Chemical Differences Made One Duchenne Therapy, Exondys 51, Succeed and Another Fail

The chemical structure of a drug can make the entire difference between a success and a failure in drug development. Of two drugs that used the same approach to treat Duchenne muscular dystrophy — Exondys 51 (eteplirsen) and Kyndrisa (drisapersen) — only one became approved.

Researchers from The Ohio State University in Columbus now explain how and why the fate of the two seemingly similar drugs’ separated, in a review published in the journal Expert Opinion on Orphan Drugs. The review was titled “Clinical trials of exon skipping in Duchenne muscular dystrophy.”

Sarepta Therapeutics’ approved Duchene treatment Exondys 51 is commonly referred to as exon skipping 51 therapy. It aims to correct the underlying genetic flaw in the dystrophin gene, causing Duchenne MD. While researchers know that people can have numerous different mutations that cause the disease, those affecting exon 51 are considered the largest group, present in about 13 percent of patients.

A gene — in this case that encodes for dystrophin — is made up of regions that code for the protein, called exons, as well as noncoding sequences. What has been particularly difficult when developing gene therapies for Duchenne is the extremely large size of the dystrophin gene.

With its 79 exons and two and a half million DNA base-pairs (or letters), it is among the largest genes that make up the human genome. The size prevented researchers from using other methods, but they realized that it might be possible to make a treatment that simply omits exon 51.

The mutations in exon 51 introduce a stop signal in the gene, and the protein-making machinery stops when only slightly more than half the protein is made. If exon 51 was omitted, it would allow a dystrophin protein to be produced.

This slightly shorter version would not be as efficient in doing its job as normal dystrophin, but it would be good enough to slow disease progression, researchers figured.

AVI BioPharma, which later changed its name to Sarepta, began developing Exondys 51, and Prosensa (later BioMarin) started development of Kyndrisa. The two drugs were intended to do the same thing, but differed in their chemical structures.

Clinical trials for Kyndrisa compared the treatment to a placebo group. Initial results were encouraging, with Duchenne boys improving their walking ability. But as the study continued, the difference between treated and control patients became smaller.

A Phase 3 study involving 125 patients who were randomized to receive either Kyndrisa or placebo also failed to improve exercise capacity, measured by the six-minute walk test.

The trials also showed that the treatment was linked to side effects such as injection site reactions that in some cases led to skin fibrosis or fragility. Tests also showed that the treatment negatively impacted the kidneys, with increased levels of protein in the urine. Some boys experienced a reduction in platelet counts.

In 2016, the U.S. Food and Drug Administration rejected BioMarin’s application to get Kyndrisa approved, and the company stopped additional testing of the compound.

This failure, Ohio State researchers explained, was caused by safety issues preventing researchers from dosing Kyndrisa high enough to be effective. A study had previously shown that the dose used in the trials, 6 mg per kg body weight (mg/kg), was the highest dose that patients tolerated. At 9 mg/kg, the treatment triggered inflammatory reactions and fever.

And although tests showed increased levels of dystrophin in muscles of treated patients, it was not sufficient to improve muscle function and prevent muscles from breaking down.

Exondys 51, on the other hand, was tried in studies lacking a placebo-treated control group. Instead, researchers compared results to untreated patients with similar exon 51 mutations who were followed in earlier studies. The trials showed that the treatment was safe, with no serious adverse events reported.

It also triggered consistent increases in muscle dystrophin, which translated to improved muscle strength. A Phase 2 trial showed that the treatment improved performance on the six-minute walk test by 151 meters after 36 weeks of treatment.

Exondys 51 also slowed the progression of disease, with only two out of 12 boys losing ambulation after three years of treatment. Among a group of 13 earlier studied boys of the same age and with the same mutation, nearly half — 46.2 percent — lost the ability to walk.

This difference became even larger after four years, as all the boys with preserved ambulation continued walking, while 85 percent of the historical control group had lost walking ability.

The data was convincing enough to allow the drug to become conditionally approved after the Phase 2 study (NCT01396239) and its long-term follow up (NCT01540409). Regulators, however, requested an additional trial that confirms the therapy’s benefits in this patient group. This Phase 3 PROMOVI trial is currently ongoing (NCT02255552).

The Phase 3 study will not, however, examine the treatment’s ability to slow the destruction of cardiac muscle, the Ohio State researchers noted. Most Duchenne patients ultimately die of heart failure, and the ability of Exondys 51 to impact heart muscle needs to be investigated, they argued.