Discovery of VU0467319: an M₁ Positive Allosteric Modulator Candidate That Advanced into Clinical Trials

Area of Science:

• Neuroscience
• Pharmacology
• Clinical Trials

Background:

• M1 muscarinic receptors are key targets for cognitive enhancement.
• Developing selective M1 Positive Allosteric Modulators (PAMs) with minimal side effects is challenging.
• Cholinergic adverse effects have limited previous CNS drug development.

Purpose of the Study:

• To disclose VU0467319 (VU319), a novel M1 PAM.
• To report the successful completion of a Phase I Single Ascending Dose (SAD) clinical trial for VU319.
• To evaluate the safety, tolerability, and target engagement of VU319.

Main Methods:

• VU319 was characterized as an M1 PAM with high CNS penetration and favorable pharmacokinetics.
• Preclinical studies assessed efficacy in cognition models and safety in rats, dogs, and nonhuman primates.
• A Phase I SAD clinical trial (NCT03220295) was conducted in healthy volunteers.

Main Results:

• VU319 demonstrated moderate M1 PAM potency with minimal M1 agonism.
• Preclinical toxicology and Phase I SAD trial showed a lack of cholinergic adverse effects.
• Target engagement signals were observed at the highest dose in the Phase I trial.
• VU319 exhibited high central nervous system (CNS) penetration and favorable multispecies pharmacokinetics.

Conclusions:

• VU319 is the first M1 PAM to successfully complete a Phase I SAD trial.
• VU319 shows feasibility in selectively targeting central M1 muscarinic receptors without cholinergic side effects.
• VU319 represents a promising clinical candidate for treating cognitive dysfunction.