Duchenne’s Muscular Dystrophy (DMD) is a genetic disorder that afflicts approximately 1 out of every 3,600 male infants. The inherited disease is caused by mutations in the gene for dystrophin- a muscle protein- resulting in muscle weakness at an early age that quickly worsens over time. Breathing difficulties and heart disease typically begin in the early twenties, eventually leading to death.
Sarepta Therapeutics, formerly Avi BioPharma, has developed an RNA based therapy designed to allow DMD patients with specific deletions in the dystrophin gene to produce active forms of the protein. Genes are comprised of exons and introns; during the translation process from DNA to protein, pre-mRNA is assembled, introns are removed and exons are spliced together to form mRNA, which is then used as a template to create proteins.
In patients with DMD, the errors can lead to what’s called an out-of-frame, or frame-shift deletion. Cells read the genetic code in sets of three nucleotides. If an exon deletion causes this set of three to become out of step, every subsequent read will be incorrect and no protein will be made. Sarepta’s exon-skipping technology can correct the reading frame, allowing functional protein to be produced. The company’s lead compound eteplirsen (AVI-4658) enables the skipping of exon 51. Additional compounds targeting other exons are also in development.
On July 24, Sarepta reported 36-week data from the open-extension portion of its Phase IIb study showing patients treated with the highest dose of eteplirsen performed significantly better on the 6-minute walk test (6MWT) compared to a cohort of placebo/delayed treatment individuals. The study was small to be sure, only 12 patients were enrolled; four each were assigned to either placebo, 50mg/kg eteplirsen, or 30mg/kg eteplirsen. Upon completion of this blinded portion, the four placebo patients were randomized to either one of the two treatment arms- the so-called placebo/delayed treatment patients.
All measurements are referenced to each patient’s baseline 6MWT distance. At 36-weeks, 50mg/kg patients saw an 8.7 meter decline in walking distance compared to a decline of 78.0 meters for the placebo/delayed treatment cohort. This translated to a 69.4 meter benefit and was highly statistically significant.
Patients receiving 30mg/kg also saw a benefit with declines of only 33.3 meters, but the difference was not statistically significant. Moreover, two of the original four patients in this group had been excluded from the analysis after being unable to “perform measures of ambulation beyond 24 weeks.” According to management, these two boys have become wheelchair bound due to their rapid disease progression. Their exclusion, however, has provided fodder for critics of the trial.
Combined results from both doses reached statistical significance with a mean 6MWT decline of 15.6 meters. (This excludes the two boys from the 30mg/kg arm who rapidly progressed.)
Additional subgroup analysis provided by the company showed boys who were under 9.5 years of age, had higher baseline 6MWT distances, or had specific mutations achieved a greater treatment benefit; (Read Full Acticle)