With a phase IIb readout coming in the third quarter of 2020, Cambridge, Mass.-based Fulcrum Therapeutics Inc. might be set up for a win in facioscapulohumeral muscular dystrophy (FSHD), a genetic muscle disorder for which there’s no treatment.

Fulcrum is testing losmapimod, a p38 kinase inhibitor licensed from Glaxosmithkline plc (GSK), of London. In the hands of GSK, the candidate fell short in more than one indication, but Fulcrum thought highly enough of the compound in April 2019 to grant GSK "a high single-digit" percentage ownership of its company. Losmapimod is said to attack the root cause of FSHD – expression of the gene double homeobox protein 4, or DUX4 – which means it could slow or halt the progressive muscle weakness that characterizes the condition.

GSK has “treated nearly 3,500 subjects with losmapimod across multiple clinical trials,” including one phase III experiment, Fulcrum acknowledged in SEC paperwork, but the pharma giant has not studied the drug in patients with FSHD or any other muscle disorder. “We have conducted extensive preclinical testing of losmapimod in patient-derived tissue-relevant cell models, and have observed that losmapimod selectively reduced DUX4-driven gene expression and restored a healthy gene expression signature with minimal impact on healthy human muscle cells or other cell types,” the company said.

FSHD affects more than 500,000 people worldwide, and represents one of the more common muscular dystrophies. It’s of concern to the FDA, which will convene a patient-focused drug development (PFDD) meeting on April 21 “to obtain patient perspectives on specific diseases and their treatments. The demand from disease advocacy groups to have the meetings quickly exceeded the agency’s capacity, and so the FDA set up a mechanism for groups to apply to organize ‘externally led’ PFDD meetings.” The disease typically manifests in the early teenage years with the loss of muscles in the face, shoulders, upper arms, legs or core, and can spread to any muscle. Around 20% of patients will need a wheelchair by age 50. More than 70% experience debilitating pain and fatigue.

Odds may favor losmapimod, since DUX4 expression is known to be highly sensitive to p38 inhibitors, and the drug reaches muscle tissues nicely. An oral 15-mg twice-daily dose yielded sustained concentrations and target engagement in skeletal muscles in the phase I study, so the same dose is being used in the phase IIb effort. Preclinical evidence has shown that losmapimod dose can suppress DUX4 expression by more than 50% at trough in vitro. It’s possible that Fulcrum could gain accelerated approval based on the DUX4 biomarker. Wainwright analyst Andrew Fein likes the story, and wrote in a March 6 report that a key opinion leader consulted by his firm noted that there is “nothing structurally wrong with FSHD muscles, which upon treatment may improve over a short period of time,” and side effects of the losmapimod are well-characterized, thanks to the large body of clinical data.

Fulcrum CEO Robert Gould, during a March 5 conference call with investors related to earnings, offered more color. He said his firm “did a phase Ia study in which we verified the pharmacokinetic [PK] properties at 7.5- and 15-mg single doses in healthy volunteers and verified that, in fact, we could achieve plasma concentrations that were equivalent to [those reported by] GSK. We then repeated these studies after 14 days of dosing in FSHD patients because GSK had previously not evaluated [the drug] in muscular dystrophy patients. We saw the same PK properties in FSHD patients as we saw in healthy volunteers. Furthermore, we wanted to ensure that losmapimod penetrated into the muscle of FSHD patients and achieved target engagement in the muscle of FSHD patients. So we had verified target engagement in the blood of healthy volunteers and in the blood of FSHD patients, and now we've verified that the drug is highly penetrating into muscle – essentially equivalent drug concentrations in the muscle of FSHD patients as we see in the plasma of those patients. We achieved the same level of target engagement in the muscle as we achieved in the blood.”

Recent failure

A recent failure in the space came in September 2019, when Acceleron Pharma Inc., of Cambridge, Mass., disclosed that its ACE-083 for FSHD missed functional secondary endpoints in a phase II trial. The drug was designed to block proteins in the TGF-beta family, such as myostatin, which are responsible for reducing muscle strength and growth. Although ACE-083 demonstrated a robust, statistically significant increase in mean total muscle volume – the primary endpoint of the trial – the increase failed to translate to statistically significant improvements in functional tests, and Acceleron said it would conduct no further trials.

After the FSHD blowup, Acceleron continued testing ACE-083 in a phase II project focused on Charcot-Marie-Tooth (CMT) disease. The study was set up to assess change in fat fraction and muscle volume, six-minute walk distance, 10-meter walk-run time, patient-reported outcomes, and safety and tolerability. ACE-083 failed in CMT, too. Acceleron reported March 9 that the drug turned up a statistically significant increase in mean total muscle volume, the trial’s primary endpoint, but such rise did not translate to statistically significant improvements in any of the functional or quality of life secondary endpoints when compared to placebo. Acceleron has quit development of the prospect entirely.

In late 2019, Fulcrum and might-have-been competitor Acceleron joined forces, inking a collaboration and license agreement to identify small molecules designed to modulate specific pathways associated with a targeted indication in the pulmonary disease space. Fulcrum collected an up-front payment of $10 million as well as reimbursement for R&D costs. The company also stands to bank research, development and commercial milestone payments of up to $295 million for a first product commercialized and up to a maximum of $143.5 million in other milestone rewards for any subsequent products commercialized. The deal includes tiered royalty payments in the mid-single-digit to low double-digit range on net sales.

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