Vivoryon Therapeutics N.V provided a comprehensive overview of the progress of the ongoing clinical development of varoglutamstat, an orally administered novel small molecule. Varoglutamstat?s mid to late-stage clinical studies, VIVIAD and VIVA-MIND, evaluating its potential to treat early Alzheimer?s disease (AD), are comprised of a broad range of key primary and secondary endpoints covering cognition, function and neuronal connectivity. Varoglutamstat Clinical Program: The clinical development program of varoglutamstat in early AD is based on a strong scientific rationale rooted in Vivoryon?s research and discovery activities in conjunction with support from leading academic partners and scientific organizations worldwide.

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 additional positive impact on tau pathology. Preclinical data supports the N3pE-Abeta hypothesis with the following key highlights: Pyroglutamate-modified Abeta (N3pE-Abeta) is a trigger of toxicity and disease pathology in AD and there is a strong rationale for targeting N3pE-Abeta to create a tailored AD therapy.

Experimental data show that N3pE-Abeta has very different physio-chemical properties compared to other Abeta variants, including its potential to form highly toxic oligomers and fibrils together with non-modified Abeta variants. Strong preclinical evidence supports the hypothesis that reducing N3pE-Abeta formation by inhibiting the enzyme QPCT, has the potential to change the course of progression of AD. Varoglutamstat is a differentiated investigational small-molecule medicine in development to treat early AD.

As an orally administered treatment which can conveniently be taken at home, varoglutamstat holds significant advantages in ease of use by patients. Importantly, in line with its mode of action, safety data to-date indicate that varoglutamstat could potentially come without comparable risks of brain swelling and bleeding (ARIA) seen with amyloid lowering mAbs. It is currently being investigated in two large Phase 2 studies, VIVIAD (NCT04498650) in Europe and VIVA-MIND (NCT03919162) in the U.S. The two studies taken together enable a deep and robust understanding of the effect of varoglutamstat on cognition and daily function of patients with early AD, capturing a range of key primary and secondary efficacy endpoints.

In addition, VIVALONG (the open label extension study) will allow for the potential confirmation of the long-term safety and health outcome benefits of varoglutamstat after patients have completed the double blinded studies VIVIAD and VIVA-MIND. The study will also help to generate relevant pharmacoeconomic data. VIVIAD (NCT04498650) is a Phase 2b study being conducted in Europe and is designed to evaluate the safety, tolerability, and efficacy of varoglutamstat in 259 subjects with mild cognitive impairment (MCI) and mild AD.

The primary endpoint, which is a combination of three elements of the Cogstate neuropsychological test battery (NTB), called ?Cogstate 3-item scale,? includes Identification, Detection and One Back tests and evaluates attention and working memory domains over 48-96 weeks. Key secondary efficacy endpoints include in hierarchical order: Cogstate Brief Battery (CBB, 4-item scale), the full Cogstate NTB (8-item scale), the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), and electroencephalogram (EEG).

The objective of the Cogstate 3-item scale (Identification, Detection, One Back) as the primary endpoint is to confirm the positive findings on working memory and attention observed in the SAPHIR study. The CBB (3-item scale plus One Card Learning), which is the first secondary endpoint, is marketed as Cognigram and has approval as a medical device by the U.S. Food & Drug Administration (FDA) and multiple other regulatory authorities to assess cognition in early AD patients. The full Cogstate NTB (8-item scale) enables an assessment of outcome on various cognitive domains.

Th A-IADL-Q is a fully validated and sensitive scale to measure the impairment of daily function in patients with early AD. The EEG captures change in large scale neuronal and synaptic activity. Theta power has been selected as a key secondary endpoint because it is well correlated to working memory and has been shown to increase (worsen) in AD.

Formal testing for significance will begin with the Cogstate NTB 3-item scale and continue until the first endpoint does not show a p value of <=0.05. Furthermore, there will be additional exploratory analysis for domains such as working, executive and episodic memory and language via the Winterlight Labs speech assessment. In sum, the analysis provides a detailed performance assessment of varoglutamstat across key relevant cognitive performance parameters.

The end of the active treatment phase in VIVIAD is estimated to occur by year end 2023, which is then followed by a period of safety follow up visits and rigorous data and statistical analysis. Vivoryon remains on track to share final topline data in the first quarter of 2024 and the full dataset at a subsequent medical meeting.