Drug Development

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Varoglutamstat (PQ912) is an oral glutaminyl cyclase inhibitor targeting amyloid-beta (Aβ) and CCL2 formation.
• Preclinical and Phase 1 data supported its evaluation in early Alzheimer's disease (AD).

Purpose of the Study:

• To determine the optimal safe and well-tolerated dose of varoglutamstat for early AD.
• To assess the drug's safety and efficacy over 72 weeks in a Phase 2 trial.

Main Methods:

• Biomarker-confirmed early AD patients were randomized to varoglutamstat or placebo.
• A sequential design tested descending doses with futility analysis at 24 weeks.
• Primary endpoint was CDR-sum-of-boxes (CDR-SB); secondary endpoints included cognitive and functional measures.

Main Results:

• The 600mg dose was selected based on safety in Phase 2A; however, the trial was terminated prematurely.
• No significant differences were observed between varoglutamstat and placebo for CDR-SB or other efficacy endpoints at 72 weeks.
• Varoglutamstat was generally safe and well-tolerated, though treatment discontinuations due to adverse events were higher than placebo.

Conclusions:

• Varoglutamstat demonstrated a favorable safety profile in early AD patients.
• The study did not show significant treatment benefits, potentially due to limited sample size.
• Pending biomarker and pharmacokinetic/pharmacodynamic (PK/PD) data may offer further insights.