Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

First publication from NEURO-TTRansform trial in the treatment of patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN)

Consistent and sustained benefit on all co-primary and secondary endpoints across patients with a diverse range of disease characteristics

Positive results from the NEURO-TTRansform Phase III trial for eplontersen in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) were published in The Journal of the American Medical Association (JAMA) today further demonstrating the benefit of eplontersen across the spectrum of the disease.¹

Results from the week 66 primary analysis demonstrated improvement across all co-primary and secondary outcomes, indicating the broad range of clinically relevant benefits from treatment with eplontersen, a ligand-conjugated antisense oligonucleotide (ASO) that inhibits hepatic transthyretin (TTR) protein production.¹ An end-of-treatment analysis also showed eplontersen continued to demonstrate sustained improvements through 85 weeks.²

Sami Khella, M.D., Chief, Department of Neurology at Penn Presbyterian Medical Center, Professor of Clinical Neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine and a Principal Investigator on the NEURO-TTRansform trial, said: “The totality of positive, consistent eplontersen data position this therapy, which can be self-administered, to be an important and empowering potential new medicine for treating hereditary transthyretin-mediated amyloid polyneuropathy. Without treatment, hereditary transthyretin-mediated amyloid polyneuropathy is a debilitating and devasting disease that can ultimately result in death. The JAMA publication reinforces the growing body of evidence showing that eplontersen significantly reduces serum transthyretin concentration, may halt progression of neuropathy impairment, and improves overall patient quality of life, providing hope to this community.”

Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Eplontersen demonstrated improvements in a wide array of disease-related endpoints across transthyretin-mediated amyloid polyneuropathy in patients with a diverse range of disease characteristics. Publication of these positive results provides further evidence of eplontersen’s ability to achieve consistent and sustained benefit in this patient population and its potential to be an important treatment option across all types of transthyretin-mediated amyloidosis.”

In the NEURO-TTRansform Phase III trial, 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).¹

Eplontersen achieved a least squares (LS) mean reduction of 82% in TTR serum concentration from baseline at 65 weeks, compared to an 11% reduction from baseline in the external placebo group (p<0.001).¹

Eplontersen demonstrated statistically significant benefits on both mNIS+7 and Norfolk QoL-DN at 35 weeks versus the external placebo group, which were further improved at 66 weeks.^1,3 Eplontersen halted disease progression by mNIS+7, resulting in a 0.3 point LS mean increase at week 66 compared to a 25.1 point increase for the external placebo group from baseline (24.8 point LS mean improvement; p<0.001).¹ Overall, 47% of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 17% in the external placebo group.¹ Among study completers, 53% of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 19% in the external placebo group.¹

Eplontersen improved QoL (on Norfolk QoL-DN) demonstrating a 5.5 point LS mean decrease at 66 weeks (improvement), compared to a 14.2 point increase (worsening) in the external placebo group (19.7 point LS mean improvement; p<0.001).¹ Overall, 58% of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 20% in the external placebo group.¹ Among study completers, 65% of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 23% in the external placebo group.¹

Eplontersen also achieved statistically significant improvements in all secondary endpoints versus the external placebo group through 66 weeks and continued to demonstrate a favourable safety and tolerability profile.^1,3 The rate of treatment emergent adverse events in the eplontersen group was comparable to the external placebo group across all major categories.¹ There were no adverse events of special interest that led to study drug discontinuation.¹

Results from the end-of-treatment analysis showed eplontersen provided sustained improvements through 85 weeks.^2,4 Eplontersen continued to demonstrate a sustained reduction in serum TTR concentration compared to baseline, continued to halt disease progression as measured by the mNIS+7, and demonstrated continued improvement in QoL measured by the Norfolk QoL-DN compared to baseline.^2,4

AstraZeneca and Ionis presented the results from both the 35- and 66-week analyses of the trial as an Emerging Science presentation at the American Academy of Neurology Annual Meeting in April.³ The results from the 85-week end-of-treatment analysis of the trial will be submitted to an upcoming medical meeting.⁴

ATTRv-PN is a debilitating disease that leads to peripheral nerve damage with motor disability within five years of diagnosis and, without treatment, is generally fatal within a decade.⁵

As part of a global development and commercialisation agreement, AstraZeneca and Ionis are seeking regulatory approval for eplontersen for the treatment of ATTRv-PN in the US and plan to seek regulatory approval in Europe and other parts of the world.³ This agreement was recently expanded to include exclusive rights for AstraZeneca to commercialise eplontersen in Latin America in addition to all other countries outside the US.⁶ In March, the US Food and Drug Administration accepted a New Drug Application for eplontersen for the treatment of ATTRv-PN.³ Eplontersen was granted Orphan Drug Designation in the US.³

Eplontersen is currently being evaluated in the CARDIO-TTRansform Phase III trial 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.^7-9