People with sickle cell disease (SCD) who also have hereditary persistence of fetal hemoglobin (HPFH) have attenuated pathology when their HbF levels exceed approximately 25%. Consequently, increasing HbF levels can potentially prevent or alleviate disease-related complications such as hemolysis, vaso-occlusive crises (VOCs), organ damage, and mortality. Pociredir is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (EED). Inhibiting EED leads to significant downregulation of key fetal globin repressors like BCL11A, resulting in increased levels of fetal hemoglobin (HbF). The drug is being evaluated in a Phase Ib PIONEER study for treating SCD.

Previously in February 2023, a Clinical hold was initiated to allow for further evaluation of a potential safety signal observed in preclinical studies. The US Food and Drug Administration (FDA) requested an updated study population in which the potential benefit balances the potential risk, and lifted the hold in August 2023. During the EHA 2024 conference, interim results from the Phase Ib PIONEER study were presented.

In 16 adults, 10 experienced 23 TEAEs at a rate of 63%, with 8 of these related to the study drug (including headache, lip numbness, diarrhea, tinnitus, fatigue, drowsiness, nausea). All TEAEs were mild and non-serious. Four TEAEs were VOCs, one classified as serious (acute chest syndrome) and deemed unrelated to the study drug due to non-adherence to pociredir. The other three VOCs were mild or moderate, treated in outpatient settings. No deaths, or discontinuations occurred due to TEAEs. All adherent participants showed induced HbF levels, with increases up to 9.8% and 10.0% over baseline in the 6 mg and 12 mg cohorts, respectively. Pociredir exhibited dose-dependent HbF increases unaffected by hydroxyurea use. Most patients demonstrated improvements in hemolysis biomarkers as well, including total bilirubin, reticulocyte count, and total hemoglobin. 

KOL insights

“Building on the encouraging clinical data generated to date shows that pociredir may shift the current standard of care. We remain very excited about pociredir’s potential to shift the current standard of care and importantly, offer a differentiated oral option.” – MD, United States.

Conclusion 

Treating SCD has been challenging for decades due to its rarity and the difficulties in managing the condition. The life-threatening nature of SCD and the lack of effective therapies have posed significant burdens, and till the last decade, only hydroxyurea was available for management. Even after being in the market for so long, there remains a challenge of low treatment adherence and high treatment discontinuation rates. However, the emergence of various new mechanisms of action, such as erythrocyte pyruvate kinase activators, cytidine deaminase (CDA) inhibitors, HbF inducers, fetal hemoglobin production stimulants, and DNA-dependent RNA polymerase inhibitors, will be expanding the treatment landscape for SCD.

Pociredir stands out as a highly differentiated oral treatment option for SCD, with the potential to significantly improve the treatment landscape. In clinical trials conducted prior to the clinical hold, pociredir was generally well-tolerated in SCD patients over a three-month period, with no serious treatment-related adverse events. The findings from the Phase Ib presented at the EHA 2024 study continued to show that the drug was well tolerated, with only eight mild and non-serious TEAEs reported, none of which led to discontinuation. Participants in the 2 mg, 6 mg, and 12 mg cohorts consistently showed increases in HbF levels.

To further its development, the company has activated additional clinical trial sites and is building key relationships with leading SCD physicians for the Phase Ib PIONEER trial. Cohort 3 of this trial will evaluate pociredir at a 12 mg once-daily dose, followed by planned Cohort 4 at a 20 mg once-daily dose, with each cohort expected to enroll approximately 10 patients.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to Sickle Cell Disease Market Insight, Epidemiology And Market Forecast – 2034 report.