Ionis, AstraZeneca Team Up to Further Develop Eplontersen

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by Steve Bryson PhD |

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Ionis Pharmaceuticals has entered into a collaboration agreement with AstraZeneca to develop and commercialize eplontersen, Ionis’ investigational therapy to treat transthyretin amyloidosis (ATTR).

ATTR amyloidosis is a group of conditions characterized by the formation of toxic aggregates or clumps of the TTR protein that build up in organs and tissues, including the heart and nerves.

Familial amyloid polyneuropathy (FAP) is a form of ATTR amyloidosis caused by inherited mutations in the TTR gene, which encodes for the TTR protein. In FAP, toxic clumps accumulate in the nerves that extend from the brain and spinal cord — known as peripheral nerves — leading to nerve damage, or polyneuropathy.

Eplontersen, formerly known as AKCEA-TTR-LRx and IONIS-TTR-LRx, is an RNA-targeted therapy designed to reduce the production of TTR protein, potentially preventing toxic clump formation. The therapy was developed with Ionis’ LIgand-Conjugated Antisense (LICA) technology.

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“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,” Brett P. Monia, PhD, CEO of Ionis, said in a press release.

Under the terms of the agreement, Ionis will continue to lead the global Phase 3 clinical trials in patients with FAP and ATTR amyloidosis with cardiomyopathy (heart muscle disease). They will also produce and supply eplontersen for ongoing trials, as well as ensure manufacturing and production process qualification.

AstraZeneca will be responsible for the therapy’s commercial supply, with the timing of transitioning from trials to the marketplace agreed upon by both companies. Except in certain Latin American countries, AstraZeneca will have an exclusive license for eplontersen outside the U.S. Further, both companies will share responsibility for medical affairs and commercial activities in the U.S.

In addition, Ionis will receive a $200 million payment in advance, up to $485 million in milestones payments related to the development and regulatory approval milestones, and up to $2.9 billion in sales-based milestone payments. The collaboration also includes development, commercial, and medical affairs cost-sharing allocations tied to specific territories. Depending on the regions, Ionis will be eligible to earn royalties.

According to the companies, the agreement is expected to become effective by the end of this year.

“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,” Monia said.

Ionis is sponsoring the ongoing Phase 3 NEURO-TTRansform trial (NCT04136184) at sites across 16 countries. It is evaluating the effectiveness and safety of eplontersen in adults with stage 1 or 2 FAP, with mild to moderate symptoms.

Enrolled participants have been randomly assigned to receive eplontersen once every four weeks or Ionis’ Tegsedi (inotersen; an approved FAP therapy) once a week for 65 weeks (over a year), both by under-the-skin injection. After about eight months, those treated with Tegsedi will switch to eplontersen until the end of the study period.

The trial’s primary goals, assessed at 66 weeks, include changes in bloodstream TTR levels, the progression of nerve damage, and quality of life. Trial treatment data will be compared with the placebo group from a previous Phase 2/3 clinical trial (NCT01737398) that evaluated Tegsedi versus placebo in adults with FAP. Ionis anticipates the NEURO-TTRansform will be complete by January 2024.

FAP is expected to be the first indication for which Ionis and AstraZeneca will apply for regulatory approval for eplontersen by the end of 2022.

Eplontersen is also being tested in the Phase 3 CARDIO-TTRansform trial (NCT04136171), which plans to enroll up to 750 adults ages 18 to 90 with inherited AATR amyloidosis with cardiomyopathy and wild-type AATR amyloidosis — a form of the disease that is acquired, age-related, and not linked to any known genetic mutations. For information on locations and contacts, click here.