A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD

NCT03919162 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: PBD-011871R01AG061146-01
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 22

Brief Summary

This is a Phase 2A multi-center, randomized, double blind, placebo-controlled, parallel group study of varoglutamstat, with a stage gate to Phase 2B. In Phase 2A there will be adaptive dosing evaluation of three dose levels with exposure to varoglutamstat or placebo for a minimum of 24 weeks, with preliminary evaluation of both cognitive function and pharmacodynamic changes on EEG spectral analysis in approximately 180 participants. In the event that the stage gate for Phase 2B is reached, then Phase 2B will assesses efficacy and longer-term safety in a larger study group, i.e., 414.

Conditions

Alzheimer Disease

Keywords

Alzheimer's Disease; Mild Cognitive Impairment; Mild Alzheimer's Disease; Early Alzheimer's disease; MCI

Outcome Measures

Primary Outcomes (6)

• Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)

  The proportion of participants, who experience any AESI during the safety evaluation period, which is from first dose to completion of 8 weeks at the full originally assigned dose. Per protocol, if the first cohort (Cohort A) does not meet the pre-specified Pocock safety stopping boundary within the active arm, that dose will be selected as safe. The dose selected as safe will be the dose carried forward for all participants in the active arm for the remainder of the study. The Pocock boundary is only valid until dose selection. If a higher dose is selected as safe, assignment to lower doses will stop, and all current participants on a lower dose will be titrated up to the selected dose according to uptitration schedule. If Cohort A does not meet the Pocock boundary only evaluation of Cohort A is required for this endpoint.

  From first dose to completion of 8 weeks on the full dose (Week 16)

• Phase 2A: Median Estimated Target Occupancy (TO) of PQ912 in Cerebrospinal Fluid (CSF) at Week 24

  The pharmacokinetics (PK) endpoints in Phase 2A are the derived median values of PQ912 levels in plasma and the corresponding calculated target occupancy (TO) in CSF, following at least 8 weeks of treatment at the dose level being tested. TO in CSF was estimated from plasma PQ912 concentrations.

  Week 24, pre-dose (trough level) and 2-3h post-dose

• Phase 2A: Median Plasma Concentrations of PQ912 at Week 24

  The pharmacokinetics (PK) endpoints in Phase 2A are the derived median values of PQ912 levels in plasma and the corresponding calculated target occupancy (TO) in CSF, following at least 8 weeks of treatment at the dose level being tested. Blood samples were obtained and PQ912 plasma concentrations were determined using a validated high-pressure liquid chromatography hyphenated with tandem mass spectrometry (LC-MS/MS) method.

  Week 24, pre-dose (trough level) and 2-3h post-dose

• Phase 2A: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) Score

  The within-participant change from baseline in the composite mean of standardized scores from a set of ADNI neuropsychological test measures, the ADNI Battery Composite (ABC, 9-item). The ABC score was calculated from the following 9 measures from the ADNI-1 Neuropsychological Test Battery: Auditory Verbal Learning Test (AVLT)-Immediate Recall, AVLT-Delayed Recall, Number Span Forward, Number Span Backward, Category Fluency, Trail Making Test A, Trail Making Test B, Digit Symbol Substitution, Boston Naming Test. Standardized scores (Z-scores) were calculated using the overall mean and standard deviation of all participants in the modified Intent-to-Treat (mITT) population at baseline as reference. The ABC score for each participant was the mean of the standardized subtest values. Range: -3 to 3; higher scores indicate less impairment.

  24 weeks

• Phase 2A: Change From Baseline in Quantitative Electroencephalogram (qEEG)

  The within-participant change from baseline of global relative theta wave power (4-8 Hz) in qEEG. qEEG was used to assess resting-state brain activity, including global relative theta power (4-8 Hz), based on spectral analysis of signals from 21 electrode positions. Higher theta power indicates greater impairment.

  24 weeks

• Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score

  The within-participant change from baseline in CDR-SB scores. The CDR-SB is a composite rating of cognition and everyday function which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview three cognitive domains (memory, orientation, and judgement/problem solving) and three everyday functional domains (community affairs, home and hobbies, and personal care). Level of impairment in each of the six domains is rated from none (score=0) to severe (score=3). The six domain scores are then summed to create the CDR-SB. Range: 0-18; higher scores indicate greater impairment.

  72 weeks

Secondary Outcomes (12)

• Phase 2B: Key Secondary Efficacy: Change From Baseline in Cognitive Functional Composite-2 (CFC2) Score, a Cognitive Functional Composite

  72 weeks

• Phase 2B: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC, 9-item) Score

  72 weeks

• Phase 2B: Change From Baseline in Quantitative Electroencephalogram (qEEG)

  72 weeks

• Phase 2B: Change From Baseline in Functional Activities Questionnaire (FAQ)

  72 weeks

• Phase 2B: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13)

  72 weeks

Study Arms (2)

PQ912

EXPERIMENTAL

All participants started at 150 mg BID and were up-titrated to 600 mg BID

Drug: PQ912

Placebo

PLACEBO COMPARATOR

Matching placebo

Other: Placebo

Interventions

PQ912 DRUG

PQ912 150 mg tablets

Also known as: Varoglutamstat

PQ912

Placebo OTHER

Placebo tablets to mimic PQ912 150 mg tablets

Placebo

Eligibility Criteria

• Age: 50 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 50-89 (inclusive) at screening
• Diagnosed as having Mild Cognitive Impairment (MCI) due to Alzheimer's disease (AD) or Mild probable AD according to workgroups of the Diagnostic Guidelines of the National Institute on Aging and Alzheimer's Association (NIA-AA)
• Mini-Mental State Examination (MMSE) score 20-30 inclusive at screening
• Montreal Cognitive Assessment score (MoCA) \< 26 at screening
• Clinical Dementia Rating global score 0.5 or 1 with memory score of \> 0.5 at screening
• Positive cerebrospinal fluid (CSF) AD biomarker signature
• A brain MRI scan within 6 months of screening consistent with a diagnosis of Alzheimer's disease
• Participants must have a study partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with study procedures.

You may not qualify if:

• Significant neurodegenerative diseases and causes of dementia, other than AD, including Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired Immunodeficiency Syndrome), or NPH (normal pressure hydrocephalus)
• Meeting Diagnostic Criteria for Possible AD according to workgroups of the Diagnostic Guidelines of the NIA-AA
• Hepatic impairment defined as Child-Pugh class A or more severe liver impairment
• History of moderate or severe skin reactions to medications or current moderate or severe disease of the skin and subcutaneous tissues
• History of a major depressive episode within the past 6 months of screening
• History of diagnosis of schizophrenia
• History of uncontrolled bipolar disorder within past five years of screening
• History of seizures within past two years of screening
• Contraindication to lumbar puncture and MRI
• Monoclonal antibody treatment with anti-amyloid or anti-tau agents intended to address the pathophysiologic processes associated with AD within the previous 180 days prior to baseline (BL)
• Participants who are planning to receive treatment with aducanumab or any Amyloid Beta Antibody during the course of the study
• Participation in another clinical trial for an investigational agent and having taken at least one dose of study drug, unless confirmed as having been on placebo, within 90 days prior to the baseline visit. The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.

Sponsors & Collaborators

• Vivoryon Therapeutics N.V.: lead
• Alzheimer's Disease Cooperative Study (ADCS): collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (22)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

The Neuron Clinic

Chula Vista, California, 91910, United States

Location

University of California

Irvine, California, 92868, United States

Location

UCSD Alzheimer's Disease Research Center

La Jolla, California, 92037, United States

Location

Cedars-Sinai Center

Los Angeles, California, 90048, United States

Location

PCND Neurology

Poway, California, 92064, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20057, United States

Location

USF Health Byrd Alzheimer's Center and Research Institute

Tampa, Florida, 33613, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

The University of Iowa Carver College of Medicine

Iowa City, Iowa, 52242, United States

Location

The University of Kentucky Sanders-Brown Center on Aging

Lexington, Kentucky, 40504, United States

Location

Northern Light Acadia Hospital

Bangor, Maine, 04401, United States

Location

NYU Langone Health Tisch Hospital

New York, New York, 10016, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

OHSU Neurology Clinic

Portland, Oregon, 97239, United States

Location

Abington Neurological Associates

Abington, Pennsylvania, 19001, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Lowcountry Center for Veterans Research (LCVR)

Charleston, South Carolina, 29403, United States

Location

UT Health San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (5)

• Feldman HH, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner RS, Lopez O, Smith A, Durant J, Lupo JL, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs DM, Salmon DP, Leger G, DeMarco ML, Weber F; ADCS VIVA-MIND Study Group. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease. J Alzheimers Dis. 2024;101(s1):S79-S93. doi: 10.3233/JAD-231126.

  PMID: 39422941 BACKGROUND

• Messer K, Jacobs DM, Salmon DP, Qiu Y, Revta C, Weber F, Kuhn-Wache K, Leger GC, Feldman HH. (2022), A novel, efficient and seamless Phase 2A-2B design to test varoglutamstat in early AD: the VIVAMIND study. Alzheimer's Dement., 18(S10): e065197.

  BACKGROUND

• Lues I, Weber F, Meyer A, Buhring U, Hoffmann T, Kuhn-Wache K, Manhart S, Heiser U, Pokorny R, Chiesa J, Glund K. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement (N Y). 2015 Oct 3;1(3):182-195. doi: 10.1016/j.trci.2015.08.002. eCollection 2015 Nov.

  PMID: 29854937 BACKGROUND

• Scheltens P, Hallikainen M, Grimmer T, Duning T, Gouw AA, Teunissen CE, Wink AM, Maruff P, Harrison J, van Baal CM, Bruins S, Lues I, Prins ND. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther. 2018 Oct 12;10(1):107. doi: 10.1186/s13195-018-0431-6.

  PMID: 30309389 BACKGROUND

• Feldman HH, Messer K, Zhang J, Quach NE, Léger GC, Jacobs DM, Edland SD, Duehring J, MacKelfresh A, Pol A, Revta C, Lupo JL, Balasubramanian A, Lama N, Wassmann T, Schaeffer M, Hoffmann T, Meyer A, Schell-Mader S, Wenzkowski C, Weber F, for the ADCS VIVA-MIND Study Group. The VIVA-MIND study: Topline Results from Phase 2 RCT of Varoglutamstat in Early AD. In press, abstract at 2025 AAIC, Alzheimer's and Dementia

  RESULT

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Limitations and Caveats

Due to the early termination of the study the intended sample size was not reached and the available sample size for the analysis was limited. However, participants enrolled in Phase 2A remained in the study for seamless inclusion in the Phase 2B evaluation (up to 72 weeks).

Results Point of Contact

• Title: Study Director
• Organization: Vivoryon Therapeutics N.V.

clinics@vivoryon.com

0049 34555599

Study Officials

• Howard Feldman

  Alzheimer's Disease Cooperative Study (ADCS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2019
• First Posted: April 18, 2019
• Study Start: November 15, 2021
• Primary Completion: July 12, 2024
• Study Completion: August 12, 2024
• Last Updated: December 12, 2025
• Results First Posted: December 12, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: January 2026
• Access Criteria: Data requestors must complete an ADCS data and sample sharing request form. Upon approval, requestors must complete a data use agreement prior to accessing the data.

Locations

US (22)