Interim Results of a Phase 1b Study (PIONEER) of an Oral HbF Inducer, Pociredir, in SCD
Authors: Minniti Caterina , Engelman William , Rivlin Kenneth , Ahn Jae , Stuart Billy 
Published: June 2024

Abstract

Presentation Date: 6/9/2024
Presentation Start Time: 1:15:00 PM

Background
Pociredir, a potent and selective orally-administered small-molecule inhibitor of Embryonic Ectoderm Development, demonstrated robust induction of fetal hemoglobin (HbF) expression up to ∼ 40% of total hemoglobin (Hb) in primary human cell and murine models of sickle cell disease (SCD). HbF (α2γ2) prevents the pathologic polymerization of HbS in the low oxygen milieu of the microcirculation. People with SCD who also possess hereditary persistence of HbF (HPFH) have attenuated pathology when HbF levels are &gt; approximately 25%. Therefore, increasing HbF can potentially prevent or reduce disease-related pathophysiology, including hemolysis, vaso-occlusive crises (VOCs), end organ damage, and mortality. Multiple ascending doses from a Phase 1 study of pociredir in healthy volunteers demonstrated robust target engagement, with potent induction of HBG (Hb subunit γ) mRNA. It was generally well tolerated, with no serious drug related safety issues.
Aim of this study is to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of pociredir in adults living with SCD.

Methods
The Phase 1b open-label study investigating pociredir is a multi-dose, sequential cohort trial conducted in adults with SCD. Cohorts 1-3 included +/- HU; subsequent cohorts will be pociredir monotherapy only. The first cohort enrolled ten adults who received pociredir, 6 mg once daily (oral) for 4 weeks, with the option to continue dosing for an additional 8 weeks at the same dose. Two adults enrolled in a 2-mg cohort for 12 weeks; a third cohort of 12 mg enrolled four adults. The 12 mg cohort is now enrolling for a 12 week dosing period. Additional cohorts may be added based on available safety and PK data from existing participants. Primary endpoints are safety, tolerability, and PK profile. Secondary and exploratory endpoints include HbF induction in peripheral blood and other SCD biomarkers and clinical endpoints. We report the results from the first three dose cohorts of 6 (n = 10), 2 (n = 2) and 12 mg (n = 4).

Results
Average age of combined cohorts (N&#3f16) is 30.25 (range: 21-48) y, with 31.25&#37; (n = 5) male. The mean HbF baseline is 9.26% (range: 3.2-19.9%). Five were on HU, and all have the HbSS genotype. As of 29 September 2023 there were 23 TEAEs in 10/16 adults (63%) with 8/23 possibly related to study drug (headache [x2], lip numbness, diarrhea, tinnitus, fatigue, drowsiness, nausea); they were all mild in severity, non-serious, and resolved quickly; all patients remained on study drug. 4/23 TEAEs were VOCs; one was reported as an SAE with acute chest syndrome and was deemed unrelated to study drug, and occurred in a patient who was non-adherent to pociredir. The other three VOCs were non-serious, mild or moderate in severity, and were treated in an outpatient setting. There were no lab-related AEs, deaths, or discontinuations due to TEAEs.
All participants adherent to therapy (based on PK measurements) had HbF induction, with absolute HbF increases up to 9.8% and 10.0% over baseline in the 6 mg and 12 mg cohorts respectively. Pociredir demonstrated dose dependent increases in HbF which were not affected by HU use. There was improvement in biomarkers of hemolysis (total bilirubin, absolute reticulocyte count, total hemoglobin) in the majority of patients.

Conclusions
Pociredir was generally well tolerated with eight mild and non-serious drug-related TEAEs and no TEAEs resulted in drug discontinuations. All adherent participants in the 2, 6 and 12 mg cohorts showed consistent increases in HbF. The study is currently enrolling in the 12 mg dose cohort. (ClinicalTrials.gov ID: NCT05169580)