Investigational SCD therapy shows stronger results at higher dose
Early trial data show increased fetal hemoglobin levels in adults
Written by |
A high dose of pociredir, Fulcrum Therapeutics’ investigational oral therapy for sickle cell disease (SCD), was associated with increased fetal hemoglobin (HbF) levels and reduced markers of red blood cell destruction in early trial data.
Those preliminary findings come from a Phase 1b clinical trial called PIONEER (NCT05169580), which is evaluating the safety, tolerability, and pharmacological properties of up to five doses of pociredir in adults with SCD. The therapy is taken once daily for up to 12 weeks, or about three months.
Initial results from 12 participants treated with the highest dose tested to date (20 mg) showed a similar safety profile and generally stronger efficacy signals compared with the previously tested 12 mg dose.
The latest findings were presented in a poster titled “Pociredir, a novel oral once-daily fetal hemoglobin inducer: Results from the Phase 1b PIONEER study in adult participants with severe sickle cell disease and hydroxyurea intolerance or unresponsiveness,” at the 2025 American Society of Hematology annual meeting, held earlier this month in Orlando, Florida, and online.
“We are highly encouraged by these initial data from the 20 mg [group], which show clear evidence of a dose-response and build on the strong profile established with the 12 mg [group],” Alex C. Sapir, Fulcrum’s president and CEO, said in a company press release. “These results reinforce pociredir’s potential as a best-in-class, once-daily oral HbF inducer.”
Higher dose shows stronger fetal hemoglobin response in early trial
All 12 participants given the high dose are expected to complete the full 12-week treatment period, with updated results expected in early 2026.
SCD is caused by mutations that lead to a faulty version of adult hemoglobin, the protein that carries oxygen in red blood cells. These faulty hemoglobin molecules bind together, forming long, rigid fibers that cause red blood cells to acquire a sickle-like shape.
This makes sickle red blood cells more likely to break down early and form clumps that block small blood vessels, triggering painful vaso-occlusive crises (VOCs).
HbF is a form of hemoglobin produced before birth that carries oxygen more efficiently than adult hemoglobin. Shortly after birth, HbF is gradually replaced by adult hemoglobin, a process partly controlled by the BCL11A protein, which suppresses HbF production.
These results reinforce pociredir’s potential as a best-in-class, once-daily oral HbF inducer.
Pociredir is designed to reduce the levels of BCL11A, which in turn increases HbF production and is expected to ease VOCs and other SCD symptoms.
Previous results from the PIONEER trial showed the 12 mg dose of pociredir was well tolerated for three months and increased HbF levels, as well as the proportion of red blood cells producing HbF.
Newly announced results focus on the 12 people with SCD who received the 20 mg dose for at least six weeks, with six having completed the full 12-week treatment as of the Nov. 11 data cutoff.
After six weeks of treatment, participants treated with 20 mg of pociredir showed a clinically meaningful 9.9% increase in HbF levels, compared with a 5.6% increase seen with the 12 mg dose.
Many patients reach fetal hemoglobin levels linked to fewer pain crises
More than half of the participants treated with the 20 mg dose achieved HbF levels of 20% or higher. These levels are associated with zero annual VOCs for more than 90% of SCD patients, according to real-world data presented by Fulcrum earlier this year.
After 12 weeks, HbF levels increased by more than 3.75 times among the subset of participants who had reached the 12-week timepoint at the data cutoff, compared with a 2.4-fold increase observed with the 12 mg dose.
Additionally, the proportion of red blood cells containing HbF (known as F-cells) increased from 31% at baseline to 58% after six weeks, suggesting early progression toward pan-cellular induction, or more evenly distributed HbF production across the red blood cells. With the 12 mg dose, the percentage of red blood cells containing HbF (F-cells) increased from 34% to about 65% after 12 weeks.
Signs of reduced red blood cell destruction, or hemolysis, were also seen after six weeks with the 20 mg dose. Mean hemoglobin levels increased by 0.8 g/dL, bilirubin and lactate dehydrogenase levels — both markers of hemolysis — decreased by 37%. These changes were similar to those observed after 12 weeks of treatment with the 12 mg dose.
“The clear dose-response observed with the 20 mg cohort, including robust early increases in HbF and evidence suggesting pan-cellular induction, is consistent with the mechanistic understanding that higher and more uniformly [produced] HbF can [suppress the binding] of sickle hemoglobin, the root cause of SCD,” said Martin Steinberg, MD, professor at Boston University Chobanian & Avedisian School of Medicine.
Also, a trend toward fewer VOCs was observed during the treatment period relative to those reported during the six to 12 months prior to enrollment. No VOCs were experienced by 67% of participants given the highest dose and by 50% of those in the 12-mg dose group.
High-dose pociredir was generally well tolerated, with no serious treatment-related adverse events reported and no treatment discontinuations due to treatment-related adverse events.
