Ionis’s Eplontersen Phase 3 Results Show Consistent and Sustained Benefit in Patients with ATTRv-PN

Rare Daily Staff

Ionis Pharmaceuticals reported that The Journal of the American Medical Association published positive results from the phase 3 NEURO-TTRansform study of eplontersen, an investigational treatment for hereditary transthyretin-mediated amyloid polyneuropathy.

Hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with ATTRv-PN experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromises their function. The damage from misfolded TTR protein accumulation leads to disability within five years of diagnosis and is generally fatal within a decade.

Eplontersen is an investigational LIgand-Conjugated Antisense (LICA) medicine designed to inhibit the production of TTR protein, which is being developed as a monthly self-administered subcutaneous injection to treat all types of ATTR.

Results from the week 66 primary analysis showed that eplontersen-treated patients demonstrated improvement across all co-primary and secondary endpoints, including serum transthyretin (TTR) concentration, neuropathy impairment and quality of life, compared to the external placebo group. An end-of-treatment analysis also showed eplontersen continued to demonstrate sustained improvements through 85 weeks.

“These data reinforce the ability of eplontersen to halt disease progression and improve quality of life throughout the 19-month treatment period,” said Eugene Schneider, executive vice president and chief clinical development and operations officer for Ionis.

In the NEURO-TTRansform phase 3 study, patients treated with eplontersen demonstrated consistent and sustained benefit on the three co-primary endpoints of serum transthyretin (TTR) concentration, neuropathy impairment measured by modified Neuropathy Impairment Score +7 (mNIS+7) and quality of life (QoL) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN).

Overall, 47 percent of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 17 percent in the external placebo group. Among study completers, 53 percent of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 19 percent in the external placebo group.

In addition, eplontersen showed improved quality of life (QoL) on the Norfolk QoL-DN, compared to a worsening QoL in the external placebo group with 58% of treated patients showing improvements in QoL at 66 weeks compared to baseline versus 20% in the external placebo group. Among study completers, 65% of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 23% in the external placebo group.

Eplontersen also achieved statistically significant improvements in all secondary endpoints versus the external placebo group through 66 weeks and continued to demonstrate a favorable safety and tolerability profile. The rate of treatment-emergent adverse events in the eplontersen group was comparable to the external placebo group across all major categories. There were no adverse events of special interest that led to study drug discontinuation.

Results from the end-of-treatment analysis showed eplontersen provided sustained improvements through 85 weeks. Eplontersen continued to demonstrate a sustained reduction in serum TTR concentration, continued to halt disease progression as measured by the mNIS+7, and demonstrated continued improvement in QoL as measured by the Norfolk QoL-DN, all compared to baseline.

Ionis and AstraZeneca presented the results from the 35- and 66-week analyses as an Emerging Science presentation at the American Academy of Neurology Annual Meeting in April. The results from the 85-week end-of-treatment analysis of the trial will be submitted to an upcoming medical meeting.

As part of a global development and commercialization agreement, Ionis and AstraZeneca are seeking regulatory approval for eplontersen for the treatment of ATTRv-PN in the U.S. and plan to seek regulatory approval in Europe and other parts of the world. This agreement was recently expanded to include exclusive rights for AstraZeneca to commercialize eplontersen in Latin America and all other countries outside the U.S. Eplontersen was granted Orphan Drug designation in the United States. The U.S. Food and Drug Administration is expected to act on its application by December 22, 2023.

Eplontersen is also currently being evaluated in the CARDIO-TTRansform phase 3 study for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), a systemic, progressive and fatal condition that typically leads to progressive heart failure and often death within three-to-five years from disease onset.