Fulcrum FSHD Drug Not Superior to Placebo in Meeting Primary Endpoint in Interim Analysis of Study

Rare Daily Staff

Fulcrum Therapeutics said results from a pre-specified interim analysis of the primary endpoint of its phase 2 ReDUX4 trial in subjects with facioscapulohumeral muscular dystrophy showed its experimental drug losmapimod was no more effective at achieving the study’s primary endpoint than a placebo.

The company’s stock lost 48 p to $8.90 on Tuesday, August 11 following the news.

The primary endpoint of the study is a reduction from baseline of DUX4-driven gene expression in affected skeletal muscle after subjects have been treated with losmapimod or placebo. Secondary and exploratory endpoints were not assessed as part of this analysis.

Results from the interim analysis in the first 29 randomized subjects indicate that DUX4-driven gene expression did not show a separation from placebo at 16 weeks. 

The company nevertheless did see positive signs to pin their hopes on. Patients with the highest pre-treatment DUX4-driven gene expression in their muscle biopsy sample showed a 38-fold reduction in DUX4-driven gene expression following treatment with losmapimod compared to a 5.4 fold reduction with placebo.

Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive and disabling disease for which there are no approved treatments. FSHD is caused by aberrant expression of DUX4 in skeletal muscle, resulting in the inappropriate presence of the DUX4 protein, which causes the death of muscle and its replacement by fat.

Losmapimod is a selective p38α/β mitogen activated protein kinase inhibitor. Fulcrum exclusively in-licensed the drug from GlaxoSmithKline following its discovery of the role of p38α/β inhibitors in the reduction of DUX4 expression and an extensive review of known compounds. Fulcrum discovered that inhibition of p38α/β reduced expression of the DUX4 gene in muscle cells derived from patients with FSHD.  

In preparatory studies, the range of DUX4 expression levels within affected muscles throughout a patient’s body have been shown to be relatively stable over time at the site of a muscle biopsy.

“Preliminary evidence from our interim analysis suggests that muscles with higher DUX4-driven gene expression in pre-treatment biopsies show greater reduction of DUX4-driven gene expression following treatment with losmapimod compared to placebo. These results, which provide evidence of the ability of losmapimod to reduce DUX4-driven gene expression, are very encouraging,” said Robert Gould, president and CEO of Fulcrum. “This initial data represents the first time a treatment is being evaluated to impact the root cause of FSHD in a placebo-controlled trial and are helping to inform our longer-term clinical strategy for losmapimod.”

The company said it remains on track to share topline results on the primary endpoint in the first quarter of 2021 and full data, including all secondary and exploratory endpoints, in the second quarter of 2021.

Photo: Robert Gould, president and CEO of Fulcrum