study, including falls, fatigue and somnolence."

Lambert-Eaton Myasthenic Syndrome: Amifampridine (Catalyst Pharmaceuticals)

Patrick J. McEnany

Amifampridine (Firdapse; Catalyst Pharmaceuticals), is an approved treatment for Lambert-Eaton myasthenic syndrome (LEMS) for patients aged 6 to 17 years of age and is the only FDA-approved medicine for adults with this syndrome. In October 2023, the FDA accepted for review the company's sNDA to increase the indicated maximum daily dosage of amifampridine tablets 10 mg from 80mg to 100mg, giving an assigned PDUFA action date of June 4, 2024.¹⁶

In a previously published study of the Catalyst product in 26 adults with LEMS, amifampridine (n = 13) demonstrated a significant benefit in quantitative myasthenia gravis (QMG) score and subject global impression compared with placebo (n = 13) at the 4-day mark. Other measures of efficacy, including Clinical Global Impression-Improvement, 3TUG, and QMG limb domain score, also improved. The most common AEs in the placebo group were muscle weakness (n = 5) and fatigue (n = 4), as anticipated from amifampridine withdrawal. Back pain (n = 1), pain in extremity (n = 1), and headache (n = 1) were reported in only the amifampridine phosphate group.¹⁷

"We are pleased by the agency's acceptance of the sNDA filing for amifampridine, marking yet another milestone in the advancement of our initiative to address an important need of LEMS patients and their physicians who desire an increased daily dosage," Patrick J. McEnany, Chairman and CEO of Catalyst, said in a statement.¹⁶ "Amifampridine has proven to be an important therapeutic option for individuals in the U.S. affected by LEMS, including those comorbid with small-cell lung cancer. If approved, this will offer additional indicated dosage options for patients with LEMS who may benefit from a amifampridine daily dosage greater than 80mg and further underscores our unwavering commitment to the patient communities we serve. We look forward to working collaboratively with the agency during the application review process."

REFERENCES
1. 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.
2. Viatris and Mapi Pharma announce FDA acceptance of new drug application filing for GA Depot for the treatment of relapsing forms of multiple sclerosis. Viatris. August 7, 2023. Accessed January 26, 2024. https://www.prnewswire.com/news-releases/viatris-and-mapi-pharma-announce-fda-acceptance-of-new-drug-application-filing-for-ga-depot-for-the-treatment-of-relapsing-forms-of-multiple-sclerosis-301894145.html
3. Mapi Pharma Announces Positive Top-Line Results from GA Depot Phase III Trial for Relapsing forms of Multiple Sclerosis (RMS). News release. Mapi Pharma. September 21, 2022. Accessed January 26, 2024. https://mapi-pharma.com/mapi-pharma-announces-positive-top-line-results-from-ga-depot-phase-iii-trial-for-relapsing-forms-of-multiple-sclerosis-rms/
4. Italfarmaco group announces new PDUFA date for givinostat DMD NDA. News release. November 29, 2023. Accessed January 26, 2024. https://finance.yahoo.com/news/italfarmaco-group-announces-pdufa-date-100000954.html
5. Italfarmaco group announces positive topline data from phase 3 trial showing beneficial effect of givinostat in patients with Duchenne muscular dystrophy. News release. June 25, 2022. Accessed January 26, 2024. https://www.businesswire.com/news/home/20220625005001/en/Italfarmaco-Group-Announces-Positive-Topline-Data-from-Phase-3-Trial-Showing-Beneficial-Effect-of-Givinostat-in-Patients-with-Duchenne-Muscular-Dystrophy
6. Supernus announces SPN-830 apomorphine infusion device NDA accepted for review by FDA. News release. November 2, 2023. Accessed January 26, 2024. https://ir.supernus.com/news-releases/news-release-details/supernus-announces-spn-830-apomorphine-infusion-device-nda
7. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomized, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759. doi:10.1016/S1474-4422(18)30239-4
8. Update on US regulatory review of Ultomiris in NMOSD. News release. AstraZeneca. September 6, 2023. Accessed January 26, 2024. https://www.astrazeneca.com/media-centre/press-releases/2023/update-on-us-review-of-ultomiris-for-nmosd.html
9. Ultomiris met primary end point in CHAMPION-NMOSD phase 3 trial in adults with neuromyeltis optica spectrum disorder. News release. AstraZeneca. May 5, 2022. Accessed January 26, 2024. https://www.astrazeneca.com/media-centre/press-releases/2022/ultomiris-nmosd-ph-iii-trial-met-primary-endpoint.html
10. Aquestive Therapeutics announces FDA acceptance of new drug application (NDA) resubmission for Libervant (diazepam) buccal film. News release. Aquestive Therapeutics. July 19, 2021. Accessed January 26, 2024. https://finance.yahoo.com/news/aquestive-therapeutics-announces-fda-acceptance-132900206.html
11. Seinfeld S, Gelfand M, Heller AH, Buan C, Slatko G. Safety and tolerability associated with chronic intermittent use of diazepam buccal film in pediatric, adolescent, and adult patients with epilepsy. Presented at: 2019 American Epilepsy Society Annual Meeting. December 6-10, 2019; Baltimore, MD. Abstract 3.444.
12. Aquestive Therapeutics Announces U.S. Food and Drug Administration Filing Acceptance of New Drug Application (NDA) for Libervant™ (diazepam) Buccal Film [press release]. Warren, NJ: Aquestive Therapeutics; Published February 10, 2020. finance.yahoo.com/news/aquestive-therapeutics-announces-u-food-120010825.html. Accessed January 26, 2024.
13. Neurocrine Biosciences announces US FDA accepts supplemental new drug application for valbenazine as a treatment for chorea associated with Huntington disease. News release. Neurocrine Biosciences. December 22, 2022. Accessed January 26, 2024. https://www.prnewswire.com/news-releases/neurocrine-biosciences-announces-us-fda-accepts-supplemental-new-drug-application-for-valbenazine-as-a-treatment-for-chorea-associated-with-huntington-disease-301709335.html
14. Neurocrine Biosciences Presents Additional Phase 3 Data for KINECT-HD Study Evaluating Valbenazine for Chorea Associated with Huntington Disease at HSG 2022. News release. Neurocrine. November 3, 2022. Accessed J January 26, 2024. https://www.prnewswire.com/news-releases/neurocrine-biosciences-presents-additional-phase-3-data-for-kinect-hd-study-evaluating-valbenazine-for-chorea-associated-with-huntington-disease-at-hsg-2022-301666869.html
15. Neurocrine Biosciences presents INGREZZA (Valbenazine) capsules interim data demonstrating sustained improvements in chorea associated with Huntington’s disease through week 50 at Huntington Study Group 2023. News release. Neurocrine Biosciences. November 2, 2023. Accessed January 26, 2024. https://www.prnewswire.com/news-releases/neurocrine-biosciences-presents-ingrezza-valbenazine-capsules-interim-data-demonstrating-sustained-improvements-in-chorea-associated-with-huntingtons-disease-through-week-50-at-huntington-study-group-2023-301969545.html
16. Catalyst Pharmaceuticals Announces FDA Acceptance of the Supplemental New Drug Application for FIRDAPSE®. News Release. Catalyst Pharmaceuticals. Published October 13, 2023. Accessed January 26, 2024. https://finance.yahoo.com/news/catalyst-pharmaceuticals-announces-fda-acceptance-120300079.html
17. Sheih P, Sharma K, Kohrman B, Oh SJ. Amifampridine Phosphate (Firdapse) Is Effective in a Confirmatory Phase 3 Clinical Trial in LEMS. J Clin Neuromuscul Dis. 2019;20(3):111-119. doi: 10.1097/CND.0000000000000239.