A First-in-Class TRPA1 Antagonist Overcomes Toxicity Hurdles to Become Cough Candidate

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after preclinical studies and a Ph. I trial showed it was well-tolerated, in contrast to prior molecules. The transient receptor potential (TRP) family of ion channels has been the subject of intensive drug discovery efforts due to their critical role in the development and progression of pain, itch, and respiratory conditions. In the Ph. IIa trial, GDC-6599 will be evaluated for its efficacy and safety in patients with chronic cough (persistent cough > 8 weeks). The challenges and promise of modulating another ion channel target in chronic cough, P2X3, has been recently discussed here. Previous TRPA1 antagonists have struggled in development, often due to PK and toxicity issues. For example, Genentech’s previous TRPA1 antagonist, GDC-0334 (Figure 1), was terminated in Ph. I (NCT03381144) due to toxicity findings in preclinical models. GDC-6599 offers a notable case study in addressing several unexpected toxicities while pursuing a novel target through mechanistic investigation.

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