PIONEER trial of pociredir still recruiting sickle cell disease patients
Study is testing how safe therapy is when taken by mouth in multiple doses
An ongoing, early-phase clinical trial of pociredir, an oral small molecule being developed by Fulcrum Therapeutics as a possible treatment for sickle cell disease (SCD), is still recruiting adult patients at locations in the U.S. and one in South Africa.
This Phase 1b trial, called PIONEER (NCT05169580), is testing how safe pociredir is when taken by mouth as capsules in multiple doses. The study is also evaluating its pharmacokinetics, that is, how the therapy moves into, through, and out of the body, and how well it works to prevent the breakdown of red blood cells.
Enrollment is complete for the first three groups of patients, who received pociredir at a daily dose of 2, 6, or 12 mg. With the go-ahead from the data monitoring committee — a group of experts who oversees the trial’s safety and efficacy data — enrollment has begun for the 20 mg dose group. Along with its current locations, six others are expected to open in the U.S. and Nigeria.
“We are pleased with the continued momentum of our lead clinical program, pociredir, in development for the treatment of sickle cell disease, including the recent initiation of the 20 mg dose cohort [group],” Alex C. Sapir, Fulcrum’s president and CEO, said in a company press release.
The trial was already in progress, with the first two groups fully enrolled and the third group’s recruitment underway, when the U.S. Food and Drug Administration (FDA) put a clinical hold on it in 2023 over concerns that pociredir, then called FTX-6058, might increase the risk of certain types of blood cancer.
The FDA later lifted the clinical hold after stricter criteria were added for who could join the trial and enrollment for the 12 mg dose group continued until it was full. None of the 16 patients in this group have dropped out and more than 90% of the doses have been taken as planned.
“The level of engagement that we’ve observed in the PIONEER trial is highly encouraging, with 16 patients enrolled in the 12 mg dose cohort and enrollment underway in the 20 mg dose cohort. We look forward to sharing data,” Sapir said. Data from the 12 mg dose group are expected in the third quarter of the year and from the 20 mg dose group by year’s end.
Resuming fetal hemoglobin production
SCD is caused by the production of a faulty version of adult hemoglobin, the protein in red blood cells that carries oxygen around the body. The faulty protein causes red blood cells to take on a sickle-like shape, making them prone to breaking down easily and blocking blood flow in small vessels, reducing oxygen delivery to tissues.
Before birth, babies produce fetal hemoglobin, which is more effective than adult hemoglobin, which begins being produced sometime after birth, at carrying oxygen. This switch is regulated by the BCL11A protein, which turns off fetal hemoglobin production.
Pociredir is designed to block a protein called embryonic ectoderm development (EED) that’s part of a larger complex called polycomb repressive complex 2 (PRC2), which normally turns off BCL11A production. Without it, the body can resume producing fetal hemoglobin, which may help ease SCD symptoms.
“We believe that pociredir has the potential to increase fetal hemoglobin to levels that could ameliorate SCD symptomology and transform the standard of care with a once daily oral treatment option,” Sapir said.
In PIONEER, patients are being assigned to one of four doses of pociredir for 12 weeks, or three months. They must have had at least four pain crises in the past year or at least two in the six months before screening. Other sickle cell complications are also considered toward eligibility. To join the trial, patients also have to be ineligible for, or tried and not responded to, or not tolerated, hydroxyurea and a stable dose of at least Adakveo (crizanlizumab), Endari (L-glutamine), or Oxbryta (voxelotor), which is now discontinued.
Data collected from 16 patients until around the time of the clinical hold showed pociredir was well tolerated, with no serious side effects related to treatment. Side effects were mild in severity and resolved while patients remained on the therapy.
The data also showed that pociredir led to dose-dependent increases in fetal hemoglobin, meaning the higher the dose, the higher the levels of fetal hemoglobin. These increases were “clinically relevant and consistent,” the company wrote in a corporate presentation.
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