Key Neurology Trial Readouts to Watch in Early 2026

As the field of neurology advances, the early months of 2026 are anticipated to bring important clinical trial readouts that may influence research and care across multiple neurological conditions. These studies span a broad spectrum of disorders and aim to clarify disease mechanisms while evaluating emerging therapeutic approaches.

Ranging from novel gene-based strategies to new pharmacologic interventions, the results may inform future treatment paradigms and clinical decision-making. This feature reviews these trials, outlining their design, objectives, and the potential implications of their findings for the evolving landscape of neurology.

Phase 3 POLARIS-AD Trial of AR1001 (AriBio) in MCI or Mild Dementia Because of AD

POLARIS-AD is an ongoing phase 3 global, multicenter, double-blind, placebo-controlled, 52-week treatment parallel group trial (NCT05531526) assessing the safety and efficacy of AR1001 (mirodenafil), a novel oral therapy targeting toxic amyloid-beta oligomers, in patients with mild cognitive impairment (MCI) or mild dementia because of Alzheimer disease (AD). The trial, which is a large-scale study of more than 1500 patients, is anticipated to have topline results readout in 2026.¹

To be considered for the trial, participants had to be between 55 and 90 years of age with MCI or mild dementia because of AD. Baseline demographics and characteristics of the trial participants were presented at the 18th Clinical Trials on Alzheimer’s Disease Conference (CTAD), held December 1-4, in San Diego, California. At baseline, patients had a Clinical Dementia Rating-Sum of Boxes (CDR-SB) mean score, the primary end point, of 3.45 (± 1.70). On other secondary outcomes, such as Alzheimer’s Disease Assessment Scale – Cognitive Subscale, 13-item (ADAS-Cog13), patients had a baseline score of 27.75 (± 8.02).

Phase 3 Trial of Buntanetap (Annovis Bio) in Early Alzheimer Disease

Recently, the FDA accepted an updated protocol for Annovis Bio’s pivotal phase 3 AD study (NCT06709014) testing the therapeutic potential of its investigational agent buntanetap, an orally available small molecule, in AD. In the original launch, the phase 3 study was intended to be 2 separate trials. The revised phase 3 study is now comprised of a 6-month symptomatic analysis along with a 12-month assessment to study disease-modifying impacts of the agent.²

In early 2024, data from the aforementioned dose-ranging phase 2/3 study (NCT05686044) provided insight on buntanetap’s potential in AD. In the study, treatment with the agent resulted in statistically significant improvements in the primary end point of Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog11) over 3 different dose groups (7.5 mg: improved 2.19 [SE, 0.87]; P = .013; 15 mg: 2.79 [SE, 0.81]; P = .001; 30 mg: 3.32 [SE, 0.82]; P <.001). Of note, investigators recorded a 3-fold difference in the proportion of patients who improved in the 30 mg group relative to placebo.³

Phase 3 ADEPT-2 Study of Xanomeline/Trospium (Bristol Myers Squibb) for Psychosis in AD

The ADEPT-2 study (NCT06126224) is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of xanomeline/trospium (Cobenfy; Bristol Myers Squibb) in patients with mild to severe AD with moderate to severe psychosis related to AD. The study is designed to evaluate the primary end point of change in the Neuropsychiatric Inventory-Clinician: Hallucinations and Delusions score and the key secondary endpoint of Clinical Global Impression-Severity, with additional assessments on safety and tolerability compared with placebo.

In the trial, participants aged 55 to 90 years with possible or probable AD disease will be randomly assigned to either an oral capsule of xanomeline/trospium or an oral capsule of placebo.⁴ Xanomeline/trospium, which is currently approved for schizophrenia in adults, has the potential to be the first treatment in a new class of pharmacologic therapies targeting agitation and psychosis based on muscarinic receptor agonism.⁵ Additional study results from the ADEPT program in psychosis associated with AD, including ADEPT-2, ADEPT-1 and ADEPT-4, are expected to be read out by the end of 2026.

Phase 4 ELEVATE-PD Trial of IPX203 (Amneal Pharmaceuticals) in Parkinson Disease

The phase 3 ELEVATE PD trial (NCT06765668) is a phase 4, open-label, multicenter study designed to assess the real-world efficacy and safety of switching to IPX203 (Crexont; Amneal Pharmaceuticals) in adults with moderately severe PD experiencing motor complications such as OFF periods and dyskinesia despite being on a stable dose of oral levodopa-based regimen.⁶ The trial, which anticipates long-term data read out in 2026, plans to enroll approximately 220 patients and will follow them for 13 to 14 months, consisting of 10 visits.

Interim data from the first 55 patients evaluated after 6 weeks of treatment demonstrated improvements in disease-related outcomes after switching to IPX203 extended-release capsules. These findings included increases in daily good ON time, reductions in OFF time, and improved motor symptom control, with gains in good ON time per dose. IPX203 is currently indicated for the treatment of PD, post encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults.

Phase 3 REMODEL Studies of Remibrutinib vs Teriflunomide in Relapsing Multiple Sclerosis

The phase 3 REMODEL studies (NCT05147220/NCT05156281) will compare remibrutinib (Novartis), a novel, potent, highly selective, covalent, oral Bruton’s tyrosine kinase (BTK) inhibitor, and teriflunomide (Aubagio; Sanofi) patients with relapsing multiple sclerosis (MS). These randomized, double-blind, double-dummy, parallel-group trials, being conducted across 246 sites in 25 countries, include approximately 800 participants with relapsing MS, and are expected to reach primary completion by April 30, 2026.⁷

Eligible participants are adults aged 18 to 55 years with relapsing MS who have experienced 1 or 2 relapses in the previous 1 or 2 years or have at least 1 gadolinium-enhancing lesion in 12 months before screening and an Expanded Disability Status Scale score of 0.0 to 5.5. The primary end point is annualized relapse rate, with key secondary end points including disability progression measured by 3- and 6-month confirmed disability progression, MRI lesion outcomes, serum neurofilament light chain concentrations, and no evidence of disease activity.

Phase 3 TRAILBLAZER-ALZ-1 of Remternetug (Eli Lilly) in Alzheimer Disease

The phase 3 TRAILRUNNER-ALZ-1 trial (NCT05463731) is investigating remternetug (Eli Lilly), a self-administered investigational monoclonal antibody targeting amyloid-ß (Aß), in patients with AD in stages 3 and 4. Remternetug targets a pyroglutamated Aß, a form of Aß involved in the aggregated amyloid plaque characteristic of AD. TRAILRUNNER-ALZ-1 includes a 52-week double-blinded period, followed by a planned open-label extension lasting up to 76 weeks.⁸

The trial, which is expected to be completed by 2026, uses percentage of patients who reach amyloid plaque clearance, measured through amyloid PET scans, as the primary outcome measure. Other secondary outcomes include time to reach complete amyloid plaque clearance, pharmacokinetics, and safety, including treatment-emergent anti-drug antibodies. In a recent analysis of TRAILRUNNER-ALZ-1, findings showed that remternetug was feasible to use in patients with AD, suggesting that the subcutaneous (SC) self-injection is a practical option for remternetug.

Phase 3 CYPRESS Study of Ampreloxetine (Theravance Biopharma) for Multiple System Atrophy

The phase 3 CYPRESS study (NCT05696717) is assessing the therapeutic potential of ampreloxetine (Theravance Biopharma), a once-daily, selective norepinephrine reuptake inhibitor, in patients with symptomatic neurogenic orthostatic hypotension (nOH) because of multiple system atrophy (MSA).⁹ CYPRESS, a large-scale trial, includes 102 patients with symptomatic nOH because of clinically diagnosed MSA. If successful, data from the study is expected to fuel a new drug application (NDA) submission, coming in early 2026.

The study comprises a screening period, an 12-week open-label period, an 8-week randomized, double-blind withdrawal period, and a long-term extension. In the study, investigators will use change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score as the primary outcome, with secondary outcomes that include change in Orthostatic Hypotension Daily Activity Scale (OHDAS) item 1 (activities that require standing for a short time) and item 3 (activities that require walking for a short time).

Phase 3 FENhance 1 of Fenebrutinib vs Teriflunomide in Relapsing Multiple Sclerosis

The FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) trials are similarly designed phase 3 multicenter, randomized, double-blind, double-dummy, parallel-group studies that investigate the efficacy and safety of fenebrutinib (Genentech) against teriflunomide in a total of 1497 adult patients with RMS. Eligible participants were randomized in a 1:1 ratio to receive either oral fenebrutinib administered twice daily with a once-daily matched placebo for oral teriflunomide, or oral teriflunomide administered once daily with a twice-daily matched placebo for oral fenebrutinib, for a minimum treatment duration of 96 weeks.¹⁰

The trial’s primary end point is annualized relapse rate (ARR) while key secondary end points include the time to onset of composite 24-week confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24). Following completion of the double-blind treatment period, participants may enter an open-label extension (OLE) phase in which all patients receive fenebrutinib. Data from FENhance 1 are expected in the first half of 2026, and if approved by the FDA, fenebrutinib would be the first BTK inhibitor indicated for both relapsing and primary progressive MS.

REFERENCES
1. Prins N, Atri A, Melgar-Somoza F, et al. POLARIS-AD: Global Enrollment in the Largest Phase 3 Trial of an Oral Multi-Mechanistic PDE5 Inhibitor for Early AD Using Biomarker-Agnostic Modalities for Amyloid Confirmation. Presented at: Clinical Trials on Alzheimer’s Disease Conference (CTAD); December 1-4; San Diego, California
2. FDA Accepts Final Protocol for Pivotal Phase 3 Alzheimer’s Disease Study, Streamlining Development Pathway. News release. Annovis Bio. January 7, 2025. Accessed January 8, 2026. https://www.biospace.com/press-releases/fda-accepts-final-protocol-for-pivotal-phase-3-alzheimers-disease-study-streamlining-development-pathway
3. Annovis Bio announces statistically significant phase 2/3 data in patients with early Alzheimer’s disease. April 29, 2024. Accessed January 8, 2026. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=7f4c17db-2a47-4e91-8059-8d07dae9de11
4. Bristol Myers Squibb announces continuation of ADEPT-2 phase 3 study in psychosis associated with Alzheimer's disease. News release. December 3, 2025. Accessed January 8, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Announces-Continuation-of-ADEPT-2-Phase-3-Study-in-Psychosis-Associated-with-Alzheimers-Disease/default.aspx
5. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. News release. FDA. September 26, 2024. Accessed January 8, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia
6. Amneal Announces Positive Interim Phase 4 ELEVATE-PD Results With CREXONT® for Parkinson’s Disease. News release. Amneal Pharmaceuticals. December 5, 2025. Accesed Janauary 8, 2025. https://investors.amneal.com/news/press-releases/press-release-details/2025/Amneal-Announces-Positive-Interim-Phase-4-ELEVATE-PD-Results-With-CREXONT-for-Parkinsons-Disease/default.aspx
7. Geladaris A, Torke S, Weber MS. Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?. CNS Drugs. 2022;36(10):1019-1030. doi:10.1007/s40263-022-00951-z
8. Hufford M, Biglan K, Stroud C, et al. Feasibility of Participants With Symptomatic Alzheimer’s Disease to Self-Administer Remternetug Subcutaneously: Results From the TRAILRUNNER-ALZ 1 Phase 3 Trial. Presented at: 2025 Clinical Trials on Alzheimer Disease conference. December 1-5; San Diego, CA. Abstract P040.
9. Theravance Biopharma Completes Enrollment in Pivotal Phase 3 CYPRESS Study of Ampreloxetine in Patients with Symptomatic Neurogenic Orthostatic Hypotension due to Multiple System Atrophy. News release. Theravance Biopharma. August 25, 2025. Accessed January 8, 2025. https://www.prnewswire.com/news-releases/theravance-biopharma-completes-enrollment-in-pivotal-phase-3-cypress-study-of-ampreloxetine-in-patients-with-symptomatic-neurogenic-orthostatic-hypotension-due-to-multiple-system-atrophy-302537380.html
10. Genentech’s Fenebrutinib Shows Unprecedented Positive Phase III Results as the Potential First and Only BTK Inhibitor in Both Relapsing and Primary Progressive Multiple Sclerosis. News release. Genentech. November 9, 2025. Accessed January 8, 2025. https://www.gene.com/media/press-releases/15089/2025-11-09/genentechs-fenebrutinib-shows-unpreceden