(M-142) Evaluating concomitant medication use in cystic fibrosis patients using real-world data (RWD) to inform drug-drug interaction risk assessment and clinical trial design of GDC-6988

Denise Boudreau, none – Senior Principal Data Scientist, Genentech; Parul Dayal, none – Principal Data Scientist, Genentech; Oona Risse-Adams, none – student, UC Berkeley; Veronica Sun, None – Data Scientist, Genentech; Gaohong She, none – Scientist, Genentech; Tom De Bruyn, none – Senior Principal Scientist, Genentech; Joshua Galanter, none – Senior Medical Director, Genentech; Fang Ma, none – Scientist, Genentech; Yuan Chen, none – Senior Fellow, Genentech; Rui Zhu, none – Distinguished Scientist, Genentech

Background: Cystic fibrosis (CF) is a rare disease characterized by mutations in the Cystic Fibrosis Transmembrane Receptor (CFTR) gene resulting in the missing or malfunctioning CFTR activity and impaired lung clearance. CFTR modulators are the standard of care for CF patients; however, they are not indicated for approximately 10% of CF patients due to their CFTR mutation type. By potentiating the calcium-activated chloride channel TMEM16A, GDC-6988 is expected to compensate for CFTR and restore mucus hydration and mucociliary clearance irrespective of the CFTR mutation in CF patients.

Objectives/

Methods: In vitro studies showed that GDC-6988 may be a moderate inhibitor and inducer of the CYP3A4 enzyme, indicating co-administration of GDC-6988 with CYP3A4 sensitive substrate concomitant medications (conmeds) may change the conmeds concentration and affect their safety and efficacy. To inform the conmeds exclusion criteria in future GDC-6988 clinical trials in CF patients, physiologically based pharmacokinetic (PBPK) model refined with GDC-6988 Phase 1b study data was used to assess the drug-drug interaction (DDI) risk.

IQVIA PharMetrics® Plus claims data between Jan 2020 and March 2021 were used to evaluate the prevalence of conmeds that are considered CYP3A substrates among CF patients with and without CFTR modulator. Detailed medication information that may further influence drug interactions including dose regimen, treatment duration (eg, acute vs. chronic), route of administration, and common diagnosis were also extracted for selected conmeds.

Results: PBPK DDI simulations showed minimal to mild (geometric mean exposure change < +/- 15%) impact of GDC-6988 as a perpetrator on midazolam. RWD showed that the majority of the most frequently used sensitive CYP3A4 substrate conmeds in the CF population are considered less sensitive to CYP3A compared to midazolam and do not have a narrow therapeutic window, except for tacrolimus and sirolimus, which are indicated for lung transplant patients who would typically be excluded from clinical studies.

Conclusions: Use of RWD allowed the DDI risk assessment to be conducted in a more realistic way by focusing on most frequently used CYP3A sensitive conmeds in the target population. Based on the PBPK modeling and RWD data, CF patients taking CYP3A4 substrates as conmeds will not be excluded from future clinical trials, and instead they will be monitored for adverse events for sensitive CYP3A substrates with narrow therapeutic window.

Citations: None