Ionis Pharmaceuticals is a biotechnology company based in Carlsbad, California that specializes in discovering and developing RNA-targeted therapeutics. The company has 3 commercially approved medicines: Spinraza, Tegsedi, and WAYLIVRA and has 4 drugs in pivotal studies: tominersen for Huntington’s disease, tofersen for SOD1-ALS, AKCEA-APO-LRx for cardiovascular disease, and AKCEA-TTR-LRx for all forms of TTR amyloidosis. The company was named Isis Pharmaceuticals until December 2015.
History
The company was founded in 1989 as Isis Pharmaceuticals by Stanley T. Crooke, a former head of research of GlaxoSmithKline, with a goal to commercialize antisense therapy. In 1992, for a genital wartsdrug candidate, the company received its first approval by the Food and Drug Administration for an investigational new drug application in 1992, marking the first time any antisense therapy was approved to be tested in humans. In 1995, the genital warts drug failed in clinical trials and Isis terminated development. By that time, Gilead Sciences and Genta had left the antisense therapy field, leaving only Isis, Hybridon, and Lynx Therapeutics working in the field. Gilead sold the patents it had developed around antisense to Isis. In December 2015, Isis changed its name to Ionis, driven in part by the negative image of "Isis" generated by the terrorist group, Islamic State of Iraq and the Levant, commonly known as ISIL or ISIS. In 2017, the company completed the corporate spin-off of its rare lipid disorder subsidiary Akcea Therapeutics.
Drug pipeline
The company's first marketed drug was fomivirsen which was used in the treatment of cytomegalovirus retinitis in immunocompromised patients, including those with AIDS. It was discovered at the NIH and was licensed and initially developed by Isis, which subsequently licensed it to Novartis. It was approved by the FDA for CMV in Aug 1998, and was the first antisense drug that was approved. Novartis withdrew the marketing authorization for fomivirsen in the EU in 2002 and in the US in 2006. While the rising incidence of CMV in people with AIDS initially created a need for drugs that treated this virus, the drug was withdrawn because the development of HAART dramatically reduced the number of cases of CMV. The antisense field anticipated that the approval of fomivirsen marked the beginning of a new age of antisense drug treatments, that would be similar to the uptake of monoclonal antibody therapy, but the next FDA approval of an antisense drug came in 2013. Part of what held up Isis and other companies in the field, was the way that the oligomers were chemically modified to prevented hydrolysis which consequently also reduced affinity to the antisense molecules' targets; around 2004 the field was shifting to second generation modifications. Clinical trials of antisense therapeutics by Isis and others in the early 2000s were also plagued by lack of efficacy and immune reactions to drug candidates. Isis cut its workforce by 40% in 2005 due to weak sales of fomivirsen and lack of confidence by the market in antisense technology. In 2007, Isis and Alnylam Pharmaceuticals, which focuses on RNA interference, formed a 50/50 joint venture, Regulus Therapeutics, to apply their intellectual property and knowledge around oligomer biotherapeutics to micro-RNA targets. In 2008, Isis and Genzyme entered into a partnered on drug candidate mipomersen, intended to treat homozygous familial hypercholesterolemia and other drug candidates; the deal included Genzyme buying $150 million of Isis stock and paying a $175 million license fee, as well as milestone fees and royalties. Mipomersen was rejected by the European Medicines Agency in 2012 and again in 2013; it was approved by the FDA in 2013. In January 2016 Ionis terminated its arrangement with Genzyme, stating that the drug had been poorly marketed. In May 2016, Ionis licensed the rights to mipomersen to Kastle Therapeutics; Kastle paid Ionis $15 million upfront with another $10 million due in May 2019, up to $70 million in milestones based on sales, and royalties, and Ionis has to pay 3% royalty and 3% of non-cash royalty it receives to Genzyme. Mipomersen has still not been approved in Europe. In December 2016, Ionis' drug nusinersen was approved by the FDA. It had been discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis and preclinical work was done at University of Massachusetts. The drug was initially developed by Ionis, which partnered with Biogen on development starting in 2012, and in 2015 Biogen acquired an exclusive license to the drug for a $75 million license fee, milestone payments up to $150M, and tiered royalties between 10 and 15% thereafter; Biogen also paid for all development subsequent to taking the license. The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor and University of Massachusetts. As of December 2016, Ionis had ten candidates for various liver diseases in clinical trials and a drug it discovered, alicaforsen, was in a Phase III trial run by another company. It also had a huntingtin gene-lowering antisense molecule for Huntington's disease in the clinic as well.
