Ionis Pharmaceuticals

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Ionis Pharmaceuticals
Isis Pharmaceuticals
Russell 1000 Component
ProductsMipomersen, nusinersen, inotersen
RevenueIncrease $507 million (2017)

Ionis Pharmaceuticals (NASDAQIONS) (known as Isis Pharmaceuticals until December 2015)[1] is a publicly traded pharmaceutical company based in Carlsbad, California, United States. The company was founded in 1989 by Stanley Crooke, a former GlaxoSmithKline head of research, with a goal to commercialize antisense therapy.[2]

The company received its first FDA approval for an investigational new drug application in 1992, marking the first time any antisense drug was approved to be tested in humans; the IND was for Isis' genital warts drug candidate.[3]

The company and others founded to bring antisense drugs to market faced early failures; Isis' lead compound for genital warts failed in clinical trials and Isis terminated development in 1995; by that time two other companies working on antisense, Gilead Sciences and Genta had left the field, leaving Isis, Hybridon, and Lynx Therapeutics working in the field.[4] Gilead sold the patents it had developed around antisense to Isis.[5]

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.[1][6]

In 2017, the company spun out[7] its rare lipid disorder subsidiary Akcea Therapeutics.[8]

Drug pipeline[edit]

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.[9] It was discovered at the NIH and was licensed and initially developed by Isis, which subsequently licensed it to Novartis.[10] It was approved by the FDA for CMV in Aug 1998, and was the first antisense drug that was approved.[11] Novartis withdrew the marketing authorization in the EU in 2002[12] and in the US in 2006.[13] While initially, the rising incidence of CMV in people with AIDS created a need for drugs that treated this virus, the drug was withdrawn because the development of HAART dramatically reduced the number of cases of CMV.[10]

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.[11] 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.[14] 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.[15] 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.[16]

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.[17]

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.[18] Mipomersen was rejected by the European Medicines Agency in 2012[19] and again in 2013;[20] it was approved by the FDA in 2013.[11] In January 2016 Ionis terminated its arrangement with Genzyme, stating that the drug had been poorly marketed.[21] 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.[22] As of December 2016 mipomersen had still not been approved in Europe, and the drug had still been poorly marketed.[15]

In December 2016, Ionis' drug nusinersen (Spinraza) was approved by the FDA.[23] It had been discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis (then Isis)[24][25][15][26] and preclinical work was done at University of Massachusetts.[27] 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.[28] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor and University of Massachusetts.[29]

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.[15] It also had a huntingtin gene-lowering antisense molecule for Huntington's disease in the clinic as well.[30]


  1. ^ a b Fikes, Bradley. "From Isis Pharma to Ionis". The San Diego Union-Tribune. San Diego Union Tribune. Retrieved 22 December 2015.
  2. ^ Crooke, Stanley T (21 July 2011). "The Isis manifesto". Bioentrepreneur. doi:10.1038/bioe.2011.7.
  3. ^ Fisher, Lawrence M. (8 March 1992). "Making a Difference; A Green Light for Isis". The New York Times.
  4. ^ Fisher, Lawrence M. (29 December 1995). "Isis Drops Human Trials of a Genetic Drug". The New York Times.
  5. ^ Jarvis, Lisa M. (April 17, 2006). "Cover Story - Back In The Game". Chemical & Engineering News.
  6. ^ Workman, Karen (20 November 2015). "When You're Named Isis for the Goddess, Not the Terror Group". The New York Times.
  7. ^ "Xconomy: Ionis Pharma Spins Out Lipid Disorder Unit Akcea with Plans for IPO". Xconomy. 2017-03-27. Retrieved 2018-07-03.
  8. ^ House, SA Editor Douglas W. (2017-06-20). "Ionis ready to spin out Akcea; IPO announced at $12 - 14/share". Seeking Alpha. Retrieved 2018-07-03.
  9. ^ Katzung, Bertram G. (2006). Basic and Clinical Pharmacology (10th ed.). New York: McGraw-Hill Medical Publishing Division. p. 817. ISBN 978-0-07-145153-6.
  10. ^ a b Bubela, Tania; McCabe, Christopher (21 July 2014). "Value-Engineered Translation: Developing Biotherapeutics That Align With Health-System Needs". American Journal of Managed Care.
  11. ^ a b c Jiang, Kevin (February 19, 2013). "Biotech comes to its 'antisenses' after hard-won drug approval : Spoonful of Medicine". Nature Medicine: Spoonful of Medicine Blog.
  12. ^ "Public Statement on Vitravene (fomiversen): Withdrawal of the Marketing Authorization in the European Union" (PDF). EMA. August 6, 2002.
  13. ^ "Initiating Coverage: Rexahn Pharmaceuticals (RNN)" (PDF). LifeSci Capital. May 23, 2016.
  14. ^ Filmore, David (June 2004). "Assessing antisense" (PDF). Modern Drug Discovery.
  15. ^ a b c d Offord, Catherine (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.
  16. ^ "Company News; Isis Pharmaceuticals to Cut 40% of Workforce". The New York Times. 11 January 2005.
  17. ^ Pollack, Andrew (7 September 2007). "Two Biotech Companies Agree to Form a Joint Venture". The New York Times.
  18. ^ Pollack, Andrew (8 January 2008). "Genzyme Wins Cholesterol Drug Deal". The New York Times.
  19. ^ "EMA committee shoots down Sanofi's cholesterol drug mipomersen". FierceBiotech. December 14, 2012.
  20. ^ "Refusal of the marketing authorisation for Kynamro (mipomersen)" (PDF). EMA. March 21, 2013.
  21. ^ Fikes, Bradley J. (January 11, 2016). "Ionis takes back heart drug Kynamro". San Diego Union Tribune.
  22. ^ "Ionis Sells Kynamro Rights to Kastle for Up to $95M+ | GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business | GEN". Genetic Engineering News. May 3, 2016.
  23. ^ Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  24. ^ Garber, K (11 October 2016). "Big win possible for Ionis/Biogen antisense drug in muscular atrophy". Nature Biotechnology. 34 (10): 1002–1003. doi:10.1038/nbt1016-1002. PMID 27727217.
  25. ^ Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science.
  26. ^ Tarr, Peter (24 December 2016). "CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL". Cold Spring Harbor Laboratory.
  27. ^ "Therapeutic Approaches". Cure SMA. Retrieved 1 January 2017.
  28. ^ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016
  29. ^ "Press release: Biogen and Ionis Pharmaceuticals Report Nusinersen Meets Primary Endpoint at Interim Analysis of Phase 3 ENDEAR Study in Infantile-Onset Spinal Muscular Atrophy". Biogen. August 1, 2016.
  30. ^ Gallagher, James (2015-10-19). "Landmark Huntington's trial starts - BBC News". BBC News. Retrieved 18 April 2016.

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