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Ionis Pharmaceuticals
Biotechnology company From Wikipedia, the free encyclopedia
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Ionis Pharmaceuticals, Inc. is a biotechnology 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.[6]
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History
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The company was founded in 1989 as Isis Pharmaceuticals by Stanley T. Crooke, a former head of research of GlaxoSmithKline, with the goal of commercializing antisense therapy.[7]
In 1992, the company received its first approval by the Food and Drug Administration for an investigational new drug application in 1992 for a genital warts drug candidate. The FDA approval marked the first time for the company to conduct any antisense therapy and to be tested in humans.[8]
In 1995, their oligonucleotide-based drug for genital warts failed in clinical trials and Isis terminated development. By that time, Gilead Sciences had left the field of antisense therapy, leaving only Isis, Hybridon, Genta and Lynx Therapeutics working in the field.[9] Gilead sold its patents, developed around antisense, to Isis.[10]
In 1998 the company launched its first drug fomivirsen (Vitravene, used to treat cytomegalovirus retinitis (CMV) in immunocompromised patients).[11] It was approved by the FDA for CMV in August 1998 as the first antisense drug.[12] Novartis withdrew the marketing authorization for fomivirsen in the European Union in 2002[13] and in the United States in 2006. It was discovered at the NIH and was licensed and initially developed by Isis, which subsequently licensed it to Novartis.[14] The drug was withdrawn because the development of HAART dramatically reduced the number of cases of CMV retinitis.[14]
In 2005 the company cut its workforce by 40% owing to weak sales of fomivirsen and waning market confidence in the company's antisense technology.[15]
In 2007, Isis and Alnylam Pharmaceuticals formed a 50/50 joint venture, Regulus Therapeutics, to apply their intellectual property and knowledge around oligomer biotherapeutics to micro-RNA targets.[16]
In 2008, Isis and Genzyme entered into a partnered drug candidate mipomersen (Kynamro), intended to treat homozygous familial hypercholesterolemia, and other drug candidates [which?]; the deal included Genzyme buying $150 million of Isis stock and paying a $175 million license fee, as well as milestone fees and royalties.[17] Mipomersen was rejected by the European Medicines Agency in 2012[18] and again in 2013;[19] it was approved by the FDA in 2013.[12] In January 2016, Ionis terminated its arrangement with Genzyme, stating that the drug had been poorly marketed.[20] In May 2016, Ionis licensed the rights to the drug to Kastle Therapeutics for $15 million upfront with another $10 million due in May 2019, up to $70 million in milestones based on sales, and royalties, with Ionis paying 3% royalty and 3% of non-cash royalty it receives to Genzyme.[21]
In December 2015, Isis Pharmaceuticals changed name to Ionis Pharmaceuticals, driven in part by the rise of an international terrorist group, Islamic State of Iraq and the Levant, commonly known as ISIL or ISIS in news media.[6][22]
In 2016 Ionis gained approval of Sprinraza which was the first approved treatment for spinal muscular atrophy. The drug would subsequently Ionis's first blockbuster.
In 2017, Ionis completed a corporate spin-off of Akcea Therapeutics, which it subsequently reacquired in 2020.[23][24]
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Current Products
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Spinraza
In December 2016, Ionis's drug nusinersen (Spinraza) was approved by the FDA.[25] It had been discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis (then Isis)[26][27][28][29] and preclinical work was done at University of Massachusetts.[30] The drug was initially developed by Ionis, which partnered with Biogen on development starting in 2012; 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.[31] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor and University of Massachusetts.[32]
Tegsedi
In July 2018, the European Commission approved Tegsedi (inotersen) for the treatment of stage 1 or 2 polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis (hATTR).[33] In October 2018, the U.S. Food and Drug Administration (FDA) granted approval for the same indication.[34] Approval was based on the Phase III NEURO-TTR trial, which demonstrated significant improvements in neurological function (mNIS+7 score) and quality of life (Norfolk QoL-DN questionnaire) compared with placebo.[35]
Tegsedi is an antisense oligonucleotide that binds to transthyretin (TTR) mRNA, reducing production of both mutant and wild-type TTR protein. This slows amyloid deposition in peripheral nerves and helps preserve neurologic function.[36] It is administered by weekly subcutaneous injection at a dose of 284 mg and carries a boxed warning for thrombocytopenia and glomerulonephritis. Regular platelet counts and renal monitoring are required; treatment interruption or discontinuation may be necessary in some patients.
While the approval of Tegsedi marked an early milestone for antisense oligonucleotide therapies in systemic amyloidosis, its utility has largely been usurped by newer generation drugs including RNA interference agents (such as patisiran) and next-generation ASOs (such as eplontersen; see below).[37]
Waylivra
In May 2019, the European Commission granted conditional marketing authorization for Waylivra (volanesorsen) as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome (FCS) at high risk for pancreatitis, for whom response to diet and triglyceride-lowering therapy had been inadequate.[38] The approval followed a positive opinion from the EMA’s CHMP in **March 2019**.[39] Waylivra is an antisense oligonucleotide (ASO) targeting **apolipoprotein C-III (apoC-III) mRNA, reducing apoC-III production which leads to lowers plasma triglyceride levels reduced pancreatitis risk in FCS patients.[40]
In Brazil, Waylivra received **regulatory approval as the first treatment for FCS, with innovative drug pricing classification, and PTC Therapeutics submitted applications for a new indication in familial partial lipodystrophy (FPL).[41][42]
The administration regimen begins with once-weekly subcutaneous injections. After three months, patients with sufficient triglyceride reduction may transition to bi-weekly dosing; further adjustments are made at six and nine months depending on response and platelet monitoring.[43]
Safety concerns have plagued Waylivra, including thrombocytopenia which require regular platelet monitoring.[44] Due in large part to these issues the drug never gained FDA approval in the US.
Qalsody
In April 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Qalsody (tofersen) for the treatment of amyotrophic lateral sclerosis (ALS) in adults with a mutation in the superoxide dismutase 1 (SOD1) gene.[45] Qalsody is an antisense oligonucleotide designed to bind to SOD1 mRNA and reduce production of the toxic SOD1 protein. Approval was based on reductions in plasma neurofilament light chain (NfL), a biomarker of neurodegeneration, rather than direct clinical improvement.[46] The decision was supported by the Phase 3 VALOR trial and its open-label extension, which showed meaningful biomarker changes despite not meeting primary clinical endpoints.[47] Continued marketing is contingent on confirmatory trials demonstrating clinical benefit. The confirmatory Phase 3 ATLAS trial is ongoing to assess whether early, pre-symptomatic treatment can delay disease onset in individuals with SOD1 mutations.[48] Early real-world data suggest some patients show stabilization or even neurological improvement, though long-term safety and efficacy remain under study.[49][50]
In May 2024, the European Medicines Agency recommended approval of Qalsody under exceptional circumstances, and the European Commission subsequently granted marketing authorization.[51]
In December 2024, the Centers for Medicare & Medicaid Services (CMS) clarified that Medicare Advantage plans must cover Qalsody, reversing earlier denials that had classified the drug as experimental.[52]
Qalsody is administered via intrathecal injection (lumbar puncture). The regimen begins with three loading doses 14 days apart, followed by maintenance doses every 28 days.[53]
Wainua
In December 2023, the U.S. Food and Drug Administration (FDA) approved Wainua (eplontersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.[54] Wainua is a ligand-conjugated antisense oligonucleotide (LICA) that reduces hepatic production of transthyretin (TTR), mitigating pathogenic amyloid deposition in peripheral nerves.[55] Approval was based on the Phase III NEURO-TTRansform trial, which demonstrated that once-monthly 45 mg subcutaneous autoinjector dosing of Wainua led to sustained reductions in serum TTR levels and improvements in neuropathy impairment (mNIS+7) and quality of life (Norfolk QoL-DN) compared to historical controls.[56]
In October 2024, the European Medicines Agency's CHMP issued a positive opinion recommending approval, and Wainua received marketing authorization in the EU in March 2025.
Wainua is administered as a self-administered subcutaneous injection of 45 mg once monthly via auto-injector.
Tryngolza
In December 2024, Ionis Pharmaceuticals secured FDA approval for Tryngolza (olezarsen), a treatment for familial chylomicronemia syndrome (FCS), a rare and life-threatening genetic condition that prevents the body from properly breaking down fats.[57][58] This marks a corporate milestone for Ionis, as it prepares for its first independent drug launch in its 35-year history. The approval was based on late-stage trial data showing that Tryngolza effectively reduced triglyceride levels and was generally well-tolerated.[59] Patients receiving the therapy were also less likely to experience pancreatitis, a severe and potentially fatal complication characterized by painful inflammation of the pancreas.[60]
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