Antisense Oligo Nucleotides: New Setbacks On a Promising Therapy

Antisense Oligo Nucleotides: New Setbacks On a Promising Therapy

By Gautam Rajpal

Gene therapy can’t get a break. But, it can certainly use one.

Just in the past few weeks, a new(er) type of gene therapy, Antisense Oligo Nucleotides, or ASOs for short, has seen two major setbacks. Two companies recently released reports detailing negative results for ASO based therapy. GlaxoSmithKline (GSK), in conjunction with Ionis (formerly Isis) Pharmaceuticals (ION), decided to pull the plug on a phase III trial designed to test its antisense drug IONIS-TTRrx, used to treat a rare heart condition known as transthyretin (TTR) amyloid cardiomyopathy. The disease has no cure and kills people within 7 years of the first signs of the disease. Nonetheless, GSK was compelled to halt its commencement into phase III due to concerns of other heart related side effects that appeared in another Ionis lead therapy, NEURO-TTR. NEURO-TTR is used to treat TTR familial amyloid polyneuropathy (FAP), a disease similar to TTR amyloid cardiomyopathy. The news saw Ionis-an ASO industry leader- stock plunge close to 40% over the news.

One More Hit

Almost at the same time, the Committee for Medicinal Products for Human Use (CHMP), part of Europe’s FDA equivalent European Medicines Agency (EMA), declined approval for BioMarin’s drisapersen (BMRN). Drisapersen is a drug used to treat Duchenne muscular dystrophy (DMD), a rare movement disorder that affects young males. Back in January, the U.S. FDA ruled against allowing the drug to hit the market, and approval for use in Europe was perhaps the last chance for drisapersen’s commercial use. The drug, designed by the small biotech firm Prosensa, was interestingly enough first backed by GSK, which returned rights to Propensa in 2014, after the drug failed to show an improvement in a walk test in young males versus placebo. BioMarin swooped in and purchased the drug- and the entire company- for $840 million, with the hopes that it could leverage its acumen in winning regulatory support to bring the drug to the market. With this new ruling, BioMarin suspended its Phase II studies on three related drugs, but still hopes to work on what its calling “Next generation ASOs”.

ASOs: A Different Beast Of Gene Therapy

ASOs are a different type of what is considered more traditional gene therapy. In the past, scientists and physicians used actual “genes” to deliver to patients, with the hopes of replacing missing or defective ones. With the advent of RNAi, researchers were able to do just exact the opposite; design short bits and pieces of genes that could complement and essentially “attack” their target gene, thus rendering it ineffective. Usually this was in the case of genes gone wild (think cancer). Both these “knockdown” and replacement therapies, however, are mediated by a virus that serves as a delivery system for genes and RNAi. Much of the concerns from gene therapy in fact comes from the virus itself.

ASOs avoid this altogether. They don’t use a virus. In fact, they are more like drugs in how they are delivered. Fomivirsen, a drug used attack viruses (namely cytomegalovirus) in immune-compromised patients, as in AIDS, was the first anti-sense drug to come on the market back in 1998. It used intraocular injections for delivery. Kynmaro, used to treat Homozygous Familial Hypercholesterolemia, a rare disorder where people cannot remove LDL (aka the “bad cholesterol”) from the bloodstream, uses a subcutaneous weekly injection to deliver the ASOs. Currently, there is only one other ASO based drug (Alicaforsen for ulcerative colitis) on the market, but there are plenty more in late stage clinical trials and in the pipeline.

What’s Next?

All is not lost for gene therapy. This past May, the second “replacement” gene therapy was approved (the first being Glybera) for treatment of Severe Combined Immunodeficiency (SCID), a disease known by the general public as the “bubble boy disease”. And there are countless ongoing trials for ASOs in diseases ranging from cancer to Huntington’s disease. ASOs are down but certainly not out in the repertoire of arsenals for gene therapy.



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