Eplontersen Granted Orphan Drug Status in US for ATTR Amyloidosis

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by Patricia Inacio PhD |

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The U.S. Food and Drug Administration (FDA) granted orphan drug status to eplontersen, an investigational therapy that seeks to prevent the buildup of toxic protein deposits in people with transthyretin (ATTR) amyloidosis — a group of disorders that also includes familial amyloid polyneuropathy (FAP).

The therapy is being co-developed by Ionis Pharmaceuticals and AstraZeneca.

“Eplontersen has the potential to be a best-in-class treatment to halt the progression of transthyretin-mediated amyloidosis and treat this fatal condition,” Mene Pangalos, PhD, executive vice president of biopharmaceuticals R&D at AstraZeneca, said in a press release.

“The FDA designation further underscores the potential for eplontersen to offer new hope to this patient population currently faced with limited treatment options,” Pangalos said.

Orphan drug status aims to encourage the development of therapies for rare and serious diseases, defined in the U.S. as disorders affecting less than 200,000 people. Treatments granted this designation receive a series of benefits and incentives, including seven years of market exclusivity if approved, credits for clinical testing, and exemption from FDA application fees, which can cost more than $2 million.

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Eplontersen, formerly called AKCEA-TTR-LRx and ION-682884, is an RNA-targeted therapy that halts the production of the TTR protein and, as a consequence, prevents its accumulation in different tissues and organs.

The formation of toxic TTR protein aggregates, or clumps, is a hallmark of ATTR amyloidosis, a group of conditions that also includes FAP, which is a type of hereditary ATTR amyloidosis. FAP is caused by inherited mutations in the TTR gene, which contains instructions for making the TTR protein.

TTR toxic clumps tend to accumulate in peripheral nerves — those found outside the brain and spinal cord — leading to nerve damage, or polyneuropathy.

Following a previous collaboration agreement, eplontersen is being co-developed by Ionis and AstraZeneca in the U.S. AstraZeneca also holds an exclusive license for eplontersen in the rest of the world, except Latin America.

The experimental therapy is being tested in the ongoing Phase 3 NEURO-TTRansform trial (NCT04136184) in adults with FAP (stage 1 or 2).

Participants were randomly assigned to receive eplontersen, delivered once every four weeks, or Ionis’ Tegsedi (inotersen), an approved FAP therapy, once a week for 65 weeks (over a year). Both are given by an under-the-skin injection.

Within eight months, patients treated with Tegsedi will switch to eplontersen until the end of the study.

The trial’s main goal is to assess changes in blood TTR levels, as well as nerve damage progression, and quality of life. The findings will be compared with those of the placebo group from a previous Phase 2/3 trial (NCT01737398) that tested Tegsedi versus a placebo in adults with FAP.

Another Phase 3 trial, CARDIO-TTRansform (NCT04136171), will test eplontersen in adults with inherited ATTR amyloidosis with cardiomyopathy (heart disease) and wild-type AATR amyloidosis — a form of the disease not linked to any known genetic mutations. The trial is actively enrolling participants and more information can be found here.

According to the press release, FAP is expected to be the first indication for which Ionis and AstraZeneca will seek eplontersen’s approval in the U.S. This application is expected to be filed by year’s end.