Following clinical failures in multiple indications, a p38 kinase inhibitor developed by Glaxosmithkline plc has found a new champion in Fulcrum Therapeutics Inc., which has licensed it for the potential treatment of facioscapulohumeral muscular dystrophy (FSHD), a genetic muscle disorder. After securing an exclusive license for the drug in exchange for granting GSK "a high single-digit" percentage ownership of its company, Fulcrum is planning to start a phase IIb study of the drug, called losmapimod, in patients with FSHD at multiple sites in the U.S. and Europe in mid-2019.
Fulcrum's president and CEO, Robert Gould, said the asset "has the potential to become the first approved therapy that targets the root cause of FSHD," expression of the gene double homeobox protein 4, or DUX4. Gould said his team also believes it may have the power "to slow or halt the progressive muscle weakness that characterizes the condition, which would significantly improve patients' quality of life."
FSHD, a progressive, degenerative disorder estimated to affect about one in 8,333 to one in 20,000 people globally, is one of the most common muscular dystrophies. Characterized by muscle weakness and wasting around the face, shoulder blades and upper arms, its signs and symptoms usually appear in adolescence, according to the National Library of Medicine. There are no known cures, but symptoms are sometimes treated with physical therapy, albuterol to increase muscle mass, surgery and other interventions.
Though GSK evaluated losmapimod in more than 3,500 healthy volunteers and patients across 24 clinical trials, it never tested the drug in muscular dystrophies, Fulcrum said. But its potential for the treatment of FSHD was uncovered by the firm's in-house product engine, which identified inhibitors of p38-alpha/beta mitogen activated protein kinase as being potent inhibitors of DUX4.
That insight arrived as far back as last year, when the company successfully raised an $80 million series B financing, led by Foresite Capital. The drug has since been validated in preclinical testing in patient-derived cell models, an evaluation that turned up "precise and potent down-regulation of DUX4 expression and restoration of a healthy muscle phenotype without an effect on myogenesis," Fulcrum said. (See BioWorld, Sept. 6, 2018.)
With the licensing now complete, Fulcrum joins the only other company with a midstage FSHD program: Cambridge, Mass.-based Acceleron Pharma Inc., shares (NASDAQ:XLRN) of which rose 3.7% to close at $41.55 on Tuesday. Acceleron is testing another class of drug, the myostatin inhibitor ACE-083, in the second part of a phase II FSHD trial, expected to read out in the second half of 2019. (See BioWorld, April 22, 2019.)
The timing of Fulcrum's intended study is unknown but, in a statement, Gould said his team would "work urgently to advance the compound through the clinic." Furthermore, the company told BioWorld that a clinical trial readiness study is underway with expectations that it will provide insights to guide the phase IIb work.
Under terms of its deal with GSK, Fulcrum obtained global development and commercialization rights to losmapimod as well as existing drug substance and drug product materials for use in its clinical trials. It also received a right of reference to INDs filed with the FDA relating to losmapimod and an exclusive license to all related patents and data, which it said "build on Fulcrum-generated intellectual property." GSK will be eligible to receive future milestone payments and royalties on losmapimod sales, should the program reach market.
GSK, which first disclosed losmapimod's existence in its pipeline in 2005, according to Cortellis, has tested the drug's potential as a treatment for rheumatoid arthritis, depression, atherosclerosis, neuropathic pain, acute coronary syndrome and chronic obstructive pulmonary disease. It finally shelved the program after a trial in focal segmental glomerulosclerosis. The out-licensing arrives amid an ongoing rebuild of the London-based company's pipeline.
Fulcrum's existence dates back to 2015, though it wasn't formally launched until July 2016, when it debuted as a spinout of Third Rock Ventures LLC with a $55 million series A to pursue its goal of restoring balance in gene expression, referenced in the company's name. (See BioWorld Today, July 20, 2016.)