SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of report (Date of earliest event reported): October 4, 2019
Fulcrum Therapeutics, Inc.
(Exact Name of Registrant as Specified in Charter)
(State or Other Jurisdiction
26 Landsdowne Street
|(Address of Principal Executive Offices)||(Zip Code)|
Registrants telephone number, including area code: (617) 651-8851
(Former Name or Former Address, if Changed Since Last Report)
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Securities registered pursuant to Section 12(b) of the Act:
Title of each class
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Common stock, par value $0.001
|FULC||Nasdaq Global Market|
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
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|Item 7.01|| |
Regulation FD Disclosure.
On October 4, 2019, Fulcrum Therapeutics, Inc. (the Company) issued a press release announcing data from its Phase 1 clinical trial of losmapimod in facioscapulohumeral muscular dystrophy patients and healthy volunteers. The Phase 1 data were presented on October 4, 2019 in an oral presentation at the 24th International Annual Congress of the World Muscle Society in Denmark, Copenhagen. A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K, and a copy of the materials to be presented during the oral presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K.
The information in Item 7.01 of this Current Report on Form 8-K, including Exhibits 99.1 and 99.2, is intended to be furnished and shall not be deemed filed for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the Exchange Act), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
|Item 9.01|| |
Financial Statements and Exhibits.
The following exhibits are furnished herewith:
|99.1||Press Release issued by the Company on October 4, 2019|
|99.2||Presentation by the Company on October 4, 2019|
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|FULCRUM THERAPEUTICS, INC.|
|Date: October 4, 2019||By:|
|Name:||Robert J. Gould|
|Title:||President and Chief Executive Officer|
Fulcrum Therapeutics Announced Results of Phase 1 Clinical Trial of Losmapimod in FSHD
Data presented in an oral presentation at World Muscle Society meeting highlighted safety, tolerability, pharmacokinetics and target engagement of losmapimod in patients with facioscapulohumeral dystrophy.
CAMBRIDGE, Mass., October 4, 2019 Fulcrum Therapeutics, Inc. (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases, today announced preliminary results of a Phase 1 clinical trial of losmapimod to treat the root cause of facioscapulohumeral dystrophy (FSHD). Losmapimod is a selective p38α/b mitogen activated protein kinase (MAPK) inhibitor. Fulcrum exclusively in-licensed losmapimod following Fulcrums discovery that the inhibition of p38α/b reduced expression of the DUX4 gene in muscle cells derived from patients with FSHD, a disease which is caused by the mis-expression of DUX4 in skeletal muscle. Results were presented today by Michelle Mellion, MD, medical director at Fulcrum Therapeutics, in an oral presentation during the 24th International Annual Congress of the World Muscle Society in Copenhagen, Denmark.
Losmapimod has previously been shown to have adequate safety and tolerability in over 3,500 patients and healthy volunteers across multiple indications, with no safety signals attributed to the drug in those trials. Until now, losmapimod had not been tested in patients with FSHD, nor was it known if it was muscle-penetrant in humans. said Dr. Mellion. The preliminary results from our Phase 1 clinical trial of losmapimod in patients with FSHD indicate that losmapimod was generally well-tolerated and achieved dose-dependent concentrations in plasma and muscle believed to be adequate for efficacy based on preclinical pharmacology studies.
The primary objective of the trial was to investigate the safety and tolerability of losmapimod in healthy volunteers and in FSHD patients. The secondary objective was to evaluate repeated dose pharmacokinetics (PK) and target engagement (TE) in FSHD patients. In the first cohort, 10 healthy volunteers were randomized to a single oral dose of losmapimod (n=8) 7.5 mg followed by a single oral dose of 15 mg after a wash out period or to single oral dose placebo (n=2) in both dosing periods. In the second cohort, 15 FSHD patients were randomized and treated with placebo (n=3) or losmapimod 7.5 mg (n=6) or 15 mg (n=6) taken orally twice daily for 14 days.
Losmapimod was well tolerated with no serious adverse events (SAEs) reported. Similar tolerability, safety and PK were observed in healthy volunteers and patients with FSHD. Treatment with losmapimod demonstrated dose-dependent PK and TE in blood. This was consistent with previously reported data from more than 3,500 patients treated with losmapimod across multiple other indications. FSHD patients treated with losmapimod also achieved dose-dependent concentrations in skeletal muscle, with a muscle to plasma exposure ratio of approximately 1:1. The losmapimod 15 mg dose taken orally twice daily demonstrated sustained drug concentrations that in preclinical models with human FSHD myotubes resulted in a robust reduction of DUX4-driven gene expression. Analysis of target engagement in muscle is ongoing. These data support the selection of the 15 mg dose of losmapimod taken orally twice daily in the Companys ongoing Phase 2b placebo-controlled 24-week clinical trial, referred to as ReDUX4, as well as its ongoing Phase 2 open label-study of losmapimod for the treatment of patients with FSHD.
There are currently no approved treatment options available for patients with FSHD. They face a lifetime of accumulating disability that can severely impact their day-to-day function and quality of life, said Diego Cadavid, MD, senior vice president of clinical development at Fulcrum Therapeutics. We are very encouraged by these results and are working rapidly to advance our development program for losmapimod.
FSHD is characterized by progressive skeletal muscle loss that initially causes weakness in muscles in the face, shoulders, arms and trunk, and progresses to weakness throughout the lower body. Skeletal muscle weakness results in significant physical limitations, including an inability to smile and difficulty using arms for activities, with many patients ultimately becoming dependent upon the use of a wheelchair for daily mobility.
FSHD is caused by mis-expression of DUX4 in skeletal muscle, resulting in the presence of DUX4 proteins that are toxic to muscle tissue. Normally, DUX4-driven gene expression is limited to early embryonic development, after which time the DUX4 gene is silenced. In people with FSHD, the DUX4 gene is turned on as a result of a genetic mutation. The result is death of muscle and its replacement by fat, leading to skeletal muscle weakness and progressive disability. There are no approved therapies for FSHD, one of the most common forms of muscular dystrophy, with an estimated patient population of 16,000 to 38,000 in the United States alone.
Losmapimod is a selective p38α/b mitogen activated protein kinase (MAPK) inhibitor that was exclusively in-licensed by Fulcrum Therapeutics following Fulcrums discovery of the role of p38α/b inhibitors in the reduction of DUX4 expression and an extensive review of known compounds. Utilizing its internal product engine, Fulcrum discovered that inhibition of p38α/b reduced expression of the DUX4 gene in muscle cells derived from patients with FSHD. Although losmapimod has never previously been explored in muscular dystrophies, it has been evaluated in more than 3,500 subjects in clinical trials across multiple other indications, including in several Phase 2 trials and a Phase 3 trial. No safety signals were attributed to losmapimod in any of these trials. Fulcrum is currently conducting Phase 2 trials investigating the safety, tolerability, and efficacy of losmapimod to treat the root cause of FSHD.
About Fulcrum Therapeutics
Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined diseases in areas of high unmet medical need, with an initial focus on rare diseases. Fulcrums proprietary product engine identifies drug targets which can modulate gene expression to treat the known root cause of gene mis-expression. Please visit www.fulcrumtx.com.
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, including statements regarding the development status of the Companys product candidates and the timing of availability of clinical trial data.. All statements, other than statements of historical facts, contained in this press release, including statements regarding the Companys strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. 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 managements 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 Fulcrums ability to obtain and maintain necessary approvals from the FDA and other regulatory authorities; continue to advance its product candidates in clinical trials; replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of losmapimod and its other product candidates; advance the development of its product candidates under the timelines it anticipates in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys 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 the Companys most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent the Companys views as of the date hereof and should not be relied upon as representing the Companys views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Companys views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so.
Berry & Company Public Relations
Stern IR, Inc.
Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement EudraCT number: 2018-004754-19 Michelle L. Mellion1, Lucienne Ronco1, Drew Thompson1, Michelle Hage1, Sander Brooks2, Emilie van Brummelen2, Lisa Pagan2, Umesh Badrising3, William Tracewell1, Shane Raines1, Baziel van Engelen4, Geert Jan Groeneveld2, Diego Cadavid1 1Fulcrum Therapeutics, Cambridge, MA, USA 2Centre for Human Drug Research (CHDR), Leiden, NL 3Leiden University Medical Centre, Leiden, NL 4Radboud University Medical Centre, Nijmegen, NL WMS2019 Congress Exhibit 99.2
Disclosures Stock/Stock Options in Biogen, Vertex Pharmaceuticals, and Fulcrum Full-time employee as Medical Director at Fulcrum Therapeutics
Aberrant expression of DUX4 causes FSHD Healthy FSHD DUX4 FSHD1 <10 repeats FSHD2 >8-20 repeats + SMCHD1/DNMT3B mutations DUX4 is a homeodomain transcription factor
Losmapimod, a selective p38α/β MAPK inhibitor, reduced DUX4 expression in FSHD myotubes n=8 n=3 HSP27 is a substrate of p38 MAP kinase pathway MBD3L2 is a DUX4-target gene
Objectives Primary Objective: Initial Safety and Tolerability in FSHD Note: Safety and tolerability previously demonstrated in 25 studies in over 3,500 healthy adult volunteers and patients across other multiple indications (see poster P.44, Cadavid D et al). Secondary Objective: PK and Target Engagement in blood and muscle Note: Muscle biopsies performed at baseline and on treatment at approx. Cmax in FSHD patients
Study design Part A: N=10 Healthy Volunteers; Single Ascending Dose; 4:1 randomization Single dose 2 placebo: 8 losmapimod 7.5mg Single dose 2 placebo: 8 losmapimod 15 mg Wash-out Note: Lower extremity muscle biopsies were performed in normal appearing muscles identified by MRI Part B: N=15 FSHD1 Patients; Double Blind; 2:2:1 Randomization; Placebo Controlled; Repeated Dose Placebo twice daily (n=3) Losmapimod 7.5 mg twice daily (n=6) Muscle Biopsy Muscle biopsy Losmapimod 15 mg twice daily (n=6) 14-day Placebo Controlled Treatment Period
Demographics Part A Healthy Volunteers Part B FSHD1 Gender (M:F) 6M:4F 6M:9F Age Mean SD Min/Max 31.4 17.2 22/64 41.6 11.6 26/64 BMI Mean SD Min/Max 22.7 2.4 19.6/27.2 24.8 3.0 20.7/31.4 Ricci (FSHD Disability Score) Mean SD Min/Max N/A 2.6 0.7 1.5/4
Safety and tolerability No Serious Adverse Events (SAE) No clinically significant changes in vital signs, laboratory analyses, ECG or urinalysis Muscle needle biopsies were well tolerated Adverse Effects (AE) (n) Part A Somnolence (5) Headache (4) Dizziness (2) Part B Headache (4) Backpain (3) Fatigue (3) Constipation (1) Dizziness (1) Pain (1)
Assessment of Pharmacokinetics (PK)
Similar PK profile in HV and FSHD1 subjects
Accumulation observed with repeated dosing Cmax (ng/ml) AUC0-12 (ng*hr/ml) Tmax (hr) mean (SD) CV % mean (SD) CV % median Part B (Day 1) 7.5 mg 40.8 (21.1) 51.7 201.5 (74.6) 37.0 4.5 15 mg 85.0 (16.7) 19.7 410.2 (50.3) 12.0 4.6 Part B (Day 14) 7.5 mg 56.3 (14.2) 25.3 394.6 (92.8) 23.5 4.5 15 mg 100.5 (34.4) 34.3 632.7 (175.4) 27.7 5.0 Accumulation Ratio: 7.5 mg: 2.0 15 mg: 1.5
Robust In Vitro inhibition of p38 activity at ≥30 ng/mL ~30 ng/mL (~78 nM)
Losmapimod 15 mg BID sustained concentrations for robust target engagement Pre-treatment muscle biopsy On-treatment muscle biopsy
Losmapimod showed dose dependent concentrations in muscle Muscle Plasma N Mean ng/g (SD) CV(%) Mean ng/ml (SD) CV(%) 7.5 mg 6 42.1 (10.5) 24.9 52.6 (15.7) 30.2 15 mg 6 63.6 (34.0) 53.5 75.0 (42.5) 56.7 Ratio to Plasma approximately 1:1
Assessment of Pharmacodynamics (PD)
Losmapimod: in vivo PK/PD in rodents Muscle:plasma exposure ratio is approximately 1 in rodents Losmapimod inhibits p38 in muscle rapidly following acute dosing.
Sustained and dose dependent target engagement in blood 15 mg PO BID dose resulted in greater inhibition of p38 activity Note: measurement of TE in on-treatment muscle biopsy is ongoing
In Vitro inhibition of p38 MAPK resulted in a reduction of DUX4 activity and muscle cell death ~30 ng/mL (~78 nM)
Conclusions Achieved clinically relevant, dose-dependent concentrations in muscle Similar exposures in plasma and muscle as shown in pre-clinical models Data supports the design of the ongoing Phase 2 clinical trials currently enrolling Open label 64-week study (NCT 04004000) Placebo-controlled 24-week study ReDUX4 (NCT 04003974) Losmapimod was safe and well tolerated in FSHD patients 15mg PO BID dose showed sustained and robust target inhibition
Acknowledgements Healthy volunteers and FSHD patients who participated in the study Fulcrum’s phase 1 study FIS 001-2018 management team Centre for Human Drug Research (CHDR) Fulcrum’s FSHD Clinical Advisory Board Centre for Human Drug Research (CHDR) Leiden University Medical Center Radboud University Medical Center Vendors: MRI imaging analysis vendor AMRA PK vendor PPD Target engagement vendor CBI