# A Seamless Phase 2A-B Randomized Double Blind Placebo Controlled Trial to Evaluate the Efficacy and Safety of PQ 912 in Patients with Early Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $3,726,446

## Abstract

PROJECT SUMMARY/ABSTRACT
We are proposing a seamless phase 2A-B Proof of Concept (POC) trial of PQ 912, a first-in-class small
molecule treatment for early Alzheimer’s disease (AD) with a unique mechanism of action. PQ 912 inhibits the
enzyme glutaminyl cyclase (QC) and its isozyme iso-QC, resulting in reduced levels of pGlu-Aβ, a post-
translationally modified form of Aβ (Glutamate 3/11 cyclization), as well as pGlu-CCL2, a post-translationally
modified form of cytokine monocyte chemoattractant protein 1 (CCL2) (Glutamine cyclisation). These proteins
are significantly overexpressed in AD where pGlu-Aβ has been shown to be synaptotoxic, proinflammatory,
promoting of self-aggregation into oligomers, and resistant to degradation, while pGlu-CCL2 has been linked to
the presence and severity of neuroinflammation. In preclinical models, these toxic effects can be attenuated
with PQ 912 treatment. PQ 912 has completed extensive preclinical AD testing, a large phase 1 program
exploring its dose range with PK PD testing, and an early phase 2A clinical trial. It is an excellent candidate to
take into further development, as it can address a set of stringent POC criteria including target validation,
suitable dose range for testing with direct PK PD measurement, with biomarkers that can evaluate relevant
downstream biological effects. Phase 2A positive results on quantitative EEG with effects on theta power and
on CSF biomarkers including YKL 40 also support further development. Based on these aggregate results, our
proposed clinical study targets early AD with the goal of improving cognition and everyday function through
improved synaptic function, and attenuating longer term disease progression through its dual pathways of PQ
912’s mode of action. The first phase of the trial, phase 2A, uses a group sequential dose design to find the
highest well tolerated and safe dose of PQ 912 to take through to phase 2B, a 72-week safety and efficacy
study. A planned interim futility analysis will be conducted at week 52. The primary efficacy outcome measure
is Clinical Dementia Rating – Sum of Boxes, and a key secondary outcome is a novel cognitive-functional
composite shown previously to be highly sensitive to change in MCI and early AD in the Alzheimer’s Disease
Neuroimaging Initiative (ADNI). Additional secondary endpoints include measurement of QC inhibition and
target occupancy in CSF, quantitative EEG with spectral analysis of theta power, ADAS-Cog 13, selected
measures from the ADNI neuropsychological test battery, Functional Activities Questionnaire, and the
Neuropsychiatric Inventory. Safety including SAEs, AEs, DAE-Is and other safety monitoring will be followed
throughout with oversight of participant safety from the DSMB. In summary, this trial will evaluate a novel
treatment for early AD that has potential for both symptomatic and disease-modifying effects while
simultaneously validating novel composite outcome measures within a trial setting.

## Key facts

- **NIH application ID:** 10356791
- **Project number:** 5R01AG061146-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Howard Feldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,726,446
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356791

## Citation

> US National Institutes of Health, RePORTER application 10356791, A Seamless Phase 2A-B Randomized Double Blind Placebo Controlled Trial to Evaluate the Efficacy and Safety of PQ 912 in Patients with Early Alzheimer's Disease (5R01AG061146-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356791. Licensed CC0.

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