Ionis and AstraZeneca Team Up on Antisense Drug for ATTR

Ionis building exterior. Photo courtesy of Ionis. 

Ionis Pharmaceuticals, based in Carlsbad, Calif., inked a collaboration deal with AstraZeneca to develop and commercialize eplontersen for transthyretin amyloidosis (ATTR). 

ATTR is a systemic, progressive and fatal illness caused by the formation and accumulation of TTR amyloid deposits in organs, including the heart, eyes, peripheral nerves, intestinal tract, kidneys, central nervous system, thyroid and bone marrow. 

Under the terms of the deal, AstraZeneca is paying Ionis $200 million up front. There is another $485 million in development and approval milestones and up to $2.9 billion in sales-related milestones. Ionis is also eligible for low double-digit royalties to mid-20s percentage, depending on the territory involved.

Ionis will continue to run a global Phase III trial in patients with hereditary ATTR amyloidosis with polyneuropathy (NEURO-TTRansform) and cardiomyopathy (CARDIO-TTRansform). Ionis will also manufacture and supply the drug for ongoing trials and process qualifications. 

AstraZeneca will handle the commercial supply of eplontersen when the timing of the changeover is determined. They will split responsibilities for regulatory issues, and commercial operations in the U.S. AstraZeneca will pick up an exclusive license for the drug outside the U.S. except for specific countries in Latin America.

Eplontersen is an antisense drug developed using Ionis’ Ligand-Conjugated Antisense (LICA) technology. It is designed to decrease the production of transthyretin to treat all forms of TTR amyloidosis. Antisense is a non-coding DNA strand of a gene. 

Normally, the antisense DNA is used by the cell as a template for producing messenger RNA (mRNA). mRNA transports the code from the DNA to the ribosomes, where proteins are manufactured. Antisense drugs typically act as a way of silencing genes by introducing a second gene that produces mRNA complementary to the one manufactured by the target gene. The two mRNAs then interact to form a double-stranded structure that can’t be used for protein synthesis.

“We believe that bringing together Ionis’ industry-leading experience in RNA-targeted therapeutics and deep knowledge of the TTR amyloidosis market with AstraZeneca’s global scale and leadership in cardiovascular drug development and commercialization will enable faster and deeper market penetration for the benefit of patients,” said Brett P. Monia, Ionis’s chief executive officer. “In addition to being the best strategy to maximize patient and shareholder value for eplontersen, this agreement also represents a key step in bolstering our commercial organization as we prepare to launch multiple products.”

In late November, Ionis announced that its development partner Pfizer provided an update on its Phase IIb trial of vupanorsen. This drug, also an antisense therapy, is being evaluated for indications of cardiovascular risk reduction and severe high triglycerides. The trial hit the primary endpoint in the dose-ranging study in patients with elevated non-HDL-C and triglycerides (TG). It had a statistically significant decrease in non-HDL-C at all doses tested at 24 weeks compared to placebo. It also demonstrated statistically significant reductions in TG and ANGPTL3 at all dose levels at 24 weeks compared to placebo.

“We were pleased to see statistically significant reductions in the primary endpoint, non-HDL-cholesterol, and in the secondary endpoint of triglycerides at all doses tested,” said Sotirios “Sam” Tsimikas, vice president of global cardiovascular development and cardiovascular franchise lead at Ionis. “The topline results of the Phase IIb study also showed that vupanorsen dose-dependently lowered its target, angiopoietin-like 3. Pfizer is continuing to review the findings to determine next steps regarding future development. We look forward to the full data set being presented at a medical meeting next year.”

Pfizer licensed fupanorsen from Ionis in November 2019.