Products
Its primary products are based on Morpholino oligomers (PMOs), synthetic nucleic acid analogs that were conceived of by James Summerton and invented by Summerton with Dwight Weller, originally developed under the name NeuGene Antisense. Since morpholino oligomers can form sequence-specific double-stranded complexes with RNA they are suitable use in antisense therapy. In one application, translation blocking, a morpholino oligomer binds to messenger RNA produced by a known disease-causing gene to prevent it from being translated into protein. Morpholinos can also work as splice-switching oligos, targeting pre-mRNA to alter splicing and so causing changes in the structure of the mature mRNA (the mechanism of the approved drug eteplirsen). Morpholinos have been tested for a wide range of applications including prevention of cardiac restenosis after angioplasty, treatment of coronary artery bypass grafts, treatment of polycystic kidney disease, redirection of drug metabolism, treatment of some mutations causing Duchenne muscular dystrophy (DMD), and inhibition of infectious diseases. Their greatest clinical and commercial success thus far has been in the treatment of DMD. A new class of Morpholino oligos, the peptide-linked Morpholinos or PPMO, are linked to an arginine-rich cell-penetrating peptide to enhance their delivery into cells and have entered clinical trials.[21]
The Morpholino drug eteplirsen, targeting exon 51 of the dystrophin mRNA, was approved as a human therapeutic by the FDA in 2016[22] and antisense oligonucleotides for Morpholinos targeting other exons are also subsequently approved.[23] Morpholinos have been used in preclinical studies to inhibit replication of a broad range of viruses, including influenza, West Nile virus, SARS, hepatitis C, dengue fever, Ebola and Calicivirus, all of which are single stranded RNA viruses. They are in advanced development for prevention and treatment of Ebola and Marburg viruses. In March 2013, the Company announced positive results from a non-human primate study of AVI-7288, the drug candidate for treatment of Marburg virus infection. The results showed that intramuscular administration of AVI-7288 resulted in survival rates up to 100 percent in monkeys exposed to this fatal virus. These results are similar to those in previous studies when the drug was given by intravenous injection. [24]
In December 2019, golodirsen (Vyondys 53) received US FDA approval[25] for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. The other approved PMO developed by Sarepta is casimersen (AMONDYS45) which is indicated for the treatment of DMD in patients amendable by exon 45 skipping.[26]
In addition to development of Morpholinos as therapeutics, AVI has conducted six human trials for colorectal and pancreatic cancers using their cancer vaccine AVICINE.
In 2019, Sarepta signed a licensing agreement with Roche for the development, and commercialization outside of USA, for SRP-9001.[27] In June 2023, ELEVIDYS (Delandistrogene moxeparvovec) was approved by the FDA for use in 4-5-year-old boys with mutations in the DMD gene.[28][29][30] The FDA granted accelerated approval to ELEVIDYS, which requires that the product be further studied to verify its clinical benefit.[30][31]
In June 2024, the U.S. Food and Drug Administration expanded approval of delandistrogene moxeparvovec to include individuals with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene who are at least 4 years of age. The FDA granted traditional approval for non-ambulatory patients and accelerated approval for non-ambulatory patients.[32]
