Fulcrum Therapeutics Announces Results from the 12 mg Dose Cohort of the Phase 1b PIONEER Trial of Pociredir in Sickle Cell Disease
Fulcrum Therapeutics (NASDAQ:FULC) announced positive results from the 12 mg dose cohort of Phase 1b PIONEER trial for pociredir in sickle cell disease (SCD). The trial demonstrated a significant 8.6% absolute mean increase in fetal hemoglobin (HbF) after 12 weeks of treatment, with 7 of 16 patients achieving HbF levels above 20%.
Key findings include pan-cellular HbF induction with F-cells increasing from 34% to 67%, meaningful improvements in hemolysis markers, and a 0.9 g/dL increase in total hemoglobin. The drug showed encouraging trends in reducing vaso-occlusive crises (VOCs) and maintained a favorable safety profile with no treatment-related serious adverse events.
The study involved 135 adults across multiple cohorts, including 103 healthy subjects and 32 SCD patients, with all treatment-related adverse events being Grade 1.
Fulcrum Therapeutics (NASDAQ:FULC) ha annunciato risultati positivi dal gruppo di dosaggio da 12 mg della fase 1b dello studio PIONEER per pociredir nella anemia falciforme (SCD). Lo studio ha evidenziato un aumento medio assoluto significativo dell'8,6% dell'emoglobina fetale (HbF) dopo 12 settimane di trattamento, con 7 pazienti su 16 che hanno raggiunto livelli di HbF superiori al 20%.
I risultati chiave includono una induzione pan-cellulare di HbF con un aumento delle cellule F dal 34% al 67%, miglioramenti significativi nei marker di emolisi e un aumento di 0,9 g/dL dell'emoglobina totale. Il farmaco ha mostrato tendenze incoraggianti nella riduzione delle crisi vaso-occlusive (VOC) e ha mantenuto un profilo di sicurezza favorevole senza eventi avversi gravi correlati al trattamento.
Lo studio ha coinvolto 135 adulti suddivisi in diversi gruppi, tra cui 103 soggetti sani e 32 pazienti con SCD, con tutti gli eventi avversi correlati al trattamento classificati come di grado 1.
Fulcrum Therapeutics (NASDAQ:FULC) anunció resultados positivos del grupo de dosis de 12 mg del ensayo de fase 1b PIONEER para pociredir en la enfermedad de células falciformes (SCD). El ensayo mostró un aumento absoluto medio significativo del 8,6% en la hemoglobina fetal (HbF) tras 12 semanas de tratamiento, con 7 de 16 pacientes alcanzando niveles de HbF superiores al 20%.
Los hallazgos clave incluyen una inducción pan-celular de HbF con un aumento de células F del 34% al 67%, mejoras significativas en los marcadores de hemólisis y un aumento de 0,9 g/dL en la hemoglobina total. El fármaco mostró tendencias alentadoras en la reducción de crisis vaso-oclusivas (VOC) y mantuvo un perfil de seguridad favorable sin eventos adversos graves relacionados con el tratamiento.
El estudio involucró a 135 adultos distribuidos en múltiples cohortes, incluyendo 103 sujetos sanos y 32 pacientes con SCD, con todos los eventos adversos relacionados con el tratamiento clasificados como grado 1.
Fulcrum Therapeutics (NASDAQ:FULC)는 겸상적혈구질환(SCD) 치료제 포시레디르의 12mg 용량군을 대상으로 한 1b상 PIONEER 임상시험에서 긍정적인 결과를 발표했습니다. 본 임상시험은 12주 치료 후 태아 헤모글로빈(HbF)의 절대 평균 8.6% 유의미한 증가를 보였으며, 16명 중 7명이 HbF 수치를 20% 이상으로 달성했습니다.
주요 결과로는 전 세포적 HbF 유도가 확인되었으며, F-세포 비율이 34%에서 67%로 증가했고, 용혈 지표가 의미 있게 개선되었으며, 총 헤모글로빈이 0.9g/dL 증가했습니다. 이 약물은 혈관폐색 위기(VOC) 감소에 긍정적인 경향을 보였고, 치료 관련 중대한 이상반응 없이 안전성 프로파일도 우수했습니다.
본 연구에는 103명의 건강한 피험자와 32명의 SCD 환자를 포함해 총 135명의 성인이 여러 코호트에 참여했으며, 치료 관련 이상반응은 모두 1등급으로 보고되었습니다.
Fulcrum Therapeutics (NASDAQ:FULC) a annoncé des résultats positifs pour la cohorte de dose de 12 mg de l'essai de phase 1b PIONEER concernant le pociredir dans la drépanocytose (SCD). L'étude a démontré une augmentation moyenne absolue significative de 8,6 % de l'hémoglobine fœtale (HbF) après 12 semaines de traitement, avec 7 patients sur 16 atteignant des niveaux d'HbF supérieurs à 20 %.
Les résultats clés incluent une induction pan-cellulaire d'HbF avec une augmentation des cellules F de 34 % à 67 %, des améliorations notables des marqueurs d'hémolyse, ainsi qu'une augmentation de 0,9 g/dL de l'hémoglobine totale. Le médicament a montré des tendances encourageantes à réduire les crises vaso-occlusives (VOC) et a maintenu un profil de sécurité favorable sans événements indésirables graves liés au traitement.
L'étude a impliqué 135 adultes répartis en plusieurs cohortes, dont 103 sujets sains et 32 patients atteints de SCD, avec tous les événements indésirables liés au traitement classés au grade 1.
Fulcrum Therapeutics (NASDAQ:FULC) gab positive Ergebnisse der 12 mg Dosisgruppe der Phase-1b-Studie PIONEER für Pociredir bei Sichelzellanämie (SCD) bekannt. Die Studie zeigte nach 12 Wochen Behandlung einen signifikanten absoluten mittleren Anstieg des fetalen Hämoglobins (HbF) um 8,6%, wobei 7 von 16 Patienten HbF-Werte über 20% erreichten.
Wesentliche Erkenntnisse umfassen eine pan-zelluläre HbF-Induktion mit einem Anstieg der F-Zellen von 34% auf 67%, deutliche Verbesserungen bei Hämolyse-Markern sowie eine Steigerung des Gesamt-Hämoglobins um 0,9 g/dL. Das Medikament zeigte vielversprechende Trends zur Reduktion vaso-okklusiver Krisen (VOCs) und behielt ein günstiges Sicherheitsprofil ohne behandlungsbedingte schwerwiegende Nebenwirkungen bei.
Die Studie umfasste 135 Erwachsene in mehreren Kohorten, darunter 103 gesunde Probanden und 32 SCD-Patienten, wobei alle behandlungsbedingten Nebenwirkungen als Grad 1 eingestuft wurden.
- Significant 8.6% absolute mean increase in fetal hemoglobin (HbF) from baseline after 12 weeks
- 7 of 16 patients achieved HbF levels >20%, associated with zero VOCs per year
- Pan-cellular HbF induction with F-cells increasing from 34% to 67%
- Meaningful improvements in hemolysis markers with 28-37% decreases
- 0.9 g/dL increase in total hemoglobin from baseline
- 50% of patients (8/16) reported no VOCs during treatment period
- Favorable safety profile with only Grade 1 treatment-related adverse events
- Base hemoglobin levels remained relatively low at 8.7 g/dL after treatment
- Limited study duration of 12 weeks requires longer-term efficacy data
- 3 VOCs occurred during the follow-up period
Insights
Fulcrum's pociredir shows clinically meaningful HbF increases and hemolysis improvements in sickle cell disease with favorable safety profile.
The Phase 1b PIONEER trial results for pociredir at the 12 mg dose represent potentially significant progress in sickle cell disease treatment. The 8.6% absolute increase in fetal hemoglobin (HbF) from baseline after 12 weeks is particularly impressive, with 7 of 16 patients achieving HbF levels >20% - a threshold associated with minimal vaso-occlusive crises (VOCs). The increase in F-cells from 34% to 67% indicates pan-cellular HbF distribution, which is crucial for preventing sickling.
The improvements in hemolysis markers are substantial and clinically meaningful: 37% reduction in indirect bilirubin, 28% decrease in LDH, 27% decrease in red cell distribution width, and 30% reduction in reticulocyte counts. These changes signal reduced red blood cell destruction and improved bone marrow function. The 0.9 g/dL increase in total hemoglobin further supports pociredir's efficacy in addressing the underlying anemia in SCD.
Most promising is the trend toward VOC reduction, with 50% of patients reporting no VOCs during treatment. This clinical outcome matters most to patients, as VOCs are the primary source of SCD-related morbidity and hospitalizations.
The clean safety profile is remarkable - no treatment-related serious adverse events and only Grade 1 treatment-related adverse events suggest pociredir could offer an appealing risk-benefit profile. As an oral, once-daily therapy, pociredir could represent a significant advancement over current treatment options, especially considering the excellent tolerability observed thus far.
The biological mechanism - increasing HbF to prevent HbS polymerization - is well-established in SCD. Patients with hereditary persistence of HbF have milder disease, and pociredir appears to pharmacologically replicate this protective effect. The pan-cellular distribution of HbF is particularly important, as it ensures the protective effect extends to a larger proportion of red blood cells.
― Robust and clinically meaningful absolute mean fetal hemoglobin (HbF) induction of
― Evidence of pan-cellular induction of HbF based on an increase in F-cells (red blood cells containing HbF) from a mean of
― Meaningful improvements in key markers of hemolysis coupled with a 0.9 g/dL mean increase in total hemoglobin (Hb) ―
― Encouraging trends in vaso-occlusive crisis (VOC) reduction compared to baseline ―
― Pociredir continued to be generally well-tolerated with no treatment-related serious adverse events (SAEs); all treatment-related adverse events (AEs) were Grade 1 ―
― Conference call and webcast scheduled for 8:00 a.m. ET today ―
CAMBRIDGE, Mass., July 29, 2025 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.® (Fulcrum) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today reported positive results from the 12 mg dose cohort of the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD).
“We are highly encouraged by these data from the 12 mg cohort of the PIONEER trial and believe they represent an important milestone in our mission to transform the treatment of sickle cell disease.” said Alex C. Sapir, Fulcrum’s President and Chief Executive Officer. “We believe that with the level of HbF induction observed coupled with improvements in key markers of hemolysis and anemia, evidence of pan-cellular induction of HbF, and an encouraging trend in VOC reduction, pociredir, as a once-daily oral therapy, has the potential to treat SCD patients around the world who continue to battle with their disease. Importantly, pociredir continued to be generally well-tolerated, with no treatment-related SAEs reported and all treatment-related AEs limited to Grade 1.”
“Patients with sickle cell disease continue to face a significantly shortened life expectancy and a lifelong burden of frequent and debilitating pain crises,” said Wally Smith, M.D., Director, VCU Adult Sickle Cell Program and Professor, VCU School of Internal Medicine. “These data, showing clinically-meaningful increases in HbF levels, reductions in pain crises, and improvements in markers of hemolysis, are both impressive and encouraging. Pociredir’s ability to induce HbF is a promising approach for treating SCD, as HbF directly interferes with the polymerization of sickle hemoglobin, the root cause of sickle cell disease. Sickle cell patients with hereditary persistence of HbF are largely protected from the clinical manifestations of the disease, and these data suggest that pociredir may replicate that protective biology. A once daily oral therapy that can meaningfully reduce hemolysis and pain crises, while maintaining a favorable safety profile, has the potential to represent a paradigm shift for sickle cell patients. I look forward to longer-term data as pociredir continues through clinical development.”
PIONEER Study 12 mg Dose Cohort Efficacy Data
Results from the 12 mg dose cohort of the Phase 1b PIONEER trial, following conclusion of the 12-week treatment period, in 16 patients are as follows:
- Mean absolute HbF increased by
8.6% at 12 weeks of treatment with pociredir, representing an increase from a baseline of7.6% to16.2% . Seven of 16 patients achieved absolute HbF levels greater than20% after 12 weeks of treatment with pociredir. HbF levels of20% are associated with approximately90% of individual patients experiencing zero VOCs per year, based on a recent analysis of real-world data conducted by Fulcrum, which has been accepted for publication at the 20th Annual Sickle Cell & Thalassaemia Conference (ASCAT), to be held in London, United Kingdom, October 1-4, 2025. - Proportion of F-cells (HbF-containing red blood cells) increased from a mean of
34% at baseline to67% at 12 weeks of treatment (n=8), consistent with pan-cellular HbF induction (evenly distributed across red blood cells). F-cells are resistant to red blood cell sickling and hemolysis because of HbF-mediated inhibition of sickle hemoglobin (HbS) polymerization. Consequently, a higher proportion of F-cells is associated with improved red blood cell health. - Markers of hemolysis and erythropoiesis improved with pociredir treatment at 12 weeks:
- Decreased indirect bilirubin (mean decrease of
37% ) - Decreased lactate dehydrogenase (LDH) (mean decrease of
28% ) - Decreased red cell distribution width (mean decrease of
27% ), indicating a more uniform red blood cell population - Decreased reticulocyte counts (mean decrease of
30% ), indicating healthier bone marrow function
- Decreased indirect bilirubin (mean decrease of
- Mean hemoglobin concentration increased by 0.9 g/dL at 12 weeks of treatment with pociredir, from a baseline of 7.8 g/dL to 8.7 g/dL. Together with the observed decrease in reticulocyte counts, the increase in total hemoglobin indicates that pociredir decreased red blood cell destruction and showed reductions in anemia.
- A trend of reduced VOC rates was observed during the study period (as assessed by VOCs reported as AEs), compared to cohort patients’ VOC frequency over the 6–12 months prior to enrollment. Eight of 16 patients (
50% ) reported no VOCs during the treatment period (12 weeks); 3 VOCs occurred during the follow-up period as of the June 26, 2025 data cut-off date.
Pociredir Safety Update
- Through the completion of the 12 mg dose cohort, pociredir has been dosed in 135 adults, including 76 subjects in multiple dose cohorts up to 12 weeks.
- 103 healthy subjects, including 44 who received pociredir from 10 to 14 days treatment duration
- 32 SCD patients who received pociredir up to 12 weeks treatment duration
- The safety profile for pociredir observed in the 12 mg dose cohort was consistent with previously reported safety data. Pociredir was generally well-tolerated, with no drug-related SAEs and no discontinuations due to treatment-emergent AEs through the completion of the 12 mg dose cohort. In addition, all treatment-related AEs were Grade 1.
- Additional observations after completion of the 4-week follow-up period for 12 mg dose cohort (ongoing) will be shared at a future medical meeting.
The 12 mg data (n=16) discussed in this press release relates to cohort 3b (incomplete prior 12 mg cohort (3a) conducted prior to study hold not included in this analysis).
Conference Call and Webcast
Fulcrum Therapeutics, Inc. will host a conference call and webcast today at 8:00 a.m. ET to discuss the results to date from the PIONEER Phase 1b trial. Individuals may register for the conference call by clicking the link here. To register to participate in the conference call, individuals can use the conference call link here. Once registered, participants will receive dial-in details and unique PIN, which will allow them to access the call. An audio webcast will be accessible through the Investor Relations section of the company’s website at www.fulcrumtx.com or by clicking here. Following the live webcast, an archived replay will also be available for 90 days.
About Fulcrum Therapeutics
Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s lead clinical program is pociredir, a small molecule designed to increase expression of fetal hemoglobin (HbF) for the treatment of sickle cell disease (SCD). Fulcrum uses proprietary technology to identify drug targets that can modulate gene expression to treat the known root cause of gene mis-expression. For more information, visit www.fulcrumtx.com and follow us on Twitter/X (@FulcrumTx) and LinkedIn.
About Pociredir
Pociredir is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that was discovered using Fulcrum’s proprietary discovery technology. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in fetal hemoglobin (HbF). Pociredir is being developed for the treatment of SCD. Initial data in SCD in the PIONEER Phase 1b clinical trial showed proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. Through the completion of the 12 mg dose cohort, pociredir was demonstrated to be generally well-tolerated in people with SCD with up to three months of exposure, with no treatment-related serious adverse events reported. Pociredir has been granted FDA Fast Track designation and Orphan Drug Designation for the treatment of SCD. To learn more about clinical trials of pociredir please visit ClinicalTrials.gov.
About Sickle Cell Disease
SCD is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with SCD typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy.
Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release are forward-looking statements, including express or implied statements regarding pociredir’s potential to transform the treatment of SCD; pociredir’s ability to replicate protective biology through HbF induction; continued clinical development of pociredir; Fulcrum’s Phase 1b PIONEER clinical trial of pociredir; Fulcrum’s ability to progress its early stage development programs and planned IND filings related thereto; among others. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrum’s ability to continue to advance its product candidates in clinical trials; initiating and enrolling clinical trials on the timeline expected or at all; obtaining and maintaining necessary approvals from the FDA and other regulatory authorities; replicating in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials; obtaining, maintaining or protecting intellectual property rights related to its product candidates; managing expenses; realize the anticipated benefits of the workforce reduction and strategic realignment and managing risks associated therewith; and raising the substantial additional capital needed to achieve its business objectives, among others. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Fulcrum’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in Fulcrum’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Fulcrum’s views as of the date hereof and should not be relied upon as representing Fulcrum’s views as of any date subsequent to the date hereof. Fulcrum anticipates that subsequent events and developments will cause Fulcrum’s views to change. However, while Fulcrum may elect to update these forward-looking statements at some point in the future, Fulcrum specifically disclaims any obligation to do so.
Contact:
Kevin Gardner
LifeSci Advisors, LLC
kgardner@lifesciadvisors.com
617-283-2856
