Eplontersen Effective in Hereditary Transthyretin-Mediated Amyloidosis Regardless of BMI Changes or Sex

Jonas Wixner, MD, PhD

Findings from a new analysis of the phase 3 NEURO-TTRansform study (NCT04136184) revealed that treatment with eplontersen (Wainua; Ionis), an FDA-approved therapy for patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), was effective in improving neuropathy impairment and quality of life (QoL) regardless of changes in modified body mass index (mBMI).¹

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.

Led by Jonas Wixner, MD, PhD, a specialist physician at the Umeá University Hospital in Umeá, Sweden, the analysis specifically focused on whether benefits observed from the original study are found in those with worsening nutritional status. The patient cohort comprised of 144 individuals with ATTR on eplontersen and 60 on placebo, with a mean age of 54.9 (SD, 15.0) years old. In addition to changes in mNIS+7, investigators also observed effects on Norfolk QoL-Diabetic Neuropathy (Norfolk QoL-DN) total score.

READ MORE: Newly Initiated ASPIRE-FTD Trial Opens Door for Gene Therapy to Treat Frontotemporal Dementia

Overall, eplontersen-treated patients continued to outperform placebo across all outcomes regardless of mBMI change during the study. For Norfolk-QoL-DN, the mean differences for active vs placebo-treated patients were –24.3 (95% CI, –38.4 to –10.2) for mBMI decreases greater than 10%, –14.9 (95% CI, –29.1 to –0.8) for decreases between <2.5 and 10%, –15.6 (95% CI, –30.8 to –0.5) for changes of –2.5 to +2.5, and –2.1 (95% CI, –13.5 to 9.2) for increases between 2.5 and 10%.

Eplontersen, a ligand-conjugated antisense oligonucleotide, was approved in December 2023 as a treatment for ATTRv-PN based on 35-week interim data from NEURO-TTRansform.² In the study, treatment with the agent led to an 81.2% least square mean reduction in TTR after 35 weeks of treatment, compared with a 14.8% reduction for the placebo group (P <.0001). Overall, the therapy showed a safe treatment profile, with a low incidence of injection site reactions (1.4%), and no serious adverse events related to treatment.

An additional analysis from the study presented at the meeting showed that eplontersen reduces neuropathy and improves QoL regardless of sex. Overall, 100 male and 44 female patients were randomized to receive eplontersen in the study, with changes observed at 66 weeks. On mNIS+7 composite score, male and female patients experienced improvements of 23.7 and 24.4, respectively, over the treatment period. Similarly, on Norfolk QoL-DN total score, these 2 groups had improvements of 11.2 and 9.8, respectively.³

REFERENCES
1. 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.
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 July 16, 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. Cruz MW, Berk J, Parman Y, et al. Eplontersen for hereditary transthyretin amyloidosis with polyneuropathy: an exploratory analysis of treatment effect in male and female patients. Presented at: 2024 International Symposium on Amyloidosis. ABSTRACT 202.