Clinical trial data on pociredir as SCD therapy expected by midyear
PIONEER Phase 1b study still enrolling patients at sites in US, South Africa
Fulcrum Therapeutics is planning to report, by midyear, new data from the ongoing PIONEER Phase 1b clinical trial that’s testing its oral therapy candidate pociredir (FTX-6058) in people with sickle cell disease (SCD), according to a new corporate presentation.
That will include data from the study’s third-highest dosing group, with data from the highest dose group due by year’s end.
PIONEER (NCT05169580) is still recruiting participants at several active sites in the U.S. and one in South Africa. A trio of new sites in both the U.S. and Nigeria also are getting ready to open.
According to the presentation, Fulcrum is “well-positioned for [a] transformational year in 2025,” with pociredir showing “best-in-class potential … to address [a] significant unmet [medical] need for people living with SCD.”
Pociredir aims to switch back on production of fetal hemoglobin (HbF)
SCD is caused by genetic mutations that lead to the production of an abnormal version of hemoglobin, the protein that helps red blood cells carry oxygen throughout the body. As a result, normally oval-shaped red blood cells take on a sickle-like shape that causes them to get trapped inside blood vessels and block blood flow. This in turn compromises oxygen delivery and causes severe pain episodes known as vaso-occlusive crises (VOCs). Sickled red blood cells are also destroyed more easily than healthy ones, oftentimes leading to a red blood cell shortage, or anemia.
Disease-causing mutations affect adult hemoglobin, a version of the protein that’s produced after birth. However, before birth, another version of the protein called fetal hemoglobin, or HbF, is produced. HbF is more effective than its adult counterpart at carrying oxygen, but its production is switched off sometime in infancy and adult hemoglobin is switched on.
Therapeutic strategies to increase HbF production have long been of interest for the treatment of SCD. To that end, Fulcrum has developed pociredir as an oral small molecule designed to induce HbF production. It works by selectively inhibiting the embryonic ectoderm development (EED) protein, part of a protein complex called polycomb repressive complex 2, or PRC2, that’s normally involved in turning off HbF production in infants.
By inhibiting EED, pociredir aims to turn HbF production back on.
Other HbF inducers are in development, and these work via various mechanisms. However, Fulcrum believes pociredir, with “demonstrated proof-of-concept,” has best-in-class potential, according to the presentation.
The experimental therapy has received fast track and orphan drug designations from the U.S. Food and Drug Administration (FDA). Such status is intended to speed a therapy’s clinical development and its potential approval.
Initial PIONEER clinical trial data showed increases in HbF levels
The ongoing Phase 1b trial is designed to evaluate the safety, tolerability, pharmacological properties, and biological activity of pociredir in adults with SCD. It has thus far enrolled approximately patients, ages 18-65.
Participants in the trial are assigned to receive one of four daily oral doses of pociredir for 12 weeks, or about three months, followed by a four-week, or about one-month, follow-up period.
Those in Cohort 1 received a 6 mg dose, while those in Cohort 2 were given a 2 mg dose. A dose of 12 mg is being given to those in Cohort 3, while those in Cohort 4 are receiving a 20 mg dose.
The trial had been ongoing, with Cohorts 1 and 2 complete and Cohort 3 underway, when the FDA placed a clinical hold on the study in 2023 due to concerns that treatments targeting PRC2 might increase the risk of certain blood cancers. The hold was lifted later that year with stricter trial inclusion criteria in place, and enrollment in Cohort 3 resumed.
To be eligible under the new criteria, patients had to have severe SCD, which was determined based on the number of VOCs and other SCD complications before their enrollment in the trial. Participants also had to be ineligible for, or tried but failed to respond to or tolerate, hydroxyurea and at least one of the following therapies: Adakveo (crizanlizumab), Oxbryta (voxelotor), or Endari (L-glutamine).
Initial data demonstrated dose dependent and clinically relevant increases in HbF levels with the treatment, along with improvements in biomarkers of red blood cell destruction and anemia.
Data from 16 trial participants as of 2023 also showed the treatment was well tolerated with no serious treatment-related adverse events.
More data from Cohort 3 are expected by mid-year, with new information from Cohort 4 by the end of the year.
In a separate Phase 1 study (NCT04586985), completed in 2022, the therapy also was found to boost HbF levels in healthy adults.
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