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 Alzheimer disease (AD).

!Ana Graf,senior global program head at Novartis

Ana Graf

The study,titled “A Phase 2,Randomized,Double-Blind,Placebo-Controlled Study to Evaluate the efficacy and Safety of VHB937 in Participants with Early Alzheimer’s Disease,” will enroll approximately 300 participants with mild cognitive impairment (MCI) due to AD or mild AD dementia. Participants will be randomized 1:1 to receive either VHB937 200mg or placebo once daily for 18 months.

VHB937 is an oral small molecule designed to selectively modulate the activity of the soluble amyloid-beta oligomers, which are believed to be a key driver of synaptic dysfunction and cognitive decline in AD. The rationale for targeting these oligomers stems from preclinical data suggesting that VHB937 can reduce their levels and restore synaptic function.

“We believe that targeting soluble amyloid-beta oligomers represents a promising therapeutic approach for Alzheimer’s disease,” said Ana Graf, senior global program head at Novartis, in a statement. “VHB937 has shown encouraging preclinical results, and we are eager to evaluate it’s potential to slow disease progression in this phase 2 study.”

The primary outcome measure will be the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score at 18 months. Secondary outcome measures will include changes in other cognitive and functional assessments, and also biomarkers of amyloid and tau pathology. safety and tolerability will also be closely monitored throughout the study.

The study is currently recruiting participants at sites across North America, Europe, and Asia. More details can be found on the clinicaltrials.gov website.

Incorporation of Mini-Mental State Exam Z-Scores may Increase Eligibility for Anti-Amyloid Treatments, Study Suggests

New research suggests incorporating mini-Mental State Exam (MMSE) z-scores could broaden access to anti-amyloid treatments for Alzheimer’s disease (AD). Currently, many clinical trials and treatment guidelines rely on MMSE scores to determine eligibility. However, this approach can exclude individuals with milder cognitive impairment who might still benefit from these therapies.

The study,presented at the Alzheimer’s Association International Conference (AAIC) 2024,proposes using MMSE z-scores instead. Z-scores account for age and education, providing a more standardized measure of cognitive function. this adjustment could identify more individuals with early-stage AD who meet the criteria for treatment.

Researchers analyzed data from the AHEAD3-45 study, a trial evaluating the anti-amyloid antibody lecanemab.They found that using MMSE z-scores would have increased the number of eligible participants by approximately 25%.This means a significant portion of individuals previously excluded based on conventional MMSE cutoffs could potentially receive these potentially disease-modifying treatments.

The AHEAD3-45 study included participants with amyloid positivity and mild cognitive impairment or mild dementia due to AD.Participants had to be 55-90 years old and have an MMSE score between 22 and 30. individuals were excluded if they had dementia from non-AD causes, significant cardiac disease or ECG abnormalities, recent stroke or TIA, or evidence of liver or kidney disease. Additional exclusions included 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 a related presentation, Graf et al shared preclinical and first-in-human data supporting VHB937’s potential as an AD treatment. In a hTREM2-APP23-PS45 amyloidosis mouse model,treatment with the agent led to reduced dystrophic neuritis. A TREM2KIxtau58.4 tauopathy model revealed lowered AT8 phosphorylated tau levels in the spinal cord of treated mice.