Eplontersen Continues Positive Display in Phase 3 Trial for Hereditary Transthyretin Amyloidosis With Polyneuropathy


Treated patients with hereditary ATTR-mediated amyloid polyneuropathy in the NEURO-TTRansform trial showed significantly lowered serum transthyretin concentrations, less neuropathy impairments, and better quality of life.

Sami Khella, MD, chief, department of neurology at Penn Presbyterian Medical Center and professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine

Sami Khella, MD

Recently published in JAMA, new data from the open-label, single-group, phase 3 NEURO-TTRansform trial (NCT04136184) showed positive results across all coprimary and secondary end points with eplontersen (Ionis, AstraZeneca), an investigational ligand-conjugated antisense oligonucleotide, among patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 85 weeks in comparison with a historical placebo.1

At week 65, the adjusted mean percentage reduction in serum transthyretin was –81.7% with eplontersen compared with -11.2% in the placebo group, showing a -70.4% difference (95% CI, –75.2 to –65.7; P <.001). The adjusted mean change from baseline to week 66 was lower with eplontersen versus placebo for modified Neuropathy Impairment Score +7 (mNIS +7) composite score (0.3 vs 25.1; difference, –24.8 [95% CI, –31.0 to –18.6]; P <.001). Similarly, the adjusted mean change from baseline was also lower with eplontersen versus placebo for Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) (–5.5 vs 14.2; difference, –19.7 [95% CI, –25.6 to –13.8]; P <.001).

Clinical Takeaways

  • The NEURO-TTRansform trial spotlights eplontersen's –81.7% reduction in serum transthyretin, positioning it as a potential option in treating ATTRv-PN.
  • The consistent and positive data highlights eplontersen's potential to empower patients with ATTRv-PN by potentially halting disease progression and improving overall quality of life.
  • Conducted across 15 countries, the trial reinforces eplontersen's global significance and offers potential hope to the ATTRv-PN community, addressing a critical medical need.

"This study showed that at a lower dose than inotersen [Tegsedi; Ionis Pharmaceuticals], eplontersen was effective in lowering serum TTR levels, and when compared with the historical control in the NEURO-TTRansform trial, it slowed the progression of the neuropathy,” principal investigator Sami Khella, MD, chief, department of neurology at Penn Presbyterian Medical Center and professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine, told NeurologyLive®. "These results provide patients with 1 more drug, in addition to the 3 other FDA-approved therapies, for the treatment of hereditary ATTR polyneuropathy. The next steps are to understand what measures to take to monitor response to therapy such as when is therapy deemed a failure and what to do in that case, and how to diagnose this disease as early as possible.”

READ MORE: Decreased Neurofilament Light in ATTR Polyneuropathy Observed With Vutrisiran and Patisiran

NEURO-TTRansform was conducted at 40 sites across 15 countries between December 2019 and April 2023 in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, who had a Neuropathy Impairment Score between 10 and 130, and had a documented TTR variant. The patients treated with placebo in the phase 3 NEURO-TTR trial (NCT01737398), a trial of inotersen with similar eligibility criteria and end points, served as a historical placebo group in the current study. Investigators noted in the current study that patients were administered 45 mg of subcutaneous eplontersen every 4 weeks (n = 144), a small reference group received 300 mg of subcutaneous inotersen weekly (n = 24), and the patients from NEURO-TTR received subcutaneous placebo weekly (n = 60).

All told, the primary efficacy end points at weeks 65 and 66 were changes from baseline in serum transthyretin concentration, mNIS+7 composite score, and Norfolk QoL-DN total score. The authors noted that the analyses of the efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Among 144 eplontersen-treated patients (mean age, n = 53 years; male, 69%), 136 (94.4%) of the patients completed follow-up at week 66. Additionally, among 60 placebo patients (mean age, n = 59.5 years; male, 68%), 52 (86.7%) of the patients completed the week 66 follow-up.

By week 66, adverse events led to discontinuation of the study in 6 patients (4%) who were in the eplontersen group compared with 2 (3%) patients in the placebo group. Through that week, 2 deaths were reported in the eplontersen group which were consistent with known disease-related sequelae such as cardiac arrhythmia and intracerebral hemorrhage. Notably, investigators had no deaths reported in the placebo group.

"These data reinforce the ability of eplontersen to halt disease progression and improve quality of life throughout the 19-month treatment period," Eugene Schneider, MD, executive vice president and chief clinical development and operations officer at Ionis, said in a statement.2 "We look forward to the upcoming FDA action date [o]n December [22, 2023] and bringing eplontersen to this underserved patient community in the US and around the world."

According to a released statement, Ionis and AstraZeneca presented the results from the 35- and 66-week analysesat the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, as an Emerging Science presentation.3,4 Also in the release, it stated that the findings from the 85-week end-of-treatment analysis of the trial are to be submitted to an upcoming medical meeting. In other news, eplontersen is currently being assessed in the phase 3 CARDIO-TTRansform study (NCT04136171) for transthyretin-mediated amyloid cardiomyopathy, a systemic, progressive and fatal condition that typically leads to progressive heart failure and often death in 3 to 5 years from disease onset.

1. Coelho T, Marques W Jr, Dasgupta NR, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. 2023;330(15):1448-1458. doi:10.1001/jama.2023.18688
2. Eplontersen Phase 3 results published in JAMA show consistent and sustained benefit. News Release. Ionis Pharmaceuticals. Published September 28, 2023. Accessed Decemeber 5, 2023. https://ir.ionispharma.com/news-releases/news-release-details/eplontersen-phase-3-results-published-jama-show-consistent-and
3. Khella S, Marques W, Dasgupta NR, et al. Eplontersen in hereditary ATTR-polyneuropathy: week 66 final analysis of the phase 3 NEURO-TTRansform study. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. LB
4. NEURO-TTRansform phase 3 resulted presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks. News release. AstraZeneca. April 24, 2023. Accessed December 5, 2023. https://www.astrazeneca-us.com/media/press-releases/2023/neuro-ttransform-phase-iii-results-presented-at-aan-showed-eplontersen-demonstrated-consistent-and-sustained-improvement-in-all-measures-of-disease-and-quality-of-life-through-66-weeks.html
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