Leo H. Wang, MD, PhD, FAAN, associate professor of neurology, University of Washington Medical Center, talked about the phase 2 study of losmapimod for facioscapulohumeral muscular dystrophy presented at the 2023 AAN Annual Meeting.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of double homeobox, 4 (DUX4), causing maladaptive tissue remodeling which results ultimately in progressive motor disability.1 Losmapimod (Fulcrum Therapeutics), designed as a treatment for FSHD, is an orally active, selective, small molecule inhibitor of p38α/β that is being currently investigated in clinical trials.
Recent long-term findings from the phase 2b ReDUX4 trial (NCT04003974) demonstrated that treatment with losmapimod slowed disease progression and showed maintenance of effect through a 96-week period in patients with FSHD. The findings were presented as an abstract presentation by lead author Leo H. Wang, MD, PhD, associate professor of neurology, University of Washington Medical Center, at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts.1
In the study, 80 adult patients between the ages of 18 and 65 years with genetically confirmed FSHD1 were randomly assigned 1:1 to 15 mg losmapimod or placebo. Of these, 76 (99%) entered the open-label extension (OLE) after 48 weeks, and 74 (97%) were enrolled at week 96. Patients were given the study drug in the OLE, and had durability of treatment response assessed through upper extremity function with Reachable Workspace (RWS).
Wang, associate professor of neurology, University of Washington Medical Center, sat down with NeurologyLive® at the meeting to provide an overview of the history of the neuromuscular disease. He also talked about the findings from the study presented at the meeting and the main pinpoint that was reported.
NeurologyLive®: What was the focus of the abstract regarding the phase 2 trial of losmapimod that was presented at AAN 2023?
Leo H. Wang, MD, PhD, FAAN: The abstract that I presented at AAN 2023 was on behalf of a group of investigators who participated in the phase 2 trial of losmapimod which was funded by Fulcrum Therapeutics, a company that's been studying FSHD.
A little bit more about FSHD: it was first described in the 1880s by French neurologists [Louis Landouzy and Joseph Dejerin] who had a pretty accurate description of the disease.2 [They described it as] affecting the face first, then the scapula, thus people would have problems raising their arms. It then goes into the trunk and the legs. It was described as a muscle disease, and a disease that affected people through generations, therefore inherited. We found that disease is inherited but at times, there are a lot of patients who don't have the disease, but are able to pass it on, and skip generations. This was also described by the French in the 1860s and 70s. It's a disease where a transcription factor that's normally dormant, suddenly gets turned on in muscles. When it gets turned on, it causes toxicity in the muscle and causes muscles to fail.
What is the mechanism of action of the small molecule, losmapimod, in preventing muscle failure?
What Fulcrum has discovered is that there's this small molecule that is able to get into the muscle and able to prevent the ducts from turning on more. That seems to be the mechanism by which it prevents muscle death from turning on, this transcription factor. What’s really nice about this drug is that it is orally available, you take it twice per day. It's been tried in other studies, and it's been found to be safe. That's something that that is always good to know.
However, the study that we're talking about, at the 96-week time point, is the longest study of this drug. I think what's most important is that this drug is orally available. It's safe in patients up to 96 weeks as of the release of this data. It is a phase 2 trial and it had about 80 patients in both the placebo arm and the losmapimod arm combined, about 40 patients in each. It failed its primary endpoint in the phase 2, but there were some signs that it was working in this OLE of about 76 patients. Four patients decided not to participate in it. This allowed us to look at a longer time point in terms of whether it helped patients or not. The patients were balanced between the placebo arm and the losmapimod arm in terms of severity, as well as in terms of the genetics.
It had great retention in the OLE. It was rare that patients did not tolerate or want to participate in it. This just showed the commitment of the patients to the study. There were no drug related severe adverse events up to 96 weeks as of this data cut so that was reassuring. The most common treatment emergent adverse events were false headaches, joint aches, back pain, pain in the extremities, nasal pharyngitis, and pyrexia.
What is the key point that you are reported from the abstract study?
The main thing that we're reporting in this abstract was the Reachable Workspace, a newer tool that utilizes the Kinect sensor that is on the Microsoft Xbox. It measures a sense of the volume, the relative surface area that a person can reach. It’s looking at range of motion. What it was measuring was, over time, how did people do in treatment versus placebo as patients went into OLE. I think the main gist of it seems to be that the RWS was stable in the treatment group and in the placebo control period, as well as the OLE period. Maybe the placebo arm got a little bit worse over time in the placebo control period, but then it stabilized once it got to the OLE. This is looking at the dominant arm, and looking at it was a little bit of weight attached to it.
Based on this data, the company has decided to focus on this as their primary outcome and to test it in the phase 3 study called REACH. There are some things that we're still trying to figure out in terms of the durability of the effect, and whether it's reproducible. As an investigator, we're very pleased that Fulcrum has decided to continue and to test whether this will help our patients. Our hope is that it does make a difference, it allows either in maintenance of strength in our patients or possibly improvement in younger patients so that makes a difference in their lives.
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Transcript edited for clarity.
Editor’s Note: Leo H. Wang disclosed that he participates as a consultant and is on the steering committee for Fulcrum Therapeutics.