New Phase 2 Trial to Test TREM2-Stabilizing Agent VHB937 in Alzheimer Disease

At the 2025 Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-5 in San Diego, California, a poster presentation highlighted the rationale and design of a phase 2 study (NCT07094516) testing the effects of investigational VHB937 (Novartis) in patients with early-stage Alzheimer disease (AD). VHB937 is a fully human monoclonal antibody designed to stabilize and activate TREM2, a receptor found on microglia.¹

This phase 2 trial, a randomized, placebo-controlled, parallel-group study currently enrolling, tests the efficacy and safety of 2 doses of VHB937 over a 72-week treatment period. In the study, patients will be placed in cohort 1 (n = 62) or cohort 2 (n = 330), where they will undergo screening, randomization, and treatment, followed by an extension and safety follow-up. Over the 72-week period, study investigators will use change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale as the primary outcome measure.

Presented by Ana Graf, senior global program head at Novartis, the study employs a few other secondary efficacy outcomes, including change on the Alzheimer’s Disease Assessment Subscale 14 (ADAS-Cog14), and the Integrated Activities of Daily Living domain on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). In addition, the trial will also assess the effect of VHB937 on safety and tolerability, pharmacokinetics/pharmacodynamics, and immunogenicity.

The study, which remains enrolling, includes adults aged 50 to 85 with a diagnosis of mild cognitive impairment due to AD or mild AD dementia, a CDR global score of 0.5 or 1.0, and biomarker confirmation of AD through CSF testing or amyloid PET. Participants must have a reliable study partner for visits and, if they are already receiving symptomatic AD treatments such as acetylcholinesterase inhibitors or memantine, must be on a stable dose before starting the trial.²

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Individuals are excluded if they have dementia from non-AD causes, significant cardiac disease or ECG abnormalities, recent stroke or TIA, or evidence of liver or kidney disease. Additional exclusions include uncontrolled major psychiatric illness, serious neurologic conditions such as traumatic brain injury or epilepsy, recent suicidal ideation or behavior, active cancer or major systemic diseases, chronic infections like HIV or hepatitis, uncontrolled endocrine disorders, or the use of medications prohibited by the study.

In the poster presentation, Graf et al shared preclinical and first-in-human data that further supported VHB937’s potential as a treatment for AD. In a hTREM2-APP23-PS45 amyloidosis mouse model, treatment with the agent led to reduced dystrophic neuritis. An additional TREM2KIxtau58.4 tauopathy model revealed lowered AT8 phosphorylated tau levels in the spinal cord of treated mice. For In Vitro and In Vivo biomarker studies, treatment with VHB937 resulted in a consistent reduction in the levels of proinflammatory biomarkers, including SPP1 and sCSF1R.¹

In a first-in-human single-ascending-dose study of 64 healthy participants, VHB937 was detectable in CSF and produced dose-dependent reductions in proinflammatory biomarkers such as SPP1, sCSF1R, and CCL3, aligning with preclinical findings. The therapy was well tolerated with no concerning safety signals relative to placebo, and its biomarker effects differed from those seen with AL002, another TREM2-targeted agent that binds a different domain and produces opposite changes in sTREM2 and sCSF1R.

In addition to AD, VHB937 is being studied as a treatment for amyotrophic lateral sclerosis (ALS) through the phase 2 ASTRALS trial (NCT06643481). This double-blind, parallel-group study features approximately 225 patients who are randomly assigned 2:1 to either VHB937 or placebo for a 40-week double-blind period, followed by an open-label extension. The study uses a composite of permanent assisted ventilation-free survival up to week 40 and change in ALS Functional Rating Scale-Revised as the primary end point.³

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REFERENCES
1. Graf A, Feuerbach D, Shimshek D, et al. VHB937, a TREM2 stabilizing and activating fully human monoclonal antibody: A Phase 2 study design in Alzheimer's disease and rationale. Presented at: 2025 CTAD Conference; December 1-5; San Diego, CA. ABSTRACT P023.
2. A Clinical Trial to Learn About the Effects of VHB937 in People With Early Alzheimer's Disease. Clinicaltrials.gov. Updated October 28, 2025. Accessed December 1, 2025. https://clinicaltrials.gov/study/NCT07094516
3. A Clinical Trial to Learn About the Effects of VHB937 in People With Amyotrophic Lateral Sclerosis (ALS) (ASTRALS). Clinicaltrials.gov. Updated November 12, 2025. Accessed December 1, 2025. https://clinicaltrials.gov/study/NCT06643481