Pending FDA Decisions in Neurology to Watch in the First Half of 2025

Several treatment decisions are anticipated in the first half of 2025 across various neurological specialties, including movement disorders, neuromuscular conditions, headache and migraine, epilepsy, and more. With the constant activity in the clinical drug pipeline, staying informed about the latest approvals can be challenging.

NeurologyLive® is closely monitoring a number of key FDA approvals and expected data readouts in 2025. Here are a few critical ones to watch:

Lecanemab (Leqembi; Eisai): IV Maintenance Dosing for Alzheimer Disease – January 25

Lecanemab (Leqembi; Eisai), which gained traditional approval in July 2023, was greenlit as a 100 mg/mL injection for patients with mild cognitive impairment or mild dementia stage of Alzheimer disease (AD), the population in which treatment was initiated in clinical trials. Formerly known as BAN2401, lecanemab is a humanized monoclonal antibody that eliminates toxic amyloid-ß protofibrils. It remains approved in other countries such as China, Japan, and South Korea, while still seeking approval in 13 other countries and regions, including the European Union.

In June 2024, the FDA accepted Eisai’s supplemental biologics license application (sBLA) for a new monthly intravenous (IV) maintenance dosing of lecanemab-irmb and has set a PDUFA action date for January 25, 2025, for the agency to give a final answer.The newly accepted sBLA was based on modeling of observed data from the phase 2 study (Study 201; NCT01767311) and its open-label extension (OLE), as well as the phase 3 Clarity AD trial (Study 301; NCT03887455), and its OLE study. Lecanemab originally was approved under accelerated approval pathway using Study 201, and was later granted traditional approval based on data from Study 301, the confirmatory trial.

Clarity AD, published in the New England Journal of Medicine, included 1795 patients with evidence of amyloid on PET or cerebrospinal fluid who were followed for around an 18-month treatment period. At the conclusion of the analysis, lecanemab met its primary end point of change in Clinical Dementia Rating-Sum of Boxes score, with treated patients demonstrating a statistically significant 27% reduction. Lecanemab remains contraindicated in patients with serious hypersensitivity to the therapy or any of the excipients of lecanemab. There are several labeled warnings and precautions to the treatment, including amyloid-related imaging abnormalities, hypersensitivity reactions, and adverse reactions.

AXS-07 (Axsome Therapeutics) for Acute Migraine – January 31

AXS-07, a novel agent, is thought to act by inhibiting calcitonin gene-related peptide (CGRP) release, reversing CGRP-mediated vasodilation, and inhibiting neuroinflammation, pain signal transmission, and central sensitization. The agent, which consists of meloxicam and rizatriptan, is enabled by Axsome’sMoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology, which results in faster absorption and longer plasma half-life.

In September 2024, the FDA accepted AxsomeTherapeutics’ resubmitted new drug application (NDA) for its novel agent AXS-07 as a treatment for acute migraine. The agency has given the oral, rapidly absorbed, multi-mechanistic investigational medicine a PDUFA action goal date of January 31, 2025.In May 2022, the company received a complete response letter for its NDA submission of AXS-07, citing issues related to the chemistry, manufacturing, and controls considerations. At the time, the agency did not request any new clinical trials to be conducted.

The original NDA, accepted for review in September 2021, was supported by data from 2 phase 3 randomized controlled clinical trials—the MOMENTUM trial (NCT03896009) and the INTERCEPT trial (NCT04163185). Overall, the studies revealed a statistically significant elimination of migraine pain with AXS-07 compared with placebo and active controls. In MOMENTUM, AXS-07 met its coprimary end points with statistical significance, first showing a greater percentage of patients achieving pain freedom (19.9%) compared with placebo (6.7%; P <.001) 2 hours after dosing. Second, the absence of the most bothersome symptom (36.9%) compared with placebo (24.4%) was significant (P = .002).

SPN-830 (Supernus Pharmaceuticals) for Parkinson Disease – February 1

SPN-830, designed as an under-the-skin continuous infusion therapy used between doses of standard levodopa-based therapy, could allow patients with Parkinson disease (PD) to administer the medication less invasively and in a more convenient fashion. In April 2024, the FDA issued a complete response letter (CRL) to the company’s new drug application (NDA) on SPN-830. The CRL indicated that the review cycle of the application is complete but it is not ready for approval in its current form.

In the CRL, the FDA cited 2 areas that require additional review or more information on SPN-830. The first area related to product quality. The other area related to the master file for the infusion device, which is proprietary to the device manufacturer.In August 2024, the FDA accepted the resubmission of the company’s NDA for the apomorphine infusion device for the continuous treatment of motor fluctuations in PD. The resubmission is considered filed, with a PDUFA date of February 1, 2025.

SPN-830 was submitted for the NDA using data from the phase 3 TOLEDO study (NCT02006121). The multicenter trial featured 106 patients with PD who received either 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. All told, treatment with SPN-830 culminated in –1.89 hours per day of better OFF time than placebo, with reductions observed within 1 week of initiating therapy.

Mirdametinib (SpringWorks Therapeutics) for Neurofibromatosis – February 28

Mirdametinib is a small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). In August 2024, the FDA accepted and granted priority review to SpringWorks Therapeutics’ NDA for mirdametinib, with a scheduled PDUFA action date of February 28, 2025.The NDA submission included data from the pivotal phase 2b ReNeu trial (NCT03962543), a multicenter, open-label study that featured 114 patients with NF1-PN (58 adult and 56 pediatric) who received mirdametinib for up to 24 months.

Presented data from ReNeu at the 2024 American Society of Clinical Oncology Annual Meeting showed that treatment with mirdametinib resulted in statistically significant objective response rate (ORR) and sustained reductions in PN volume. Coupled with improvements in pain severity, pain interference, and health-related quality of life (HRQoL), results showed that the tablet therapy may be a potentially therapeutic option for patients with NF1 PN across all ages.

Patients in the study received the investigational therapy as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 week on/1 week off 28-day cycles. Minimum clinically relevant ORR, the primary end point, was defined as at least a 23% reduction of target PN volume for adults (≥18 yrs) and 20% for pediatrics (2-17 yrs). As of the September 20, 2023, data cutoff, blinded independent central review (BICR)-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P <.001 vs null) in adults and 52% (95% CI, 38-65; P <.001 vs null) in pediatric patients treated with mirdametinib.

Diazoxide choline extended release tablets (Soleno Therapeutics) for Prader-Willi Syndrome – March 27

In early 2025, the FDA will make a decision on diazoxide choline (DCCR), a novel, proprietary extended-release dosage form containing diazoxide choline, as a new treatment for Prader-Willi syndrome (PWS) in individuals 4 years and older who have hyperphagia. It was originally set to have a decision made in December 2024; however, the FDA extended the review period in November to allow for more time to evaluate the drug’s application.

The parent molecule, diazoxide, has been used for decades in thousands of individuals in a few rare diseases in neonates, infants, children and adults, but is not approved for use in PWS. All together, the DCCR development program is supported by data from 5 completed phase 1 clinical studies in healthy volunteers and 3 completed phase 2 clinical studies, 1 of which was in individuals with PWS. DESTINY PWS, the 13-week, randomized, double-blind, placebo-controlled phase 3 trial randomly assigned 127 participants with PWS aged 4 years and older with hyperphagia 2:1 to either DCCR or placebo.

Results from DESTINY-PWS published in the journal of clinical endocrinology and metabolism showed that DCCR did not significantly improve hyperphagia (HQ-CT least-square [LS] mean, −5.94 [SE, 0.879] vs −4.27 [SE, 1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean, −9.67 [SE, 1.429] vs −4.26 [SE, 1.896]; P = .012). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).

Ataluren (PTC Therapeutics) for Nonsense Mutation Duchenne Muscular Dystrophy – PDUFA tbd, expected first half

In 2025, presumably the first half of the year, the clinical community is expected to hear back from the FDA regarding ataluren, a protein restoration therapy for boys with nonsense mutation Duchenne muscular dystrophy (nmDMD). Because this was a new drug applicaiton (NDA) resubmission following a complete response letter filed several years ago, the FDA is not obligated to follow PDUFA review timelines and thus, did not provide an action date for the therapy when the NDA was accepted in November 2024. Ataluren, marketed under the name Translarna, has been approved under conditional marketing authorization in Europe since 2014.

The NDA includes data from the pivotal study 041 (NCT00592553) as well as analyses from the STRIDE registry that could support the benefit of the therapy. Published in Neurology in 2023, the placebo-controlled study 041 randomly assigned boys with nmDMD to either ataluren or placebo for a 72-week period, followed by a 72-week open-label extension. In the study, investigators observed significant differences in 6-Minute Walk Distance in both the intent-to-treat (ITT) population (ataluren, n = 183; placebo, n = 176) and the subgroup of boys with 300 m to 400 m 6MWD (ataluren, n = 86; placebo, n = 83).The change from baseline and rate of change favored ataluren in the ITT population (14.4 m; 0.20 m per week; P = .0248) and 300 m to 400 m 6MWD subgroup (24.2 m; 0.34 m per week; P = .0310). These findings, the authors noted, represented a 21% and 30% slowing of the decline rate in 6MWD in these groups, respectively.

Ataluren originally gained conditional nod in Europe based on data from study 007 (NCT00592553), a phase 2b randomized placebo-controlled trial of patients aged 5 years and older with nonsense mutation dystrophinopathy. All told, daat from the study showed favorable, but not statistically significant, differences vs placebo on the primary end point of change in 6MWD at week 48. In 2017, when the European Medicines Agency renewed ataluren’s conditional clearance, PTC agreed to use data from a third trial, the aforementioned study 041, to confirm the drug’s benefit-risk profile.

STS101 (Satsuma Pharmaceuticals) for Acute Migraine – PDUFA tbd, expected first half

In November 2024, Satsuma resubmitted its NDA for its investigational candidate STS101, a dihydroergotamine (DHE) nasal powder, for the treatment of patients with acute migraine with or without aura. According to the company, the NDA resubmission addressed all outcomes noted in the complete response letter given earlier in the year. The FDA's prior CRL raised no concerns about STS101's clinical trial results or safety but included CMC-related formulation comments, prompting the company to plan discussions and consider reapplying for approval.

The therapy’s original NDA was supported by data from a phase 1 comparative pharmacokinetic and safety trial (NCT03874832) and the phase 3 ASCEND trial (NCT04406649). Although not required for the application, the results from the phase 3 SUMMIT trial (NCT04406649) were also considered. In ASCEND, among those exclusively treated with STS101 (n = 172), freedom from pain by 2 hours post-treatment was achieved for 34.2% of all treated attacks, while freedom from the most bothersome symptom at this time point was achieved in 53.4% of all treated attacks. In terms of safety, nasal discomfort (13.9%), dysgeusia (7.7%), and nasal congestion (6.2%), were among the most commonly reported AEs, while postural orthostatic tachycardia syndrome and cholecystitis—considered serious AEs—were observed in 1 individual each, and were not deemed related to the study treatment.

DHEs have been a long-standing treatment for acute migraines, particularly effective for severe cases or migraines that do not respond to triptans. STS101, which binds to serotonin receptors, also modulates the trigeminovascular system, reducing the release of inflammatory neuropeptides like calcitonin gene-related peptide. There is belief that STS101 could hold advantages over traditional DHEs, including faster onset and easier self-administration via a portable device.

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