Background: Osivelotor is a sickle hemoglobin (HbS) polymerization inhibitor being investigated as a potential treatment for sickle cell disease (SCD), and promising results have been reported previously for preliminary analysis from a phase 2 trial. Here, we report results at completion of the phase 2 trial and longer-term data from an open-label extension (OLE) study through the time of termination.

Methods: A seamless phase 2/3 study (NCT05431088) was designed to evaluate osivelotor in participants with SCD, and the phase 2 portion is now complete. The phase 2 portion was a randomized (1:1), open-label, 12-week, dose-finding study of oral osivelotor in participants with SCD (HbSS/HbSβ0 genotype) aged 18–65 years and with hemoglobin (Hb) 5.5–10.5 g/dL. Participants received loading doses twice-daily for 4 days then 100 or 150 mg once-daily maintenance doses through Week 12. The primary endpoint was change from baseline in Hb through Week 12. Eligible participants completing Week 12 could enter the OLE study (NCT05632354).

Results: In the phase 2 study, 54 participants were randomized and received osivelotor 100 mg (n=27) or 150 mg (n=27). Overall, median age was 24 (range 18–59) years, 30/54 (55.6%) participants were female, 52/54 (96%) had HbSS and 2 (4%) had HbSβ0 genotype, and 20/54 (37%) were receiving hydroxyurea at screening. Median (range) exposure for the 100 and 150 mg osivelotor groups, respectively, was 12.1 (10.1–12.6) weeks and 12.0 (1.0–13.1) weeks. At baseline, mean (standard deviation [SD]) Hb levels for the 2 groups were 8.4 (1.0) and 8.5 (1.2) g/dL. For the phase 2 study primary analysis, substantial Hb increases were observed by Week 2 and maintained to Week 12: for 100 and 150 mg, respectively, adjusted least-squares mean (95% confidence interval [CI]) changes from baseline at Week 2 were +2.3 (1.9–2.8; n=25) and +3.1 (2.7–3.5; n=25) g/dL and at Week 12 were +2.6 (2.1–3.1; n=24) and +3.4 (2.8–3.9; n=23) g/dL. Of participants in the 2 groups with Week 12 Hb measurements, 23/24 (95.8%) and 22/23 (95.7%) had a Hb increase of >1 g/dL; 17/24 (70.1%) and 18/23 (78.3%) had an increase of >2 g/dL. Changes in Hb were accompanied by improvements in markers of hemolysis. At phase 2 study completion, most participants continued to the OLE; for participants not immediately continuing osivelotor in the OLE, Hb values returned to baseline levels by the 6-week follow-up assessment. Descriptive analyses across the phase 2 and OLE studies (combining data for all 54 participants receiving osivelotor 100 or 150 mg) showed mean (SD) changes from the phase 2 baseline of +2.6 (2.0) g/dL (n=40) at Week 24 of the OLE and +2.4 (2.2) g/dL (n=38) at Week 36 of the OLE. In exploratory analysis for the same group, the annualized rate (95% CI) of vaso-occlusive crisis (VOC) was 1.9 (1.5–2.4) events/year pre-screening versus 1.2 (0.8–1.7) events/year on-treatment, over total participant-years follow-up of 54 years pre-screening and 52.1 years on-treatment. Treatment-emergent adverse events (TEAEs) were evaluated separately for the phase 2 study and OLE. In the phase 2 study, TEAEs were reported for 42 participants (77.8%); most TEAEs were Grade 1 or 2 and few (n=3) led to treatment interruption. Treatment-emergent serious AEs (SAEs) were reported for 9 participants (16.7%), none of the SAEs were considered treatment-related. In the OLE, safety analyses included 23 participants from each group who received ≥1 dose of osivelotor. Median (range) exposure was 47.1 (6.0–73.1) weeks for the 100 mg group and 50.0 (24.6–91.7) weeks for the 150 mg group. In the OLE, TEAEs were reported for 38/46 (83%) participants; most TEAEs were Grade 1 or 2. During the studies, there were 3 deaths (in the phase 2 study: 1 due to cerebrovascular accident and malaria, 1 due to malaria; in the OLE, 1 due to hemolysis); all were deemed unrelated to osivelotor.

Conclusions: In adults with SCD, osivelotor was generally well tolerated in both the 12-week phase 2 study and OLE study. With osivelotor treatment, substantial and clinically meaningful increases in Hb were observed, and Hb improvements were sustained in the OLE. No SAEs or fatal events were considered treatment-related, and no increase in VOC events was observed with osivelotor over the phase 2 study and OLE. Overall, these results support ongoing clinical development of osivelotor as a potential treatment for individuals with SCD.

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2025
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