Fulcrum Therapeutics (NASDAQ:FULC) shared full 12-week results from the 20-mg cohort of its phase 1b PIONEER trial evaluating pociredir in patients with sickle cell disease, expanding on partial data previously presented at the American Society of Hematology (ASH) meeting in December 2025. Management highlighted rapid fetal hemoglobin (HbF) induction, improvements in hemolysis and anemia biomarkers, encouraging trends in vaso-occlusive crises (VOCs), and a safety profile described as generally well tolerated.
Trial snapshot and patient population
Head of Clinical Development Iain Fraser said PIONEER’s 20-mg update reflects a data cutoff of Dec. 23, 2025. Thirteen patients were enrolled, with 12 considered evaluable for the pharmacodynamic analysis. One patient discontinued due to a death on day one that was deemed unrelated to study drug, the company said.
HbF and F-cell responses at 20 mg
CEO Alex Sapir said pociredir at 20 mg produced a “rapid and robust” HbF increase over 12 weeks, with mean HbF rising from 7.1% at baseline to 19.3% at week 12, a mean absolute increase of 12.2 percentage points. Fraser added that all 12 patients showed substantial HbF increases, with all patients improving by at least 6.5%. Seven of the 12 patients (58%) reached an HbF level of at least 20% at week 12, which Sapir described as a historical threshold associated with clinically meaningful protection.
On F cells (red blood cells containing HbF), Fraser reported a rise from a baseline of roughly 31% to 63% at week 12—about a doubling. He cautioned that an apparent dip from week 10 to week 12 reflected missing data at certain time points due to sample logistics for the single-site assay, rather than an across-the-board decline. Two patients with relatively high F-cell percentages at week 10 were not represented at week 12, he said, while two lower F-cell values appeared at week 12 but were missing at week 10. Fraser stressed that all patients showed increases in F-cell percentage, including those with low baseline F-cell values.
Downstream biomarkers: hemolysis and anemia
Fraser described biomarker changes as consistent with HbF-driven protection of red cells and reduced hemolysis. At week 12, the company reported:
- A 34% reduction in lactate dehydrogenase (LDH)
- A 40% reduction in indirect bilirubin
- A 42% decrease in reticulocytes
- Red cell distribution width (RDW) trending toward normalization
Total hemoglobin increased by a mean of 1.1 g/dL at week 12 in the 20-mg cohort, compared with a 0.9 g/dL rise in the 12-mg cohort, Fraser said. He emphasized again that the 20-mg cohort had no transfusions during the treatment period.
In Q&A, Fraser characterized HbF as the proximal marker, while hemolysis markers and hemoglobin were described as “lagging indicators” that may take longer than 12 weeks to fully reflect a new steady state. He also noted LDH and bilirubin can be influenced by factors beyond hemolysis, including tissue damage and liver function.
VOCs: exploratory trends in a short study
Fraser said seven of 12 patients in the pharmacodynamic analysis subset reported no VOCs during the 12-week treatment period, despite high baseline VOC burden. Based on baseline VOC history, the company estimated 16 events would have been expected over 12 weeks and observed six events in five patients during treatment. Fraser reiterated the study was not powered for VOC outcomes but called the trend encouraging and consistent with what was seen in the 12-mg cohort.
Asked about timing and distribution of VOCs, Fraser said events were spread throughout the treatment period and that patients had not reached steady state HbF levels. He added that more VOCs occurred in patients with lower HbF increases, though the company did not provide patient-level details.
Later, management clarified that three additional VOCs were observed during the safety follow-up period (for a total of nine when combining treatment plus follow-up in the pharmacodynamic subset). Fraser also noted a separate safety analysis set included 10 VOCs, reflecting inclusion of the patient who entered the study experiencing a VOC and later discontinued following the unrelated day-one death.
Dr. Martin Steinberg, a professor at Boston University School of Medicine and guest speaker on the call, cautioned against overinterpreting VOC counts in a short, non-adjudicated study, but said decades of sickle cell disease biology support the expectation that higher HbF is associated with fewer events.
Safety, dose selection, and regulatory path
Fraser said pociredir at 20 mg remained “generally well tolerated,” with no treatment-related serious adverse events and no treatment-related discontinuations. Three patients experienced treatment-related adverse events that resolved with continued dosing, he said, and the overall safety profile was described as similar to what was presented in December 2025. Fraser added that pociredir has been dosed in “almost 150 adults” to date.
On dose selection, Fraser said the PIONEER protocol allowed escalation up to 30 mg once daily, but the company decided not to advance further. He cited first-in-human healthy volunteer data showing dose-responsive induction of HBG mRNA up to 20 mg, with no further induction from 20 to 30 mg. Sapir said Fulcrum plans to take the 20-mg dose forward in FDA discussions.
Regarding next steps, Sapir said Fulcrum expects to provide an update on the next trial design in Q2 2026 after receiving FDA meeting minutes. Pending FDA feedback, the company’s current plan is to initiate a “potential registration-enabling” trial in the second half of 2026. Fulcrum also plans to engage the European Medicines Agency in mid-2026 for protocol assistance and is activating sites for an open-label extension study to assess longer-term safety and durability of response.
Steinberg said the field’s “major unmet need” remains an oral agent capable of inducing high HbF levels, and he compared the 12-week PIONEER biomarker profile with results from controlled hydroxyurea studies. He said that if replicated in later-stage trials, pociredir could potentially be used as first-line standalone therapy and could also be considered for combination approaches due to a different mechanism of action than hydroxyurea.
About Fulcrum Therapeutics (NASDAQ:FULC)
Fulcrum Therapeutics, Inc is a clinical-stage biopharmaceutical company focused on discovering and developing precision medicines that modulate gene expression through epigenetic control. Leveraging a proprietary target discovery platform, Fulcrum seeks to identify small‐molecule therapeutics that restore normal gene function in diseases caused by genetic dysregulation. The company’s core research efforts center on transcriptional regulators and chromatin-modifying proteins, aiming to address underlying disease mechanisms rather than downstream symptoms.
Fulcrum’s most advanced programs include FTX-6058, an oral therapeutic candidate designed to elevate fetal hemoglobin levels in patients with sickle cell disease and beta-thalassemia, and a preclinical program targeting facioscapulohumeral muscular dystrophy (FSHD) by inhibiting a key epigenetic driver of aberrant gene expression.
