varoglutamstat (PQ912) / Vivoryon, Simcere - LARVOL DELTA

Glutaminyl Inhibitor Varoglutamstat Fails to Show Efficacy in Phase 2 VIVA-MIND Study of Early Alzheimer Disease (NeurologyLive) - P2 | N=112 | VIVA-MIND (NCT03919162) | Sponsor: Vivoryon Therapeutics N.V. | "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...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)...In terms of..."

P2 data • Alzheimer's Disease

A 3D pocket-aware lead optimization model with knowledge guidance and its application for discovery of new glutaminyl cyclase inhibitors. (PubMed, Brief Bioinform) - "Diffleop was further applied to optimize 5-methyl-1H-imidazole, our newly discovered lead compound targeting human glutaminyl cyclases (QCs). Three synthesized compounds exhibit substantially improved inhibitory activities against QCs, with the most effective one showing an IC50 value of 8 nM and 3.5-fold better than clinical candidate PQ912."

Journal

An Overview of Glutaminyl Cyclase as a Promising Drug Target for Alzheimer's Disease. (PubMed, Biomedicines) - "pEAβ acts as the seed for the formation of Aβ plaques, thus preventing the formation of pEAβ via QC inhibition, and offers a promising therapeutic strategy against AD. Here, we offer an overview of the pathway QCI research has followed-from the initial testing of imidazole-based inhibitor scaffolds to QCI structural optimization via pharmacophore identification, Varoglutamstat entering clinical trials, and further avenues of bettering specificity and potency for future QCI development."

Journal • Alzheimer's Disease • CNS Disorders • Psychiatry

Varoglutamstat improves eGFR and offers a new approach to treat diabetic kidney disease (DKD): meta-analysis from two independent phase 2 studies (ERA 2025) - P2 | "Varoglutamstat is a first in class glutaminyl cyclase (QPCT/L) inhibitor which showed a significant and clinically meaningful improvement of eGFR which was prospectively included as safety / exploratory parameter in two independent studies in older patients with and without diabetes. This finding was replicated in both trials independently and provides a strong credibility of the results. The next step is planned to be a dedicated phase 2b trial in patients with diabetic kidney disease (patients with diabetes and CKD stage 3b/4)."

P2 data • Retrospective data • Alzheimer's Disease • Chronic Kidney Disease • CNS Disorders • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • CCL2 • CX3CL1

Vivoryon Therapeutics N.V. Expands Intellectual Property Portfolio with New U.S. Composition of Matter Patent Granted for Varoglutamstat (GlobeNewswire) - "Vivoryon Therapeutics N.V...announced that the United States Patent and Trademark Office (USPTO) has granted an additional patent covering the Company’s lead drug in development, varoglutamstat. The new patent was granted after an accelerated examination process....The newly granted composition of matter US patent (US 12,312,335) covers the only polymorph of the salt form used in the drug product of Vivoryon’s unique QPCT/L inhibitor varoglutamstat. The patent has a scheduled runtime through 2044, with the subsequent opportunity for a patent term extension of up to five years to 2049 under the Hatch-Waxman Act."

Patent • CNS Disorders

Vivoryon Therapeutics N.V. to Host Virtual R&D Update with KOL Speakers on February 18, 2025 (GlobeNewswire) - "Vivoryon Therapeutics...announced to host a virtual R&D update with KOL (Key Opinion Leader) speakers on February 18, 2025....The webcast will include presentations from management and KOLs discussing further analyses and data on varoglutamstat’s observed beneficial effect on kidney function, an update on the Company’s anticipated clinical development plan for varoglutamstat in kidney disease, varoglutamstat’s potential market positioning, and an opportunity for investor and analyst questions."

Clinical • Renal Disease

Vivoryon Therapeutics N.V. Presents Topline Phase 2 Data from VIVA-MIND Strongly Supporting Varoglutamstat’s Potential to Improve Kidney Function (GlobeNewswire) - P2a | N=112 | VIVA-MIND (NCT03919162) | Sponsor: Vivoryon Therapeutics N.V. | "Vivoryon Therapeutics N.V...today announced positive Phase 2 topline data from its U.S. VIVA-MIND study of varoglutamstat (PQ912), an investigational oral glutaminyl cyclase (QPCT/L) inhibitor, in early AD. Analysis of kidney function data revealed a statistically significant improvement of >4mL/min/1.73m2 in the estimated glomerular filtration rate (eGFR) in patients treated with varoglutamstat 600mg BID versus placebo across all visits and all patients (weighted average weeks 4-72; p<0.001; total treated n=109; varoglutamstat n=52, placebo n=57)...Analysis of VIVA-MIND data in AD showed no clinically meaningful and no statistically significant differences between varoglutamstat 600mg BID and placebo for the primary endpoint of CDR-SB...The Company will provide further detail on the topline VIVA-MIND data on December 10, 2024, in its Q3 financial results webcast."

P2a data • Alzheimer's Disease • CNS Disorders

Varoglutamstat Increases Glomerular Filtration in Elderly Patients without Signs of Proteinuria and Potentially Offers a New Approach to Treat Diabetic Kidney Disease (DKD) (KIDNEY WEEK 2024) - P2 | "The significant increase in eGFR and several findings of the VIVIAD study support a further development in a new indication like diabetic kidney disease. The precise molecular mechanism of action of varoglutamstat is under investigation. Importantly, a clinical study in a relevant population and with additional endpoints like measures of albuminuria/proteinuria (UACR/UPCR), inflammation and fibrosis-related biomarkers, in addition to eGFR slope analysis, is in planning."

Clinical • Late-breaking abstract • Alzheimer's Disease • Chronic Kidney Disease • CNS Disorders • Cognitive Disorders • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease

Vivoryon Therapeutics N.V. Presents Outstanding Phase 2b Results of Varoglutamstat on Kidney Function at ASN Kidney Week 2024 (GlobeNewswire) - P2b | N=259 | VIVIAD (NCT04498650) | Sponsor: Vivoryon Therapeutics N.V. | "eGFR improved significantly for varoglutamstat compared to placebo and above baseline in both total population and diabetes subgroup, with the latter revealing a substantially higher treatment effect5 of >8.2mL/min/1.73m2/year (p=0.02; varoglutamstat n=20 / placebo n=12) compared to the overall VIVIAD study population (3.4mL/min/1.73m2/year (p<0.001; varoglutamstat n=141 / placebo n=117)). Results and effect size were consistent using a set of diverse and validated methods for eGFR assessment...Urine dipstick analysis showed no evidence of increased proteinuria in the treatment group compared to placebo...Robust safety data confirmed varoglutamstat’s excellent safety profile consistent across two years study duration with no adverse kidney effects and no meaningful differences observed in renal and metabolic systems adverse event."

P2b data • Alzheimer's Disease • Diabetic Nephropathy • Renal Disease

Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease. (PubMed, J Alzheimers Dis) - P2 | "Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CCL2

Vivoryon Therapeutics N.V. Shares Highlights from Virtual Kidney Disease KOL Event (Vivoryon Press Release) - P2b | N=259 | VIVIAD (NCT04498650) | Sponsor: Vivoryon Therapeutics N.V. | "Observations from the VIVIAD Phase 2b study have shown that varoglutamstat, with its novel mode of action targeting inflammatory and fibrotic pathways and promising efficacy and safety profile to date, could become an interesting treatment option for patients, if proven successful in double blinded, randomized prospective clinical studies...Analysis of data from the VIVIAD study employing this method has yielded consistent findings for eGFR with varoglutamstat, with a substantial treatment effect on the eGFR slope seen for varoglutamstat compared to placebo in the overall population driven by an even larger effect in patients with type 2 diabetes....Available results from VIVIAD together with good statistical planning enables an efficient design of a Phase 2 study in patients with DKD stage 3/4 with an interim futility analysis after 62 patients treated for at least 24 weeks."

P2b data • Alzheimer's Disease • CNS Disorders • Diabetic Nephropathy • Renal Disease • Type 2 Diabetes Mellitus

Vivoryon Therapeutics N.V. Announces Late-breaking Oral Presentation at the American Society of Nephrology Kidney Week 2024 (GlobeNewswire) - "Vivoryon Therapeutics....announced that the Company’s abstract...has been selected for a late-breaking oral presentation at the American Society of Nephrology (ASN) Kidney Week 2024 in San Diego, California, held October 23 to 27."

Clinical • Late-breaking abstract • Chronic Kidney Disease • Diabetic Nephropathy • Renal Disease

VIVA-MIND: A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD (clinicaltrials.gov) - P2 | N=112 | Terminated | Sponsor: Vivoryon Therapeutics N.V. | N=414 ➔ 112 | Active, not recruiting ➔ Terminated; It has been made the strategic decision to terminate the study. This decision to terminate the study early is not being made for safety reasons.

Enrollment change • Trial termination • Alzheimer's Disease • CNS Disorders

Developing Topics. (PubMed, Alzheimers Dement) - P2, P2a | "The use of MMSE and DSST/WAIS-IV together with CSF biomarkers is a valuable tool in identifying and recruiting patients with MCI or mild AD. The strategy of recruiting individuals with evidence of baseline deficits on the WAIS-IV Coding test has successfully enriched the study cohort with respect to deficits in attention and working memory, enabling reliable assessment of potential cognitive improvement after treatment."

Biomarker • Clinical • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CSF P-tau

VIVA-MIND: A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD (clinicaltrials.gov) - P2 | N=414 | Active, not recruiting | Sponsor: Vivoryon Therapeutics N.V. | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model. (PubMed, J Med Chem) - "Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease...In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease • CCL2

Synthesis and Evaluation of a Novel PET Radioligand for Imaging Glutaminyl Cyclase Activity as a Biomarker for Detecting Alzheimer's Disease. (PubMed, ACS Sens) - "The PET probe was developed with 99.9% radiochemical purity, a molar activity of 965 Ci.mmol-1, and an IC50 of 56.3 nM, comparable to those of the parent PQ912 inhibitor (62.5 nM)...Further, in vivo PET imaging with [18F]PB0822 revealed that AD 5XFAD mice harbor significantly higher QC activity than WT counterparts. The data also suggested that QC activity is found across different brain regions of the tested animals."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders

VIVA-MIND: A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD (clinicaltrials.gov) - P2 | N=414 | Recruiting | Sponsor: Vivoryon Therapeutics N.V. | Phase classification: P2b ➔ P2 | Trial completion date: Nov 2023 ➔ Sep 2024 | Trial primary completion date: Nov 2023 ➔ Sep 2024

Phase classification • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders

Vivoryon Therapeutics N.V. Reports Full Year 2023 Financial Results and Provides Varoglutamstat and Strategic Updates (GlobeNewswire) - "Research and development expenses decreased by EUR 2.6 million to EUR 17.6 million in the year ended December 31, 2023, compared to EUR 20.2 million in the year ended December 31, 2022. The decrease is primarily attributable to EUR 2.7 million lower third-party expenses, mainly due to EUR 3.6 million lower manufacturing costs, partially offset by EUR 1.7 million higher clinical costs, mainly due to the progress of the Phase 2b VIVIAD clinical study."

Commercial • Alzheimer's Disease • CNS Disorders

Vivoryon Therapeutics N.V. Reports Full Year 2023 Financial Results and Provides Varoglutamstat and Strategic Updates (GlobeNewswire) - "Vivoryon announced today that, based on the ongoing review of VIVIAD data published March 4, 2024, and an assessment of funding needs, the Company has decided jointly with its principal investigator, to voluntarily discontinue the Phase 2 VIVA-MIND study in early AD in the U.S. in the second half of 2024. This will enable accelerated analysis of the results and will contribute to the overall dataset informing varoglutamstat’s development strategy moving forward. Initial data from the study is anticipated by the end of 2024....In line with the Company’s cost reduction measures and given the developments of VIVIAD and VIVA-MIND, Vivoryon has decided to stop VIVALONG OLE study preparation activities."

P2a data • Trial termination • Alzheimer's Disease • CNS Disorders

VIVIAD: A Study to Evaluate Safety and Tolerability of Different Doses and Efficacy of PQ912 in Subjects With MCI and Mild AD (clinicaltrials.gov) - P2 | N=259 | Completed | Sponsor: Vivoryon Therapeutics N.V. | Active, not recruiting ➔ Completed | Phase classification: P2b ➔ P2

Phase classification • Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Vivoryon Therapeutics N.V. Provides Update on VIVIAD Phase 2b Study of Varoglutamstat in Early Alzheimer’s Disease (GlobeNewswire) - P2b | N=259 | VIVIAD (NCT04498650) | Sponsor: Vivoryon Therapeutics N.V. | "Vivoryon Therapeutics N.V...today announced topline results from its Phase 2b European VIVIAD study of varoglutamstat (PQ912)....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."

P2b data • Alzheimer's Disease • CNS Disorders

Vivoryon Therapeutics N.V. to Host Investor Meetings in January 2024 (GlobeNewswire) - "Vivoryon Therapeutics N.V...today announced that members of its management team including CEO Frank Weber, MD, CBO Michael Schaeffer, PhD, and CS & IRO Anne Doering, CFA, will host investor meetings, January 8 – 10, 2024, in San Francisco, CA. Vivoryon’s management team will discuss its lead program varoglutamstat, a differentiated investigational small-molecule medicine in development to treat Alzheimer’s disease (AD). The Company remains on track to share VIVIAD Phase 2b final topline data, comprising primary and comprehensive secondary endpoints data as well as safety data, during the end of the first quarter of 2024 and the full dataset at a subsequent medical meeting."

P2b data • Alzheimer's Disease • CNS Disorders

Vivoryon Therapeutics N.V. Reports Third Quarter 2023 Financial Results and Highlights Operational Progress (GlobeNewswire) - "On track to report VIVIAD final topline Phase 2b data during end of Q1/2024...Research and development expenses of EUR 10.4 million in the nine months ended September 30, 2023, decreased by EUR 5.6 million compared to the nine months ended September 30, 2022. This decrease is primarily attributable to EUR 3.0 million lower expenses related to our clinical trial VIVIAD and EUR 2.6 million lower manufacturing cost for study drug production."

Commercial • P2b data • Alzheimer's Disease • CNS Disorders

Vivoryon Therapeutics N.V. Reports Positive Outcome from Independent Data Safety Monitoring Board with Unanimous Decision for VIVA-MIND U.S. Study of Varoglutamstat in Alzheimer’s Disease to Proceed at Highest Investigated Dose (GlobeNewswire) - "Vivoryon Therapeutics N.V...today announced that the study’s independent data safety monitoring board (DSMB) unanimously recommend that the VIVA-MIND study of varoglutamstat should proceed with a dose of 600mg twice daily (BID) through the remainder of Phases 2a and 2b....The DSMB’s dose decision recommending that the highest dose of varoglutamstat of 600mg BID be selected for the remainder of the trial follows its September 18, 2023 quarterly safety review of adverse events, and labs, and its October 19, 2023 analysis of treatment-emergent adverse events of special interest (AESI) pertaining to skin and subcutaneous tissue disorders and hepatobiliary disorders, as well as target occupancy and plasma pharmacokinetic (PK) data."

DSMB • Alzheimer's Disease • CNS Disorders