Ionis Pharmaceuticals, Inc. is a biotechnology company that specializes in discovering and developing antisense therapy, as well as RNA interference and CRISPR therapeutics. The company was founded in 1989 is based in Carlsbad, California. The company was previously known as Isis Pharmaceuticals until December 2015.
History
First generation Ionis Pharmaceuticals was founded in 1989 by Stanley Crooke, under the name ISIS Pharmaceuticals, in order to develop antisense therapy. The company started with $5 million in initial funding. It made a series of partnerships with pharmaceutical and biotech businesses early on. Its first major contract was a $30 million drug development agreement with Swiss pharmaceutical company Ciba-Geigy, who also invested in Ionis. At first, the company developed antisense methodologies in general, without targeting a specific drug or disease. At the time, there was a lot of interest in antisense therapy, but no commercially available pharmaceuticals yet. Ionis went public on Nasdaq in 1991, as a startup with 60 employees at the time. Ionis grew or shrunk over time depending on the level of public support for antisense therapy. It struggled in the 1990s, as scientific publications and regulators were skeptical of antisense, saying it didn't "making sense." The "first generation" of antisense therapy often had issues with not being potent or long-lasting enough. This made it difficult for Ionis to get grants, research partnerships, or drug approvals. In 1992, Ionis got approval for the first human testing of an antisense therapy medication, when the Food and Drug Administration allowed testing of a treatment for the human papilloma virus, which causes genital warts. However, in 1995, Ionis abandoned the clinical trials. The company said there wasn't enough of a market for the drug to justify developing the slow-release version. Ionis had a second public offering that year. ISIS 2302, a treatment for Crohn's disease, was expected to prove the viability of antisense, but instead failed in stage 3 clinical trials in 1999, prompting a layoff of 40% of Ionis' staff. A lung cancer treatment developed in 2003 in partnership with Eli Lily failed clinical trials as well. It took longer than anticipated for Ionis to develop antisense technology to a point where the company made useful medicines.
Second generation In the mid-1990s, Ionis and its research partner Ciba-Geigy discovered one of the main reason first-generation antisense medications had potency and duration issues. The phosphorothioates that replace an oxygen molecule in a DNA strand with a sulfur molecule to prompt genetic modification was decreasing the effectiveness of the RNA to bind to cells in order to modify the cell's protein production. Ionis changed its approach by modifying the ribose ring of the DNA strands instead, eliminating the introduction of sulfur. Second generation antisense used a methoxyethyl modification and had five-to-ten times the potency of Ionis' first-generation antisense. This also prompted a shift from focusing on cancer treatments in first-generation antisense to things like heart disease and metabolism issues and allowed patients to take antisense pharmaceuticals in higher doses. In 1997, ISIS 2302 became the first antisense medication to be effective when injected, rather than applying it directly to the affected area. The following year, Ionis' fomivirsen (Vitravene) became the first antisense therapy drug approved by the FDA. Vitravene was a treatment for an eye condition known as cytomegalovirus (CMV) that affected those with AIDS. It was developed by the National Institute of Health and licensed by Ionis. However, sales were negligible. It was taken by eye injection and relevant to a small number of cases. Vitravene was seen as a vindication of antisense for getting a drug approved, but it was discontinued in 2004. Several other Ionis drugs failed clinical trials afterward. Ionis started converting its drug development pipeline to second generation technology. Over time, the controversy around antisense faded and support increased. Ionis was able to rehire many of the previously laid-off staff. It started developing 3-5 drugs per-year. Ionis also started rebounding after June 2000, when it presented data from its research into diabetes treatments. Afterwards, it signed a series of big contracts with biotech and pharma companies. In 1998, competitor Gilead Sciences abandoned antisense research and sold its patents to Ionis. In 2000, one of Ionis' largest backers, Novartis Pharmaceuticals, ended their partnership with Ionis. Many of the larger pharma and biotech companies abandoned research for antisense methodologies. By this time, Ionis was one of the only companies still developing antisense compounds.
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