Eplontersen Gains FDA Fast Track Designation for Transthyretin-Mediated Amyloid Cardiomyopathy


The antisense oligonucleotide will continue to be assessed in a large-scale phase 3 study, CARDIO-TTRansform, which will have data read out in 2025.

Eugene Schneider, MD, executive vice president and chief medical development officer at Ionis

Eugene Schneider, MD

Months after the FDA approved Ionis’ eplontersen (Wainua) as a treatment for polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN), the agency has granted fast track designation for an extended indication to treat adults with ATTR cardiomyopathy (ATTR-CM). The therapy is currently being assessed in the global, phase 3 CARDIO-TTRansform study (NCT04136171), a 1400-patient cohort trial that’s considered the largest of ATTR-CM to date.1

"Receiving Fast Track designation from the FDA reinforces our belief that eplontersen has the potential to be a transformational treatment for patients with ATTR-CM, which remains a progressive and fatal condition for hundreds of thousands of people worldwide despite available treatment options,” Eugene Schneider, MD, executive vice president and chief medical development officer at Ionis, said in a statement.1 "CARDIO-TTRansform is the largest, most comprehensive study ever conducted in ATTR-CM patients, with results expected as early as next year."

CARDIO-TTRansform, a multicenter, double-blind study, will randomize patients to receive subcutaneous injections of either eplontersen or placebo once every 4 weeks for up to 140 weeks. Participants will also receive daily supplemental doses of the recommended daily allowance of vitamin A. The primary outcome is the composite outcome of cardiovascular (CV), mortality, and recurrent CV clinical events up to 140 weeks while secondary outcomes include change in 6-minute walk test (6MWT) distance and change in Kansas City Cardiomyopathy Questionnaire scores at week 121.

The study excludes those with cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy due to hypertension, valvular heart disease, or ischemic heart disease. Additionally, those with current or previous treatment with inotersen (Tegsedi) or patisiran (Onpattro) or other oligonucleotide or ribonucleic acid therapeutic are ineligible as well. Notably, this does not apply to those with the COVID-19 mitochondrial vaccinations.

"We are committed to accelerating innovation and addressing the spectrum of unmet patient needs in amyloidosis,” Sarah Walters, vice president of US cardiovascular, renal, and metabolic diseases at AstraZeneca, said in a statement.1 "Together with our partner Ionis, AstraZeneca is building on our heritage in cardiovascular disease and RNA-targeted therapeutics to bring a potential best-in-class treatment for people living with ATTR-CM."

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In December 2023, the FDA approved eplontersen, a ligand conjugated antisense oligonucleotide, as a treatment for patients with ATTRv-PN. With the decision, it became the only marketed therapy for ATTRv-PN that can be self-administered via an autoinjector.2

Eplontersen was approved based on data from an interim analysis of the phase 3 NEURO-TTransform trial (NCT04136184), a long-term study where patients were randomly assigned 6:1 to eplontersen (n = 144) or inotersen, AstraZeneca’s previously approved therapy for hATTR, for a 66-week double-blind period, followed by an open-label extension. Results presented at the 2022 American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting showed a least square mean percent reduction of 81.2% for TTR after 35 weeks of treatment, vs 14.8% reduction for those on placebo (P <.0001). In addition, eplontersen resulted in reductions in neuropathy impairment and improvements in quality of life compared with placebo.3

On secondary end points, eplontersen treatment resulted in a statistically significant difference in change from baseline in the Neuropathy Impairment Score plus 7 (mNIS+7) and the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (QoL-DN) compared with external placebo (P <.0001 for both). The treatment effect and efficacy of eplontersen were consistent across disease stage and mutation type for the mNIS+7 and Norfolk QoL-DN end points, and with previous treatment by stabilizers for mNIS+7.

In another analysis of the study, eplontersen resulted in halted neuropathy progression and improved quality of life at 85 weeks in patients with ATTRv-PN.2 At week 85, investigators observed a mean reduction of 81.8% in serum TTR concentration relative to baseline for eplontersen-treated patients vs a 70.4% (95% CI, –75.2 to –65.7%; P <.0001) LSMD at week 65 for those on placebo. Patients on eplontersen showed improvement in neuropathy impairment through 19 months of treatment, indicated by mean reductions of –2.9 in mNIS+7 composite score.4

1. Eplontersen granted US fast track designation for patients with transthyretin-mediated amyloid cardiomyopathy. News release. Ionis. February 8, 2024. Accessed February 26, 2024. https://ir.ionispharma.com/news-releases/news-release-details/eplontersen-granted-us-fda-fast-track-designation-patients
2. WAINUA™ (eplontersen) granted regulatory approval in the U.S. for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis. News Release. Ionis Pharmaceuticals. Published December 21, 2023. Accessed February 26, 2024. https://www.prnewswire.com/news-releases/wainua-eplontersen-granted-regulatory-approval-in-the-us-for-the-treatment-of-adults-with-polyneuropathy-of-hereditary-transthyretin-mediated-amyloidosis-302021385.html
3. Eplontersen continued to show improvement in ATTRv-PN through 85 weeks. News release. Ionis Pharmaceuticals. July 10, 2023. Accessed February 26, 2024. https://www.prnewswire.com/news-releases/eplontersen-continued-to-show-improvement-in-attrv-pn-through-85-weeks-301872558
4. Coelho T, Cruz M, Chao C, et al. Eplontersin in Attr-Polyneuropathy: Results From the 35-Week Interim Analysis of Neurottransform. Presented at: AANEM 2022; September 21-24; Nashville, TN. Poster 30.
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