Eplontersen Gains Positive CHMP Approval Recommendation for ATTR Polyneuropathy

Brett P. Monia, PhD

According to a new announcement, the Committee for Medicinal Products for Human Use (CHMP) has recommended approval for Ionis’ and AstraZeneca’s eplontersen (Wainua) as a treatment for adults with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). Eplontersen, the only self-administered treatment for ATTRv-PN via an auto-injector, was first approved in the United States last December.^1,2

The CHMP’s opinion was based on findings from the phase 3 NEURO-TTRansform trial (NCT04136184), a global, open-label, randomized trial that assessed the therapy over an 85-week period. In the data, published in the JAMA, eplontersen demonstrated benefits across the spectrum of ATTRv-PN at 35, 66, and 85 weeks of treatment. Eplontersen, a once-monthly RNA-targeted medicine that provides upstream suppression of transthyretin (TTR) production, is an injection treatment administered subcutaneously in 45 mg doses.

"Hereditary transthyretin-mediated amyloidosis with polyneuropathy remains a progressive and debilitating disease in Europe and other parts of the world, despite currently available medicines," Brett P. Monia, PhD, chief executive officer at Ionis, said in a statement.¹ "The CHMP recommendation is an important step toward making WAINZUA available in Europe, which, if approved, will be the only medicine in the EU for the treatment of transthyretin-mediated amyloidosis with polyneuropathy that can be self-administered monthly via an auto-injector."

He added, "We are proud to partner with AstraZeneca whose global leadership and expertise positions our alliance to rapidly and effectively bring WAINZUA to many people living with hereditary transthyretin-mediated amyloidosis with polyneuropathy in Europe, pending the EMA's decision."

In NEURO-TTRansform, patients with ATTRv-PN were randomly assigned 6:1 to either eplontersen (n = 144) or inotersen (Tegsedi), AstraZeneca’s previously approved therapy for hATTR, for a 66-week double-blind period, followed by an open-label extension. The study also included a 60-patient external placebo control group. After 35 weeks of treatment, interim data showed a least square mean percent reduction of 81.2% in TTR for eplontersen-treated patients vs a 14.8% reduction for those on placebo (P <.0001).

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Quality of life, evaluated through the Norfolk QoL-DN, was substantially improved in treated patients, with mean changes of –6.2 from baseline at week 85. In comparison, at week 66, there was a least square mean difference (LSMD) of –19.7 (95% CI, –25.6 to –13.8; P <.0001) when comparing with placebo. At week 66, 57.6% of treated patients showed improvements on Norfolk QoL-DN compared with only 20.0% of those on placebo.

Earlier this year, an analysis of NEURO-TTransform showed that eplontersen was effective in improving neuropathy impairment and quality of life regardless of changes in modified body mass index (mBMI). Presented at the 2024 International Symposium on Amyloidosis, the analysis categorized patients by change from baseline in mBMI at week 66 (>10% decrease; <2.5 to 10% decrease; –2.5 to +2.5% change; >2.5 to 10%; >10% increase). Overall mean differences in modified Neuropathy Impairment Score +7 (mNIS+7), a secondary end point, were –29.5 (95% CI, –45.5 to –13.5) for greater than 10% mBMI decrease, –17.8 (95% CI, –30.1 to –5.5) for <2.5 to 10% decrease, –17.8 (95% CI, –30.8 to –3.4) for –2.5 to +2.5% change, and –8.8 (95% CI, –22.9 to 5.3) for between 2.5 and 10% increase.³

Eplontersen is also currently being studied in the phase 3 CARDIO-TTRansform trial (NCT04136171) for the treatment of amyloid transthyretin cardiomyopathy (ATTR-CM), a serious and progressive condition that causes heart failure and leads to death within about four years of diagnosis. The primary endpoint of the trial is a comparison between the two treatment arms in terms of cardiovascular (CV) mortality and recurrent CV clinical events up to week 140. Secondary endpoints include changes from baseline in the 6-minute walk test and Kansas City Cardiomyopathy Questionnaire scores at week 121, along with CV mortality rates, CV clinical events, and all-cause mortality at week 140. The trial has successfully completed enrollment, with over 1400 patients participating.⁴

REFERENCES
1. WAINZUA (eplontersen) recommended for approval in the EU by CHMP for the treatment of adults with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. Ionis Pharmaceuticals. October 21, 2024. Accessed October 21, 2024. https://www.prnewswire.com/news-releases/wainzua-eplontersen-recommended-for-approval-in-the-eu-by-chmp-for-the-treatment-of-adults-with-polyneuropathy-associated-with-hereditary-transthyretin-mediated-amyloidosis-302281460.html
2. Eplontersen continued to show improvement in ATTRv-PN through 85 weeks. News release. Ionis Pharmaceuticals. July 10, 2023. Accessed October 21, 2024. https://www.prnewswire.com/news-releases/eplontersen-continued-to-show-improvement-in-attrv-pn-through-85-weeks-301872558
3. Wixner J, Conceicao I, Berk J, et al. Neuropathy impairment and nutritional status with eplontersen in patients with hereditary transthyretin-mediated amyloidosis. Presented at: 2024 International Symposium on Amyloidosis. ABSTRACT 174.
4. Ionis completes enrollment in landmark Phase 3 CARDIO-TTRansform study in patients with TTR-mediated amyloid cardiomyopathy. News release. July 31, 2023. Accessed October 21, 2024. https://www.prnewswire.com/news-releases/ionis-completes-enrollment-in-landmark-phase-3-cardio-ttransform-study-in-patients-with-ttr-mediated-amyloid-cardiomyopathy-301888878.html