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Novel Oral Drug for Duchenne Muscular Dystrophy Leads to Improved Function in Phase 2 Study

CHARLOTTE, NC—Edasalonexent, an oral small molecule drug that inhibits NF-kappa-B (NF-κB), showed an array of improvements, including function in young boys with Duchenne muscular dystrophy (DMD), according to findings presented here at the annual meeting of the Child Neurology Society.

Better treatment is needed for DMD, a rapidly progressive form of muscular dystrophy affecting males and caused by mutations to the DMD gene, said Richard S. Finkel, MD, chief of the division of pediatric neurology at Nemours Children's Health System in Orlando, FL.

Activation of NF-κB is a key factor in DMD progression involving skeletal and cardiac muscle, Dr. Finkel explained, and the oral drug is being developed both as a monotherapy and potentially in combination with other dystrophin-targeted therapies.

Thirty-one patients participated in the phase 2 trial, including 16 patients involved in a six-month off-treatment period to serve as controls. The study participants, who ranged in age from 4 to 8 years old, could not concurrently be treated with corticosteroids.

Researchers found that NF-κB target gene levels rose during the off-treatment period, but they observed a pattern of declining levels when treatment was resumed in the phase 2 study. They also found that muscle enzymes, including creatinine kinase (CK), significantly decreased with edasalonexent treatment, suggesting the drug was having a positive effect (p< 0.05 for baseline compared with weeks 12 through 72).

Five lower leg muscles showed significant improvement on MRI T2 through week 48 of the treatment period compared with the off-treatment control period (p= 0.018).

Function declined during the off-treatment period, but it stabilized during the treatment period on several tests: The North Star Ambulatory Assessment, a 17-item measure for DMD patients; the 4-stair climb, the 10-meter walk/run; and time to stand.

The drug also showed signs that it might have a cardiac benefit: The average resting heart rate significantly decreased from 99 to 92 beats per minute. The researchers noted that the heart rate reduction was more pronounced in those with a higher initial resting rate (p< 0.01)

The most common adverse events were diarrhea, upper abdominal pain, and nausea, but researchers said they tended to be mild and transient.

Growth curves for those on the drug were similar to boys without disease, Dr. Finkel said.

"It showed clinically meaningful slowing of disease progression on edasalonexent compared to the off-treatment control," Dr. Finkel said. "We saw that there were positive biomarkers such as the CK stabilization and the MRI. We showed that the drug was well-tolerated. And, finally, we feel that this data collectively supports the development of a phase 3 clinical trial."

The researchers recently completed enrollment in the phase 3 trial enrollment across 40 sites and data are expected in about a year, he said.

Commenting on the study, Ann H. Tilton, MD, FAAN, professor of neurology and pediatrics and section chair of child neurology at Louisiana State Health Science Center in New Orleans, said the drug is a breakthrough because it casts a wider net than the other newly developed drugs that have only targeted individual mutations.

"This is a novel new DMD drug, which is oral and is shown in the initial studies to affect multiple associated abnormalities—because this is a huge gene there can be multiple different types of deletions and of different sizes," Dr. Tilton said.

Also important, she said, is that "it might make a difference in the heart."

"I think this is innovative and it's much easier and less expensive in the delivery (than other drugs that are intravenous)," Dr. Tilton said. "If it can truly meet all those parameters—which are biochemical, measurement by imaging, and measurement of function—it is exciting but we will just have to wait for the phase 3 trial and see what happens."

She said she will be curious about the cost of the drug, especially considering the duration of treatment that will be needed: "This is probably a lifelong therapy."

Dr. Finkel is a principal investigator in clinical trials for Catabasis, which provided funding for the study; he also serves as an advisory board member for Catabasis.

Link Up for Related Information:

Finanger E, Vandenborne K, Finkel RS, et al. Phase 1 study of edasalonexent (CAT-1004), an oral NF-κB inhibitor, in pediatric patients with Duchenne muscular dystrophy. J Neuromuscul Dis 2019;6(1):43–54.