QPCT

VIVIAD Phase 2b study did not meet its primary and key secondary endpoints Varoglutamstat was generally well tolerated with low discontinuation rates due to adverse events and no evidence of symptomatic ARIAs in the clinical setting VIVIAD is a comprehensive, diligently designed and high-quality study; baseline demographics in the study were highly representative of early AD patient population Company is conducting an in-depth analysis of the results, including analyses of additional pre-specified and exploratory endpoints Further update expected to be provided no later than with publication of Company’s full year 2023 financial results March 4, 2024 – Vivoryon Therapeutics N.V. (Euronext Amsterdam: VVY; NL00150002Q7) (Vivoryon), a clinical stage company focused on the discovery and development of small molecule medicines to modulate the activity and stability of pathologically altered proteins, today announced topline results from its Phase 2b European VIVIAD study of varoglutamstat (PQ912), an investigational oral glutaminyl cyclase (QPCT) inhibitor in development for the treatment of early Alzheimer’s disease (AD). The VIVIAD study did not meet its primary endpoint and did not show a statistically significant difference in change over time on cognition, as measured by a combined score (Z-score) of the Detection test, the Identification test and the ‘One Back’ test (attention and working memory domains) of the Cogstate neuropsychological test battery (NTB), called “Cogstate 3-item scale”. Additionally, the study did not meet key secondary endpoints measuring cognition (Cogstate Brief Battery, CBB, and complete Cogstate NTB), Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) and electroencephalogram (EEG) global theta power. Varoglutamstat was generally well tolerated and showed rates similar to placebo of serious and severe treatment emergent adverse events (TEAEs), low discontinuation rates due to adverse events and no evidence of symptomatic ARIAs (amyloid-related imaging abnormalities) in the clinical setting. The Company is conducting an in-depth analysis of the results, including analyses of additional pre-specified exploratory endpoints (e.g. WAIS-IV coding test, executive function and episodic memory domains, Winterlight Labs speech assessment, cerebrospinal fluid (CSF) biomarkers and additional EEG analysis) and distinct patient cohorts as defined in the statistical analysis plan, including ApoE4 status, tau level, dose level and pre-treatment. “We are profoundly disappointed by the outcome of the VIVIAD Phase 2b study of varoglutamstat in the early AD patient population given the huge unmet need for new safe and effective oral therapies,” said Frank Weber, M.D., CEO of Vivoryon. “I would like to express our gratitude to the patients, their families and caregivers, as well as the investigators for participating in the VIVIAD study, and to our incredible team at Vivoryon for their tireless efforts. While these results are not what we had hoped for, VIVIAD is a comprehensive, diligently designed and high-quality study and we are doing all we can to fully analyze the dataset as quickly as possible to gain insights into key findings that might influence varoglutamstat clinical development and help advance the science and understanding of this devastating disease.” A further update is expected to be provided no later than with the publication of the Company’s full year 2023 financial results which are expected in mid to late April 2024. Varoglutamstat (PQ912) is a differentiated oral small-molecule targeting the toxic Abeta species N3pE which is being developed as disease-modifying therapy and is designed to target AD pathology upstream of Abeta-antibody focused approaches. Varoglutamstat blocks the enzyme glutaminyl cyclase (QPCT) and its isoenzyme QPCTL. QPCT catalyzes the formation of N3pE amyloid, a particularly neurotoxic variant of Abeta peptides, which is only found in patients with AD and not present in the brains of healthy individuals. N3pE amyloid in the brain acts as a seeding element for Abeta aggregation, thus providing a starting point for plaque formation. It has been described to correlate with the cognitive ability of patients with AD. Beyond Abeta pathology, varoglutamstat has also been shown to impact synaptic impairment. Through a second mode of action, the inhibition of full CCL2 maturation via QPCTL, varoglutamstat modulates pro-inflammatory signaling and tau pathology, thereby simultaneously addressing multiple hallmarks of AD. Vivoryon has received Fast Track designation for varoglutamstat in early AD by the U.S. Food and Drug Administration (FDA). It is being investigated in two Phase 2 clinical studies, one in Europe (VIVIAD, NCT04498650) and one in the U.S. (VIVA-MIND, NCT03919162). Varoglutamstat has not yet been approved by any regulatory authority and the safety and efficacy have not yet been established. VIVIAD is a state-of-the-art Phase 2b study conducted in Europe and designed to evaluate the safety, tolerability, and efficacy of varoglutamstat in 259 participants with mild cognitive impairment (MCI) and mild AD (collectively referred to as “early AD”). The primary endpoint is the change over time on working memory and attention as measured by a combined score (Z-score) of the Detection test, the Identification test and the ‘One Back’ test (attention and working memory domains) of the Cogstate neuropsychological test battery (NTB), called “Cogstate 3-item scale”. Key secondary efficacy endpoints include in hierarchical order: Cogstate Brief Battery (CBB, 4-item scale), the complete Cogstate NTB (8-item scale), the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), and electroencephalogram (EEG) global theta power. Vivoryon is a clinical stage biotechnology company focused on developing innovative small molecule-based medicines. Driven by our passion for ground-breaking science and innovation, we strive to change the lives of patients in need suffering from severe diseases. We leverage our in-depth expertise in understanding post-translational modifications to develop medicines that modulate the activity and stability of proteins which are altered in disease settings. Beyond our lead program, varoglutamstat, which is in Phase 2 clinical development to treat Alzheimer’s disease, we have established a solid pipeline of orally available small molecule inhibitors for various indications including cancer, inflammatory diseases and fibrosis. www.vivoryon.com The content above comes from the network. if any infringement, please contact us to modify.

Pictured: Alzheimer's disease illustration/iStock, Artur Plawgo Vivoryon Therapeutics announced Monday that its drug candidate to treat Alzheimer’s disease failed to reach both its primary and secondary endpoints, causing the company’s stock price to nosedive by almost 90%. Vivoryon’s drug varglutamstat, an oral glutaminyl cyclase inhibitor, is being developed to treat early Alzheimer’s disease (AD). However, the Phase IIb VIVIAD study did not reach the primary endpoint. The results did not show a statistically significant difference in the change over time in cognition, measured by a combined score of the detection test, identification test, and the ‘one back’ test for attention and working memory. The results also did not hit the secondary endpoints investigating cognition, instrumental activities of the daily living questionnaire and electroencephalogram global theta power. Vivoryon said that it is performing an in-depth evaluation of the results, including the analysis of additional exploratory endpoints and other elements of the trial such as tau level, dose level and pre-treatment. “We are profoundly disappointed by the outcome of the VIVIAD Phase IIb study of varoglutamstat in the early AD patient population given the huge unmet need for new safe and effective oral therapies,” Vivoryon CEO Frank Weber said in a statement. “While these results are not what we had hoped for, VIVIAD is a comprehensive, diligently designed and high-quality study and we are doing all we can to fully analyze the dataset as quickly as possible to gain insights into key findings that might influence varoglutamstat clinical development and help advance the science and understanding of this devastating disease.” The company also touted that the drug was well tolerated and had low discontinuation rates related to adverse events, along with no evidence of symptomatic amyloid-related imaging abnormalities. Vivoryon said it will provide an update in April 2024 when it posts the company’s 2023 financial results. Alzheimer’s treatments have been missing the mark as of late, with Otsuka Pharmaceuticals announcing earlier this month that its candidate, AVP-786, did not reach its primary endpoint in a Phase III trial. However, more data readouts are expected this year for Alzheimer’s treatments such as Alector Therapeutics’ monoclonal antibody, Axsome Therapeutics’ drug designated to treat Alzheimer’s related agitation and Prothena’s fast-tracked anti-amyloid antibody, among others. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

Vivoryon is conducting an "in-depth analysis of the results, including analyses of additional pre-specified exploratory endpoints …. and distinct patient cohorts." The notoriously tricky indication of Alzheimer’s disease has defeated another candidate, with Vivoryon Therapeutics’ lead asset missing all endpoints in a phase 2 trial and sending the company’s stock plunging 90%. The European phase 2b study, dubbed VIVIAD, involved 259 patients with mild cognitive impairment and mild Alzheimer's receiving either a 600 mg twice daily dose of the glutaminyl cyclase inhibitor varoglutamstat or placebo. The primary endpoint was change over time on working memory and attention, with secondary endpoints assessing other measures of cognitive function and ability to perform everyday tasks. The drug didn’t show “a statistically significant difference in change over time on cognition” or hit any of the other endpoints, Vivoryon said in a pre-market release Monday. The 600 mg dose did at least seem to maintain the safety stats seen in preliminary readouts, with varoglutamstat “generally well tolerated” and producing similar rates of serious and severe treatment-emergent adverse events to placebo along with low discontinuation rates caused by adverse events. There was also no evidence of symptomatic amyloid-related imaging abnormalities (ARIA), a side effect that has haunted amyloid-lowering monoclonal antibody treatments for Alzheimer’s. Still, it’s tough news for Vivoryon, which as recently as December was anticipating “potential discussions with the FDA” in the wake of the VIVIAD readout. A phase 2 study in the U.S., called VIVA-MIND, is ongoing. For now, the biotech is conducting an “in-depth analysis of the results, including analyses of additional pre-specified exploratory endpoints …. and distinct patient cohorts as defined in the statistical analysis plan, including ApoE4 status, tau level, dose level and pre-treatment.” “We are profoundly disappointed by the outcome of the VIVIAD phase 2b study of varoglutamstat in the early AD patient population given the huge unmet need for new safe and effective oral therapies,” Vivoryon CEO Frank Weber, M.D., said in this morning’s release. “While these results are not what we had hoped for, VIVIAD is a comprehensive, diligently designed and high-quality study and we are doing all we can to fully analyze the dataset as quickly as possible to gain insights into key findings that might influence varoglutamstat clinical development and help advance the science and understanding of this devastating disease,” Weber added. Investors didn’t appear reassured, sending Vivoryon’s shares crashing 90% to 76 euro cents when the Stuttgart stock exchange opened this morning from a Friday closing price of 8.36 euros. The strong market reaction is likely because varoglutamstat is Vivoryon’s only clinical-stage asset. Last year, the biotech began the process of identifying oral QPTC/L inhibitors that could have potential as second-generation compounds to treat early-stage Alzheimer's. In a Monday morning note, Jefferies analysts said that despite the additional analyses, “given primary and secondary endpoints were all missed, it is difficult to see a path forward for varoglutamstat.” “We note the trial's baseline demographics are reported to be highly representative of an early AD patient population, as planned, suggesting the failure was not down to recruitment of the 'wrong' patients, as has previously been a problem for AD trials,” the analysts added.