Progress in the treatment of myodystrophy
Experimental golodirsen coped with Duchenne muscular dystrophy
Sarepta Therapeutics has developed a correction of the dystrophin gene mutation with the omission of exon 53
Quotes from Sarepta Therapeutics added 17% after the announcement of interim results of phase I/II clinical trials of the antisense morpholine oligomer golodirsen (golodirsen), or SRP-4053, experimental therapy for Duchenne muscular dystrophy among patients with a confirmed mutation of the dystrophin gene, leading to the omission of exon 53. There are approximately 8% of the total population of such patients suffering from this rare degenerative neuromuscular disease linked to the X chromosome.
80% of patients with Duchenne muscular dystrophy are suitable for antisense therapy that skips exons.
Clinical studies involving 25 boys recorded a 100 percent response and achievement of the primary endpoint after weekly intravenous injections of holodirsen for 48 weeks. Western blotting showed an average expression of dystrophin up to 1.019% of the normal level of this protein against the initial state of 0.095% of the norm (p<0.001) – a 10.7-fold increase. In addition, the use of holodirsen demonstrated a statistically significant increase in dystrophin immunofluorescence, which confirms the expression and distribution of sarcolemma-associated dystrophin.
In September 2016, the US Food and Drug Administration (FDA) approved Exondys 51 (Exondys 51, eteplirsen), which Sarepta focused on Duchenne myodystrophy with the omission of exon 51 – there are 13% of such patients. Permission for this antisense morpholine oligonucleotide was obtained without clear evidence of clinical efficacy in improving motor skills.
Sarepta Therapeutics Drug Pipeline
Phase III clinical trials of ESSENCE holodirsen are ongoing – the main results regarding improvement in the six-minute walk tests will be ready only in the second half of 2019. However, regulators can make a positive verdict much earlier: holodirsen turned out to be much more effective than eteplirsen, which managed to raise the level of dystrophin relatively modestly: from the initial 0.16% to 0.44% of the normal indicator – a 2.8-fold increase.
According to industry experts, the clinically significant effectiveness of any therapy for Duchenne muscular dystrophy is the output of dystrophin synthesis to at least 10% of its normal formation in a healthy body. Neither golodirsen nor eteplirsen are capable of this.
An industry pipeline of candidate drugs for the treatment of Duchenne muscular dystrophy. Image: EP Vantage.
Meanwhile, by September 28, the FDA should deal with the application for Translarna (Translarna, ataluren) for the treatment of Duchenne muscular dystrophy with nonsense mutations - in Europe, PTC Therapeutics received the go–ahead for it in October 2014. Hope, however, is weak here, given the regulator's refusal in early 2016.
Ataluren, being a transcription modulator, refers to protein-restoring drugs for those suffering from genetic pathologies caused by nonsense mutations. The latter are changes in the genetic code that prematurely stop the synthesis of essential proteins. Ataluren makes ribosomes less sensitive to premature stop codons by arranging the insertion of certain related tRNAs near the nonsense codon site, thereby making the functional protein look like an unmutated endogenous one.
Currently, five drugs based on antisense oligonucleotide therapy have been approved: Vitraven (Vitravene, fomivirsen), Macugen (Macugen, pegaptanib), Kinamro (Kynamro, mipomersen), Exondys 51 (Exondys 51, eteplirsen) and Spinraza (Spinraza, nusinersen). Image: EMBO Molecular Medicine.
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08.09.2017