WS05.02 A Phase-1 multiple ascending dose healthy volunteer study to evaluate the safety, tolerability, and pharmacokinetics of GDC-6988, a dry powder formulation of a selective inhaled potentiator of TMEM16A

Objectives: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are not indicated for ~10% of people with CF and may not fully restore CFTR function. GDC-6988 is a potent and selective potentiator of TMEM16A and is expected to enhance calcium-induced anion transport, increase airway fluid secretion, and promote mucus hydration and clearance. We previously reported outcomes in healthy volunteers with a nebulized formulation of GDC-6988. Here we present blinded outcomes from an ongoing Phase 1 study of a dry powder (DP) formulation of GDC-6988. Methods: This randomized, double-blind, placebo-controlled study (GB43838) assesses the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses of inhaled DP GDC-6988 with and without albuterol pretreatment in healthy volunteers. Subjects received GDC-6988 or placebo twice daily (BID) for 14 days, with albuterol pretreatment starting on Day 8. Results: Ten subjects received GDC-6988 11.2 mg BID or matching placebo (in an 8:2 ratio). Eight adverse events (AEs) were observed in 3 subjects, all Grade 1 and non-serious. One AE (intermittent chest tightness) was related to GDC-6988, occurred 30 mins after dosing on Days 1–6, and resolved without treatment. No dose-limiting AEs were seen. Decreases in FEV1 of 10–20% from baseline to 30 mins after ≥1 dose were seen in 4 subjects, were asymptomatic except for chest tightness in 1 subject, and were mitigated by albuterol pretreatment in 3 subjects. No PK accumulation was observed, consistent with the short half life of GDC-6988. Mean Cmax and AUC trended slightly higher with albuterol pretreatment. Cmax was ~47% lower and AUC at steady state was ~38% higher than that seen with an equivalent nebulized dose (45 mg BID). Conclusion: GDC-6988 was generally safe and well-tolerated at 11.2 mg BID. Systemic exposure levels of GDC-6988 were low. Additional cohorts at higher doses are ongoing, and a Phase 2 study in patients with CF is planned.