Eyeing Neurology Drug Development: 2H Trial Readouts to Watch for in 2025

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Key Takeaways

Tolebrutinib, a selective BTK inhibitor, is being tested in the PERSEUS trial for its efficacy in delaying disability progression in primary progressive multiple sclerosis.
Azetukalner, a KCNQ2/3 potassium channel opener, is undergoing phase 3 trials for focal onset seizures, with primary efficacy measured by seizure frequency reduction.
Lu AG09222, targeting PACAP, is in the PROCEED trial for migraine prevention, aiming to establish optimal dosing for future studies.
KYV-101, a CD19 CAR T-cell therapy, is being evaluated in myasthenia gravis, with interim data expected to inform its potential in autoimmune diseases.
Semaglutide, a GLP-1 receptor agonist, is in phase 3 EVOKE trials for Alzheimer's, focusing on slowing cognitive decline and disease progression.

Neurology experts anticipate groundbreaking clinical trial results in 2025, potentially transforming treatment strategies for various neurological conditions.

As 2025 moves into its second half, the neurology community is looking ahead to another wave of pivotal clinical trial readouts that could reshape the landscape of care. These upcoming results span a broad spectrum of neurological conditions and represent critical steps in the development of both established and emerging therapies. From novel neuromodulation devices to first-in-class small molecules and cell-based interventions, the data expected in the coming months may refine diagnostic strategies, guide treatment decisions, and expand therapeutic possibilities. In this feature, NeurologyLive® highlights the trials to watch, detailing their design, objectives, and the potential impact of their findings on the future of neurologic care.

PERSEUS Trial of Tolebrutinib

Tolebrutinib (Sanofi) is a highly selective, oral, irreversibleBruton tyrosine kinase (BTK) inhibitor. It is distinguished from other investigational BTK inhibitors by targeting BTK with a high degree of selectivity, aiming to minimize off-target effects and reduce adverse events, particularly in the central nervous system. Later this year, Sanofi is anticipated to readout data from its ongoing phase 3, randomized, double-blind, PERSEUS study (NCT04458051), testing the effects of tolebrutinib in delaying disability progression compared with placebo in patients with primary progressive multiple sclerosis (PPMS).

Across 277 study sites, the trial also has several secondary objectives, including MRI lesions, cognitive performance, physical function, and quality of life. Investigators will also evaluate the safety and tolerability as well as the population pharmacokinetics of tolebrutinib in PPMS and its relationship to efficacy and safety. Additionally, the study will assess the pharmacodynamics of tolebrutinib among participants. Enrolled participants are aged 18 to 55 years with a diagnosis of PPMS according to the 2017 McDonald criteria and an Expanded Disability Status Scale (EDSS) score between 2.0 and 6.5. The duration of the trial will vary by each participant, with a treatment duration of approximately 12 to 60 months.

To date, the agent has been previously assessed in other clinical studies, including for patients with non-relapsing secondary progressive MS (nrSPMS) in the phase 3 HERCULES study (NCT04411641) and patients with relapsing MS in the 2 phase 3 studies (GEMINI 1 [NCT04410978] and GEMINI 2 [NCT04410991]. Sanofi used the data from those trials for tolebrutinib’s regulatory submission to the FDA as a potential treatment for nrSPMS , which the agency accepted in late March 2025.¹ With a PDUFA date scheduled for September 28, 2025, tolebrutinib could become the first and only brain-penetrant BTK inhibitor approved for the treatment of MS and the first specifically indicated for rSPMS.

Phase 3 Trial of Azetukalner

Azetukalner (Xenon Pharmaceuticals), formally known as XEN1101, is a potent small-molecule selective KCNQ2/3 potassium channel opener that is among many antiseizure medications (ASMs)currently being assessed in clinical trials.The agent is being evaluated for primary generalized tonic-clonic seizures and major depressive disorder in addition to its clinical development for focal onset seizures (FOS). Later this year, Xenon expects a topline data readout for its 2 identical phase 3 clinical trials (X-TOLE2, NCT05614063; X-TOLE3, NCT05716100) of azetukalner in FOS.²

Modeled after the phase 2b X-TOLE trial (NCT03796962), the phase 3 X-TOLE studies are both multicenter, randomized, double-blind, placebo-controlled studies assessing the clinical efficacy, safety, and tolerability of azetukalner 15-mg or 25-mg administered orally with food as adjunctive treatment, with approximately 360 participants in each study. Participants enrolled in the trials include adults aged at least 18 years who are diagnosed with FOS.The primary efficacy endpoint of the trials is the median percent change (MPC) in monthly seizure frequency from baseline through the 12-week double-blind period (DBP) of azetukalner compared with the placebo.³

Eligible participants will have up to 9.5 weeks of baseline to assess the frequency of seizures, followed by 12 weeks of blinded treatment. Participants must also be treated with a stable dose of 1 to 3 allowable ASMs for at least 1 month before screening, during baseline, and throughout the double-blind treatment period of the trial. During the DBP, patients will be instructed to orally take the agent or placebo once daily with a meal in the evening. Those who complete the 12-week DBP will have the opportunity to qualify and enroll in a separate OLE study for continued treatment with azetukalner. In addition, patients who do not enroll in the OLE will enter a post treatment follow-up period of 8 weeks.

PROCEED Trial of Lu AG09222

After years of calcitonin gene-related peptide (CGRP)-targeting treatments, a new wave of therapies–those focused on pituitary adenylate cyclase-activating polypeptide (PACAP)–are starting to emerge. Later this year, Lundbeck is expected to read out promising data from its phase 2 PROCEED trial, which tests investigational Lu AG09222, a PACAP-targeting agent, as a potential preventive for patients with migraine.

This double-blind, placebo-controlled trial, spans across Europe, Japan, and the United States, assessing 4 different doses of the candidate treatment vs placebo over a 3-month treatment period. Comprising 498 patients, the trial is intended to establish the optimal dose for future global pivotal studies, setting it up to be the first approved migraine treatment in the PACAP class. Notably, it will include patients who’ve struggled to control their disease, with a prerequisite of failing 2-4 different migraine preventives in the past 10 years.

Lu AG09222 first gained notoriety after a successful phase 2 study called HOPE (NCT05133323) demonstrated its effects on patients with migraine. In the study (n = 237), treatment with high doses of the humanized monoclonal antibody led to a 2.0-day difference in monthly migraine days (95% CI, –3.5 to –0.6; P = .0106) at the 4-week point relative to placebo. HOPE, which featured patients with episodic and chronic migraine, showed that the drug was safe, with no concerns documented, and an anti-drug antibody incidence of 11% (16 of 142).^4,5

Phase 2a Trial of KYV-101

Uniquely designed, KYV-101 (Kyverna Therapeutics) is an autologous, fully human CD19 CAR T-cell product candidate with highly potent CD28 co-stimulation and designed for tolerability, which is under investigation for B-cell-driven autoimmune diseases. Later this year, the company expects to release interim data from its phase 2 KYSA-6 trial (NCT6193889) in myasthenia gravis (MG), giving the clinical community a fresh look at how CAR T-cell approaches may treat this patient population.

The expected data will include the initial 6 patients from the 20-patient cohort. KYSA-6, a 24-week trial, uses change in Myasthenia Gravis Activities of Daily Living (MG-ADL) as the primary efficacy end point, with safety as the other major objective. In the study, patients receive a single infusion of 1 x 108 CAR T cells following lymphodepletion (fludarabine 30 mg/m2/day, cyclophosphamide 300 mg/m2/day; 3 days).

If positive, these results could have major implications on the development of CAR T-cell approaches for autoimmune conditions like MG. In a recent update, Kyverna noted it will continue to engage in positive dialogue with the FDA and will provide an update on the registrational path of KYV-101 when applicable. To date, the agent has already received regenerative medicine advanced therapeutic (RMAT) designation and fast track designation from the FDA as well as orphan drug designation from both the FDA and European Medicines Agency for this program.^6,7

Phase 1-3 Study of Zilganersen

Later this year, Ionis Pharmaceuticals is expected to readout topline data from its phase 1-3 trial (NCT04849741) testing zilganersen, an antisense oligonucleotide, in patients with Alexander disease (AxD), an ultra-rare, progressive and ultimately fatal type of leukodystrophy. AxD, a disease characterized by cognitive dysfunction and progressive neurologic deterioration, has no FDA-approved treatments to date.

The phase 1-3 trial, a unique double-blind, multiple-ascending dose study, includes patients with AxD aged 2 to 65 who are randomly assigned to either zilganersen or control for a 60-week treatment period, followed by a 180-week open-label extension. Percent change in 10-meter walk test, an assessment of gait speed, is the primary end point, while other secondary outcomes include change in patients’ self-identified Most Bothersome Symptom score, Patient Global Impression of Severity score, Patient Global Impression of Change Score, and Clinician Global Impression of Change.

If successful, the study could represent significant progress in the treatment of AxD, which has had little drug development over the years. A unique aspect of the phase 1-3 trial includes an open-label sub-study of patients under the age of 2 years with AxD, which continued enrollment this year. In addition to the aforementioned end points, the trial will also test changes in motor function, quality of life, autonomic symptoms, and glial fibrillary acidic protein (GFAP) levels.^8,9

COMPASS PWS Trial of ACP-101

An intranasal formulation of carbetocin, known as ACP-101, is in development for the treatment of hyperphagia in patients with Prader-Willi syndrome (PWS).Prior studies have shown that carbetocin has improved properties over oxytocin, such as a longer half-life and greater specificity for the oxytocin receptor versus vasopressin receptors, which may offer meaningful efficacy and a favorable safety profile in patients with PWS.Acadia Pharmaceuticals is expecting a readout of topline data later this year from its phase 3 COMPASS PWS trial (NCT06173531) assessing the investigational nasal spray drugfor hyperphagia in PWS.¹⁰

Initiated in November 2023, the trial is a 12-week, double-blind, randomized, placebo-controlled global phase 3 study investigating the efficacy and safety of carbetocin nasal spray 3.2 mg 3 times daily in approximately 170 pediatric patients and adult patients aged 5 to 30 years with PWS. The primary efficacy endpoint of the trial is the change from baseline to week 12 on the hyperphagia questionnaire for clinical trials (HQ-CT) score. Participants who complete the study will be eligible to enroll in a long-term, open-label extension study (NCT06420297), which will assess the safety and tolerability of long-term treatment with ACP-101 in 36-months.¹¹

If findings from the COMPASS PWS trial of ACP-101 are positive, Acadia noted that the company will anticipate submitting a new drug application to the FDA in the first quarter of 2026.Previously, the agency granted the nasal drug orphan drug, fast track, and rare pediatric disease designations for the treatment of PWS. Originally, ACP-101 was developed by Levo Therapeutics, but Acadia acquired worldwide rights to the drug in June 2022. If received approval by the FDA, ACP-101 could be the first treatment approved for Prader-Willi syndrome, specifically for hyperphagia in the rare genetic disorder.

LunAIRo trial of AD109

AD109 (Apnimed), a combination of aroxybutynin and atomoxetine, is currently being assessed in patients with mild to severe obstructive sleep apnea (OSA). Later this year, Apnimed expects topline results from its phase 3 LunAIRo study (NCT05811247), a randomized, double-blind, placebo-controlled, 1-year parallel-arm study of AD109 in OSA. Enrolling at least 660 patients, the trial is designed to evaluate the efficacy and safety of the investigational oral therapy compared with placebo. The primary end point of the trial includes measuring the proportion of participants who experience a reduction in apnea-hypopnea index (AHI) via polysomnography at 6 months and 1 year.¹²

Eligible participants of the study were adult patients aged 18 years or older who met specific polysomnography parameters, including an AHI greater than 5, with no more than 25% of events classified as central or mixed apneas and a periodic limb movement arousal index of 15 or less. Patients also needed to report significant fatigue, as indicated by a PROMIS-Fatigue raw score of at least 17. Additional requirements of the trial included intolerance to or refusal of positive airway pressure therapy and a body mass index ranging from 18.5 to 40 kg/m² for men or up to 42 kg/m² for women.

If proven effective, AD109 may become the first treatment to target both the underlying causes of OSA, including nighttime airway collapse and oxygen deprivation, and its daytime symptoms, such as fatigue. Taken once nightly at bedtime, this novel combination therapy works by activating neurological pathways that stimulate the upper airway dilator muscles, helping to keep the airway open during sleep. Designed for patients across a range of disease severities, AD109 holds the potential to offer a safe, effective, and more patient-friendly alternative to existing OSA treatments, which may be often invasive or poorly tolerated.

EVOKE Trials of semaglutide

Later this year, data is expected to be released from the phase 3 EVOKE trials, 2 landmark phase 3 studies testing semaglutide (Ozempic; Novo Nordisk), a GLP-1 receptor agonists (GLP-1RA), for its potential to slow cognitive decline in early Alzheimer disease (AD). These studies hold critical significance, as they are considered the first large-scale phase 3 trials testing a GLP-1RA in early-AD, focusing on a disease-modifying approach rather than only symptom management. Plus, if results are positive, oral semaglutide, which is already approved for diabetes and obesity, could be the first oral AD therapy to slow disease progression.

The studies are each expected to include around 1840 participants, aged between 55-85 with mild cognitive impairment or mild dementia due to AD, confirmed with amyloid positivity. The treatment schedule includes an 8-week titration period, followed by a 104-week main treatment and 52-week extension, using change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score at week 104 as the primary end point.¹³

EVOKE and EVOKE+ will also include several other secondary measures, such as ADCS-ADL, Mini-Mental State Exam, and Neuropsychiatry Inventory, in addition to CDR-SB. Investigators will also collect data on MRI/CT scans, amyloid PET, and cerebrospinal fluid biomarkers, as well as neuroinflammation markers. Notably, there is a planned CSF sub-study comprising around 210 patients that will assess an extensive panel of CSF biomarkers, organized into several key pathophysiological domains. Among those include AD pathology, neuroinflammation, neurodegeneration and synaptic injury, and oxidative stress, blood-brain barrier integrity, and vascular health.