Vivoryon Therapeutics N.V. provided a clinical development update highlighting the progress of its unique N3pE-amyloid-targeting small molecule varoglutamstat in Alzheimer’s disease (AD). The update included data presented at the Alzheimer's Association International Conference (AAIC), being held July 16-20, 2023, in Amsterdam, the Netherlands. The Company is also providing updates from the ongoing clinical Phase 2 studies VIVIAD in Europe and VIVA-MIND in the U.S. Varoglutamstat Clinical Program: Varoglutamstat is a differentiated investigational small-molecule medicine in development to treat Alzheimer’s disease.

It is currently being investigated in two large Phase 2 studies, VIVIAD (NCT04498650) in Europe and VIVA-MIND (NCT03919162) in the U.S., where it continues to show evidence of a favorable safety profile at the therapeutic dose of 600 mg twice daily (BID), a dose demonstrated to result in a target occupancy of nearly 90%. 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.

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. VIVIAD (NCT04498650) 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 259 (final number of randomized participants) subjects with mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD).

Data from AAIC 2023: P1-18 /P1-904 Poster #82642 – “VIVIAD, a Phase 2b Study Investigating Varoglutamstat in Patients with MCI or Mild AD: Analysis of Baseline Cognition Data.” These data demonstrate that Vivoryon’s strategy of recruiting individuals with evidence of baseline deficits on the WAIS-IV Coding test, a well-known measure of cognitive function, successfully enriches study cohorts with respect to deficits in attention and working memory, enabling reliable assessment of potential cognitive improvement after treatment. A new enrichment strategy was applied in the VIVIAD study to ensure that study participants exhibited rescuable deficits in attention and working memory at baseline. VIVIAD uses the WAIS-IV Coding test to select patients with rescuable cognitive deficits in the target domains.

The study inclusion criteria encompassed a score of at least 0.5 SD (standard deviations) below age-adjusted mean on the WAIS-IV Coding subtest. Approximately 20% of screened patients did not meet the inclusion criteria during screening due to good performance on the WAIS-IV Coding test. In addition, for selecting patients with mild disease, the MMSE cut-off was set at 20, leading to 8% of patients not meeting the inclusion criteria due to falling under this cut-off value.

The WAIS-IV Coding test performance shows reasonably good correlation with the measures that comprise the primary outcome, i.e. detection (DET), identification (IDN) and one back test (ONB) of the Cogstate NTB as judged by the Spearman correlation coefficients of 0.27, 0.44, and 0.47, respectively, using the blinded baseline data of all randomized patients. The use of MMSE and WAIS-IV Coding test, together with inclusion criteria based on CSF biomarkers (Abeta and p-tau) are valuable tools in identifying and recruiting patients with MCI or mild AD who already have deficits in working memory and attention. Safety Results: Data from all 259 randomized patients showed no clinical signs of ARIA at the cutoff date of June 14, 2023.

Both the total number of SAEs and the discontinuation rate were considerably lower than the respective numbers at the 800 mg BID varoglutamstat dose in Vivoryon’s completed Phase 2a SAPHIR study, while retaining a similar level of target inhibition at the dosing in both studies. After carefully reviewing the updated safety data, the independent Data Safety Monitoring Board (DSMB) decided in its recent meeting on June 22, 2023, that the study should continue as planned and that no additional DSMB meeting will be required until study completion. The study is on track for the final data readout in Q1/2024.

Open label extension (OLE) study: Vivoryon commenced preparations for an OLE study to provide a long-term treatment option to patients after completion of treatment under the VIVIAD or VIVA-MIND protocol. The launch of the OLE study is contingent on the outcome of VIVIAD. VIVA-MIND (NCT03919162) is a complementary Phase 2 study for varoglutamstat conducted in the U.S. which seeks to enroll 180 patients with early AD into the Phase 2a adaptive dose finding portion and enroll a further 234 patients in the Phase 2b portion of the study.

Study Updates: The first cohort was fully randomized into the study as planned and the study is now recruiting participants into the second cohort, with 19 sites open across the U.S. In its June 12, 2023, meeting, the study’s independent DSMB recommended to continue the study without modification, supporting the rationale for accelerated uptitration to 600 mg BID dosing. The Company anticipates a decision on final trial size following the data readout of the VIVIAD study. Vivoryon intends to provide a study update in Q4/2023.