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.
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 commercialisation agreement,
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
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, randomised 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 standardised, 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
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of
References
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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.
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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).
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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.
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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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