The dust has settled in the race to see which exon-skipping therapy would be the first approved for Duchenne muscular dystrophy (DMD), and a thorough review recently published in the Expert Opinion of Orphan Drugs
by Drs. Mendell, Sahenk, and Rodino-Klapac sets the record straight on why one drug [Exondys-51 (etepelrisen)] got approved and one drug [Kyndrisa (drisapersen)] did not.
DMD is a degenerative muscle disease due to a person having low levels of the protein dystrophin, which acts as a shock absorber for muscles; without dystrophin, the muscles slowly die. Symptoms of the disease begin in boys around the age of 4 or 5, and by the time they are in their teens, they are generally non-ambulatory. Most patients with DMD do not live past their early 20s without treatment.
Currently, only one disease-modifying drug has been approved for DMD; Exondys 51 (eteplirsen). The therapy is effective in an estimated 13% of DMD patients who are amenable to exon 51 skipping therapy. A second exon-skipping therapy, also for patients amenable to exon skipping 51 therapy, was drisapersen.
The review by Mendell et al provides an excellent overview of the 2 drugs, and explains why one proved to be so effective while the other was plagued by safety issues that limited its dosing.
To understand how the drugs work, it is necessary to understand the pathophysiology of DMD.
DMD is due to a mutation in the Dystrophin
gene that leads to a low production of the protein dystrophin. The gene is extremely large and encodes 79 exons and has 2.5 million base pairs of DNA. In patients with DMD, gene mutations at numerous different spots on the gene can alter the reading frame during transcription to RNA.
The end result is that patients can be grouped according to where those different mutations spots are and based on where the mutation is, a drug that can ‘skip over’ the exon near that mutation to allow the reading frame to be back on track and possibly allow the dystrophin protein to by synthesized. The protein may be shorter and may not be as effective as the original dystrophin. It will, however, be synthesized.
That is the concept behind exon-skipping therapy: the drug tricks the transcription and translation processes to jump over an exon that would prematurely stop the synthesis of the protein so that it will continue to be made.
In the aforementioned 13% of amenable DMD patients, having a drug that would skip over exon 51 of the Dystrophin
gene would allow for the production of a sufficient amount of the dystrophin protein to slow the progression of the disease.
Drisapersen is a
2′-O-methyl-phosphorothioate oligonucleotide (2OMePS) with a negatively-charged phosphorothioate linkage.
Early clinical studies with drisapersen were promising, but as Mendell et al point out in their review, when the clinical trials got larger, longer, and more controlled, results were not as promising and many of the problems appeared to stem from trying to get a dose high enough to be effective but also tolerable.
The companies who had drispersen (ProSensa and later BioMarin) weren’t able to find that balance. For example, a placebo controlled phase 2 study showed the drug to be effective for the first half the the 48-week trial, but as the study continued, the differences between the placebo group and the drisapersen group became less apparent. In addition, adverse events were proving to be a problem with many boys having injection site reactions, as well as mild proteinuria and raised urinary α1-microglobulin levels.
A Phase 3 study was conducted to prove if the drug was ultimately effective. That study failed to reach its primary endpoint (the 6MWT) and it was assumed that it would go no further in clinical development by the developers of the drug, ProSensa. Then BioMarin bought the drug from ProSensa and presented it to the FDA for review. In early 2016, an advisory board for the FDA voted that there was no conclusive benefit from drispersen and in May 31, 2016, BioMarin stopped its drispesen clinical program.
Mendell et al noted that one problem that plagued the use of drisapersen from being a safe and effective treatment for DMD was its dosing limitation. At 6 mg/kg/week, which was the dose used in its larger clinical studies, the drug simply was not as effective as it needed to be. Unfortunately, at higher doses (9 mg/kg/week) that may have been more effective, the adverse events made the drug unsafe.
Eteplirsen is a morpholino-based oligonucleotide with a neutral charged phosphorodiamidate linker.
Unlike drisapersen, the safety profile for eteplirsen was very favorable allowing for more flexibility in developing an effective dose. What constantly plagued the eteplirsen studies was, unlike the drisapersen studies, there was never a well-designed, placebo-controlled study to compare the drug to. While that was always a concern with the FDA (and the regulatory agency approved the drug in September 2016 with the caveat that a proper placebo controlled study needs to be performed), Mendell et al in indicated that it is fairly apparent that the drug is safe and effective.
While the phase 2 study that led to the drug approval was frought with design flaws, it had 2 important outcome measures that were hard to ignore. First, after a staggering 36 months of treatment, DMD boys taking eteplirsen could walk 151 meters further in the 6MWT compared to an age-matched, mutation-matched, and corticosteroid-treated control group (P
< .01) Second, the drug delayed disease progression. After 36 months of treatment, only 2 eteplirsen-treated DMD boys were no longer ambulatory (17%) compared to 6 of 13 (46.2%) in a historical control group. And after 4 years, the remaining ambulatory boys taking eteplirsen could still walk while in the historical control group, 85% ( 11 of 13) could not.
These functional assessments were backed up by analyses showing the boys dystrophin levels were also elevated, indicating that the drug was in fact, skipping over exon 51 and allowing for dystrophin protein to be synthesized. Finally, the data showed that the drug was very well tolerated with no serious adverse events.
Finally, Mendell et al note that while we wait for the final Phase 3 study to be completed for eteplirsen, one potential limitation of the drug is that it it has not been shown to affect cardiac muscle. While keeping skeletal muscle functioning is a key to attenuating DMD progression, those boys eventually die of cardiac failure. New formulations that address that problem should be considered for eteplirsen as well as some of the other exon-skipping drugs in development by Sarepta.
This article is a brief summary of the review by Mendell and colleagues published in Expert Opinion of Orphan Drugs
. Readers are strongly encouraged to read the review
article in its entirety to fully understand how eteplirsen got approved and drisapersen did not.
Mendell JR, Sahenk Z, Rodino-Klapac LR. Clinical Trials of Exon skipping in Duchenne Muscular Dystrophy. Exp Opin Orpahn Drugs. Published online August 17, 2017. http://dx.doi.org/10.1080/21678707.2017.1366310
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