Fulcrum Therapeutics, Inc., a clinical-stage biopharmaceutical company, focuses on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need.
The company’s clinical-stage product candidate, pociredir, is being developed for the potential treatment of sickle cell disease, or SCD.
In January 2023, the company announced interim data from its Phase 1b clinical trial of pociredir in SCD. The company completed enrollment in...
Fulcrum Therapeutics, Inc., a clinical-stage biopharmaceutical company, focuses on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need.
The company’s clinical-stage product candidate, pociredir, is being developed for the potential treatment of sickle cell disease, or SCD.
In January 2023, the company announced interim data from its Phase 1b clinical trial of pociredir in SCD. The company completed enrollment in the 6 mg and 2 mg dose cohorts, and does not plan to enroll additional subjects in these cohorts. Although the company commenced enrollment in the 12 mg dose cohort, in February 2023 the FDA placed a full clinical hold on the IND application for pociredir for SCD, which was lifted in August 2023. Following the clinical hold, the company amended the protocol to revise the inclusion and exclusion criteria for the Phase 1b clinical trial to target subjects with higher disease severity. The company reinitiated the Phase 1b clinical trial at the 12 mg once daily dose level in the fourth quarter of 2023, with that cohort expected to enroll approximately 10 subjects, to be followed by an additional cohort of approximately 10 subjects at the 20 mg once daily dose level. Subjects are evaluated over a 12-week treatment period. The company has enrolled 10 patients in the 12 mg dose cohort, and expects to provide clinical data from the 12 mg dose cohort in mid-2025 and from the 20 mg dose cohort by the end of 2025.
In September 2024, the company announced topline results from its Phase 3 REACH clinical trial of losmapimod in facioscapulohumeral muscular dystrophy, or FSHD. The Phase 3 REACH trial did not achieve its primary endpoint of change from baseline in relative surface area with losmapimod compared to placebo. In addition, secondary endpoints did not achieve nominal statistical significance. The safety and tolerability profile of losmapimod was consistent with previously reported studies. Based on the results of the REACH trial, the company has suspended future development of losmapimod. The company plans to present the results from the Phase 3 REACH trial on March 19, 2025, at the 2025 MDA Conference being held in Dallas, Texas.
In September 2024, the company also announced a strategic plan to reprioritize research and development activities and is now focused on advancing pociredir for the treatment of SCD, novel therapeutic agents for the potential treatment of inherited aplastic anemias, such as DBA, Shwachman-Diamond syndrome, and Fanconi anemia, and the company’s other discovery programs. The plan reduced the company’s workforce from 80 to 51 full-time employees, including a reduction of positions across both research and development and general and administrative functions.
In addition to the company’s product candidates, the company developed a discovery approach that it employs to systematically identify and validate cellular drug targets that can potentially modulate gene expression to treat known root causes of genetically defined rare diseases. The company’s discovery approach led to the identification of pociredir for SCD, as well as other drug candidates.
Pipeline
Using the company’s discovery approach, it has generated a pipeline of potentially disease-modifying therapies that address the known root causes of rare genetic diseases.
Strategy
The key components of the company’s strategy are to rapidly develop pociredir for the treatment of SCD; continue to apply its discovery efforts, including pursuing in-licensing or acquisition opportunities to grow its portfolio of product candidates for the treatment of genetically defined rare diseases; and maximize the commercial potential of its product candidates.
Pociredir
The company is developing pociredir, which is designed to elevate the level of fetal hemoglobin, or HbF, for the treatment of people with SCD.
Approach to Address the Root Cause of SCD
The company’s strategy to address the root cause of SCD was to identify a drug mechanism that induces expression of HbF.
Identification of the Drug Target for SCD
The company conducted target identification and validation activities using human umbilical cord blood-derived erythroid progenitor 2, or HUDEP2, cells as a model to study HbF reactivation. HUDEP2 cells are immature RBCs. By screening the company’s small molecule probe library and a CRISPR library, it identified several potential drug targets that activated the HBG1/2 genes and resulted in HbF elevation. Each screening approach identified the same protein complex, PRC2, which plays an important role in the expression of genes responsible for the production of HbF. The company conducted additional validation experiments in which it observed that inhibition of several components of this complex resulted in the desired elevation of HbF. It also observed that inhibition of these components did not adversely affect important cell health markers.
The company selected a component of this protein complex, EED, for drug discovery activities following an assessment of its tractability as a drug target. The normal physiological role of EED is to facilitate a post-translational protein modification, and the goal of its medicinal chemistry program was to optimize inhibitors of EED. The company developed in vitro and in vivo target engagement assays, as well as enabled X-ray crystallography, to discover and develop pociredir, a novel small molecule inhibitor of the EED subunit of PRC2.
Pociredir
Pociredir is an oral HbF inducer that is in development for SCD. Pociredir is designed to bind to EED and inhibit the transcriptional silencing activity of PRC2. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in HbF. EED is a member of the PRC2 complex, which also includes EZH2. There are approved products in the EZH2 class of medications, and their approved labeling outlines safety risks, including an increased risk of hematologic malignancies. The company initiated its Phase 1b clinical trial of pociredir in SCD in the fourth quarter of 2021. In February 2022, the FDA granted orphan drug designation to pociredir for the treatment of SCD. In December 2022, the FDA granted fast track designation to pociredir for SCD. In February 2023, the FDA placed the IND for pociredir for the potential treatment of SCD on full clinical hold. Accordingly, the company suspended enrollment and dosing in the Phase 1b trial of pociredir and withdrew its separate IND for pociredir in ß-thalassemia. The FDA’s clinical hold referenced the data from toxicology studies in rats and dogs that the company submitted to the IND in April, October, and December 2022, as well as a response to an early February 2023 information request from the FDA about these toxicology studies that the company submitted in mid-February 2023.
As part of the company’s pociredir development program, it has conducted numerous non-clinical toxicology studies, including studies conducted under good laboratory practice, or GLP. These toxicology studies have included repeat-dose maximum tolerated dose and dose range finding studies; 28-day, 13-week, 17-week, and 26-week studies in rats; and 28-day, 13-week, and 39-week studies in dogs. In connection with the clinical hold, the FDA noted that the profile of hematological malignancies observed in the toxicology studies of pociredir is similar to that observed with other inhibitors of PRC2, and that hematological malignancies have been reported clinically with other inhibitors of PRC2.
In August 2023, the FDA lifted the full clinical hold on the IND for pociredir for the potential treatment of SCD. The Phase 1b clinical trial has been re-initiated at the 12 mg once daily dose level, with that cohort expected to enroll approximately 10 patients, followed by an additional cohort of approximately 10 patients at the 20 mg once daily dose level. Patients are evaluated over a 12-week treatment period. The protocol was amended to revise the inclusion and exclusion criteria to target patients with higher disease severity. Key inclusion criteria include patients with certain frequencies of vaso-occlusive crises and/or other specified measures of severity, previous experience with hydroxyurea, and previous experience with a stable dose of voxelotor, crizanlizumab, or L-glutamine, or lack of access to these advanced therapies. Key exclusion criteria exclude subjects currently on or having received hydroxyurea within 60 days prior to initiating pociredir.
Clinical Trial: Phase 1b
In January 2023, the company announced Phase 1b data from subjects in the 6 mg dose cohort, as well as completion of enrollment in the 6 mg and 2 mg dose cohorts and commencement of enrollment in the 12 mg dose cohort. Until being placed on clinical hold in February 2023, the Phase 1b trial was evaluating subjects both on and off background hydroxyurea therapy.
Phase 1b data from subjects in the 6 mg dose cohort (n=10) showed up to 9.5% absolute HbF increases from baseline. These data suggested no difference in response in subjects on (n=3) and off (n=7) background hydroxyurea. The company also observed improved biomarkers of hemolysis in evaluable subjects dosed at 6 mg.
The company has completed enrollment and dosing in the 6 mg and 2 mg dose cohorts. Data from subjects in the 2 mg dose cohort (n=2) showed up to 4.6% absolute HbF increases from baseline.
Data from subjects in the 12 mg dose cohort (n=3), prior to the suspension of the trial in February 2023, showed up to 10.0% absolute HbF increases from baseline, or total HbF of ~25.0%, after 42 days of treatment (the full three months of treatment was interrupted by the clinical hold). Subjects with asterisks were on background hydroxyurea.
Increases in HbF have been shown to reduce the frequency or severity of a broad range of SCD symptoms, including VOC, anemia, pain, infection, stroke, and others. Based on a large body of genetic, clinical, and observational evidence showing the effects of higher levels of HbF in people with SCD, for a given patient, even small increases in total HbF are associated with clinical benefit, with levels in the upper 20% to lower 30%-range being associated with significant reductions in the manifestations of SCD.
Pociredir was generally well-tolerated through the end of 2023. There have been 23 treatment emergent adverse events, or TEAEs, reported as of the data cutoff date, eight of which were reported as possibly related to study drug (headache, lip numbness, diarrhea, fatigue, somnolence, nausea, or tinnitus), none of which were severe and were deemed non-serious. There have been no discontinuations due to TEAEs as of the data cutoff date. Four of the 23 TEAEs were characterized as VOCs, and were deemed unrelated to pociredir; one of these was reported as a serious adverse event, or SAE, with acute chest syndrome in a subject who was non-adherent to study drug administration.
Clinical Trial: Phase 1 Healthy Volunteers
In the fourth quarter of 2020, the company initiated a Phase 1 clinical trial of pociredir in healthy adult volunteers. The Phase 1 randomized, double-blind, placebo-controlled trial was designed to evaluate the safety, tolerability, and pharmacokinetics, or PK, of ascending doses of pociredir. In the single ascending dose, or SAD, cohorts, healthy volunteers received one dose of either placebo or 2, 4, 10, 20, 30, 40, or 60 mg of pociredir. In the multiple ascending dose, or MAD, cohorts, healthy volunteers received a once-daily dose of placebo or 2, 6, 10, 20, or 30 mg of pociredir for 14 consecutive days. Each MAD cohort had six subjects on drug and two on placebo. Food effect was also studied in a separate 20 mg dose cohort. Exploratory measures were included in the MAD cohorts to assess target engagement, changes in human hemoglobin messenger RNA, or HBG mRNA, and HbF-containing reticulocytes, or F-reticulocytes.
The company reported data from the 2, 4, 10, 20, 30, and 40 mg SAD cohorts and the 2, 6, and 10 mg MAD cohorts in healthy volunteers in August 2021, and it reported data from the 60 mg SAD cohort and the 20 and 30 mg MAD cohorts in healthy volunteers, as well as data from the 20 mg cohort assessing food effect in December 2021.
Pociredir was generally well-tolerated in healthy adult volunteers with no SAEs reported and no discontinuations due to TEAEs across all SAD and MAD cohorts. Data continued to show dose-proportional PK, with a mean half-life of approximately 6-7 hours in the MAD cohorts, supporting once-daily dosing, and no food effect was observed with pociredir. Data from the MAD cohorts continued to show robust target engagement, as evidenced by an approximately 75-95% reduction from baseline in H3K27me3 after 14 days of treatment. Based on the company’s preclinical studies, this level of target engagement is predicted to result in robust induction of HBG1/2 and subsequently increase HbF production.
Data from the MAD cohorts also showed time- and dose-dependent HBG mRNA induction demonstrating proof-of-biology. Persistent HBG mRNA induction was observed for 7-10 days after treatment. In preclinical studies of pociredir, increases in HBG mRNA have consistently translated to the same fold increases in HbF protein.
Pociredir Activity in Preclinical Studies
The company has observed in vitro and in vivo activation of the HBG1/2 genes in preclinical studies with pociredir. It observed that pociredir elevated levels of HbF with minimal adverse effects on important cellular health markers. The company also observed in vitro upregulation of HbF in primary human CD34+ cells differentiated into RBCs from 14 donors, including nine different healthy human donors, four SCD donors, and one sickle cell trait donor, after seven days of drug treatment. Pociredir showed a significant elevation of HbF over baseline in each of these 14 donor cell lines. The company has conducted additional preclinical profiling in CD34+ derived cells and observed that treatment with pociredir increased HbF levels to approximately 30% of total hemoglobin, as measured by mass spectrometry, high-performance liquid chromatography, and fast protein liquid chromatography techniques. Notably, based on a review of data from other mechanisms, HbF fold induction in CD34+ cells has translated reliably into the clinic.
Additionally, the company compared the effect of pociredir in CD34+ derived cells relative to that of hydroxyurea. It observed that hydroxyurea had a minimal impact on HbF elevation, whereas pociredir significantly elevated HbF. In cells treated with the combination of pociredir and hydroxyurea, the company observed an increased effect relative to either compound alone.
Additionally, the company studied pociredir in a mouse model of SCD, known as the Townes mouse model. In this model, mouse globin genes have been replaced with human globin genes, thereby allowing investigations of mechanisms that may regulate human hemoglobin gene expression. The Townes mouse model has been widely used to study potential treatments for SCD. The company observed that pociredir resulted in a significant increase in HbF-expressing cells, or F-cells, and HbF protein levels after 13 days of dosing at 5 mg/kg once per day, whereas hydroxyurea resulted in modest increases in F-cells and HbF.
The company quantified the percentage of F-cells as a percentage of total cells (%F-cells) for the three treatment conditions from mouse blood, shown as a percentage of vehicle-alone-treated SCD mice. It determined the level of human HbF protein for the three treatment conditions, quantifying HbF protein as a percentage of total hemoglobin. Each value represents the mean value from eight mice per treatment after 13 days of treatment. In these studies, the company used a conventional method of assessing statistical significance known as a one-way analysis of variance, or ANOVA. The p-value for pociredir was less than 0.001 for both studies, and the p-value for hydroxyurea in the study depicted on the right was less than 0.01.
Discovery Programs
The company has utilized its expertise to discover the target that it is pursuing with a small molecule for SCD. It is leveraging its discovery approach to discover drug targets for other rare, genetically defined diseases. The company continues to advance its program for the potential treatment of inherited aplastic anemias, such as Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome, and Fanconi anemia, and it plans to submit an IND for DBA during the fourth quarter of 2025.
License Agreements and Collaborations
Collaboration and License Agreement with MyoKardia, a wholly-owned subsidiary of Bristol-Myers Squibb Company
In July 2020, the company entered into a collaboration and license agreement with MyoKardia to identify biological targets that are capable of modulating genes of interest with relevance to certain genetically defined cardiomyopathies. Under the terms of the agreement, the company granted MyoKardia an exclusive worldwide license under certain intellectual property rights to research, develop, make, have made, use, have used, sell, have sold, offer for sale, have offered for sale, import, have imported, export, have exported, distribute, have distributed, market, have marketed, promote, have promoted, or otherwise exploit products directed against certain biological targets identified by the company that are capable of modulating certain genes of interest with relevance to certain genetically defined cardiomyopathies.
License Agreement with CAMP4
In July 2023, the company entered into a license agreement with CAMP4 pursuant to which it received a worldwide exclusive license (including the right to sublicense) from CAMP4 to rights under its DBA program, which includes certain small molecule compounds, composition of matter and method of use patent rights, and know-how for the company to research, develop, manufacture, use, commercialize, or otherwise exploit therapeutic products in any indication, including the grant of a sublicense under certain intellectual property rights that CAMP4 has licensed under an agreement with Children’s Medical Center Corporation, or CMCC.
Losmapimod Agreements
In May 2024, the company entered into a collaboration and license agreement with Sanofi, pursuant to which the company granted Sanofi an exclusive license under certain intellectual property rights to commercialize losmapimod for the treatment of FSHD outside of the United States. On December 18, 2024, the company received written notice of Sanofi’s election to terminate for convenience the collaboration and license agreement. In accordance with the agreement, the termination will become effective on April 17, 2025, which is 120 days following the date of receipt of the notice by the company.
In February 2019, the company entered into a right of reference and license agreement with affiliates of GSK, as amended in September 2020, pursuant to which GSK granted the company a right of reference to certain INDs filed with the FDA and controlled by GSK or its affiliates relating to losmapimod, and an exclusive worldwide license under certain patent rights related to losmapimod. The agreement also provides the company with an exclusive worldwide license to certain of GSK’s preclinical and clinical data with respect to losmapimod.
Intellectual Property
The company generally files patent applications directed to its key programs in an effort to secure its intellectual property positions vis-a-vis these programs. As of February 18, 2025, the company owned or in-licensed eight U.S. patents, nine U.S. pending non-provisional patent applications and related pending foreign patent applications, and one pending U.S. provisional patent application.
Pociredir
The company’s patent portfolio related to pociredir includes three issued U.S. patents directed to composition of matter that is expected to expire in 2040, one U.S. non-provisional application and related granted patents and pending patent applications in Canada and Mexico, Europe, Africa, Australia and New Zealand, South America, and Asia that, if issued, are expected to expire between 2039 and 2040. The company also owns three U.S. non-provisional applications and related patent applications pending in Europe directed to solid forms and methods of using pociredir, and one pending U.S. non-provisional application directed to pociredir methods of use and formulations, that, if resulting in issued patents, would be expected to expire between 2042 and 2043.
The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which the company files, the patent term is 20 years from the earliest date of filing a non-provisional patent application.
Research and Development
The company’s research and development expenses were $63.4 million for the year ended December 31, 2024.
History
Fulcrum Therapeutics, Inc. was founded in 2015. The company was incorporated in Delaware in 2015.
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