Edasalonexent, Potential DMD Therapy in Phase 3 Trial, Seen to Preserve Bone Health in Test in Mice Against Corticosteroid

Catabasis Pharmaceuticals announced new preclinical data showing that, in a mouse model of Duchenne muscular dystrophy (DMD), the small molecule edasalonexent preserved bone health, whereas the corticosteroid prednisolone caused bone loss.

An ongoing double-blind and randomized Phase 3 trial (NCT03703882), called PolarisDMD, is evaluating the effectiveness and safety of oral edasalonexent in boys against placebo. Two children will be randomized to treatment for each child given a placebo in the yearlong study expected to conclude in June 2020.

Edasalonexent has shown potential as a possible treatment for all forms of DMD in early clinical trials. This small molecule works by inhibiting NF-kB, which is a transcription factor — a protein that helps turn genes “on” or “off,” depending on the needs of the cell. Sustained activation of NF-kB causes muscle degeneration, so blocking it would help to preserve patients’ muscle function.

It’s common for people with DMD to be treated with corticosteroids like prednisolone, because these drugs can help to maintain muscle function. However, corticosteroids can cause bone cells to die, diminishing bone health. This is particularly concerning because many children with DMD experience serious fractures before they reach adolescence.

A Catabasis-sponsored study compared the effects on bone health of edasalonexent and prednisolone. In the study, mdx mice (a mouse model of DMD) were treated with clinically relevant doses of either treatment for six months; untreated mdx mice served as a control group.

Mice given prednisolone had lower cortical density and cortical thickness (measures of bone strength) than control mice. The prednisolone-treated mice also had shorter femurs than control animals, suggesting lesser bone growth in addition to weaker bones.

In contrast, mice treated with edasalonexent had cortical densities, cortical thicknesses, and femur lengths that were comparable to those of control mice — suggesting no such deterioration in bone health.

These mouse results are also supported, indirectly, by existing data from a Phase 1/2 clinical trial (NCT02439216), in which 17 DMD children were treated with varying doses of edasalonexent. They grew at rates typical for people their age, suggesting increased bone growth compared to what might be expected in people with DMD treated with a corticosteroid. They also were reported to show preserved muscle function and slowed disease progression.

The Phase 3 trial of edasalonexent aims to enroll 125 DMD boys, ages of 4 to 7, regardless of underlying disease-causing mutation and who have not been treated with steroids for at least 6 months. (Patients on a stable dose of Exondys 51 [eteplirsen] may be eligible to enroll.) The 52-week study, whose main goal is changes at one-year from baseline or study start in motor abilities as measured by the North Star Ambulatory Assessment scores, may still be recruiting at sites across the U.S., Australia, Canada, Europe and Israel. Information is available here .

Although not a primary trial goal (endpoint), bone health will also be assessed via dual-energy X-ray absorptiometry, a technique that measures bone density, because of its importance as a potential area of “differentiation,” Catabasis said in a press release.

Results from this trial are expected in late 2020.