Drisapersen

Drisapersen (also known as PRO051 and GSK2402968^[1]) is an experimental drug that is under development by Prosensa for the treatment of Duchenne muscular dystrophy. The drug is a 2'-O-methyl phosphorothioate oligonucleotide that alters the splicing of the dystrophin RNA transcript, eliminating exon 51 from the mature dystrophin mRNA.

Mechanism of action

Duchenne muscular dystrophy (DMD) is caused when a mutation in the DMD gene changes the DMD RNA so that it no longer codes for functional dystrophin protein, usually due to a mutation that alters the reading frame of the RNA downstream of the mutation. If an exon with an appropriate number of bases lies near the mutation, by removing that exon the downstream reading frame can be corrected and production of partially functional dystrophin can be restored. This is the general strategy used for designing exon-skipping oligonucleotides for DMD; as there are 79 exons in the longest splice form of the dystrophin transcript, many different oligos are needed to address the range of mutations present in the population of people with DMD.

Clinical studies

The compound has completed Phase III trials and did not meet its primary endpoint.^[2][3]

An long term open-label extension study (DEMAND IV) suggests that giving the drug at an earlier age and treating the boys for longer may delay progression of the disease. This corresponds with the earlier Phase III trials (DEMAND III) data that shows a potentially clinically meaningful difference in a subgroup of patients age 7 or younger.^[4]

A similar drug is also in clinical trials, eteplirsen, which is a Morpholino antisense oligomer that, like drisapersen, also targets skipping of dystrophin exon 51. The difference in backbone chemistry is significant, since the 2'-O-methyl phosphorothioate employed in drisapersen triggers renal toxicity ^[5], and limits the maximum therapeutic dosage; whereas the morpholino backbone is less toxic and allows higher dosing and seemingly better efficacy.

Current status

The Phase III trials were sponsored by GlaxoSmithKline but GSK terminated the collaboration agreement between GSK and Prosensa and Prosensa has regained all rights from GSK to drisapersen. Prosensa was then acquired by Biomarin ^[6], which claims to be committed to moving forward with Drisapersen^[7] and is concurrently working with similar exon skipping therapies for other exons.^[8]

References