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. 2024;101(s1):S79-S93.
doi: 10.3233/JAD-231126.

Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease

Howard H Feldman  1   2   3 , Karen Messer  1   2 , Yuqi Qiu  4 , Marwan Sabbagh  5 , Douglas Galasko  1   2   3 , R Scott Turner  6 , Oscar Lopez  7   8 , Amanda Smith  9 , January Durant  1   2 , Jody-Lynn Lupo  1   2 , Carolyn Revta  1   2 , Archana Balasubramanian  1   2 , Kerstin Kuehn-Wache  10 , Tanja Wassmann  10 , Sylvia Schell-Mader  10 , Diane M Jacobs  1   2   3 , David P Salmon  1   2   3 , Gabriel Léger  1   2 , Mari L DeMarco  11   12 , Frank Weber  10 ; ADCS VIVA-MIND Study Group
Affiliations

Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease

Howard H Feldman et al. J Alzheimers Dis. 2024.

Abstract

Background: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer's disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD.

Objective: Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ.

Methods: Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment.

Conclusions: 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.

Keywords: Alzheimer’s disease; CCL2; N3pE-Aβ; QPCT; QPCTL; amyloid β-peptides; cerebrospinal fluid; glutaminyl cyclase; mild cognitive impairment; pGlu-Aβ.

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Conflict of interest statement

For this manuscript, Howard Feldman reports grant funding from Vivoryon Therapeutics (Probiodrug) for the VIVA-MIND trial as well as grant development support including travel prior to the trial. All funds were directed to UCSD. Relationships outside of this manuscript include: grant support from Annovis (QR Pharma), Biohaven Pharmaceuticals, AC Immune, and LuMind Foundation and consulting fees from LuMind, Genentech, Roche/Banner, Tau Consortium, Samus Therapeutics, Biosplice Therapeutics, Axon Neurosciences, Novo Nordisk Inc. (including travel), Janssen Research & Development LLC, and Arrowhead Pharmaceuticals with no personal funds received and all payments to UCSD. He also reports a philanthropic donation from the Epstein Family Alzheimer’s Disease Collaboration for therapeutic research in AD. Unrelated to the current manuscript, he receives royalty payments for patent “Detecting and Treating Dementia” Serial Number 12/3-2691 U.S. Patent No. PCT/US2007/07008. Washington, DC: U.S. Patent and Trademark Office.

Douglas Galasko is a paid consultant for Eisai, Biogen, GE Healthcare and Artery Therapeutics.

Gabriel Léger is a paid consultant for Eisai.

Kerstin Kuehn-Wache is an employee of Vivoryon Therapeutics N.V. and holds shares in Vivoryon Therapeutics N.V.

Oscar Lopez received consulting fees from Novo Nordisk, Lundbeck, and Eisai.

Marwan Sabbagh reports ownership interest (stock or stock options) in NeuroTau, Athira, Lighthouse Pharmaceuticals, Alzheon, and Reservoir Neuroscience. He receives consulting fees from Roche-Genentech, Eisai, Lilly, Synaptogenix, NeuroTherapia, T3D, Signant Health, Novo Nordisk, Corium, Prothena, KeiferRx and serves on the CervoMed board of directors. Dr. Sabbagh is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

Amanda Smith receives grant support from Eli Lilly, Janssen, Biogen, Eisai, Cassava, and Vivoryon and serves as a site PI on the VIVA-MIND trial.

R. Scott Turner receives consulting fees from Re:Cognition Health, Jupiter Neuroscience, and NeuroNascent. He reports grant support to Georgetown University from Biogen, Eisai, Lilly, Roche/Genentech, Janssen, Vaccinex, Vivoryon, and Cognition Therapeutics.

Sylvia Schell-Mader is working as a contractor of Vivoryon Therapeutics N.V.

Tanja Wassmann is an employee of Vivoryon Therapeutics N.V.

Mari DeMarco reports consulting fees from Siemens and Eisai, and consulting and lecturing fees from Roche.

Frank Weber is an employee of Vivoryon Therapeutics N.V. and owns stock equity in Vivoryon Therapeutics N.V. He is also an employee of Zambon Biotech SA Lugano. Frank Weber is the owner of LifeScience&Innovation GmbH and has received fees from Unicyte AG, Switzerland and from Santhera AG Basel CH.

All other authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
pGlu-Aβ as a therapeutic targeta. Aβ is cleaved by dipeptidyl peptidase 4 (DPP4), meprin β, or aminopeptidases, between residues 2 (alanine [A]) and 3 (glutamate [E]). This exposes glutamate at the N-terminus, which is subsequently modified to N-terminal pyroglutamate (pGlu) by dehydration catalyzed by glutaminyl cyclase (QC) activity. The resultant peptide (pGlu-Aβ) has altered biochemical properties with severe pathological consequences. The enhanced toxicity is likely due to the higher aggregation propensity and the longer bioavailability of the pGlu-Aβ oligomers. Additionally, an isoenzyme of QC converts the N-terminus of chemokine ligand 2 (CCL2) into pGlu-CCL2 which is associated with neuroinflammation. Varoglutamstat inhibits both QC and iso-QC. aFigure and caption are adapted from Jawhar, Wirths, and Bayer (2011) (CC BY 4.0 DEED), https://creativecommons.org/licenses/by/4.0/#
Fig. 2
Fig. 2
The pharmacokinetic/pharmacodynamic relationship between varoglutamstat concentration and QC inhibition in CSF and seruma. QC, glutaminyl cyclase; CSF, cerebrospinal fluid; ng, nanogram; mL, milliliter. aData on file with Vivoryon Therapeutics.
Fig. 3
Fig. 3
Study schematic. BID, twice per day; mg, milligram; EEG, electroencephalogram.
Fig. 4
Fig. 4
Stage Gate framework for proceeding to phase 2B. Ph2A, phase 2A; EEG, electroencephalogram; PK, pharmacokinetic; ADNI Battery Composite, Alzheimer’s Disease Neuroimaging Initiative sum of 9 standardized cognitive test scores.
See this image and copyright information in PMC

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