PI-053 - A PHASE 1 MICROTRACER STUDY EVALUATING THE MASS BALANCE, EXCRETION, AND PHARMACOKINETICS OF [14C]-GBT021601, AN ORAL SICKLE HEMOGLOBIN POLYMERIZATION INHIBITOR, IN HEALTHY PARTICIPANTS.

E. Zimmerman¹, E. Callegari², R. Sharma², A. Adenola¹, J. Volpe³, K. Seetharaman⁴, C. Zhang⁵, K. Duchin⁶, G. Walker²; ¹Pfizer Inc, New York City, NY, USA, ²Pfizer Inc, Groton, CT, USA, ³Pfizer Inc, Cambridge, MA, USA, ⁴Pfizer Inc, La Jolla, CA, USA, ⁵Vividion Therapeutics, San Francisco, CA, USA, ⁶eRIC Solutions, Hallandale, FL, USA.

Background: Sickle cell disease (SCD) is a life-limiting disorder in which polymerization of sickle hemoglobin (HbS) leads to chronic hemolytic anemia, vaso-occlusive crises, and progressive end-organ damage. GBT021601 is a small molecule, next-generation HbS polymerization inhibitor with high whole blood to plasma ratio (>200) and a relatively long elimination half-life (~30 days). We report results from a phase 1, open-label, single-center microtracer study (NCT05718687) that assessed the mass balance, excretion, and pharmacokinetics (PK) of GBT021601 using 14C-radiolabeled drug in healthy participants.

Methods: Participants received a single oral dose of GBT021601 200 mg containing ~74 kBq [14C]-GBT021601 after an overnight fast. A single inpatient stay from Days -1 to 29 was followed by 11 visits of 24-h duration between Days 35 and 206 to capture complete drug elimination, with data interpolation during noncontinuous sample collection to estimate dose recovery. GBT021601 PK and total radioactivity (TRA) were analyzed using liquid chromatography–mass spectrometry and accelerator mass spectrometry, respectively.

Results: A total of 9 healthy participants were enrolled and included in PK analysis. Total mean (SD) recovery of TRA was 87.6 (5.9)% of the total dose in excreta, with 47.2 (5.0)% in urine and 40.4 (6.3)% in feces. The GBT021601 whole blood and plasma concentration-time profiles reflected those of TRA, and the area under the curve (AUC) ratio for TRA/GBT0210601 in whole blood and plasma was 1.15 and 0.84, respectively. The major drug component in whole blood was GBT021601 and represented 98.3% of circulating radioactivity. In plasma the major drug components were GBT021601 and PF-0805414, a glucuronide, at 68.1% and 19.7% of circulating radioactivity, respectively.

Conclusion: A microtracer study design with continuous and noncontinuous sample collection up to 7 months enabled comprehensive data capture for a long half-life drug. High excreta recovery (87.6%) was observed. Whole blood and plasma data suggest the absence of a long-lived metabolite, and the parent drug accounted for the majority of TRA species in systemic circulation. These findings provide unique insights into the absorption, metabolism, and excretion of GBT021601 and support its ongoing clinical development in SCD.