This designation offers Fulcrum Therapeutics financial support to develop this treatment, as well as a waiver from the FDA’s fees and seven years of marketing exclusivity in the U.S. in the event of regulatory approval.
“We are pleased to have been granted Orphan Drug Designation for losmapimod in FSHD as it underscores the critical need for treating this rare muscular dystrophy that has no approved therapies,” Robert J. Gould, PhD, Fulcrum’s president and CEO, said in a press release.
Fulcrum also announced the publication of a U.S. patent (10,537,560) covering the use of other investigational treatments with losmapimod’s mechanism of action in FSHD. The patent now issued joins a previous one (10,342,786), issued in July 2019, that covers losmapimod’s use for the same indication. Protection in both patents runs until 2038.
Losmapimod is a selective inhibitor of p38 alpha and p38 beta. These two proteins belong to a family of enzymes called mitogen-activated protein kinases (MAPKs), which are important for the regulation of DUX4 activity.
Early experiments using patient-derived muscle cells and animal models demonstrated that losmapimod was able to inactivate DUX4 and its target genes in a dose-dependent manner without affecting normal muscle regeneration.
The preliminary results of a Phase 1 clinical trial of losmapimod in people with FSHD, announced by Fulcrum last year, showed the therapy was generally well-tolerated and had positive results. Treatment with losmapimod achieved clinically-relevant concentrations in the blood and muscle, which — based on preclinical studies — are believed to have a therapeutic effect.
Based on the promising data, Fulcrum moved the treatment forward into two Phase 2 clinical trials currently ongoing: a Phase 2b study celled ReDUX4 (NCT04003974) and an open-label pilot study (NCT04004000).
ReDUX4 is recruiting by invitation at clinical sites in the U.S., with other locations in Canada and the EU. More information about eligibility criteria, contacts, and location can be found here.
The trial expects to enroll 66 participants, ages 18-65, with a confirmed diagnosis of FSHD1 — the most common form of this muscular dystrophy, caused by DNA deletions in a part of chromosome 4 called the D4Z4 region. The study will evaluate the safety and efficacy of a daily dose of 30 mg of losmapimod versus a placebo, both given for 24 weeks.
The primary goal is to determine losmapimod’s ability to block the abnormal activity of the DUX4 gene — considered the root cause of FSHD — in skeletal muscles, which are responsible for voluntary movement.
Normally, DUX4 is turned off in skeletal muscles. But in patients with FSHD, the gene is abnormally reactivated due to mutations or other DNA alterations. This is thought to adversely impact the activity of other genes, resulting in the loss of muscle fibers and FSHD symptoms.
ReDUX4 also will assess the treatment’s safety and tolerability, as well as losmapimod’s levels in the blood and skeletal muscle, and its ability to interact with its target. Top-line results are expected in the second half of 2020.
The other Phase 2 trial will be evaluating the safety and efficacy of the therapy, and examining biomarker changes after treatment with 30 mg of losmapimod over a period of 52 weeks, or one year.
Its primary goal is to assess the safety and tolerability of long-term dosing with losmapimod. Secondary goals include target engagement of losmapimod in the blood and skeletal muscles, along with evaluating its distribution and availability in the body.
This trial is ongoing in the Netherlands and is expected to be completed by January 2021.
“We believe losmapimod represents a promising, novel approach to treat the known root cause of FSHD and remain on-track to announce data from the Phase 2b ReDUX4 clinical trial in the third quarter of 2020,” Gould said.
“Our recently issued patent also expands our intellectual property protection relating to the use of other clinical-stage p38 inhibitors for the treatment of FSHD, strengthening our position as a leader in the treatment of genetically defined diseases,” he added.
Although losmapimod is being tested for muscular dystrophies for the first time, it has already been shown to have adequate safety and tolerability. The medicine has been tested in more than 3,500 patients and healthy volunteers in clinical trials for other indications, Fulcrum says.