Drisapersen (also known as Kyndrisa, PRO051 and GSK2402968) is an

experimental drug An experimental drug is a medicinal product (a drug or vaccine) that has not yet received drug approval, approval from governmental regulatory agency, regulatory authorities for routine use in human medicine, human or veterinary medicine. A medicin ...

that was under development by BioMarin, after acquisition of

Prosensa Prosensa was a biotechnology company engaged in the discovery, development and commercialization of RNA-modulating therapeutics. The company targets genetic disorders with a large unmet medical need, with a primary focus on neuromuscular and neur ...

, for the treatment of

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pe ...

. The drug is a 2'-O-methyl phosphorothioate

oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, Recombinant DNA, research, and Forensic DNA, forensics. Commonly made in the laboratory by Oligonucleotide synthesis, solid-phase ...

that alters the splicing of the

dystrophin Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costa ...

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

transcript, eliminating

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

51 from the mature dystrophin mRNA.

Mechanism of action

Duchenne muscular dystrophy (DMD) is caused when a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

in the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

changes the

so that it no longer codes for functional dystrophin

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

. This usually happens due to a mutation that alters the

reading frame In molecular biology, a reading frame is a specific choice out of the possible ways to read the nucleic acid sequence, sequence of nucleotides in a nucleic acid (DNA or RNA) molecule as a sequence of triplets. Where these triplets equate to amino ...

of the RNA downstream of the mutation, so-called

frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet natur ...

. If an

with an appropriate number of bases lies near the mutation, removing that exon can correct the downstream reading frame, restoring the production of partially functional dystrophin. This is the general strategy used in the design of exon-skipping

s for DMD. As there are 79 exons in the longest

splice form Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

of the dystrophin transcript, many different oligonucleotides 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. In January 2016, the FDA rejected drisapersen (Kyndrisa) largely on the basis of toxicity which limits dosing, and so efficacy. This effectively shifted focus of exon skipping therapy to a competing drug, eteplirsen.

Eteplirsen Eteplirsen (brand name Exondys 51) is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. ...

is another exon skipping drug, but has a different backbone chemistry (it is a

Morpholino A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. Its molecular structure contains ...

antisense In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...

oligomer) which gives it different pharmacology while still targeting the same site on the dystrophin gene, exon 51. The hope is that lower toxicity of that backbone chemistry will allow higher dosing and greater efficacy. A 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.

History

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 Pharmaceutical BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme re ...

, which continued the development of drisapersen and was concurrently working with similar

exon skipping In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation. Mechanis ...

therapies for other exons. Both drisapersen and the similar drug eteplirsen have filed a

New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

(NDA) for review with the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA). In January 2016, the FDA rejected drisapersen (Kyndrisa) after it concluded that the standard of substantial evidence of effectiveness had not been met, effectively shifting focus to rival Sarepta's eteplirsen. The Prescription Drug User Fee Act ( PDUFA) goal dates for these are December 27, 2015 for drisapersen and February 26, 2016 for eteplirsen.

Current status

In May 2016, BioMarin announced they intended to discontinue clinical and regulatory development of drisapersen as well as related first generation compounds currently in Phase 2 studies for distinct forms of Duchenne muscular dystrophy. The company claim they will continue to look into DMD and the next generation oligonucleotides.

References

{{Other drugs for disorders of the musculo-skeletal system Antisense RNA Muscular dystrophy Therapeutic gene modulation Muscle protectors