PI-054 - A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL DESIGN, STUDY TO EVALUATE PHARMACOKINETIC COMPARABILITY OF TWO PF-07940367 FILM-COATED TABLET FORMULATIONS ADMINISTERED AS 150 MG UNDER FASTED CONDITIONS IN HEALTHY PARTICIPANTS

S. Adhikari¹, J. Volpe², D. Franjic³, A. Murphy¹, K. Seetharaman⁴, A. Adenola³, V. Purohit¹, B. Malhotra³, E. Zimmerman³; ¹Pfizer Inc, Groton, CT, USA, ²Pfizer Inc, Cambridge, MA, USA, ³Pfizer Inc, New York City, NY, USA, ⁴Pfizer Inc, La Jolla, CA, USA.

Background: Sickle cell disease (SCD) is a severe disorder where sickle hemoglobin (HbS) polymerization causes chronic anemia, vaso-occlusive crises, and organ damage. PF-07940367 is a small molecule HbS polymerization inhibitor with a high whole blood-to-plasma ratio (>200) and a long elimination half-life (~30 days). We report results from a phase 1, open-label, parallel design study (NCT06190561) that evaluated the pharmacokinetic comparability of two tablet formulations in healthy adult participants.

Methods: Forty participants were randomized (1:1) to receive a single 150 mg oral dose of PF-07940367 following an overnight fast: Formulation II (test) or Formulation I (reference). This occurred during a 5-day inpatient stay and was followed by 5 follow-up visits (2 in-clinic, 3 by phone). Safety and tolerability were monitored, and PK samples were collected through 336 hours postdose, which were analyzed using a validated LC-MS method. An adaptive design was employed with an option to recruit additional participants based on PK variability for the initial cohort of 40 participants. Whole blood truncated AUC to 336 hours postdose and Cmax were used to inform bioavailability, given the long half-life of the drug.

Results: Following a planned preliminary analysis, the geometric %CV for AUC0-336 was below the pre-established criterion of 30%, so no additional participants were enrolled. All 40 participants were included in the PK analysis, and the adjusted geometric means of AUC0-336 and Cmax for Test Formulation II relative to Reference Formulation I were 102.3% (90% CI: 92.6%–113.1%) and 102.1% (90% CI: 91.4%–114.1%), respectively (Table).

Conclusion: The decision not to enroll additional participants was based on the observed geometric %CV, which suggested N = 40 provided sufficient precision to estimate bioavailability. The PK comparability of Formulation II to Formulation I was confirmed as the geometric mean ratios (test/reference) for AUC0-336 and Cmax and 90% confidence intervals (CIs) were within the pre-specified PK comparability bounds of 70% to 143%. Moreover, the 90% CIs were contained within formal bioequivalence bounds (80%, 125%). Thus, the adaptive study design efficiently informed PK comparability of a long half-life compound while limiting trial burden.