Efficacy and safety of osivelotor in participants with sickle cell disease in a 12-week, phase 2, multicenter, open-label, dose-finding trial and extension study
Santosh L Saraf, Shehu U Abdullahi, Adeseye M Akinsete, Foluke A Fasola, Modupe Idowu, Sharon Pennington, Sheinei S Alan, Marshall Patrick Stagg, Earl J Fields, David R Archer, Aliya Zaidi, Patrick Hines, Yuvika Paliwal, Denis Rybin, Eric I Zimmerman, Adeyemi Adenola, Mira Patel Pochron, Eleanor A Lisbon, Geoffrey AllenAbstract
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
The phase 2 portion of a combined phase 2/3 study (NCT05431088) was a randomized (1:1), open-label, 12-week, dose-finding study of oral osivelotor in participants with SCD (HbSS/HbSβ0) aged 18–65 years 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 at sites in North America or sub-Saharan Africa 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 had HbSS and 2 HbSβ0 genotype, and 20/54 (37%) were receiving hydroxyurea. At baseline, mean (standard deviation [SD]) Hb values for the 2 groups were 8.4 (1.0) and 8.5 (1.2) g/dL. 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 with Week-12 Hb measurements, 23/24 (95.8%) and 22/23 (95.7%) had Hb increase >1 g/dL; 17/24 (70.1%) and 18/23 (78.3%) had an increase >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. 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 (events/year, 95% CI) of vaso-occlusive crisis (VOC) was 1.9 (1.5–2.4) pre-screening versus 1.4 (0.9, 2.3) on-treatment in the phase 2 study, and 1.2 (0.8–1.7) on-treatment across the phase 2 and OLE studies, over a total follow-up of 54 participant-years pre-screening, 12.2 participant-years on-treatment in the phase 2 study, and 52.1 participant-years on-treatment across the phase 2 and OLE studies. 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, all occurred in sub-Saharan Africa (phase 2 study: 1 due to cerebrovascular accident and malaria, 1 due to malaria; OLE, 1 due to hemolysis). All deaths were deemed unrelated to osivelotor.
Conclusions
In adults with SCD, osivelotor was generally well tolerated in both the 12-week phase 2 and OLE studies. 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 the annualized rate of VOCs suggested a decrease in the VOC event rate 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. © American Society of Hematology (2025). Reused with permission.