Positive high-level results from the NEURO-TTRansform Phase III trial in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) showed eplontersen met its co-primary endpoints through 66 weeks. The results were consistent with the positive 35-week findings announced in June 2022.¹

At 66 weeks, patients treated with eplontersen continued to demonstrate a statistically significant and clinically meaningful change from baseline versus an external placebo group on the co-primary endpoints of modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression,² and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). The trial also met its third co-primary endpoint demonstrating a statistically significant reduction in serum TTR concentration versus an external placebo group. TTR reductions were consistent with those reported at week 35. Eplontersen continued to demonstrate a safety and tolerability profile consistent with that observed at 35 weeks.

Sami Khella, M.D., Chief, Department of Neurology, Penn Presbyterian Medical Center and Professor of Clinical Neurology, University of Pennsylvania School of Medicine, said: “The positive results from the 66-week analysis of the Phase III NEURO-TTRansform trial show that eplontersen provided consistent and sustained transthyretin protein reduction and that a substantial number of patients improved in measures of both neuropathy progression and quality of life. This builds on the favorable 35-week results, which first demonstrated eplontersen’s potential to significantly improve outcomes in this underserved population.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “These results further underscore eplontersen’s potential to be a best-in-class treatment across all forms of transthyretin-mediated amyloidosis, including polyneuropathy and cardiomyopathy which can lead to heart failure. With limited treatment options currently available, there is an urgent unmet medical need for new therapies and earlier, accurate diagnosis across the different types of this systemic, progressive and fatal condition.”

Eugene Schneider, M.D., Executive Vice President and Chief Clinical Development Officer for Ionis, said: “These latest results from our NEURO-TTRansform study represent an important step towards delivering a potential new therapy for ATTRv-PN patients living with this debilitating and fatal disease. We are encouraged by the sustained benefit demonstrated by eplontersen and what a self-administered treatment could mean for patients and families affected by ATTRv-PN. Together, with our partner AstraZeneca, we look forward to sharing detailed results from this study at the upcoming American Academy of Neurology Annual Meeting.”

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.³

As part of a global development and commercialization 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. Earlier this month, the US Food and Drug Administration accepted a New Drug Application for eplontersen for the treatment of ATTRv-PN.⁴ Eplontersen was granted Orphan Drug Designation in the US.⁴

Eplontersen is currently being evaluated in the Phase III CARDIO-TTRansform trial for transthyretin amyloid cardiomyopathy (ATTR-CM),⁵ a systemic, progressive and fatal condition that typically leads to progressive heart failure and often death within three to five years from disease onset.^6-8

The results from both the 35 and 66-week analyses of the trial will be presented as an Emerging Science presentation at the American Academy of Neurology Annual Meeting in April.

Notes

TTR Amyloidosis

ATTR cardiomyopathy and polyneuropathy are progressive systemic diseases caused by aging or genetic mutations, resulting in misfolded TTR protein and accumulation as amyloid fibrils in the cardiac myocardium and peripheral nerves, respectively.^5,6,8 In patients with ATTR, both hereditary and wild type (non-hereditary), TTR protein builds up as fibrils in tissues, such as the peripheral nerves and heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow.^5,9 The presence of TTR fibrils interferes with the normal functions of these tissues.⁸ As the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor QoL and eventually death.⁸ Worldwide, there are an estimated 300,000 - 500,000 patients with ATTR-CM⁹ and about 40,000 patients with ATTRv-PN.^8,9

NEURO-TTRansform

NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN.^6,10 The trial has enrolled adult patients with ATTRv-PN Stage 1 or Stage 2 and will be compared to the external placebo group from the TEGSEDI^® (inotersen) NEURO-TTR registrational trial that Ionis completed in 2017.^6,10 The final analysis comparing eplontersen to external placebo was completed at week 66 and all patients will be followed on treatment until week 85, when they will have the option to transition into an open-label extension study.¹⁰ The 66-week analysis evaluated percent change from baseline in serum TTR concentration, changes in the mNIS+7 and Norfolk-QOL-DN in the eplontersen group versus an external placebo group.¹⁰ The mNIS+7 uses highly standardized, quantitative and referenced assessments to quantify muscle weakness, muscle stretch reflexes, sensory loss and autonomic impairment.² The Norfolk QoL-DN is a patient-reported questionnaire capturing neuropathy-related QoL.¹⁰

Eplontersen

Eplontersen is a ligand-conjugated antisense (LICA) investigational medicine designed to reduce the production of transthyretin, or TTR protein, to treat all types of ATTR, a systemic, progressive and fatal disease.^6,9

AstraZeneca in CVRM

Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improving outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases, and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References

1. AstraZeneca [Internet]. Press release. Eplontersen met co-primary and secondary endpoints in interim analysis of the NEURO-TTRansform Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) [last accessed 16 March 2023]. Available from: https://www.astrazeneca-us.com/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
2. Dyck P, et al. Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7. J Neurol Sci. 2019 Oct 15;405:116424.
3. Cortese A, et al. Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy.J Neurol Neurosurg Psychiatry. 2017;88(5):457-458.
4. Ionis Pharmaceuticals [Internet]. Press release. Ionis announces FDA acceptance of New Drug Application for eplontersen for the treatment of hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) [last accessed 16 March 2023]. Available from: https://ir.ionispharma.com/news-releases/news-release-details/ionis-announces-fda-acceptance-new-drug-application-eplontersen.
5. Viney N, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Failure. 2020; 8:652-661.
6. Coelho T, et al. Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen. Neurol Ther 12, 267–287 (2023).
7. Columbia University Irving Medical Center [Internet]. Drug Reduces Death from Underdiagnosed Form of Heart Failure [last accessed 22 March 2023]. Available from: https://www.cuimc.columbia.edu/news/drug-reduces-deaths-underdiagnosed-form-heart-failure.
8. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16:70.
9. Ionis Pharmaceuticals [Internet]. Annual Report, 2022 [last accessed 16 March 2023]. Available from: https://ir.ionispharma.com/static-files/db9dff5d-8683-485a-a517-15e264fe7532.
10. Coelho T, et al. Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx(ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy.Neurol Ther. 2021 Jun;10(1):375-389.

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