Issues in Development The 10th Oligonucleotide Therapy Approved: Golodirsen for Duchenne Muscular Dystrophy

On December 12, 2019, the Food and Drug Administration (FDA) granted accelerated approval to Sarepta Therapeutics for golodirsen to treat Duchenne muscular dystrophy (DMD) patients with eligible mutations (www .drugs.com/newdrugs/fda-approves-vyondys-53-golodirsenduchenne-muscular-dystrophy-dmd-patients-amenable-skip ping-exon-5119.html). This brings the number of FDA and/or European Medicines Agency (EMA) approved oligonucleotide drugs to 10 and the number of oligonucleotide drugs for treatment of DMD to 2 (Table 1). The approval is less controversial than that of previously approved eteplirsen, but it was still not a smooth ride. The idea to use splice modulating as a therapy for DMD stems from the fact that lack of functional dystrophin causes severe progressive muscle wasting, while mutations that allow the production of partially functional dystrophins are associated with a less progressive disease, Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated splicing modulation for DMD aims to modulate splicing such that DMD patients can produce BMD-like dystrophin. As not all DMD patients carry the same mutation, this approach is mutation specific. However, most mutations cluster in a hotspot region and as such the skipping of certain exons applies to larger groups of patients, for example, exon 51 skipping would apply to 14% of patients, whereas exon 45 and exon 53 skipping would apply to an additional 9% and 8% of DMD patients [1,2]. Golodirsen (exon 53 skipping) and eteplirsen (exon 51 skipping) are both developed by Sarepta Therapeutics and are both phosphorodiamidate morpholino oligomers. Eteplirsen received accelerated approval in 2016 from the FDA based on increased expression in dystrophin in treated patients. As already mentioned, this approval was controversial, and the issues involved have been discussed in detail previously [3]. In brief, according to FDA, functional benefits from treatment had at that time not been convincingly shown by Sarepta Therapeutics, whereas the increases in dystrophin in a skeletal muscle biopsy were minimal: *0.4% after 48 weeks and *0.9% after 188 weeks of treatment [3]. Notably, dystrophin quantification is very challenging and Sarepta Therapeutics invested a lot of effort in making its Western blotting system acceptable to FDA [4]. Still, it is questionable how accurate one can quantify very minute increases [5]. Sarepta Therapeutics has until 2021 to show evidence to FDA that eteplirsen treatment and the related minor increases in dystrophin expression slow down disease progression in a placebo-controlled trial. Thus far, functional effects such as slower decline in ambulatory and respiratory function have been presented, but these all use historic controls from natural history studies [6,7]. For golodirsen, approval was again only based on increases in dystrophin expression. Once again, no clinical benefit was shown. Golodirsen was tested in a two-stage clinical trial, where eight patients received weekly intravenous infusion with increasing doses up to 30 mg/kg golodirsen, while four patients received a placebo. Then these 12 patients were enrolled in an open label phase where they and an additional 13 patients received weekly doses of 30 mg/kg of golodirsen. Muscle biopsy analysis detected an increase of on average 0.9% in dystrophin after 48 weeks of treatment. This result suggests that golodirsen outperforms eteplirsen treatment, which required 188 weeks to achieve this increase. However, FDA initially did not approve golodirsen and Sarepta Therapeutics received a complete response letter in August 2019 wherein FDA outlined concerns of golodirsen treatment (www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211970 Orig1s000OtherActionLtrs.pdf). The first concern involved an infection risk for treated patients related to the intravenous ports installed to facilitate weekly infusions. The second concern related to renal toxicity observed in animal models at a 10-fold higher dose than the one used in humans (www .drugs.com/nda/golodirsen_190819.html). Sarepta Therapeutics addressed the issues and will monitor the kidney function of treated patients carefully. In addition, they will need to provide evidence to FDA that golodirsen treatment results in clinical benefit, that is, results in a slower disease progression as measured by functional outcome measures, by 2024. A double-blind placebo-controlled confirmatory trial is currently ongoing (https://clinicaltrials.gov/ ct2/show/NCT02500381? term=golodirsen&cond=Duchenne+ Muscular+Dystrophy&draw=2&rank=4). With the approval of golodirsen, *22% of DMD patients in the United States now, in theory, have access to a dystrophin-restoring drug. However, not everyone who is eligible for treatment will be treated with this drug. First, the cost of the drug will likely be in the same range as eteplirsen (several hundreds of thousands of dollars per patient per year,