DUX4 gene modulators(Double homeobox protein 4 gene modulators), MAPK11 inhibitors(mitogen-activated protein kinase 11 inhibitors), p38α inhibitors(P38 α mitogen-activated protein kinase inhibitors)

Therapeutic Areas

Infectious DiseasesNervous System DiseasesCardiovascular Diseases+ [7]

Active Indication-

Inactive Indication

Acute Coronary SyndromeAtherosclerosisCOVID-19+ [15]

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

Fulcrum Therapeutics, Inc.

License Organization

GSK Plc

Sanofi

Fulcrum Therapeutics, Inc.

Drug Highest PhaseSuspendedPhase 3

First Approval Date-

RegulationFast Track (United States), Orphan Drug (United States), Orphan Drug (European Union)

Structure/Sequence

Molecular FormulaC22H26FN3O2

InChIKeyKKYABQBFGDZVNQ-UHFFFAOYSA-N

CAS Registry585543-15-3

Clinical Trials associated with Losmapimod

NCT05397470

/ TerminatedPhase 3

A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH)

This is a study to evaluate the safety and efficacy of losmapimod in treating participants with Facioscapulohumeral Muscular Dystrophy (FSHD). Participants diagnosed with Facioscapulohumeral muscular dystrophy type 1 (FSHD1) or Facioscapulohumeral muscular dystrophy type 2 (FSHD2) will participate in Part A (Placebo-controlled treatment period) and will be randomized in a 1:1 ratio to receive losmapimod 15 milligrams (mg) or placebo orally twice daily (BID). Upon completion of Part A, participants will have the option to rollover into Part B (open-label extension) to evaluate the long-term safety, tolerability, and efficacy of losmapimod and will receive losmapimod 15 mg orally BID.

Start Date16 Jun 2022

Sponsor / Collaborator

Fulcrum Therapeutics, Inc.

NCT05002231

/ CompletedPhase 1

A Phase 1, Open-Label, 3-Period, Randomized, Single-Dose, Crossover Study to Assess the Relative Bioavailability and the Effect of Food on the Pharmacokinetics of a New 15 mg Tablet of Losmapimod Versus the Current 7.5 mg Tablet

This is a study to assess the relative bioavailability and the effect of food on the pharmacokinetics of a new 15 mg tablet formulation of losmapimod

Start Date19 Aug 2021

Sponsor / Collaborator

Fulcrum Therapeutics, Inc.

NCT04511819

/ TerminatedPhase 3

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Losmapimod in Adult Subjects With COVID-19 (LOSVID STUDY)

The therapeutic hypothesis for the use of losmapimod in COVID-19 disease is that increased mortality and severe disease is caused by p38 mitogen-activated protein kinase (MAPK)-mediated exaggerated acute inflammatory response resulting from SARS-CoV-2 infection.
The study Sponsor hypothesizes that the early initiation of p38α/β inhibitor therapy in patients hospitalized with moderate COVID-19 who are at increased risk of a poor prognosis based on older age and elevated systemic inflammation will reduce clinical deterioration including progression to respiratory failure and death.
To address this hypothesis, Fulcrum Therapeutics is conducting a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that will evaluate the safety and efficacy of losmapimod versus placebo in subjects 40 and older who are hospitalized with moderate COVID-19 disease.

Start Date28 Aug 2020

Sponsor / Collaborator

Fulcrum Therapeutics, Inc.

100 Clinical Results associated with Losmapimod

100 Translational Medicine associated with Losmapimod

100 Patents (Medical) associated with Losmapimod

Literatures (Medical) associated with Losmapimod

01 Sep 2025·ATHEROSCLEROSIS

Early anti-inflammatory therapy in acute myocardial infarction: A network meta-analysis of timing-dependent effects in 23 randomized trials and 28,220 patients

Article

Author: Saldaña-García, Jesús ; Rivero-Santana, Borja ; Jurado-Román, Alfonso ; Cantolla-Pablo, Paula ; Moreno, Raúl ; Gil-Fernández, Marta ; Fernández-Velasco, María ; Tardif, Jean-Claude ; López-Sendón, José

BACKGROUND AND AIMS:

The timing of anti-inflammatory therapy in acute myocardial infarction (AMI) may be critical, yet has not been systematically assessed. While several agents have shown benefit in secondary prevention, their efficacy during the early inflammatory phase of AMI remains uncertain. This study evaluated the effectiveness of anti-inflammatory therapies in AMI and whether early initiation within 24 h of symptom onset modifies clinical outcomes.

METHODS:

We conducted a network meta-analysis of 23 randomized controlled trials including 28,220 patients with AMI. Interventions included colchicine, anakinra (IL-1β inhibitor), tocilizumab (IL-6 inhibitor), varespladib (PLA2 inhibitor), losmapimod (p38 MAPK inhibitor), cyclosporine (mitochondrial pore inhibitor), and pexelizumab (complement C5 inhibitor). Primary outcomes were major adverse cardiovascular events (MACE), heart failure (HF), and ischemic events. Treatment effects were summarized as incidence rate ratios (IRRs), defined as the ratio of incidence rates between intervention and control groups. Subgroup analyses stratified trials by treatment initiation ≤24 h vs > 24 h from symptom onset.

RESULTS:

Colchicine significantly reduced MACE ([IRR] 0.71; 95 % confidence interval [CI] 0.53-0.97) and ischemic events (IRR 0.65; 95 % CI 0.43-0.98). Anakinra reduced HF events (IRR 0.38; 95 % CI 0.16-0.89). These effects were observed exclusively when treatment was initiated within 24 h. No benefit was seen with delayed therapy, and no other intervention showed clinical efficacy. Safety outcomes, including infection risk, were neutral across treatments.

CONCLUSIONS:

This network meta-analysis demonstrates that anti-inflammatory therapy improves outcomes in AMI only when initiated early. Colchicine and anakinra were the only effective agents, highlighting a narrow therapeutic window and supporting a time-sensitive approach to inflammation-targeted treatment in AMI.

01 May 2025·Journal of Neuromuscular Diseases

The participants’ perspective on facioscapulohumeral muscular dystrophy trials in The Netherlands – A qualitative study

Article

Author: Lenssen, Emma ; Oortwijn, Wija ; Kools, Joost ; van Engelen, Baziel GM ; de Haas, Ria ; Sanders, Eline ; Lanser, Anke ; Voermans, Nicol C ; Stinissen, Lizan ; Bouma, Sietse

Background::

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary muscle disease without an available cure. The first trials with potentially disease-modifying therapies have started, including a phase ll open-label study and a phase lll double-blind randomized placebo-controlled trial assessing the safety and efficacy of losmapimod. Having a more in-depth understanding of the patient's experience of these trials will further enhance the design and recruitment of future trials.

Objective::

To explore the motivation, expectations, concerns, and experiences of FSHD patients in the first clinical trials in the Netherlands resulting in recommendations for future trials.

Methods::

Semi-structured interviews with participants of phase II and III losmapimod trials were conducted. The interview guide was based on previous conducted literature reviews and consultation of a patient representative. Participants were selected through convenience sampling. Four main themes were discussed: motivation for participation, expectations regarding study drug and trial visits, trial participation experience, and recommendations for future trials. The interviews were transcribed, anonymized, and analyzed using Atlas.ti version 23.1.1 using a deductive approach.

Results::

Thirteen participants were interviewed; six phase II participants and seven phase III participants. The primary motivations to participate concerned altruistic motives, contribute to science or improve their own health status. The participants had realistic expectations of the effect of the study drug before trial participation. Overall, participants were positive about their trial participation. Specifically, the personal and transparent communication within a trusting and dedicated trial team was appreciated. The phase III participants reported a higher than expected psychological burden on participating in a placebo-controlled trial. Recommendations consisted of more frequent updates on the overall progress and results of the trials.

Conclusions::

This study presents the participants’ perspective on FSHD trials, providing important key findings for future clinical trial design, study site practices and patient education.

01 Apr 2025·FREE RADICAL BIOLOGY AND MEDICINE

Methylglyoxal deteriorates macrophage efferocytosis in diabetic wounds through ROS-induced ubiquitination degradation of KLF4

Article

Author: Zhu, Hanting ; Wang, Jizhuang ; Liu, Yan ; Wang, Jiaqiang ; Wang, Wenao ; Yang, Peilang ; Liu, Dan ; Chen, Xuelian ; Zhu, Jiajun

Diabetic wounds are a leading cause of disability and mortality in patients with diabetes, and persistent low-grade inflammation plays a significant role in their pathogenesis. Methylglyoxal (MGO), an active product of glucose metabolism, often induces chronic inflammation and is considered a major risk factor in the healing of diabetic wounds. Efferocytosis, the process by which macrophages clear apoptotic cells, is crucial for terminating the inflammatory response and tissue repair. However, the role of MGO in macrophage efferocytosis remains unclear. This study aimed to investigate whether MGO regulates macrophage efferocytosis and the underlying mechanisms. In this study, we observed impaired efferocytosis in diabetic wounds, leading to the accumulation of apoptotic neutrophils and a relative deficiency of M2 macrophages, with MGO being a significant cause. MGO promotes the production of ROS, which not only activates the MAPK p38 pathway, but also upregulates the transcription of the E3 ubiquitin ligase FBXO32, catalyzing the ubiquitination of the transcription factor KLF4 and suppressing the transcription of MerTK mRNA, thereby affecting the phagocytic function of macrophages. Inhibition of the MAPK p38 pathway or knockdown of FBXO32 reduced the ubiquitination and degradation of KLF4, thus mitigating the impairment of efferocytosis caused by oxidative stress. This study reveals the mechanism by which MGO inhibits efferocytosis in diabetic wounds, providing a new target and theoretical basis for the treatment of chronic diabetic wounds.

146

News (Medical) associated with Losmapimod

29 Oct 2025

·www.globenewswire.com

Fulcrum Therapeutics Announces Recent Business Highlights and Financial Results for Third Quarter 2025

― Announced encouraging results in July 2025 from the 12 mg dose cohort of the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD) ― ― Enrollment complete in the 20 mg dose cohort (n=12) of the PIONEER trial; on track to provide data from the 20 mg dose cohort by year-end ― ― Ended Q3 2025 with $200.6 million in cash, cash equivalents, and marketable securities; cash runway into 2028 ― CAMBRIDGE, Mass., Oct. 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 financial results for the third quarter of 2025 and provided a business update. “We are extremely pleased with the compelling data from the 12 mg dose cohort of the PIONEER trial, which demonstrated that pociredir has the potential to meaningfully improve outcomes for people living with sickle cell disease,” said Alex C. Sapir, Fulcrum’s President and Chief Executive Officer. “The strength of those results has generated significant interest and engagement from investigators and patients, reflected in the over-enrollment of the 20 mg dose cohort. We look forward to sharing results from the 20 mg dose cohort by the end of 2025.” Recent Business Highlights Announced encouraging results from the 12 mg dose cohort of the PIONEER trial, following conclusion of the 12-week treatment period. Results demonstrated a dose-dependent and clinically meaningful increase in fetal hemoglobin (HbF), evidence of pan-cellular induction of HbF, improvements in markers of hemolysis, increases in total hemoglobin, and encouraging trends in vaso-occlusive crisis (VOC) reductions. Pociredir continued to be generally well-tolerated, with no drug-related serious adverse events (SAEs) and no discontinuations due to treatment-emergent adverse events through the completion of the 12 mg dose cohort.Completed patient enrollment in the 20 mg dose cohort of the PIONEER trial, with greater than 90% rates of adherence to study drug to date. The mean and median baseline HbF levels for the 12 evaluable patients (excluding 1 discontinuation that was previously disclosed) enrolled in the 20 mg dose cohort are 7.1% and 7.3%, respectively. Fulcrum plans to present additional clinical data at the 67th American Society of Hematology (ASH) Congress, being held December 6-9, 2025, in Orlando.Initiating an open label extension trial to allow patients to continue receiving pociredir after completing the PIONEER trial, enabling longer-term evaluation of safety and durability of response. Presented real-world data at the 20th Annual Sickle Cell & Thalassemia (ASCAT) Conference demonstrating the quantitative correlation between increased HbF levels and reduced VOC rates in SCD. Read the presentation here.Fulcrum continues to advance its program for the potential treatment of bone marrow failure syndromes, such as Diamond-Blackfan anemia (DBA), 5q deletion syndrome, Shwachman-Diamond syndrome, and Fanconi anemia, and plans to submit an investigational new drug application (IND) during the fourth quarter of 2025.Presented preclinical data for FTX-6274, an oral embryonic ectoderm development (EED) inhibitor candidate, at the European Society for Medical Oncology (ESMO) Congress 2025, demonstrating robust efficacy in castration resistant prostate cancer models. Read the presentation here. Third Quarter 2025 Financial Results Cash Position: As of September 30, 2025, cash, cash equivalents, and marketable securities were $200.6 million, as compared to $241.0 million as of December 31, 2024. The decrease of $40.4 million is primarily due to cash used to fund operating activities in 2025.R&D Expenses: Research and development expenses were $14.3 million for the three months ended September 30, 2025, as compared to $14.6 million for the three months ended September 30, 2024. The decrease of $0.3 million was primarily due to decreased costs associated with the discontinuation of our losmapimod program and the reimbursement from the global development cost sharing under the now-terminated collaboration with Sanofi, partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial of pociredir.G&A Expenses: General and administrative expenses were $7.6 million for the three months ended September 30, 2025, as compared to $8.4 million for three months ended September 30, 2024. The decrease of $0.8 million was primarily due to decreased professional services costs.Net Loss: Net loss was $19.6 million for the three months ended September 30, 2025, as compared to a net loss of $21.7 million for the three months ended September 30, 2024. Cash Runway Guidance Based on its current operating plans, Fulcrum expects that its current cash, cash equivalents, and marketable securities will be sufficient to fund its operating requirements into 2028. About Fulcrum TherapeuticsFulcrum 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 HbF for the treatment of 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 X (@FulcrumTx) and LinkedIn. About PociredirPociredir is an investigational oral small-molecule inhibitor of 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 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 SAEs 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 DiseaseSCD 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 Fulcrum’s Phase 1b PIONEER clinical trial of pociredir, including planned data announcement for such trial; the potential of pociredir to increase HbF to levels that could ameliorate symptoms of SCD and transform the standard of care; Fulcrum’s ability to progress its early stage development programs and planned IND filings related thereto; and its projected cash runway, 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, including progressing early stage candidates into the clinic; 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; realizing 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. Fulcrum Therapeutics, Inc.Selected Consolidated Balance Sheet Data(In thousands)(Unaudited) September 30,2025 December 31,2024 Cash, cash equivalents, and marketable securities $200,645 $241,021 Working capital(1) 194,231 238,879 Total assets 214,858 260,718 Total stockholders’ equity 198,366 243,034 (1) Fulcrum defines working capital as current assets minus current liabilities. Fulcrum Therapeutics, Inc.Consolidated Statements of Operations(In thousands, except per share data)(Unaudited) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2025 2024 2025 2024 Collaboration revenue — — — 80,000 Operating expenses: Research and development 14,296 14,639 40,687 51,673 General and administrative 7,562 8,424 21,389 28,732 Restructuring expenses — 2,063 — 2,063 Total operating expenses 21,858 25,126 62,076 82,468 Loss from operations (21,858) (25,126) (62,076) (2,468)Other income, net 2,263 3,430 7,530 9,311 Net (loss) income $(19,595) $(21,696) $(54,546) $6,843 Net (loss) income per share, basic $(0.31) $(0.35) $(0.87) $0.11 Net (loss) income per share, diluted $(0.31) $(0.35) $(0.87) $0.11 Weighted-average common shares outstanding, basic 62,597 62,409 62,537 62,200 Weighted-average common shares outstanding, diluted 62,597 62,409 62,537 63,688 Contact: Kevin GardnerLifeSci Advisors, LLCkgardner@lifesciadvisors.com617-283-2856

Phase 1Clinical ResultFinancial StatementASHFast Track

29 Jul 2025

·www.globenewswire.com

Fulcrum Therapeutics Announces Recent Business Highlights and Financial Results for Second Quarter 2025

― Announced results from the 12 mg dose cohort (n=16) of the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD); pociredir was generally well-tolerated with no treatment-related serious adverse events (SAEs) ― ― Observed robust and rapid pan-cellular increases in fetal hemoglobin (HbF); meaningful improvements in key markers of hemolysis and anemia; encouraging trends in vaso-occlusive crises (VOCs) ― ― On track to provide clinical data from the 20 mg dose cohort by the end of 2025 ― ― Ended Q2 2025 with $214.1 million in cash, cash equivalents, and marketable securities; cash runway into 2028 ― 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 financial results for the second quarter of 2025 and provided a business update. “Fulcrum has made substantial progress this quarter, having reported very promising results from the 12 mg cohort of the PIONEER trial,” said Alex C. Sapir, Fulcrum’s President and Chief Executive Officer. “We believe that this data demonstrates 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. We look forward to reporting the 20 mg data later this year and progressing pociredir into later-stage development.” Recent Business Highlights Announced results from the 12 mg dose cohort of the PIONEER trial, following conclusion of the 12-week treatment period. Results included a robust mean increase of 8.6% in HbF, evidence of pan-cellular induction of HbF shown by a mean of 67% F-cells, improvements in markers of hemolysis and a 0.9 g/dL increase in total hemoglobin, and encouraging trends in VOC reductions. Pociredir was generally well-tolerated, with no drug-related SAEs and no discontinuations due to treatment-emergent adverse events through the completion of the 12 mg dose cohort. In addition, all treatment-related AEs through completion of the 12 mg dose cohort were Grade 1.The 20 mg dose cohort is ongoing, and Fulcrum plans to share data from this cohort by the end of 2025.Two abstracts were presented at the 2025 European Hematology Association (EHA) Congress in Milan, Italy, which took place June 12-15, 2025. The abstracts highlight preclinical target engagement and gene expression reversibility data of pociredir and clinical data from our previously completed Phase 1 healthy volunteer study.Fulcrum 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 plans to submit an investigational new drug application (IND) for DBA during the fourth quarter of 2025. Second Quarter 2025 Financial Results Cash Position: As of June 30, 2025, cash, cash equivalents, and marketable securities were $214.1 million, as compared to $241.0 million as of December 31, 2024. The decrease of $26.9 million is primarily due to cash used to fund operating activities in 2025.Collaboration Revenue: Collaboration revenue was zero for the three months ended June 30, 2025, as compared to $80.0 million for the three months ended June 30, 2024. The decrease of $80.0 million was primarily due to the recognition of the $80.0 million upfront license payment received from Sanofi during the second quarter of 2024.R&D Expenses: Research and development expenses were $13.0 million for the three months ended June 30, 2025, as compared to $17.3 million for the three months ended June 30, 2024. The decrease of $4.3 million was primarily due to decreased employee compensation costs as a result of the reduction in workforce implemented in the third quarter of 2024 as well as decreased costs associated with the discontinuation of our losmapimod program, partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial of pociredir.G&A Expenses: General and administrative expenses were $6.8 million for the three months ended June 30, 2025, as compared to $10.2 million for the three months ended June 30, 2024. The decrease of $3.4 million was primarily due to decreased professional services costs as well as decreased employee compensation costs as a result of the reduction in workforce implemented in the third quarter of 2024.Net Loss: Net loss was $17.3 million for the three months ended June 30, 2025, as compared to net income of $55.4 million for the three months ended June 30, 2024. Updated Cash Runway Guidance Based on its current operating plans, Fulcrum now expects that its current cash, cash equivalents, and marketable securities will be sufficient to fund its operating requirements into 2028. About Fulcrum TherapeuticsFulcrum 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 HbF for the treatment of 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 PociredirPociredir 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 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 DiseaseSCD 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 Fulcrum’s Phase 1b PIONEER clinical trial of pociredir, including planned data announcement for such trial; the potential of pociredir to increase HbF to levels that could ameliorate symptoms of SCD and transform the standard of care; Fulcrum’s ability to progress its early stage development programs and planned IND filings related thereto; and its projected cash runway, 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; realizing 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. Fulcrum Therapeutics, Inc.Selected Consolidated Balance Sheet Data(In thousands)(Unaudited) June 30,2025 December 31,2024 Cash, cash equivalents, and marketable securities $214,111 $241,021 Working capital(1) 210,388 238,879 Total assets 228,838 260,718 Total stockholders’ equity 214,378 243,034 (1) Fulcrum defines working capital as current assets minus current liabilities. Fulcrum Therapeutics, Inc.Consolidated Statements of Operations(In thousands, except per share data)(Unaudited) Three Months EndedJune 30, Six Months EndedJune 30, 2025 2024 2025 2024 Collaboration revenue — 80,000 — 80,000 Operating expenses: Research and development 12,987 17,261 26,391 37,034 General and administrative 6,828 10,247 13,827 20,308 Total operating expenses 19,815 27,508 40,218 57,342 (Loss) income from operations (19,815) 52,492 (40,218) 22,658 Other income, net 2,519 2,917 5,267 5,881 Net (loss) income $(17,296) $55,409 $(34,951) $28,539 Net (loss) income per share, basic $(0.28) $0.89 $(0.56) $0.46 Net (loss) income per share, diluted $(0.28) $0.87 $(0.56) $0.45 Weighted-average common shares outstanding, basic 62,544 62,205 62,506 62,095 Weighted-average common shares outstanding, diluted 62,544 63,587 62,506 63,684 Contact: Alan MussoChief Financial Officeramusso@fulcrumtx.com

Phase 1Financial StatementFast TrackClinical ResultOrphan Drug

21 Nov 2024

·www.fiercebiotech.com

Novartis, assessing peers’ muscular dystrophy failures, pens $1.1B deal for gene therapy biotech

Novartis is “really thinking about, how can we learn from the experiences of the first wave of companies that have had failures and perhaps some success with targeting these diseases,” CEO Vas Narasimhan, M.D., said.\n Novartis had one eye on the struggles its peers have encountered in the muscular dystrophy space when it decided to acquire Kate Therapeutics, according to the Big Pharma’s CEO.The Swiss drugmaker signed off on $1.1 billion in a combination of upfront cash and potential milestone payments to buy the gene therapy biotech, it announced today. San Diego-based Kate is focused on preclinical programs aimed at Duchenne muscular dystrophy (DMD), facioscapulohumeral dystrophy (FSHD) and myotonic dystrophy type 1 (DM1).These programs have been developed using the biotech’s Directed Evolution of AAV Capsid Leveraging In Vivo Expression of Transgene RNA (DELIVER) platform to produce “liver de-targeted muscle-tropic capsids, which transduce both skeletal muscle and cardiac tissue with potency and selectivity in vivo, while avoiding the liver,” according to a Nov. 21 release.This year has been a stark reminder of what tricky indications muscular dystrophies can be. Pfizer suffered a $230 million financial hit over the summer when its DMD gene therapy flunked a phase 3 trial while Fulcrum Therapeutics’ losmapimod encountered its own late-stage failure just four months after Sanofi bet $80 million on the FSHD candidate. Explaining the thinking behind the Kate acquisition during his opening presentation at the Meet Novartis Management event in London this morning, CEO Vas Narasimhan, M.D., said the pharma is “very interested” in FSHD, DM1 and the other muscular dystrophies.Novartis is “really thinking about, how can we learn from the experiences of the first wave of companies that have had failures and perhaps some success with targeting these diseases,” he added.Kate has “really solved some of the challenges of delivering the right targets or the right genes for patients with FSHD and DM1, and we\'ll see how we can also broaden that capability to help our own pipeline also advance in the neuromuscular space,” Varasimhan explained.Novartis—which markets the gene therapy Zolgensma for spinal muscular atrophy—has been working in neuroscience for “many years,” the CEO pointed out in his presentation, namechecking multiple sclerosis, neuromuscular disease and neurodegeneration.“We are now, I think, at a place where we think our gene therapy capabilities and the capabilities we brought in-house with the various vectors from Regenxbio and other partners will allow us to solve the biology that we did solve with Zolgensma, but then struggled to solve for other monogenic or polygenic neuromuscular diseases,” he added.

AcquisitionGene TherapyPhase 3

100 Deals associated with Losmapimod

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KEGG	Wiki	ATC	Drug Bank
D09639	Losmapimod	-	DB12270

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	United States	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	Canada	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	Denmark	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	France	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	Germany	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	Italy	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	Netherlands	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	Spain	Fulcrum Therapeutics, Inc.	16 Jun 2022
Facioscapulohumeral Muscular Dystrophy 1B	Phase 3	United Kingdom	Fulcrum Therapeutics, Inc.	16 Jun 2022
Muscular Dystrophy, Facioscapulohumeral	Phase 3	United States	Fulcrum Therapeutics, Inc.	16 Jun 2022

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04004000 (FSHD, CTgov)	Phase 2	Facioscapulohumeral Muscular Dystrophy 1a	14	Losmapimod	jejcoshafr = dautodnjhj ewetxvtfne (fyjeuttfrc, ggwfpkflkt - hixvaobhyf) View more	-	02 Dec 2025
NCT05397470 (REACH, CTgov)	Phase 3	Muscular Dystrophy, Facioscapulohumeral \| Facioscapulohumeral Muscular Dystrophy 1B	260	Losmapimod (Part A: Placebo-controlled Treatment Period: Losmapimod)	dralkewsll(bkkcizsipa) = rqjlrvgyoa kqzonabxhg (atgiftmvoc, xwngdvaozg - lfoglcjlwu) View more	-	07 Nov 2025
				Placebo oral tablet (Part A: Placebo-controlled Treatment Period: Placebo)	dralkewsll(bkkcizsipa) = ccjhvvpwnv kqzonabxhg (atgiftmvoc, cawywiwguo - mwnbcogpzc) View more
NCT04264442 (ReDUX4, CTgov)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	76	Losmapimod	zpkrdxueil = farlmuhauv codrhtclhx (gyojdjtcee, srwvunjvho - ugldemeskl) View more	-	30 Sep 2025
NCT05397470 (REACH, GlobeNewswire) Manual	Phase 3	Muscular Dystrophy, Facioscapulohumeral	260	Losmapimod 15 mg	ykqkkfmhuy(mibalsvbpr) = mreubmlvgd ftfjtupzus (vbsgxdinnh ) View more	Negative	12 Sep 2024
				Placebo	ykqkkfmhuy(mibalsvbpr) = icjqyfbjzb ftfjtupzus (vbsgxdinnh ) View more
NCT04003974 (FSHD \| ReDUX4, CTgov)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	80	Placebo oral tablet	wfasafikty(sfqzppzpln) = tymxlibqjv woqpylatur (tigmgtudxc, 0.6491) View more	-	10 Jul 2024
NCT04511819 (LOSVID, CTgov)	Phase 3	COVID-19	52	Placebo oral tablet	juvcdztqjn = vsougeysmw wdnnwsgnbf (klcywnieul, haaeacrwka - qgxnstnwnr) View more	-	13 Mar 2024
AAN2023	Phase 2	Muscular Dystrophy, Facioscapulohumeral	-	Losmapimod 15 mg	kudqhcwwfx(gfmlgykmcm) = beeskcwnfh vkmuyhfohi (sjpngsyzjj ) View more	Positive	25 Apr 2023
				Placebo	kudqhcwwfx(gfmlgykmcm) = vvkdoemifv vkmuyhfohi (sjpngsyzjj ) View more
NCT04264442 (ReDUX4, MDA2023) Manual	Phase 2	Muscular Dystrophy, Facioscapulohumeral	74	Losmapimod 15 mg (LOS/LOS)	cslmcpbwsy(dciosijwar) = Fall (22.4%), headache (14.5%), arthralgia (7.9%), and back pain (7.9%) ehihgdbiuo (jcdkzgfeqn ) View more	Positive	19 Mar 2023
				Placebo+Losmapimod 15 mg (PBO/LOS)
NCT04003974 \| NCT04264442 (ReDUX4, MDA2022)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	-	Losmapimod 15 mg	ztomgmscse(vqkqahmyng) = skrchwopjl eigghvovoc (yqpmdczyij ) View more	-	13 Mar 2022
				Placebo	ztomgmscse(vqkqahmyng) = wkgogpngwk eigghvovoc (yqpmdczyij ) View more
NCT04003974 \| NCT04264442 (ReDUX4, MDA2022)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	80	Losmapimod 15 mg	emzlzpawhw(nglvfshazf) = the losmapimod arm had either improvements or no worsening, particularly in Q1 and Q3 (above shoulder), and Q5 (posterior inferior) eaoxeasyiq (acpzmpntmb )	-	13 Mar 2022
				Placebo

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