Sickle cell drug at high dose eases anemia symptoms in severe SCD
Use of pociredir in small trial shown to reduce red blood cell destruction
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A high dose of pociredir, Fulcrum Therapeutics’ oral drug candidate for sickle cell disease (SCD), boosted fetal hemoglobin (HbF) levels and reduced red blood cell destruction — thereby easing symptoms of anemia — in a small group of patients with the blood disorder.
These are the latest results from the Phase 1b PIONEER clinical trial (NCT05169580), which is evaluating up to five daily doses of pociredir over 12 weeks, or about three months, in adults with severe SCD. The new analysis centers on the 12 participants who finished the entire 12-week course at the highest dose studied to date, 20 mg.
“The 12-week data from the complete 20 mg [patient group] demonstrated robust and rapid HbF induction … accompanied by reductions in markers of hemolysis [red blood cell destruction] and associated improvements in anemia,” Alex C. Sapir, Fulcrum’s president and CEO, said in a company press release detailing the findings.
“These encouraging results in a severe patient population strengthen our conviction as we prepare for discussions with regulators regarding the design of the next study,” Sapir said.
Fulcrum plans to launch a potential registration-enabling trial — one designed to generate high-quality safety and efficacy data that, if positive, will support an application for the therapy’s approval — in the second half of this year. Additional details about the trial’s design are expected by the end of June.
The company also plans to meet mid-year with the European Medicines Agency, which evaluates and monitors drug treatments in the European Union, to request protocol assistance and obtain feedback on the proposed trial design.
SCD results from genetic mutations that lead to an abnormal form of adult hemoglobin, the protein that transports oxygen in red blood cells. It tends to stick together, distorting red blood cells into a sickle-like shape. This makes the cells prone to destruction, resulting in anemia, or low levels of healthy red blood cells, and blocking blood flow in small blood vessels. That leads to painful vaso-occlusive crises (VOCs), the most common cause of hospitalization related to SCD.
HbF is the version of hemoglobin made before birth. After birth, HbF production gradually declines while adult hemoglobin increases. This transition is partly regulated by the BCL11A protein, which reduces HbF production.
Pociredir aims to boost production of fetal hemoglobin
Formerly known as FTX-6058, pociredir works by lowering BCL11A levels, thereby boosting HbF production. It aims to reduce VOCs and relieve other SCD symptoms.
Early PIONEER data showed that 12 weeks of pociredir at the 12 mg dose were well tolerated and increased HbF levels, as well as the proportion of F-cells, the red blood cells that produce HbF.
The 20 mg dose group completed enrollment last October, and preliminary results, covering at least six weeks of treatment, were similar to those of the 12 mg dose group.
As of late last year, all 12 evaluable patients in the 20 mg group had completed the 12-week treatment period. Data showed their mean HbF level rose by 12.2%, from a pretreatment value of 7.1% to 19.3% after 12 weeks. By comparison, patients in the 12 mg group previously showed an 8.6% increase at the same time point.
Achieving HbF levels in this range represents an important step toward understanding the potential of pociredir to improve clinical outcomes for patients living with sickle cell disease.
The researchers noted that all 12 patients experienced clinically meaningful increases in HbF levels. More than half (58%) achieved HbF levels of 20% or higher by week 12.
According to real-world data reported by Fulcrum last year, HbF levels of 20% result in zero annual VOCs in more than 90% of SCD patients.
“Achieving [fetal hemoglobin levels] in this range represents an important step toward understanding the potential of pociredir to improve clinical outcomes for patients living with sickle cell disease,” said Martin Steinberg, MD, a professor of medicine, pediatrics, pathology, and laboratory medicine at the Boston University Chobanian & Avedisian School of Medicine.
Developer: Pociredir may alter disease’s underlying processes
Pociredir treatment also increased the proportion of F-cells from a mean of 31% at the study’s start to 63% at week 12. This increase suggests progress toward so-called pan-cellular HbF induction, meaning HbF is distributed across a large share of red blood cells, according to Fulcrum.
Blood levels of hemolysis markers were also reduced. Specifically, indirect bilirubin levels fell by 40% (versus 37% with 12 mg), lactate dehydrogenase (LDH) decreased by 34% (versus 28% with 12 mg), and the number of immature red blood cells dropped by 42% (versus 31% with 12 mg).
In addition, mean hemoglobin levels increased by 1.1 g/dL, rising from 7.3 g/dL at the study’s start to 8.4 g/dL at week 12. In the 12 mg group, the increase was 0.9 g/dL at the same time point.
Based on physician-documented medical records from the six to 12 months before enrollment, about 16 VOCs would have been expected during the 12 weeks of the study. Six VOCs were reported altogether, and more than half of the patients (58%) experienced none, the data showed.
“The magnitude of HbF induction observed at 20 mg, together with the concomitant increase in F-cells and associated reductions in markers of hemolysis and improvements in anemia, is consistent with what we would expect from a therapy that may be capable of altering the underlying [mechanisms] of sickle cell disease,” Steinberg said.
No serious side effects seen with sickle cell drug in trial
Safety findings from the 20 mg dose group were consistent with previously reported results. Pociredir was generally well tolerated, with no serious treatment-related adverse events and no patients discontinuing treatment due to such events.
Fulcrum is activating clinical trial sites for an open-label extension study for patients completing PIONEER. The study will evaluate pociredir’s long-term safety and efficacy.
