Eplontersen treatment resulted in a significant reduction in transthyretin, neuropathy impairment, and improvement in quality of life in the phase 3 NEURO-TTRansform study of patients with hereditary transthyretin amyloidosis.
Teresa Coelho, MD
Data from recent phase 3 NEURO-TTransform trial (NCT04136184) of eplontersen (Ionis, AstraZeneca) suggest that the investigational treatment for hereditary transthyretin (hATTR) amyloidosis reduced serum transthyretin (TTR) at 35 weeks.1
All told, the least square mean percent reduction of TTR was 81.2% from baseline to Week 35 in those treated with eplontersen, compared with a 14.8% reduction for the placebo group (P <.0001). Also of note, the treatment also resulted in reductions in neuropathy impairment and improvements in quality of life compared with placebo.
Teresa Coelho, MD, neurologist and neurophysiologist at Hospital Santo António, and colleagues presented the results at the 2022 American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting. The trial enrolled 168 patients, of whom 144 were randomly assigned to the eplontersen arm, and 24 to a reference arm, who were treated with inotersen (Tegsedi; Akcea Therapeutics), with an external placebo group of 60 patients. Participants with amyloidosis and polyneuropathy were enrolled in the phase 3, multicenter, open-label, trial. Eplontersen, an investigational ligand-conjugated antisense oligonucleotide, is designed to degrade hepatic transthyretin mRNA and inhibit transthyretin protein synthesis.
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). Coelho and colleagues noted that 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.
As for safety, treatment-emergent adverse events (AEs) related to study drug and drug discontinuation rates were lower or similar for the eplontersen compared with the external placebo. Overall, the authors deemed the treatment favorably safe and tolerated, with a low incidence of injection site reactions (1.4%), and no serious AEs related to treatment.
Adult patients enrolled were aged 18 to 82 years diagnosed with amyloidosis and polyneuropathy were randomly assigned by the ratio of 6:1 to receive 45-mg subcutaneous eplontersen every 4 weeks, or the 300-mg subcutaneous inotersen weekly for 34 weeks and then eplontersen.
Previously, Coelho et al presented data at the International Symposium on Amyloidosis that suggested the phase 3 NEURO-TTRansform study of eplontersen was positive, with the investigational treatment for hereditary transthyretin-mediated amyloid polyneuropathy demonstrated significant changes for the coprimary and secondary end points compared with the placebo. Coelho said in a statement at the time that, "eplontersen showed clinically meaningful improvement in neuropathy impairment and quality of life measures relative to baseline. The significant efficacy, combined with a favorable safety and tolerability profile, indicate that eplontersen has the potential to be an important therapeutic option for patients living with this debilitating and fatal disease."2