Glutaminyl Inhibitor Varoglutamstat Fails to Show Efficacy in Phase 2 VIVA-MIND Study of Early Alzheimer Disease

Howard H. Feldman, MDCM, FRCP

Detailed data from the phase 2 VIVA-MIND study (NCT03919162) of varoglutamstat (Vivoryon Therapeutics) revealed that the oral small molecule inhibitor of glutaminyl cyclases was safe in patients with early-stage Alzheimer disease (AD) but had no effect on primary and secondary efficacy outcomes.¹

Presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31 in Toronto, Canada, the comprised patients from the first dose cohort testing 600 mg of varoglutamstat (n = 52) vs placebo (n = 57). Of these, 74% completed the 24-week treatment period and 31% lasted through week 72. At week 72, investigators observed no statistically significant least-square (LS) mean differences between the investigational cohort and placebo in Clinical Dementia Rating-Sum of Boxes (CDR-SB), the primary end point (–0.05; 95% CI, –1.03 to 0.92).

Vivoryon noted it will still announce biomarker results and pharmacokinetic/pharmacodynamic (PK/PD) data in the future. The trial was originally going to test 3 descending doses (600 mg, 300 mg, 150 mg BID) of varoglutamstat; however, following the negative data, it was terminated prematurely.

In the latest analysis, led by Howard H. Feldman, MDCM, FRCP, a professor of neurosciences at the University of California, San Diego, patients on the investigational therapy failed to distinguish themselves from placebo on a number of secondary outcomes as well. These included CFC2 (LS mean difference, 0.97; 95% CI, –3.34 to 5.28), ABC score (0.10; 95% CI, –0.10 to 0.30), FAQ (–0.60; 95% CI, –4.22 to 3.01), Alzheimer’s Disease Assessment Scale-cognitive subscale 13 (2.03; 95% CI, –2.29 to 6.36), or Neuropsychiatric Inventory (–3.09; 95% CI, –7.81 to 1.62).

In terms of safety, varoglutamstat was considered safe and well tolerated, although there were more treatment discontinuations because of adverse events (AEs) in the investigational arm (11.3%) than placebo (3.4%). At least 1 treatment-emergent AE occurred in 84.9% of varoglutamstat-treated patients vs 76.8% of those on placebo. Serious AEs and AEs of special interest occurred in 18.9% and 1.9% of those on varoglutamstat, respectively, compared with 8.9% and 5.4% of those on placebo.

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Otherwise known as PQ912, varoglutamstat is one of the unique agents in the AD pipeline, acting as an oral inhibitor of glutaminyl cyclases, which are known to reduce the pyroglutamate formation of amyloid-ß and CCL2. In the trial, more patients were apolipoprotein e-4 carriers (72.9%) and more had an initial diagnosis of mild cognitive impairment due to AD (62.4%) than mild probable AD (37.6%). Coming into the trial, both groups had similar baseline Montreal Cognitive Assessment total scores, Mini-Mental State Exam scores, and CDR-SB scores.

In December 2024, Vivoryon announced new data from VIVA-MIND supporting varoglutamstat’s potential to improve kidney function. An analysis of kidney function data demonstrated a statistically significant improvement of at least 4 mL/min/1.73 m2 in the estimated glomerular filtration rate in patients treated with 600 mg BID of varoglutamstat vs placebo across all visits and all patients (weighted average weeks 4-72; P = 0.004*; total treated n=109; varoglutamstat n=52, placebo n=57). Overall, these data reinforced the potential of varoglutamstat as a treatment for diabetic kidney disease (DKD) and backed the previously completed phase 2b VIVIAD study (NCT04498650).²

VIVIAD, a European-based trial testing varoglutamstat in 259 patients with MCI and mild AD, failed to meet its primary end point of a combined z-score of the Detection test, the Identification test, and the ‘One Back’ test of the Cogstate Neuropsychological test battery. In addition, the study did not meet its key secondary end points measuring cognition, Instrumental Activities of Daily Living Questionnaire, and electroencephalogram global theta power.³

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REFERENCES
1. Feldman HH, Messer K, Zhang J, et al. The VIVA-MIND study: Topline Results from Phase 2 RCT of Varoglutamstat in Early AD. Presented at: AAIC 2025; July 27-31; ABSTRACT 105693
2. Vivoryon Therapeutics N.V. Presents Topline Phase 2 Data fromVIVA-MIND Strongly Supporting Varoglutamstat’s Potential toImprove Kidney Function. News release. Vivoryon Therapeutics. News release. December 9, 2024. Accessed July 28, 2025. https://www.vivoryon.com/vivoryon-therapeutics-n-v-presents-topline-phase-2-data-fromviva-mind-strongly-supporting-varoglutamstats-potential-toimprove-kidney-function/
3. Vivoryon Therapeutics N.V. Provides Update on VIVIAD Phase 2b Study of Varoglutamstat in Early Alzheimer’s Disease. News release. Vivoryon Therapeutics. March 4, 2024. Accessed July 28, 2025. https://www.vivoryon.com/vivoryon-therapeutics-n-v-provides-update-on-viviad-phase-2b-study-of-varoglutamstat-in-early-alzheimers-disease/