Ionis Pharmaceuticals

Drug pipeline

The company's first marketed drug was fomivirsen (Vitravene) which was used in the treatment of cytomegalovirus retinitis (CMV) 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 in the EU in 2002 and in the US in 2006. The drug was withdrawn because while there was a high unmet need for drugs to treat CMV when the drug was initially discovered and developed due to the CMV arising in people with AIDS, 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 treated to make them into drugs which prevented some hydrolysis but 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 had to 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, partnered to form a 50/50 joint venture, Regulus Therapeutics, to apply their intellectual property and know-how around oligomer biotherapeutics to micro-RNA targets.

In 2008 Isis and Genzyme entered into a partnership agreement for the drug candidate mipomersen (Kynamro), intended to treat homozygous familial hypercholesterolemia and other drug candidates; the deal included Genzyme buying $150M of Isis stock and paying a $175M 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. As of December 2016 mipomersen had still not been approved in Europe, and the drug had still been poorly marketed.

In December 2016, Ionis' drug nusinersen (Spinraza) was approved by the FDA. It had been discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis (then Isis) 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-lowering antisense molecule for Huntington's disease in the clinic as well.