Benefits Seen With Losmapimod ‘First’ for FSHD Trial, Fulcrum Says

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by Forest Ray PhD |

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Losmapimod, a potential oral treatment for facioscapulohumeral muscular dystrophy (FSHD), missed its main goal in a recent Phase 2 clinical trial, but its developer, Fulcrum Therapeutics, sees this as a constructive failure.

Lessons learned will help to shape losmapimod’s continued development, which is supported by the secondary trial goals — and clinically relevant benefits — seen over placebo after almost a year of treatment.

“I think the take-home message is that … losmapimod has the potential to slow or halt disease progression demonstrated by clinical endpoints [goals] and patient-reported endpoints and, in fact, on MRI by looking at structural endpoints,” Chris Morabito, MD, Fulcrum’s chief medical officer, said in an interview with Muscular Dystrophy News Today.

The ReDUX4 trial

Losmapimod’s safety and efficacy were recently tested in the Phase 2b ReDUX4 trial (NCT04003974), whose main goal was to measure changes in activity of the DUX4 gene. The aberrant activity of this gene causes FSHD in more than 90% of all patients.

Although losmapimod’s use ultimately failed to significantly reduce DUX4-driven gene activity, it did result in clinically relevant improvements in secondary measures after 48 weeks, including changes in muscle fat infiltration, and reachable workspace (RWS) — a measure of the range of motion a person has in their upper limbs.

Fulcrum broadly attributes the primary endpoint failure to the wide variation in participants’ starting levels of DUX4 activity, and to the needle biopsy approach used that proved to be too imprecise.

The high variation in starting DUX4 activity, in particular, came as a surprise to Fulcrum, as it contrasted with results obtained in animal models of FSHD.

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Over the course of the trial,” Morabito said, “we continued to see this significant amount of variability. Some patients had levels go up, some patients had levels go down, in both treatment groups. And in the end, there was no difference; in fact, there was no change detected in DUX4 through the course of the study.”

Fulcrum suspects that the biological reasons for this have to do with the variable way in which DUX4 is expressed in muscle cells.

Unlike many other cells, muscle cells contain multiple nuclei (called myonuclei) spread along their length. Only a few of these, however — perhaps between 1 in 1,000 and 1 in 3,000, Morabito estimates — contain active DUX4 at the level leading to FSHD-related alterations. When taking a sample of that muscle tissue, then, location matters.

“It’s actually a rare event for us to be able to go in and sample a myonucleus that will have this aberrant DUX4,” Morabito said. “And then, technically, to do that twice is very challenging — you have to find the exact same muscle, the exact same fiber, and ideally myonuclei that are also expressing DUX4.” 

While this procedure had been relatively easy to perform in animals, he added, it proved “very difficult” to repeat in humans.

Although unexpected, Fulcrum views this finding as a teachable moment.

“That gives us a lot of information about how we think about designing future clinical trials,” Morabito. “It becomes much less about understanding muscle biopsy-detected DUX4-driven gene expression and all about how patients feel and function.”

Unexpected benefits

The bigger surprise to the company and to trial investigators wasn’t the difficulty in measuring DUX4 so much as the improvements seen in other measures of health, such as reachable workspace, fat infiltration, and limb strength.

RWS describes the degree to which a person can fully rotate their arms in multiple directions, while holding an object roughly similar in weight to a plate, meant to simulate the sort of load an individual might experience in daily living.

Importantly about reachable workspace,” Morabito said, “is that it’s been correlated to quality of life quite closely. In fact, significant changes in [RWS] predict the change in one’s ability to be independent to one’s requirement to be dependent on others for activities of daily living.”

Patients taking losmapimod in the ReDUX4 trial improved their RWS, compared with those on a placebo.

Likewise, those on losmapimod experienced significantly less fat infiltration in muscle than did placebo patients, and showed improvements in their shoulder and ankle strength.

“Ultimately, while the biomarker ended up being challenging to measure, we were extremely pleased,” said Brian Stuart, Fulcrum’s CEO. “We did recognize benefit for the first time in a FSHD trial in all these other areas.”

Changes in measures such as in muscle fat fraction were not statistically significant. But investigators continue to monitor for changes that might occur with more time in the trial’s ongoing long-term extension study (NCT04264442).

Notably, nearly all participants elected to continue with, or start on, losmapimod in the extension study.

“Here we have structural evidence, we have clinical evidence in terms of strength, and then we have RWS, or relative surface area, that correlates directly with quality of life and independence, all associated with losmapimod,” Morabito said. “And that directly relates, of course, to how patients feel.”

Next steps

The company is communicating with the FDA regarding how best to proceed, while considering how to apply what’s been learned to future studies.

At this point, our focus is really on finding our path forward with the program. Certainly … the unmet need here is very meaningful,” Stuart said. “Our goal is to be able to progress and make this a treatment that is accessible to patients.”

Fulcrum consulted with FSHD patients when designing the ReDUX4 trial, and intends to do the same in coming trials.

“Patients have said loud and clear that what they are looking for in a medicine to treat their disease is something that slows or halts disease progression,” Morabito said. “You see tantalizing evidence of that in this trial, that go beyond what we could see in a primary endpoint of DUX4-driven gene expression. So our emphasis is going to be on the clinical and functional outcomes.”

Fulcrum remains optimistic that its efforts, and the discoveries made along the way, will result in a much-needed FSHD therapy.

“Muscular dystrophy is an area where there has not been as much clinical development as there should be,” Stuart said. “Being able to derive endpoints that, as we mentioned, could show benefit in such a heterogeneous disease was not simple. It was really the result of a lot of partnership with patients, and with caregivers, and with clinicians, and that has been invaluable.”