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
- 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
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- Ionis Pharmaceuticals [Internet]. Annual Report, 2022 [last
accessed 16 March 2023]. Available from:
https://ir.ionispharma.com/static-files/db9dff5d-8683-485a-a517-15e264fe7532.
- 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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