2021-12-30| R&D

AstraZeneca, Ionis Close $3.5+ Billion Deal for Rare Protein Misfolding Disorder

by Joy Lin
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AstraZeneca and Ionis Pharmaceuticals, an RNA-focused company based in California, has closed a deal worth over $3.5 billion to advance eplontersen, a treatment for a rare protein misfolding disorder that results in heart failure and peripheral nerve dysfunction. The two companies previously announced the collaboration over eplontersen on December 7.

AstraZeneca is paying Ionis $200 million upfront and up to $485 million following regulatory approvals. Ionis could receive up to $2.9 billion in milestone payments if eplontersen passes $500 million to $6 billion in sales. Additionally, Ionis could collect “low double-digit to mid-twenties” royalties depending on the regions where the drug is sold. 

Ionis is handling eplontersen production and supply as the drug undergoes clinical trials and approval, while AstraZeneca will take over commercial supply when the drug is approved for marketing. 

Eplontersen, an Antisense Answer for ATTR


ATTR results from aging or genetic mutations could cause misfolding of the transthyretin protein. Misfolded proteins build up as amyloid fibrils in organs and tissues, such as the heart and peripheral nerves. ATTR is progressive and fatal if left untreated, as amyloid accumulation in tissues result in heart failure and nerve damage. There are hereditary and wild-type forms of the disease. 

Eplontersen is designed to treat all types of ATTR, by reducing the production of transthyretin. The drug consists of a liver-targeting molecule (ligand) linked to an antisense oligonucleotide, which prevents translation of transthyretin.

The drug was previously shown to reduce transthyretin levels by up to 94% in Phase 1 trial. In July, Ionis announced that it has completed patient enrollment in a Phase 3 trial called NEURO-TTRansform. The study will investigate treatment of eplontersen in over 160 patients with hereditary transthyretin-mediated amyloid polyneuropathy. 

The company has mentioned that an interim readout of the NEURO-TTRansform is expected in mid-2022, while it would file for a new drug application by the end of the year.

Ionis is also evaluating the drug in a Phase 3 study called CARDIO-TTRansform in patients with hereditary and wild-type cardiomyopathy. 

Eplontersen was formerly known as IONIS-TTR-LRx and AKCEA-TTR-LRx. It was once developed by Akcea, a subsidiary of Ionis which spun out as a standalone company in 2017. After three years of regulatory ups and downs and staff shakeups, Akcea merged back into Ionis in 2020. 

Competitors in the ATTR Space


AstraZeneca is entering a busy space of ATTR treatments. 

Approved therapies for various forms of ATTR include Alnylam’s Onpattro (patisiran), Pfizer’s Vyndaqel (tafamidis) and Ionis’ own Tegsedi (inotersen). 

Intellia Therapeutics has taken aim at ATTR with its gene therapy, NTLA-2001, intended as a one-time treatment for the disease. 

Meanwhile, BridgeBio reported a flop earlier this week for its treatment for ATTR-related cardiomyopathy, acoramidis, in a Phase 3 study.  

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