Two Novel Alzheimer's Therapies Advance in Phase 2 Trials: Oral PRI-002 and TREM2-Targeting VHB937
核心洞察
The PRImus-AD phase 2a trial is testing PRI-002, an oral synthetic peptide that directly targets toxic amyloid-beta oligomers (搜索), in 304 patients across 40 European study sites with results expected in October 2026.
A separate phase 2 study is evaluating VHB937, a monoclonal antibody designed to stabilize and activate TREM2 (搜索) receptors on microglia, with enrollment ongoing for up to 392 patients over a 72-week treatment period.
Both therapies represent novel mechanisms of action for Alzheimer's disease (搜索) treatment, with PRI-002 offering the convenience of oral administration and VHB937 targeting neuroinflammation through microglial activation.
Two innovative approaches to Alzheimer's disease (搜索) treatment are advancing through phase 2 clinical trials, offering potential alternatives to current amyloid-clearing therapies. The PRImus-AD trial is testing an oral synthetic peptide targeting toxic amyloid oligomers, while a separate study evaluates a monoclonal antibody designed to enhance microglial function.
PRImus-AD Trial Tests Oral Amyloid Oligomer Inhibitor
The PRImus-AD phase 2a randomized, double-blind, placebo-controlled study is evaluating PRI-002, a novel oral therapy developed by PRInnovation (搜索) that directly targets toxic amyloid-beta oligomers (搜索). The trial, presented at the 18th Clinical Trials on Alzheimer's Disease (搜索) Conference in San Diego, has enrolled 304 patients from 540 screened across 40 study sites in six European countries.
Led by Dieter Willbold, PhD, director of the Institute for Physical Biology at Heinrich Heine University (搜索) in Germany, the study randomizes participants to receive either 300 mg PRI-002, 600 mg PRI-002, or placebo. The trial employs an adaptive design with treatment duration ranging from 48 to 96 weeks, with the first patient enrolled in February 2024 and results anticipated in October 2026.
PRI-002 is a synthetic peptide containing 12 D-configurated amino acid residues provided in capsules for oral administration. Unlike monoclonal antibodies that clear amyloid-beta plaques (搜索), PRI-002 is designed to directly target and destabilize toxic amyloid-beta oligomers (搜索), which are believed to play a central role in neuronal damage and cognitive decline in Alzheimer's disease (搜索).
The primary efficacy endpoint is the Clinical Dementia Rating-Sum of Boxes (CDR-SB), while the primary safety endpoint measures the incidence of drug-related adverse events. Secondary endpoints include assessments of ARIA-E, ARIA-H, participant discontinuation, clinical outcomes, and biomarker evaluations.
Prior phase 1 studies published in Alzheimer's & Dementia in 2020 demonstrated that PRI-002 was safe and well tolerated in both single-ascending dose (40 participants) and multiple-ascending dose (24 participants) cohorts. The studies showed rapid drug exposure that increased proportionally to dose, with plasma levels in humans matching those observed in successful transgenic mouse studies.
VHB937 Targets Microglial TREM2 Receptors
A separate phase 2 trial is testing VHB937, a fully human monoclonal antibody developed by Novartis that stabilizes and activates TREM2 (搜索) receptors found on microglia. The randomized, placebo-controlled, parallel-group study is currently enrolling patients with early-stage Alzheimer's disease (搜索) for a 72-week treatment period.
The study design includes two cohorts: cohort 1 with 62 participants and cohort 2 with 330 participants. The primary outcome measure is change in CDR-SB scale over the 72-week period. Secondary efficacy outcomes include changes on the Alzheimer's Disease (搜索) 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).
Preclinical Evidence Supports Novel Mechanisms
Preclinical data presented by Ana Graf, senior global program head at Novartis, demonstrated VHB937's therapeutic potential across multiple disease models. In a hTREM2-APP23-PS45 amyloidosis mouse model, treatment with VHB937 led to reduced dystrophic neuritis. An additional TREM2KIxtau58.4 tauopathy model revealed lowered AT8 phosphorylated tau levels in the spinal cord of treated mice.
Biomarker studies showed that VHB937 treatment resulted in consistent reductions in proinflammatory biomarkers, including SPP1 and sCSF1R. In a first-in-human single-ascending-dose study of 64 healthy participants, VHB937 was detectable in cerebrospinal fluid 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. Notably, VHB937's biomarker effects differed from those seen with AL002, another TREM2 (搜索)-targeted agent that binds a different domain and produces opposite changes in sTREM2 and sCSF1R.
Expanding Applications Beyond Alzheimer's
VHB937 is also being investigated for amyotrophic lateral sclerosis (搜索) treatment through the phase 2 ASTRALS trial, which features approximately 225 patients randomly assigned 2:1 to either VHB937 or placebo for a 40-week double-blind period. This study uses a composite of permanent assisted ventilation-free survival and change in ALS Functional Rating Scale-Revised as the primary endpoint.
Both trials represent significant advances in Alzheimer's disease (搜索) research, offering distinct mechanisms of action that could complement or provide alternatives to existing amyloid-clearing therapies. The oral availability of PRI-002 and the microglial-targeting approach of VHB937 address different aspects of Alzheimer's pathophysiology, potentially expanding treatment options for patients with this devastating neurodegenerative disease.