Vivoryon Therapeutics N.V. provided an update on both clinical studies of its lead candidate, varoglutamstat, a small molecule medicine in development for the treatment of Alzheimer's disease (AD), VIVA-MIND and VIVIAD. Furthermore, the Company presents updated safety data from its European Phase 2b study, VIVIAD, at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders in Gothenburg, Sweden. Vivoryon is pursuing a unique and highly differentiated approach to AD treatment, with a meticulously designed clinical development strategy. Grounded in the discovery that the enzyme glutaminyl cyclase (QPCT) catalyzes formation of the neurotoxic Abeta variant N3pE- Abeta, a key driver of AD pathology, Vivoryon is pioneering small molecule-based therapies to block this disease pathway. Varoglutamstat is designed to prevent N3pE- Abeta formation, rather than aiming to clear existing plaques, making it an intervention upstream of other approaches such as monoclonal antibodies (mAbs). Through a second mode of action, varoglutamstat also modulates neuroinflammation via the CCL2 pathway, which, in turn, has an impact on tau pathology. Following a meticulously designed clinical development strategy, varoglutamstat was shown to be well-tolerated in both a completed first-in-human Phase 1 study in over 200 participants and the subsequent first-in-patient Phase 2a study, SAPHIR (NCT02389413), which enrolled 120 patients suffering from early AD. Importantly, after only 12 weeks of treatment, this study showed evidence of improving not only pathological hallmarks, but also synaptic function and connectivity, cognition, memory and attention in AD patients, including statistically significant changes from baseline in working memory. Building on these encouraging results, Vivoryon based the selection of endpoints for both VIVIAD and VIVA-MIND on the outcome of SAPHIR, as well as on the regulatory draft guidelines for AD drug development introduced by FDA and EMA in 2018. With these two complementary studies, the Company intends to assess if potential cognitive improvements in patients in the European VIVIAD study will translate into an established clinical endpoint in patients in the U.S. VIVA-MIND study. VIVIAD is a state-of-the-art Phase 2b study being conducted in Europe and designed to evaluate the safety, tolerability and efficacy of varoglutamstat in 250 subjects with mild cognitive impairment and mild AD compared to placebo over the course of 48 to 96 weeks of treatment. The higher dose investigated in the study (600 mg twice daily) was selected by an independent Data Safety Monitoring Board as final dose after the dose-escalation portion of the study. Enrollment was completed and the study was adapted to enable longer average treatment duration of participants in the third quarter of 2022. The primary endpoint is a composite of the Neuropsychological Test Battery (NTB) focusing on changes in working memory and attention with secondary endpoints including multiple cognitive, safety and biomarker assessments.
VIVA-MIND is a complementary Phase 2 study being conducted in the U.S., coordinated by the Alzheimer's Disease Cooperative Study (ADCS) at the University of California San Diego (UCSD) School of Medicine and supported by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH) with a $15 million grant (NIA award number R01AG061146). The study seeks to enroll 180 patients into the Phase 2a adaptive dose-finding portion with the Phase 2b portion, enrolling an additional 234 patients treated at the selected dose for at least 72 weeks, with a total of 414 patients being treated on stable doses of varoglutamstat for 18 months. The VIVA-MIND design was adapted in the third quarter of 2022 to enable all 180 patients to be treated for at least 72 weeks, allowing for the opportunity to progress seamlessly to a potential Phase 3 study. The flexible study design is aimed at increasing the probability of success by broadening option space for adjustments in clinical development based on learnings from VIVIAD and other developments in the field. The primary endpoint for this study is clinical dementia rating scale - sum of boxes (CDR-SB), an established approvable endpoint measuring a combination of cognitive abilities and activities of daily living. Secondary efficacy endpoints include quantitative EEG theta power, ADAS-Cog 13 and others. Exploratory endpoints include mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), quantitative EEG alpha power, relative QPCT activity in CSF and others.