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

Nervous System DiseasesCongenital DisordersSkin and Musculoskeletal Diseases+ [1]

Active Indication

Facioscapulohumeral Muscular Dystrophy 1a

Inactive Indication

Acute Coronary SyndromeAtherosclerosisCOVID-19+ [12]

Originator Organization

GSK Plc

Active Organization

Fulcrum Therapeutics, Inc.

Inactive Organization

GSK Plc

Drug Highest PhasePhase 2

First Approval Date-

RegulationFast Track (US), Orphan Drug (EU)

Structure

Molecular FormulaC22H26FN3O2

InChIKeyKKYABQBFGDZVNQ-UHFFFAOYSA-N

CAS Registry585543-15-3

Clinical Trials associated with Losmapimod

NCT05397470 / Active, not recruitingPhase 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 Oct 2024·Biomedicine & Pharmacotherapy

Losmapimod ameliorates doxorubicin-induced cardiotoxicity through attenuating senescence and inflammatory pathways

Article

Author: Grant, Marianne K O ; Daniel, Mary R ; Abdelgawad, Ibrahim Y ; Dabour, Mohamed S ; Sadaf, Bushra ; Zordoky, Beshay N ; Seelig, Davis

Irreversible cardiotoxicity limits the clinical application of doxorubicin (DOX). DOX-induced cardiotoxicity has been associated with induction of senescence and activation of the p38 MAPK pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. In this study, we determined the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6 N mice. Five-week-old C57BL/6 N mice were fed diet containing LOSM (estimated daily intake 12 mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4 mg/kg) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Activation of p38, JNK, and ERK1/2 MAPKs were assessed by immunoblotting in the heart and liver. Gene expressions of senescence, inflammatory, oxidative stress, and mitochondrial function markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Our results demonstrated that LOSM attenuated p38 MAPK activation, ameliorated DOX-induced cardiac dysfunction, and abrogated DOX-induced expression of the senescence marker p21^Cip1. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac Il-1α and Il-6 gene expression in DOX-treated mice. Systemic inflammation, assessed by serum cytokine levels, showed decreased IL-6 and CXCL1 in both DOX-treated mice and mice on LOSM diet. LOSM significantly increased mitofusin2 gene expression, which may enhance mitochondrial fusion. These findings underscore the potential therapeutic efficacy of p38 MAPK inhibition, exemplified by LOSM, in ameliorating DOX-induced cardiotoxicity, senescence, and inflammation.

01 Jul 2024·Journal of the Neurological Sciences

An open-label pilot study of losmapimod to evaluate the safety, tolerability, and changes in biomarker and clinical outcome assessments in participants with facioscapulohumeral muscular dystrophy type 1

Article

Author: Mitelman, Olga ; van Engelen, Baziel G M ; Kools, Joost ; Jiang, John G ; Voermans, Nicol ; Mellion, Michelle L ; Ramana, Vivekananda

INTRODUCTIONFacioscapulohumeral muscular dystrophy (FSHD) is a genetic disease caused by aberrant DUX4 expression, leading to progressive muscle weakness. No effective pharmaceutical treatment is available. Losmapimod, a small molecule selective inhibitor of p38 α/β MAPK, showed promising results in a phase 1 trial for the treatment of FSHD, prompting additional studies. We report the findings of an open-label phase 2 trial (NCT04004000) investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of losmapimod in participants with FSHD1.METHODSThis study was conducted at a single site in the Netherlands from August 2019 to March 2021, with an optional, ongoing open-label extension. Participants aged 18 to 65 years with FSHD1 took 15 mg of losmapimod twice daily for 52 weeks. Primary endpoints were measures of losmapimod safety and tolerability. Secondary endpoints were assessments of losmapimod pharmacokinetics and pharmacodynamics.RESULTSFourteen participants were enrolled. No deaths, serious treatment-emergent adverse events (TEAEs), or discontinuations due to TEAEs were reported. Losmapimod achieved blood concentrations and target engagements that were previously associated with decreased DUX4 expression in vitro. Clinical outcome measures showed a trend toward stabilization or improvement.CONCLUSIONSLosmapimod was well tolerated and may be a promising new treatment for FSHD; a larger phase 3 study is ongoing.

01 May 2024·The Lancet Neurology

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial

Article

Author: Leung, Doris G ; LoRusso, Samantha ; Johnson, Nicholas ; Gibson, Summer ; Reyes-Leiva, David ; Statland, Jeffrey M ; Morabito, Christopher ; Gould, Robert J ; Accorsi, Anthony ; Freimer, Miriam ; Goyal, Namita A ; Lochmüller, Hanns ; Widholm, Per ; Cadavid, Diego ; Ronco, Lucienne ; Wang, Leo H ; Sacconi, Sabrina ; Wagner, Kathryn R ; Pestronk, Alan ; Moxham, Christopher M ; van Engelen, Baziel ; Kools, Joost ; Mellion, Michelle L ; Hayward, Lawrence J ; Diaz-Manera, Jordi ; Shieh, Perry B ; Genge, Angela ; Odueyungbo, Adefowope ; Leinhard, Olof Dahlqvist ; Tracewell, William G ; Muelas, Nuria ; Shoskes, Jennifer ; Tawil, Rabi ; Jiang, John G ; Vilchez, Juan J ; Subramony, S H ; Rojas, Luis Alejandro ; Alonso-Perez, Jorge ; Hamel, Johanna I

BACKGROUNDFacioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy.METHODSWe did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing.FINDINGSBetween Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study.INTERPRETATIONAlthough losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy.FUNDINGFulcrum Therapeutics.

132

News (Medical) associated with Losmapimod

13 Nov 2024

·www.globenewswire.com

Fulcrum Therapeutics Announces Recent Business Highlights and Financial Results for Third Quarter 2024

― Patient enrollment and site activation progressing in Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD) ― ― Ended the third quarter of 2024 with $257.2 million in cash, cash equivalents, and marketable securities; cash runway into at least 2027 ― ― Conference call and webcast scheduled for 8:00 a.m. ET today ― CAMBRIDGE, Mass., Nov. 13, 2024 (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 2024 as well as a business update. “In the third quarter, we made progress enrolling patients and activating new sites in the Phase 1b PIONEER trial of pociredir in sickle cell disease and advancing our preclinical pipeline,” said Alex C. Sapir, Fulcrum’s president and chief executive officer. “The need for effective therapeutic options for patients with sickle cell disease has become even more urgent due to the recent withdrawal of OXBRYTA® globally. Based on the initial data generated in the Phase 1b trial, we believe that pociredir has the potential to increase fetal hemoglobin to levels that could ameliorate symptoms of sickle cell disease. While we were disappointed with the results of the Phase 3 REACH trial announced in September, we remain committed to improving the lives of patients with genetically defined diseases in areas of high unmet medical need like sickle cell disease. We are focused on progressing the development of pociredir as expeditiously as possible and remain on track to provide data from the PIONEER trial in 2025.” Recent Business Highlights Patient enrollment and site activations continue to progress in the Phase 1b PIONEER trial evaluating pociredir in patients with SCD. Cohort 3 of the Phase 1b trial is evaluating pociredir at the 12 mg once daily dose, which will be followed by Cohort 4 at the 20 mg once daily dose. Each cohort is expected to enroll up to 10 patients. Fulcrum plans to share clinical data from the PIONEER trial in 2025.Following recent interactions with the FDA, Fulcrum plans to initiate Phase 1 clinical studies in healthy volunteers in support of the overall pociredir development program.Following the REACH trial results disclosed in September 2024, Fulcrum suspended development of losmapimod and has focused its research and development activities on advancing pociredir for the treatment of SCD, as well as advancing novel therapeutic agents for the potential treatment of inherited aplastic anemias, such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia, and its early discovery programs. Third Quarter 2024 Financial Results Cash Position: As of September 30, 2024, cash, cash equivalents, and marketable securities were $257.2 million, as compared to $236.2 million as of December 31, 2023. The increase is due to the $80.0 million upfront payment received from Sanofi in the second quarter of 2024, partially offset by cash used to fund operating activities in 2024.Collaboration Revenue: Collaboration revenue was zero for the three months ended September 30, 2024, as compared to $0.8 million for the three months ended September 30, 2023. The decrease of $0.8 million was due to the completion of research services under the collaboration agreement with MyoKardia during the fourth quarter of 2023.R&D Expenses: Research and development expenses were $14.6 million for the three months ended September 30, 2024, as compared to $18.2 million for the three months ended September 30, 2023. The decrease of $3.6 million was primarily due to the reimbursement from the global development cost sharing under the collaboration with Sanofi for losmapimod, partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial.G&A Expenses: General and administrative expenses were $8.4 million for the three months ended September 30, 2024, as compared to $10.0 million for three months ended September 30, 2023. The decrease of $1.6 million was primarily due to decreased employee compensation costs as a result of the reduction in workforce implemented in the third quarter of 2024.Net Loss: Net loss was $21.7 million for the three months ended September 30, 2024, as compared to a net loss of $24.0 million for the three months ended September 30, 2023. Cash Guidance Based on its current operating plans, Fulcrum expects to end 2024 with approximately $240.0 million of cash, cash equivalents, and marketable securities, and expects its cash burn for the full year 2025 will be approximately $55.0 million to $65.0 million. Fulcrum also expects that its cash, cash equivalents, and marketable securities as of September 30, 2024 will be sufficient to fund its current operating requirements into at least 2027. Conference Call and Webcast Fulcrum Therapeutics, Inc. will host a conference call and webcast today at 8:00 a.m. ET to review the third quarter 2024 financial results and recent business highlights. Individuals may register for the conference call by clicking the 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 Fulcrum's website at www.fulcrumtx.com or by clicking here. Following the live webcast, an archived replay will also be available. 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 program in clinical development is pociredir, a small molecule designed to increase expression of fetal hemoglobin and in development 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 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 demonstrated proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. In clinical trials conducted prior to the clinical hold, which was lifted by the FDA in August 2023, pociredir was generally well-tolerated in people with SCD with up to three months of exposure, with no serious treatment-related adverse events reported. Pociredir has been granted FDA Fast Track designation and Orphan Drug Designation for the treatment of SCD. To learn more about these trials please visit ClinicalTrials.gov. About Sickle Cell Disease 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 Fulcrum’s Phase 1b PIONEER clinical trial of pociredir, including status of enrollment, number of patients per cohort and planned data announcement for such trial; the potential of pociredir to increase fetal hemoglobin to levels that could ameliorate symptoms of SCD; resumption of Phase 1 clinical studies in healthy volunteers ; Fulcrum’s ability to progress its early stage development programs; the effects of the reduction in workforce; and its projected year end cash position, cash runway and cash burn for 2025, 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. Fulcrum Therapeutics, Inc. Selected Consolidated Balance Sheet Data (In thousands) (Unaudited) September 30, 2024 December 31, 2023 Cash, cash equivalents, and marketable securities $257,234 $236,221 Working capital(1) 252,980 228,524 Total assets 279,008 257,694 Total stockholders’ equity 257,291 235,193 (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 Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Collaboration revenue $— $759 $80,000 $1,934 Operating expenses: Research and development 14,639 18,238 51,673 52,802 General and administrative 8,424 9,961 28,732 31,804 Restructuring expenses 2,063 — 2,063 — Total operating expenses 25,126 28,199 82,468 84,606 Loss from operations (25,126) (27,440) (2,468) (82,672)Other income, net 3,430 3,423 9,311 10,093 Net (loss) income $(21,696) $(24,017) $6,843 $(72,579)Net (loss) income per share, basic $(0.35) $(0.39) $0.11 $(1.19)Net (loss) income per share, diluted $(0.35) $(0.39) $0.11 $(1.19)Weighted-average common shares outstanding, basic 62,409 61,823 62,200 61,121 Weighted-average common shares outstanding, diluted 62,409 61,823 63,688 61,121 Contact: Chris Calabrese LifeSci Advisors, LLC ccalabrese@lifesciadvisors.com 917-680-5608

Phase 1Financial StatementFast TrackOrphan DrugPhase 2

12 Sep 2024

·www.fiercebiotech.com

Sanofi's $80M bet on Fulcrum's dystrophy drug ends in phase 3 failure after 4 months

Fulcrum Therapeutics said it would use its $273.8 million in cash and equivalents to swiftly pivot to its remaining pipeline. Just four months after Sanofi bet $80 million in upfront cash on Fulcrum Therapeutics’ losmapimod, the program has ended in a phase 3 failure.The licensing deal with the Big Pharma was agreed upon while counting down to the release of late-stage data in the progressive muscle wasting disorder facioscapulohumeral muscular dystrophy (FSHD) which, if successful, could have opened the door to the p38 inhibitor becoming the first approved therapy for the disease.But the results are just in, and it looks like a wipeout. Not only did the 260-patient study miss its primary endpoint of showing an improvement in an individual’s arm reach when taking a 15-mg losmapimod tablet twice a day compared to placebo, but the study’s secondary endpoints like muscle fat infiltration and patient-reported improvements “did not achieve nominal statistical significance,” Fulcrum explained in a Sept. 12 premarket release.Specifically, the primary endpoint of reachable workspace (RWS)—an analysis of how far an individual can reach—saw a 0.013 improvement among patients receiving losmapimod at Week 48 compared to a 0.010 improvement among those who received placebo. Fulcrum’s chief medical officer Pat Horn, M.D., Ph.D., blamed the results on the lack of deterioration among the placebo cohort.“These results in patients receiving losmapimod when compared to baseline were similar to those observed in our phase 2 study,” Horn said. “However, in contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status as measured by RWS and shoulder dynamometry over the 48 weeks of the study.”The safety and tolerability of losmapimod was consistent with previously reported studies, according to Fulcrum, which said it will fully evaluate the data before sharing the results at an upcoming medical meeting.“We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the phase 2 ReDUX4 trial,” Fulcrum’s CEO Alex Sapir said in the release. “In light of these results, we plan to suspend the losmapimod program in FSHD.”The biotech’s stock plummeted 70% in premarket trading Thursday morning to $2.60 from a Wednesday closing price of $8.85.Massachusetts-based Fulcrum said it would use its $273.8 million in cash and equivalents to swiftly pivot to its remaining pipeline. This is headed up by pociredir, a phase 1-stage small molecule designed to treat sickle cell disease by increasing expression of fetal hemoglobin. Today’s results mark a fork in the road for Fulcrum, which could have been on track to get the first-ever FSHD drug to market if the phase 3 data had shown promise. Losmapimod had a two- to three-year head start on Roche’s myostatin inhibitor that is being targeted at FSHD, while Avidity Biosciences and Arrowhead Pharmaceuticals both have antibody-oligonucleotide complexes in clinical development for the condition.It also means Fulcrum can wave goodbye to potentially $975 million in milestone payments that were tied to the Sanofi licensing deal. When the French Pharma secured the ex-U.S. rights to losmapimod in May, the drugmaker’s global head of rare disease Burcu Eryilmaz pointed to “meaningful clinical benefits” shown in phase 2 studies that “underscore the disease-modifying potential and opportunity to address the high unmet need for a safe and effective drug that slows disease progression.”But losmapimod already had a number of clinical misses on its scorecard. Fulcrum rescued the molecule in 2019 from the vault of GSK, where losmapimod had failed a phase 3 trial in patients with acute coronary syndrome and a midstage study in chronic obstructive pulmonary disease. Under its new owner, it had also failed a phase 2 trial in FSHD in 2021, although Fulcrum was heartened by phase 2b data showing losmapimod could still slow disease progression and improve function in FSHD patients.

Phase 2License out/inPhase 3Clinical ResultOligonucleotide

12 Sep 2024

·www.globenewswire.com

Fulcrum Therapeutics Announces Topline Results from Phase 3 REACH Clinical Trial of Losmapimod in Facioscapulohumeral Muscular Dystrophy (FSHD)

― Losmapimod failed to show an improvement in relative surface area (RSA), a measure of reachable workspace (RWS), versus placebo at week 48 ― ― Fulcrum to suspend future losmapimod development ― ― Robust cash position enables Fulcrum to continue its mission to develop therapies addressing diseases of high unmet need including pociredir for the treatment of sickle cell disease (SCD) ― CAMBRIDGE, Mass., Sept. 12, 2024 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.® (the “Company”) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today announced that its Phase 3 REACH trial evaluating losmapimod in patients with FSHD, did not achieve its primary endpoint of change from baseline in RSA 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. The Company will complete a full evaluation of the data it received this week and plans to share the results at an upcoming medical meeting. “We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the Phase 2 ReDUX4 trial,” said Alex C. Sapir, Fulcrum’s president and chief executive officer. “In light of these results, we plan to suspend the losmapimod program in FSHD. We would like to thank the FSHD patients who participated in losmapimod clinical trials, their families, the investigators, the FSHD Society, and the broader FSHD community for their unwavering support for this program.” Top-line REACH study results: Reachable Workspace (RWS): Participants receiving losmapimod demonstrated a 0.013 (±0.007) improvement in RSA at week 48 compared to placebo patients who showed a 0.010 (±0.007) improvement in RWS (p-value = 0.75).Muscle Fat Infiltration (MFI) as measured by Magnetic Resonance Imaging (MRI): Participants receiving losmapimod demonstrated an increase of 0.42% in MFI at week 48 compared to participants receiving placebo who showed an increase of 0.576% in MFI (p-value = 0.16).Shoulder Abductor Strength as measured by Hand-Held Dynamometry: Participants receiving losmapimod demonstrated a 9.63% improvement in abductor strength at week 48 compared to a 2.24% improvement in abductor strength seen in the placebo arm of the study (p-value = 0.51).Patient Reported Outcomes (PRO): Across the two PRO secondary endpoints in the REACH study, Patient Global Impression of Change (PGIC) and the Neuro QoL Upper Extremity, there were no statistically significant differences observed.Safety and Tolerability: The rate of treatment-related adverse events was similar in the two treatment arms, and there were no treatment-related serious adverse events in participants receiving losmapimod. “These results in patients receiving losmapimod when compared to baseline were similar to those observed in our Phase 2 study,” said Dr. Pat Horn, Fulcrum’s chief medical officer. “However, in contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status as measured by RWS and shoulder dynamometry over the 48 weeks of the study. As the largest interventional study ever completed in FSHD, we intend to share the full trial results with patients, study investigators, and the broader FSHD community to ensure others developing treatments for FSHD can benefit from these data.” As previously disclosed, Fulcrum had approximately $273.8 million in cash, cash equivalents, and marketable securities as of June 30, 2024. Fulcrum intends to use these resources to advance pociredir for the treatment of SCD, novel therapeutic agents for the treatment of Diamond-Blackfan Anemia (DBA), and early discovery programs. About the REACH TrialREACH (NCT05397470) is a Phase 3 multi-center, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of losmapimod for the treatment of FSHD. The trial enrolled 260 patients who were randomized 1:1 to receive either losmapimod, administered orally as a 15 mg tablet twice a day, or placebo over a 48-week treatment period. The primary endpoint was the absolute change from baseline in Reachable Workspace (RWS). Secondary endpoint measurements included Muscle Fat Infiltration (MFI) as measured by MRI, shoulder abductor strength as measured by hand-held dynamometry, Patient Global Impression of Change (PGIC), and the Neuro QoL Upper Extremity. About LosmapimodLosmapimod is a selective p38α/β mitogen activated protein kinase (MAPK) inhibitor. Fulcrum exclusively in-licensed losmapimod from GSK following Fulcrum’s discovery of the role of p38α/β inhibitors in the reduction of DUX4 expression and an extensive review of known compounds. Although losmapimod had never previously been explored in muscular dystrophies, it had been evaluated in more than 3,600 subjects in clinical trials across multiple other indications with no safety signals attributed to losmapimod. Losmapimod has been granted U.S. Food and Drug Administration (FDA) Fast Track designation and Orphan Drug Designation for the treatment of FSHD. About FSHDFSHD is a serious, rare, progressive and debilitating disease for which there are no approved treatments. It is characterized by fat infiltration of skeletal muscle leading to muscular atrophy involving primarily the face, scapula and shoulders, upper arms, and abdomen. Impact on patients includes relentless and accumulating muscle and functional loss impacting their ability to perform activities of daily living, loss of upper limb function, loss of mobility and independence, and chronic pain. FSHD is one of the most common forms of muscular dystrophy and has an estimated patient population of 30,000 in the United States alone. 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 two lead programs in clinical development are losmapimod, a small molecule in development for the treatment of facioscapulohumeral muscular dystrophy (FSHD), and pociredir, a small molecule designed to increase expression of fetal hemoglobin and in development 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. Forward-Looking StatementsThis 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 fact, contained in this press release are forward-looking statements, including express or implied statements regarding suspending losmapimod development and the future of the program; completing a full evaluation of the REACH data and sharing the same; intended use of cash and cash equivalents and marketable securities; further advancement of pociredir and Fulcrum’s earlier stage program for DBA and other discovery programs; 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 continued development of losmapimod; resuming development of losmapimod following an unsuccessful Phase 3 trial; sufficiency of Fulcrum’s cash resources; ; Fulcrum’s ability to advance any earlier stage product candidates in or into clinical trials; initiating and enrolling clinical trials on the timeline expected or at all; 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 any product candidates; obtaining and maintaining necessary approvals from the FDA and other regulatory authorities;; managing expenses; managing executive and employee turnover; 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: Chris CalabreseLifeSci Advisors, LLCccalabrese@lifesciadvisors.com917-680-5608

Clinical ResultPhase 2Orphan DrugPhase 3Fast Track

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
Acute Coronary Syndrome	Phase 1	RO	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Phase 1	TW	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Phase 1	UA	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Phase 1	AU	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Phase 1	BE	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Preclinical	RU	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Preclinical	BG	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Discovery	CZ	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Discovery	CA	GSK Plc	03 Jun 2014
Acute Coronary Syndrome	Discovery	IT	GSK Plc	03 Jun 2014

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05397470 (REACH, GlobeNewswire) Manual	Phase 3	Muscular Dystrophy, Facioscapulohumeral	260	Losmapimod 15 mg	xfyoznuuds(qsmytyuwxq) = bppopeaksd gfkapcutuk (uaiknuarli ) View more	Negative	12 Sep 2024
				Placebo	xfyoznuuds(qsmytyuwxq) = hgksfmznhy gfkapcutuk (uaiknuarli ) View more
NCT04003974 (FSHD \| ReDUX4, CTgov)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	80	Placebo oral tablet	jxrrsgjvbp(acerpcgzne) = xqdhzgaczw tpwczqqphw (ppmfwznrzf, kjtzshhxme - fymksiblhr) View more	-	10 Jul 2024
NCT04511819 (LOSVID, CTgov)	Phase 3	COVID-19	52	Placebo oral tablet	tzsrilycoh(ytcbvsjcxg) = qrztgxtcca zeqsflwmgd (fgycbuetsw, ztibndppdf - englmrhzvu) View more	-	13 Mar 2024
AAN2023	Phase 2	Muscular Dystrophy, Facioscapulohumeral	-	Losmapimod 15 mg	todzilzpln(xoflzqxven) = cjkqblpcmk ttphmnrqph (gpjwnrgckr ) View more	Positive	25 Apr 2023
				Placebo	todzilzpln(xoflzqxven) = nbdzlualhd ttphmnrqph (gpjwnrgckr ) View more
NCT04264442 (ReDUX4, MDA2023) Manual	Phase 2	Muscular Dystrophy, Facioscapulohumeral	74	Losmapimod 15 mg (LOS/LOS)	(bvlgmcfhlt) = Fall (22.4%), headache (14.5%), arthralgia (7.9%), and back pain (7.9%) okdvkbgakp (vqhcltsaey ) View more	Positive	19 Mar 2023
				Placebo+Losmapimod 15 mg (PBO/LOS)
ReDUX4 (MDA2022)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	80	Losmapimod 15 mg	zxmgpombqw(mgrllxcrkc) = the losmapimod arm had either improvements or no worsening, particularly in Q1 and Q3 (above shoulder), and Q5 (posterior inferior) bhhyjchgbw (qnoroupxbj )	-	13 Mar 2022
				Placebo
ReDUX4 (MDA2022)	Phase 2	Muscular Dystrophy, Facioscapulohumeral	-	Losmapimod 15 mg	yutmdycquh(jzyqjwjzkj) = dwysigtjyu zlcntzdgle (cejbrcwwkk ) View more	-	13 Mar 2022
				Placebo	yutmdycquh(jzyqjwjzkj) = tjkbrekpto zlcntzdgle (cejbrcwwkk ) View more
NL68539.056.18 (Pubmed \| Br J Clin Pharmacol)	Phase 1	Muscular Dystrophy, Facioscapulohumeral	-	Losmapimod 7.5 mg	etypbopazl(lrtmxmwahj) = were mild and self-limited mqxqaqmbwt (qvxumvnryc )	-	30 Apr 2021
				Losmapimod 15 mg
NCT04003974 (ReDUX4, Corporate Publications) Manual	Phase 2	Muscular Dystrophy, Facioscapulohumeral DUX4-driven gene Expression	29	Losmapimod	kttltpnuhq(iotnpdljxc) = Losmapimod arm:-38 fold（in 3 muscle biopsies pts）；+3.7 fold（in all 15 pts); Placebo:-5.4 fold（in 5 muscle biopsies pts）；+2.8 fold（in all 14 pts） zluasiwzly (fknwoowmqj )	Positive	11 Aug 2020
				Placebo
AAN2020	Phase 1	Muscular Dystrophy, Facioscapulohumeral DUX4	-	Losmapimod 7.5 mg	(wbxoniwkmo) = mlswqtfwni huwicjjepe (qjipyytwoj )	Positive	14 Apr 2020
				Losmapimod 15 mg	(wbxoniwkmo) = ggtrbkcvig huwicjjepe (qjipyytwoj )

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