“With any brand new technology, you never know when the world will be ready for it.” So said Paul Boni, an analyst at Punk, Ziegel & Knoll, in 1998 (as quoted by the New York Times), after the US Food and Drug Administration (FDA) approved its first gene-silencing ‘antisense therapy’, a drug known as Vitravene (fomivirsen), for the treatment of cytomegalovirus infections in individuals with weakened immune systems.
The arrival of Vitravene, a short strand of 21 DNA molecular units that blocks viral replication, was hailed as a major milestone for the biotech industry and was widely anticipated to usher in a new era of antisense products. But no more came. And by the middle of the last decade, Isis Pharmaceuticals, the Carlsbad, California–based company behind Vitravene, ended up pulling the therapy from the market because improvements in other antiretrovirals had effectively eliminated the drug’s target market. Boni’s cautionary words proved all too prescient.
Making antisense of the drug pipeline: Antisense therapies in mid- to late-stage clinical development.
Fifteen years after that first approval, however, antisense technology finally seems ready to make an impact. Late last month, Isis won approval for another antisense drug—Kynamro (mipomirsen), for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder in which the body lack the ability to remove ‘bad’ cholesterol from the bloodstream. The drug is now being marketed by the French giant Sanofi, and several other antisense products are currently in late-stage clinical development.
“This is the end of the beginning for antisense,” says Isis’s chief executive Stanley Crooke. “We feel this is a critical step in the final validation of the technology.”
First developed 35 years ago, the strategy of silencing genes by introducing short antisense stretches of DNA or other nucleic acids that are complementary to an mRNA target has proven useful in laboratory experiments, but translating the technology into the clinic has presented a challenge. For Kynamro, the key was a chemical alteration at both ends of the DNA strand. With this change, the product has an enhanced half-life, stronger affinity for its target RNA and a reduced proinflammatory side effect—all improvements in areas that have previously sunk antisense candidates in clinical testing.
This modification, Crooke says, “is the critical step that we took about 12 years ago, the product of thousands of tiny incremental steps.” Isis currently has 26 candidate antisense drugs in its preclinical and clinical pipeline for treating a range of cardiovascular, metabolic and other types of disorders—the vast majority of which incorporate this chemistry, including an antisense drug that rescued hearing in a mouse model of human deafness, as reported earlier this month in Nature Medicine.