Eplontersen Shows Significant Benefits in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy Treatment


The investigational Ionis and AstraZeneca treatment showed clinically meaningful changes in serum TTR concentration and modified Neuropathy Impairment Score +7 measures. The companies intend to file an NDA based on the findings of the NEURO-TTRansform study.

Teresa Coelho, MD, neurologist and neurophysiologist, Hospital Santo António, Centro Hospitalar Universitário do Porto, in Portuga

Teresa Coelho, MD

New data presented at the International Symposium on Amyloidosis (ISA) in Heidelberg, Germany, suggest that the phase 3 NEURO-TTRansform study (NCT04136184) of eplontersen (Ionis, AstraZeneca) was positive, with the investigational treatment for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) demonstrating significant changes for the coprimary and secondary end points compared with placebo.1

Originally noted in a June 2022 announcement of the topline findings from this interim analysis, the companies reiterated their declared intention to file a new drug application (NDA) to the FDA for eplontersen to treat ATTRv-PN.2

Ultimately, the data reveal that treatment with eplontersen resulted in an 81.2% mean reduction in serum TTR concentration—a coprimary end point—compared with baseline, which was significant (P <.0001). Additionally, modified Neuropathy Impairment Score +7 (mNIS+7) scores—the other coprimary end point—were also significantly changed from baseline compared with placebo (P <.0001).

"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," study investigator Teresa Coelho, MD, neurologist and neurophysiologist, Hospital Santo António, Centro Hospitalar Universitário do Porto, in Portugal, said in a statement.1 Coelho presented data from the interim analysis at ISA.

NEURO-TTRansform also met the key secondary end point, change from baseline in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), which suggested that treatment with eplontersen significantly improved patient-reported quality of life compared with the external placebo group (P <.0001). Ionis noted that these data are consistent with the clinical profile that has been observed in its other Ligand-Conjugated Antisense (LICA) platforms.

As for safety, eplontersen treatment showed a favorable safety and tolerability profile, as the rate of treatment emergent adverse events (AEs) in the treatment group was lower or similar to the placebo group across all major categories. There were no reported treatment-emergent AEs of special interest leading to drug discontinuation.

"The promising results from NEURO-TTRansform show that eplontersen had a positive impact on disease progression and improved quality of life in a substantial number of patients. We are excited about the potential for delivering a new treatment option to patients living with this relentless and devastating disease," Eugene Schneider, MD, executive vice president and chief clinical development officer, Ionis, said in a statement.1

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Previously, the treatment, formerly known as IONIS-TTR-LRX, was granted an orphan drug designation, and is also being evaluated in the phase 3 CARDIO-TTRansform study (NCT04136171) assessing it in the treatment of amyloid transthyretin cardiomyopathy (ATTR-CM), a systemic, progressive and fatal condition that leads to progressive heart failure and death within 4 years of diagnosis.

Previously, in a phase 1 trial (NCT03728634) of healthy volunteers, injections of eplontersen at a dose of 90 mg per month showed a mean reduction in TTR levels of 94% after 13 weeks of treatment. Eligible participants were assigned to 1 of 3 multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomly assigned 10:2 (active: placebo) to receive a total of 4 subcutaneous doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 subcutaneous dose in the single-dose cohort.3

All randomized participants completed the treatment period with no serious adverse events (AEs) reported. In the multiple-dose cohorts, those on eplontersen 45, 60, and 90 mg demonstrated reduced TTR levels of –85.7% (SD, 8.0), –90.5% (SD, 7.4), and –93.8% (SD, 3.4), compared with –5.9% (SD, 14.0) for pooled placebo (<.001). A maximum mean reduction in TTR levels of –86.3% (SD, 6.5) from baseline were achieved after the single-dose 120 mg of eplontersen.

1. Ionis presents positive results from Phase 3 NEURO-TTRansform study at International Symposium on Amyloidosis. News release. Ionis Pharmaceuticals. September 7, 2022. Accessed September 8, 2022. https://www.prnewswire.com/news-releases/ionis-presents-positive-results-from-phase-3-neuro-ttransform-study-at-international-symposium-on-amyloidosis-301618729.html
2. Eplontersen met co-primary and secondary end points in interim analysis of the NEURO-TTRansform phase 3 trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). News release. June 21, 2022. Accessed June 23, 2022. https://www.astrazeneca-us.com/content/az-us/media/press-releases/2022/eplontersen-met-co-primary-and-secondary-endpoints-in-interim-analysis-of-the-neuro-ttransform-phase-III-trial-for-hereditary-transthyretin-mediated-amyloid-polyneuropathy.html
3. Viney NJ, Guo S, Tai LJ, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Fail. 2021;8(1):652-661. doi:10.1002/ehf2.13154
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