Analysis of Failed DMD Therapy Kyndrisa Shows Potential Benefit for Younger, Less Impaired Boys

Clinical data from a Phase 3 trial revealed that Kyndrisa (drisapersen) could not significantly improve the walking ability of boys with Duchenne muscular dystrophy (DMD) due to mutations amenable with exon 51 skipping.

Still, additional analysis of the DEMAND III trial (NCT01254019) showed this therapy may still be beneficial for younger, less impaired patients. This result underscores the importance of early treatment to delay disease progression and preserve the child’s functional ambulatory capacity.

BioMarin, Kyndrisa’s developer, halted development of Kyndrisa in 2016 after both the U.S. Food and Drug Administration and the FDA’s European equivalent both refused to approve the DMD therapy. GlaxoSmithKline had backed out of development several years earlier.

The results of the trial were reported in a study titled, “A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy,” published in Neuromuscular Disorders, the journal of the World Muscle Society.

In a post-hoc analysis of a subgroup of 80 patients who presented less impaired functioning (6MWD 300-400 meters and the ability to rise from floor) at the beginning of the study, Kyndrisa appeared to significantly improve walking ability in these boys.

“[These] results suggest that [Kyndrisa] could have benefit in a less impaired population of DMD subjects,” the researchers stated.

“Even though these results were promising and subjects treated with drisapersen [Kyndrisa] have maintained stable ambulatory function in an extension study for 3.4 years (NCT01910649), further clinical development of [Kyndrisa] has been terminated by the study sponsor,” they added.

Kyndrisa belongs to the antisense oligonucleotide (AON) class of compounds. It was designed by BioMarin to specifically bind to dystrophin’s RNA sequence and mediate exon 51 skipping during its processing.

This exon-skipping strategy promotes the production of a shorter but functional version of the dystrophin protein, a strategy that can overcome the effects of DMD-associated genetic mutations in about 13 percent of patients.

Two previous Phase 2 trials (NCT01153932 and NCT01462292) showed that subcutaneous injection of 6 mg/kg per week of Kyndrisa for 24 weeks could significantly improve the physical capacity of DMD boys, as measured by the 6-minute walk distance (6MWD) test, compared to placebo.

Supported by these results, the safety and efficacy of Kyndrisa was evaluated in the DEMAND III Phase 3 trial (NCT01254019). The trial enrolled 186 boys ages 5 and older from 44 centers in 19 countries. The boys had confirmed Duchenne due to an exon 51 skipping amenable mutation.

As in previous trials, the patients received 6 mg/kg per week of Kyndrisa or placebo. The total treatment time was 48 weeks.

The results showed the treatment was well tolerated overall. The most common adverse events reported during the trial period were injection-site reactions and renal events.

An evaluation of changes from baseline in the 6MWD test revealed that Kyndrisa is not effective at preventing disease progression, although a positive trend was reported at week 48.

A similar result was obtained on other functional walking tests, including the North Star Ambulatory Assessment 4-stair climb ascent velocity and the 10-meter walk/run velocity tests.

The lack of statistical significance in the tests was thought to be largely due to “greater data variability and subgroup heterogeneity,” the researchers wrote.