PII-066 - EVALUATION OF CYTOCHROME P450 2C9, 2C19 AND 2D6 INHIBITION ON THE PHARMACOKINETICS OF AFICAMTEN IN HEALTHY PARTICIPANTS

N. Maharao¹, J. Lutz¹, T. Simkins², Y. Shaw³, J. Li⁴, P. Solanki⁵, A. Griffith¹, S. Heitner⁶, S. Kupfer², P. German¹; ¹Department of Clinical Pharmacology, Cytokinetics, Inc, San Francisco, CA, USA, ²Department of Clinical Research, Cytokinetics, Inc, San Francisco, CA, USA, ³Department of Clinical Operations, Cytokinetics, Inc, San Francisco, CA, USA, ⁴Department of Biostatistics, Cytokinetics, Inc, San Francisco, CA, USA, ⁵Department of Drug Safety and Pharmacovigilance, Cytokinetics, Inc, San Francisco, CA, USA, ⁶Department of Clinical Research, Cytokinetics, Inc, Department of Clinical Research, Cyotkinetics, San Francisco, CA, USA.

Background: Aficamten (AFI) is a next-in-class small molecule, selective cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy and optimized to have multiple pathways of metabolism to minimize the potential for significant drug-drug interactions (DDIs). In vitro studies indicate involvement of multiple P450s (CYPs) in AFI metabolism (CYPs 2D6, 3A4, 2C9 and 2C19). A previous clinical study demonstrated a small contribution of CYP3A (fraction metabolized [fm]=26%). No meaningful difference in AFI clearance was noted between CYP2D6 poor vs non-poor metabolizers, suggesting a minor CYP2D6 role. Carbamazepine (strong P450 inducer) decreased AFI exposure by 51%, indicating contribution from CYPs other than CYPs 2D6 and 3A.
The study aimed to 1) evaluate worst-case scenario of multiple CYP inhibition on AFI metabolism, 2) elucidate CYP2C9 and 2C19 contribution, and 3) definitively determine the level of CYP2D6 involvement.

Methods: This was an open-label, fixed-sequence, DDI study in healthy participants (n=17/cohort). AFI was given alone and with multiple daily doses (≥9 days before AFI dosing) of fluconazole (FLZ; Cohort 1: strong CYP2C19 inhibitor, moderate CYP 2C9/CYP3A inhibitor), paroxetine (PRX; Cohort 2: strong selective CYP2D6 inhibitor), and fluoxetine (FLX; Cohort 3: strong CYP2C19 and 2D6 inhibitor). Plasma samples of AFI and its metabolites (CK 3834282 and CK 3834283) were collected postdose over 216 h.
Geometric least-square mean ratios and their 90% CIs (AFI + inhibitors vs AFI alone) were calculated. Safety was monitored throughout the study.

Results: All subjects completed the study except n=1 in Cohorts 1 and 3 (personal reasons).
Considering a small CYP3A contribution, the FLZ-mediated increase in AFI exposure was attributed to CYP2C9 and/or 2C19 inhibition (FLZ, Table).
CYP2D6 played a minor role in AFI metabolism (PRX, Table).
FLX increased AFI exposure comparably to PRX, suggesting a minor role of CYP2C19 (FLX, Table).
There were no serious adverse events (AEs) or discontinuations due to AEs.

Conclusion: AFI was primarily eliminated by CYP2C9 (fm=50%), with contributions from CYP3A (fm=26%) and CYP2D6 (fm=21%), and minimally by CYP2C19 (fm=3%). Only weak DDIs are likely from strong inhibition of any one pathway and only moderate DDIs are expected with moderate-to-strong multi-pathway inhibitors.