Isis Pharmaceuticals and partner Genzyme announced this week that the US Food and Drug Administration has approved their antisense drug Kynamro, known generically as mipomersen, for the treatment of homozygous familial hypercholesterolemia.
According to the companies, the FDA specifically cleared the drug as a 200 milligram weekly subcutaneous injection as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein, apolipoprotein B, total cholesterol, and non-high density lipoprotein in patients with HoFH. The rare disease is characterized by severe elevations in cholesterol and is typically fatal by early adulthood.
The ruling was not unexpected, given that the FDA's Endocrinologic and Metabolic Drugs Advisory Committee last year recommended Kynamro's approval.
However, the path toward approval was not without controversy. The advisory committee's vote was split 9 to 6 amid concerns over liver toxicity and a possible cancer risk associated with the drug, which led to the drug not receiving a positive recommendation by a European Medicines Agency advisory panel. Isis is also facing a series of investor lawsuits over the greater than 20 percent decline, to around $10.27, its shares took on news of the safety concerns (GSN 1/3/2013).
In early morning trading after the approval was announced, however, Isis shares shot up almost 9 percent to $14.57, flirting with a 52-week high of $15.61.
Importantly, Kynamro represents the first systemic antisense drug to reach the market, which is being viewed a key step toward establishing oligonucleotides as a true drug-development platform alongside small molecules and biologics.
According to Art Krieg, President and CEO of RaNA Therapeutics and a veteran of the nucleic acids field, those watching the progress of oligonucleotide therapeutics development have long been waiting for a commercial success to validate the space.
“No matter how many mouse studies you do, no matter how many human clinical trials you've done, until there is a product that's been approved by a leading regulatory authority and is being prescribed by physicians and making money for the manufacturer, you don't have a new drug platform,” he said.
To date, there have only been two oligo-based drugs approved by the FDA: the vascular endothelial growth factor-targeting aptamer Macugen, which is used to treat wet age-related macular degeneration, and Isis' Vitravene, an antisense molecule designed to inhibit the gene that causes cytomegalovirus retinitis in immunocompromised patients such as those with HIV/AIDS.
While Macugen continues to be successfully marketed, Vitravene was pulled from the market a few years after approval amid poor sales. Notably, the drug also did not appear to work through a true antisense mechanism of action, Krieg pointed out. Its effect, he said, was probably due to an unintended immune response.
“And, of course, it was not a commercial success — it did not even pay back the cost of developing it,” he added.
Given that Kynamro is addressing a market with high unmet need, and in light of the robust clinical data on the drug generated by Isis and Genzyme, Krieg expects it to be the first truly successful drug to come out of the antisense arena.
But even if Kynamro doesn't become a huge money-maker, the validation of its FDA approval is likely to boost acceptance of antisense, RNAi, and other oligonucleotide drug technologies by the broader scientific community, he said.
Kynamro is, “hopefully, going to be the first in a series of oligonucleotide drugs coming along to commercial success that will demonstrate to everyone that oligonucleotides are a real platform for drug development,” Krieg said.