Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the First Half of 2025

As neurology continues to evolve, the first half of 2025 is set to be a crucial period, with key clinical trial results expected to shape the field. These trials, covering a wide range of neurological disorders, have the potential to deepen our understanding of complex diseases and open the door to new treatment options. From cutting-edge gene therapies to innovative drug interventions, the outcomes of these studies could significantly impact clinical practices and improve patient outcomes. This article will explore these trials in detail, examining their goals, methods, and the potential implications of their findings for the future of neurology.

PROCEED study of Lu AG09222 (Lundbeck) in Migraine

While calcitonin gene-related peptide (CGRP)-targeting therapies were considered a massive success for the migraine community, there are still patients who don’t respond well to this class of medications. Pituitary adenylate cyclase-activating polypeptide (PACAP) represents a new, novel pathway to treating migraine, with several agents like Lu AG09222 in development.

PROCEED is a double-blind, dose-finding, placebo-controlled study with an anticipated cohort of 498 patients to further the test efficacy and safety of Lu AG09222 in patients with migraine. Expected to complete in the second half of 2025, the study is intended to establish the optimal dose for future global pivotal trials and remains one of the few advancing pivotal studies testing a PACAP-targeting agent. Overall, the trial will assess 4 different doses of the therapy vs placebo, administered subcutaneously once monthly for 3 months.

It acts as a follow-up to the previously completed HOPE trial (NCT05133323), a successful phase 2 study that first demonstrated the effects of Lu AG09222 in patients who’ve failed 2-4 different preventive medications. In HOPE, treatment with the therapy led to a change in mean monthly migraine days of –6.2 (SE, 0.66) in the high-dose Lu AG09222 group, –6.0 (SE, 0.94) in the low dose group, and –4.2 (SE, 0.67) for those on placebo.¹

CALLIPER study of IMU-838 (Immunic) in Progress Multiple Sclerosis

Topline data for the phase 2 CALLIPER trial (NCT05054140) assessing Immunic’s investigational agent IMU-838 in patients with progressive multiple sclerosis (PMS) is expected to be released in April. The trial is comprised of 467 patients with primary PMS, or active or non-active secondary PMS, who are randomly assigned to either 45 mg daily doses of IMU-838, or vidofludimus calcium, or placebo, for a 120-week period. This international, multicenter, double-blind trial will measure the annualized percent brain volume change as the primary endpoint, with secondary endpoints including whole brain atrophy rate and time to 24-week confirmed disability progression on the EDSS.

IMU-838 is a highly selective inhibitor of the enzyme dihyroorotate dehydrogenase (DHOD), a key enzyme in the metabolism of overreactive immune cells and virus-infected cells. In an interim analysis of CALLIPER, results showed that serum neurofilament light levels were reduced by 22.4% (P = .01) after 24 weeks of treatment, with consistent treatment effects seen across each progressive MS subtype. Notably, the IMU-838 group displayed a 10% decrease compared with a 20% increase sNfL for placebo among those with an Expanded Disability Status Scale score no more than 5.5.²

The agent was previously studied in the phase 2 EMPhASIS trial (NCT03846219), a placebo-controlled trial of 268 patients with relapsing-remitting MS. Data published earlier this year showed that daily doses of 30-mg and 45-mg of the drug, but not 10-mg, decreased the cumulative number of active lesions compared with placebo, thus establishing the lowest efficacious dose. In the cohort, the mean cumulative combined unique active (CUA) lesions was 5.8 (95% CI, 4.1-8.2) for placebo (n = 81), 5.9 (95% CI, 3.9-9.0) for 10-mg treatment group (n = 47), 1.4 (95% CI, 0.9-2.1) for 30-mg treatment group (n = 71), and 1.7 (95% CI, 1.1-2.5) for 45-mg treatment group (n = 69) over 24 weeks.³

Essential3 study of ulixacaltamide (Praxis Precision Medicines) in Essential Tremor

Praxis Precision Medicines is planning to release an interim analysis of Study 1 of its phase 3 Essential3 program (NCT06087276), a multi-trial project testing ulixacaltamide as a potential treatment for essential tremor. Study 1 is a parallel design, placebo-controlled study of 400 participants while Study 2 is a randomized withdrawal study (n = 200), both of which are anticipated to be used as supportive data for a future regulatory submission.

The studies use a decentralized approach, incorporating in-home and telehealth visits to evaluate ulixacaltamide (60 mg QAM) against placebo, as well as the maintenance and durability of response through a randomized withdrawal (RW) design. Primary end points include changes in TETRAS-Activities of Daily Living (TETRAS-ADL) scores and the proportion of participants maintaining response after RW. Secondary end points will assess responder rates, mADL11 score changes at 12 weeks, additional TETRAS-ADL changes, clinician- and patient-reported severity measures, and safety outcomes.

Ulixacaltamide previously showed promising data in a randomized withdrawal sub-study and long-term extension of a phase 2b Essential1 study (NCT05021991). During the initial 8-week double-blind period, patients treatedulixacaltamide demonstrated a mean improvement of 3.09 (95% CI, 0.98-5.2) points on mADL11. After continuing on to the 6-week open-label extension, patients gained an additional mean improvement of 1.7 points in mADL11, totaling 4.81 (95% CI, 2.38-7.23) at 14 weeks. Above all, the therapy continued to show a safety profile that was consistent with previous observations. Ulixacaltamide is a differentiated and highly selective small molecule inhibitor of T-type calcium channels designed to block abnormal neuronal burst firing in the Cerebello-Thalamo-Cortical (CTC) circuit correlated with tremor activity.⁴

STEER study of OAVIT101 (Novartis) in Spinal Muscular Atrophy

After announcing positive data in early January, Novartis expects to share additionaldata from its pivotal STEER study (NCT05089656) testing an intrathecal formulation (IT) of Zolgensma as a treatment for children with spinal muscular atrophy (SMA) later this year. According to the company, the plan is to share these results with regulatory agencies with the goal of bringing this IT formulation to market.

STEER is a pivotal sham-controlled study with more than 100 patients with SMA Type 2 who were randomly assigned to either OAVIT101, the IT formulation of Zolgensma, or a sham, for a 52-week period, followed by a crossover phase. All told, results from the study showed that the treatment met its primary end point, demonstrating enhancements in total Hammersmith Functional Motor Scale-Expanded (HFMSE) scores, considered a gold standard for SMA-specific assessment of motor ability and disease progression.⁵

Zolgensma, which came into market in 2019, is the first and only FDA-approved gene therapy for patients with SMA. An adeno-associated, virus vector-based, one-time treatment, Zolgensma was first approved in an intravenous infusion for patients less than 2 years of age with mutations in the SMN1 gene. In addition to STEER, OAV101IT has been tested in the phase ½ STRONG study (NCT03381729) and the phase 3b STRENGTH study.

SHIMMER study of CT1812 (Cognition Therapeutics) in Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) presents unique challenges in drug development and treatment approval due to its complex pathophysiology, overlapping features with other neurodegenerative disorders, and variability in symptom presentation. At the 2025 International Lewy Body Dementia Conference, held in January 29-31, in Amsterdam, the Netherlands, investigators are expected to present detailed data from the phase 2 SHIMMER study (NCT05225415), a promising signal-finding study of CT1812, a therapeutic in development for DLB.

In SHIMMER, patients with mild-to-moderate DLB receive 1 of 2 oral doses of CT1812 or placebo daily for 6 months. Participants were evaluated using various assessments: the Neuropsychiatric Inventory (NPI) to measure changes in hallucinations, anxiety, and delusions; the Montreal Cognitive Assessment (MoCA) and Cognitive Drug Research Battery (CDR) to assess cognitive performance; the Clinician Assessment of Fluctuation (CAF) to examine the frequency and duration of cognitive fluctuations; and Part III of the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) as an objective measure of parkinsonism.

Topline data announced in late December 2024 showed that the treatment met its primary end point of safety and tolerability, with data also showing improvement in behavioral, functional, cognitive, and movement measures among those treated vs placebo at 6 months. Among 130 adults with mild-to-moderate DLB, CT1812 treatment slowed neuropsychiatric decline by 82%, with significant reductions in anxiety, hallucinations, and delusions. Caregiver distress also decreased, indicating an improved quality of life for patients. Additionally, CT1812 slowed cognitive decline across three measures, including a 91% reduction in attention fluctuations compared with placebo.⁶

Phase 2a trial of RAP-219 (Rapport Therapeutics) in Focal Epilepsy

Later this year, Rapport Therapeutics is expected to announce topline results from a phase 2a trial of its investigational agent RAP-219, which selectively targets TARPγ8,7 as a potential treatment for focal epilepsy. TARPγ8 is a receptor-associated protein linked to the neuronal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, a clinically validated target in epilepsy.

The ongoing phase 2a proof-of-concept study is notable for enrolling adults with drug-resistant epilepsy who have implanted responsive neurostimulation (RNS) devices. These devices continuously capture intracranial electroencephalography (iEEG) data and record the frequency of long episodes (LE). Approximately 20 participants, aged 18–65, undergo an 8-week open-label treatment period, receiving 0.75 mg/day of RAP-219 for the first 5 days, followed by 1.25 mg/day for the remainder of the treatment. During the follow-up phase, data collection includes RNS system recordings, monthly pharmacokinetics, and clinical seizure diaries.

Key end points include changes in LE frequency per 28 days during the second 4 weeks of treatment compared to both retrospective and prospective baselines. Additional outcomes include LE frequency responder analysis, changes in estimated electrographic seizures (EES), clinical seizure frequency, and other iEEG biomarkers per 28 days.⁷

GRAND CANYON Extension of Sevasemten (Edgewise Therapeutics) in Becker Muscular Dystrophy

Becker muscular dystrophy, a severe condition that leads to progressive loss of motor function, currently has no approved therapies for patients with thecondition.Edgewise Therapeutics’ GRAND CANYON, an extension to the phase 2 CANYON trial (NCT05291091), is expected to complete recruitment by the first quarter of 2025. This multicenter, double-blind, placebo-controlled cohort further evaluates efficacy and safety of investigational sevasemten, formerly known as EDG-5506, in adults with Becker, using change in the North Star Ambulatory Assessment (NSAA) over an 18-month period as the primary end point. The study, anticipated to include 120 patients with the disease, will serve as supplemental supporting data for a future marketing application, if positive.

In December 2024, the company announced positive topline data from the CANYON trial, with results showing that sevasemtenmet its primary end point in change of creatine kinase (CK) among patients with Becker. The placebo-controlled, double-blind study featured 40 adults and 29 adolescents with Becker who were randomly assigned to either sevasemten or placebo for a 12-month treatment period, followed by a 4-week follow-up period. All told, over months 6 through 12, results revealed a 28% average difference in CK decrease among sevasemten-treated patients vs those on placebo (P = .02). According to Edgewise, this was the largest interventional trial to date in Becker and the first to achieve its primary end point.⁸

Phase 2 Study of ATH434 (Alterity Therapeutics) in Multiple System Atrophy

Multiple system atrophy (MSA) is a rare, neurodegenerative disease characterized by failure of the autonomic nervous system and impaired movement. In December 2024, Alterity Therapeutics announced that the last patient in the ATH434-201 phase 2 trial (NCT05109091) of ATH434, a randomized, double-blind, placebo-controlled investigation in early-stage MSA, completed the study. With the achievement of this milestone, the company anticipatestopline results to be reported in late January or early February. The study enrolled 77 adults who were randomly assigned to receive one of two dose levels of ATH434 or placebo. Participants received treatment for 12 months which will provide an opportunity to detect changes in efficacy endpoints to optimize design of a definitive phase 3 study.⁹

In July 2024, the company announced interim data from a phase 2 open-label study (NCT05864365) which showed that treatment with ATH434 was safe, with noted improvements in disability and biomarker assessments after 6 months in patients with MSA. After 6 months of treatment with ATH434 75 twice daily, 43% (3 of 7) of patients had lowered scores on the Unified MSA Rating Scale (UMSARS). Overall, among these patients, UMSARS scores increased by 1.7 (SD, 5.1) points at 6 months, a favorable outcome in comparison with historical data in a similar MSA population. In addition, 29% (2 of 7) of participants were stabilized or improved on the Clinical Global Impression of Change scale and Patient Global Impression of Change scales.¹⁰

PERSEUS study of Tolerbutinib (Sanofi) in Primary Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease that results in accumulation of irreversible disabilities over time. Disability accumulation remains the significant unmet medical need for patients with MS.In September 2024, Sanofi announced that the results from the ongoing PERSEUS phase 3 study (NCT04458051)of tolebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, patients with primary progressive multiple sclerosis (PPMS)areanticipated in the second half of 2025.¹¹ The primary objectiveis to assess the efficacy of tolebrutinib compared with placebo in delaying disability progression in PPMS.

Presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, in Copenhagen, Denmark, late-breaking results from the phase 3 HERCULES trial (NCT04411641) showed that tolebrutinib had a significant effect on disability accumulation compared with placebo in patients with nonrelapsing secondary progressive MS (nrSPMS). In the trial, findings showed that tolebrutinib delayed the time to onset of 6-month confirmed disability progression, the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026) in patients with nrSPMS. Additional results of the secondary end points revealed that the number of patients who experienced confirmed disability improvement increased by nearly 2-fold, 10% for those treated with tolebrutinib compared with 5% those in the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).¹²

RewinD-LB Trial of Neflamapimod (CervoMed) in Alzheimer Disease

Dementia with Lewy bodies (DLB) is the third most common degenerative disease of the brain with approximately 700,000 patients affected in each of the United States and Europe. In December 2024, CervoMed announced that the full data set from the double-blind phase of the RewinD-LB trial (NCT05869669)of neflamapimodis expected to be available to the company in January 2025 and the data from the first 16 weeks of the open label extension portion of the trial are anticipated to be available in the late second quarter of 2025.

In RewinD-LB, 160 patients with DLB were randomized 1:1 to 40 mgneflamapimod or placebo for a 16-week treatment period, followed by a 32-week open-label extension phase.Participants in the trial were in the early stage of their disease, demonstrated by Clinical Dementia Rating scale scores of less than 1, and had a normal plasma phosphorylated-tau (p-tau)181 levels. Topline data from RewinD-LB revealed that the study did not meet its primary end point of change in the CDR sum of boxes or any of its key secondary end points including change from baseline in Timed Up and Go test, change from baseline in a Neuropsychological Test Battery, and the Clinician’s Global Impression of Change.¹³

VacSYn study of ACI-7104.056 (AC Immune SA) in Parkinson Disease

In Parkinson disease (PD), the accumulation of α-synuclein protein has been known to play a key role inits development, showing to cause inflammatory stress in cells and contribute to the degeneration of neurons in the brain.In November 2024, AC Immune SAannounced that the company may decide to initiate Part 2 of VacSYn trial (NCT06015841) of ACI-7104.056, an anti-α-synuclein (a-syn) active immunotherapy, based on further interim data to be reported in the first half of 2025. In Part 2 of the trial, with up to 150 patients, participants will also be assessed for motor and non-motor symptoms of the disease, as well as digital, imaging, and fluid biomarkers.The company noted that the trialis designed to establish early proof-of-concept and identification of disease-specific biomarkers for rapid transition into a pivotal study.¹⁴

The trial comprises a screening period lasting up to 8 weeks, a 74-week double-blind treatment period, and a 26-week post-treatment follow-up period. It includes up to 3 cohorts comprised of 16 participants each, with 12 under the study vaccine and 3 under placebo. In an interim update from Part 1 of the study, which included analyses from over 30 patients randomized to either ACI-7104.56 or placebo in a 3:1 ratio, revealed that treatment with the immunotherapy induced an increase in anti-a-syn antibodies on average 16-fold higher than the placebo background level after 3 immunizations.

FORWARD-53 study of WVE-N531 (Wave Life Sciences) in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD), a fatal X-linked genetic neuromuscular disorder, is caused predominantly by out-of-frame deletions in the dystrophin gene, resulting in absent or defective dystrophin protein. In September 2024, Wave Life Sciences announced that it expects to complete the phase 2 FORWARD-53 study (NCT04906460) of WVE-N531, an investigational antisense oligonucleotide for DMD amenable to exon 53 skipping, in the first quarter of 2025, andanticipates using feedback from regulators to provide guidance for an accelerated approval.¹⁵

Interim data from FORWARD-53showed that treatment with WVE-N531 resulted in substantial dystrophin expression among boys with DMD amenable to exon 53 skipping. A total of 11 enrolled boys amenable to exon 53 skipping received 10 mg/kg infusions of WVE-N531 every 2 weeks (Q2W), with muscle biopsies taken after 24 and 48 weeks of dosing. At 24 weeks, interim results revealed a mean absolute muscle content-adjusted dystrophin expression of 9.0% (range, 4.6%-13.9%) and a mean absolute unadjusted dystrophin expression that was 5.5% of normal (range, 3.3%-8.3%), as measured by Western Blot. Notably, 89% of ambulatory participants (n = 10) achieved muscle content-adjusted dystrophin levels of at least 5%.

REFERENCES
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7. Motley WW, Friedman D, Davis KA, et al. Novel design of a focal epilepsy proof-of-concept study of RAP-219, a negative allosteric modulator of the y8 transmembrane AMPA receptor-associated regulatory protein (TARPy8). Presented at: 2024 American Epilepsy Society (AES) Annual Meeting; December 6-10; Los Angeles, CA.
8. Edgewise Therapeutics Announces Positive Topline Results from the CANYON Phase 2 Trial of Sevasemten in Individuals with Becker Muscular Dystrophy (Becker). News release. December 16, 2024. Accessed January 13, 2024. https://investors.edgewisetx.com/news/news-details/2024/Edgewise-Therapeutics-Announces-Positive-Topline-Results-from-the-CANYON-Phase-2-Trial-of-Sevasemten-in-Individuals-with-Becker-Muscular-Dystrophy-Becker/default.aspx
9. Alterity Therapeutics Completes Last Patient Visit in ATH434-201 Phase 2 Clinical Trial in Early-Stage Multiple System Atrophy. News Release. Alterity Therapeutics. Published December 4, 2024. Accessed January, 13, 2025. https://alteritytherapeutics.com/investor-centre/news/2024/12/04/alterity-therapeutics-completes-last-patient-visit-in-ath434-201-phase-2-clinical-trial-in-early-stage-multiple-system-atrophy/
10. Alterity Therapeutics Reports Positive Interim Data from ATH434-202 Phase 2 Clinical Trial in Multiple System Atrophy. Alterity Therapeutics. July 17, 2024. Accessed January 13, 2025. https://alteritytherapeutics.com/investor-centre/news/2024/07/17/alterity-therapeutics-reports-positive-interim-data-from-ath434-202-phase-2-clinical-trial-in-multiple-system-atrophy/
11. Tolebrutinib demonstrated a 31% delay in time to onset of confirmed disability progression in non-relapsing secondary progressive multiple sclerosis phase 3 study. News Release. Sanofi. Published September 20, 2024. Accessed January 14, 2025. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-20-09-30-00-2949552
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13. CervoMed Announces Topline Data from RewinD-LB Phase 2b Clinical Trial in Patients with Dementia with Lewy Bodies. News Release. CervoMed. Published December 10, 2024. Accessed January 14, 2025. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-topline-data-rewind-lb-phase-2b-clinical
14. AC Immune Reports Positive Interim Results from Phase 2 Trial of ACI-7104.056 Active Immunotherapy in Early Parkinson’s Disease. News release. AC Immune SA. November 14, 2024. Accessed January 15, 2025. https://ir.acimmune.com/news-releases/news-release-details/ac-immune-reports-positive-interim-results-phase-2-trial-aci
15. Wave Life Sciences Announces Positive Interim Data from FORWARD-53 Clinical Trial Evaluating WVE-N531 in Boys with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping. Wave Life Sciences. September 24, 2024. Accessed January 15, 2025. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-interim-data-forward-53