PUBLISHED28 September 2023

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 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.³ This agreement was recently expanded to include exclusive rights for AstraZeneca to commercialize 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

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.^4,5 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.^4,7 The presence of TTR fibrils interferes with the normal functions of these tissues.⁵ As the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor QoL and eventually death.⁵ Worldwide, there are an estimated 300,000 - 500,000 patients with ATTR-CM⁷ and about 40,000 patients with ATTRv-PN.^5,7

NEURO-TTRansform

NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN.⁸ 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 2017.⁸ 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.⁸ 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.⁸ The mNIS+7 uses highly standardized, quantitative and referenced assessments to quantify muscle weakness, muscle stretch reflexes, sensory loss and autonomic impairment.⁹ The Norfolk QoL-DN is a patient-reported questionnaire capturing neuropathy-related QoL.⁸

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.^7,10

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.

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. Please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

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References

1. Coelho T, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. Sep 28. Available from: https://jamanetwork.com/journals/jama/fullarticle/2810248?resultClick=1
2. Coelho T, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy [Supplemental material]. JAMA. Sep 28. Available from: https://cdn.jamanetwork.com/ama/content_public/journal/jama/0/joi230110supp2_prod_1695838011.82373.pdf?Expires=1698937283&Signature=2pUFxqrvrdsqFEq9UMbg-9Q392Pb~W9vhOVXdEWIW8AqEl35g-H~Dxmyl1gh85R8iRv6JsX-2YVLKt70y91~BEFC4N7rwhKAKmjdtkQLGpWUyb2N1P3SduE57w2vjHbniRl1aEYS3WbMVaNqZCf3a0kvllqokl9YDh7sVlWUAfG3Bt1e9q-c6HI3RTQuy8mGlO4zhPEKJ4SJmIXiqibxSoskqMFHnWGz1RgbWcSpJldHgnHDg5fBTI-uFJkCinw2wwXElrwpMAF57kTpEGKERe7e1-41MQabtFe7PBcb~t3qQ~LoLCCD3MEBpe7DOjzRwjT9K69VFwagtArYn~6KoA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA.
3. AstraZeneca [Internet]. Press release. 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 [last accessed 5 Sep 2023]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2023/neuro-ttransform-phase-iii-results-presented-at-aan-showed-eplontersen-demonstrated-consistent-and-sustained-improvement.html.
4. Ionis Pharmaceuticals [Internet]. Press release. Eplontersen continued to demonstrate improvement in ATTRv-PN through 85 weeks [last accessed 5 Sep 2023]. Available from: https://ir.ionispharma.com/news-releases/news-release-details/eplontersen-continued-show-improvement-attrv-pn-through-85-weeks.
5. 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.
6. Ionis Pharmaceuticals [Internet]. Press release. Ionis expands eplontersen agreement with AstraZeneca to include exclusive rights in Latin America [last accessed 5 Sep 2023]. Available from: https://ir.ionispharma.com/news-releases/news-release-details/ionis-expands-eplontersen-agreement-astrazeneca-include.
7. 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.
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. Columbia University Irving Medical Center [Internet]. Drug Reduces Death from Underdiagnosed Form of Heart Failure [last accessed 5 Sep 2023]. Available from: https://www.cuimc.columbia.edu/news/drug-reduces-deaths-underdiagnosed-form-heart-failure.
10. Ionis Pharmaceuticals [Internet]. Annual Report, 2022 [last accessed 5 Sep 2023]. Available from: https://ir.ionispharma.com/static-files/db9dff5d-8683-485a-a517-15e264fe7532.
11. 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.