REG - AstraZeneca PLC - Eplontersen Ph III trial met co-primary endpoints

AstraZenecaAnnouncement

21/06/2022 07:00

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RNS Number : 6049P  AstraZeneca PLC  21 June 2022

21 June 2022 07:00 BST

 

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)

 

New Drug Application filing anticipated based on positive data from interim
analysis

 

Positive high-level results from the NEURO-TTRansform Phase III trial in
patients with hereditary transthyretin-mediated amyloid polyneuropathy
(ATTRv-PN) showed AstraZeneca and Ionis' eplontersen met its co-primary
endpoints in a planned interim analysis at 35 weeks. In the trial, eplontersen
reached a statistically significant and clinically meaningful change from
baseline for its co-primary endpoint of percent change in serum transthyretin
(TTR) concentration, reducing TTR protein production. Eplontersen also reached
its co-primary endpoint of change from baseline in the modified Neuropathy
Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression(1),
versus external placebo group.

 

High-level results showed the trial also met its secondary endpoint of change
from baseline in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy
(Norfolk QoL-DN) showing treatment with eplontersen significantly improved
patient-reported quality of life versus external placebo group. In the trial,
eplontersen demonstrated a favourable safety and tolerability profile with no
specific concerns.

 

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). Eplontersen, formerly known as
IONIS-TTR-L(Rx), is a ligand-conjugated antisense (LICA) investigational
medicine designed to reduce the production of TTR protein at its source to
treat both hereditary and non-hereditary forms of ATTR(2,4-6).

 

Teresa Coelho, M.D., a neurologist and neurophysiologist at Hospital Santo
António, Centro Hospitalar Universitário do Porto, Portugal and an
investigator for the NEURO-TTRansform trial, said: "These encouraging data
reinforce the safety profile of eplontersen and demonstrate clear evidence of
its potential to provide much needed therapeutic benefit to patients living
with hereditary transthyretin-mediated amyloid polyneuropathy."

 

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D,
AstraZeneca, said: "Amyloid transthyretin polyneuropathy is a rare and fatal
disease that can affect up to 40,000 people worldwide. These promising results
show eplontersen has the potential to be a new and much needed treatment
where limited options exist and significant unmet medical need remains."

 

Based on the 35-week interim trial results, the companies will seek regulatory
approval for eplontersen and plan to file a new drug application with the US
Food and Drug Administration in 2022. ATTRv-PN is expected to be the first
indication for which AstraZeneca and Ionis will seek regulatory approval for
eplontersen. The results from the 35-week interim analysis of the trial will
be submitted for presentation at a forthcoming medical meeting.

 

As part of a global development and commercialisation agreement
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/astrazeneca-and-ionis-close-eplontersen-deal.html)
with Ionis, eplontersen will be jointly developed and commercialised by both
companies in the US and will be developed and commercialised in the rest of
the world by AstraZeneca (with the exception of Latin America).

 

Eplontersen was granted Orphan Drug Designation in the US
(https://www.astrazeneca.com/content/astraz/media-centre/medical-releases/eplontersen-granted-orphan-drug-designation-in-the-us-for-transthyretin-amyloidosis.html)
and is also currently being evaluated in the CARDIO-TTRansform Phase III trial
for amyloid transthyretin cardiomyopathy (ATTR-CM)(4,6), a systemic,
progressive and fatal condition that leads to progressive heart failure and
death within four years from diagnosis(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(2,6-8). 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(7,8,10). 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 quality of life (QoL) and eventually death(8). Worldwide,
there are an estimated 300,000 - 500,000 patients with ATTR-CM(10) and about
40,000 patients with ATTRv-PN(8).

 

NEURO-TTRansform

NEURO-TTRansform is a global, open-label, randomised trial evaluating the
efficacy and safety of eplontersen in patients with ATTRv-PN(2,5). 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(2,5). The final
primary endpoint analysis will be completed at week 66 and all patients will
be followed until week 85, when they will have the option to transition into
the open-label extension trial(2). The co-primary endpoints in the interim
analysis were percent change from baseline in serum TTR concentration and
change in the mNIS+7 versus external placebo group at week 35(2,5). The mNIS+7
uses highly standardised, quantitative, and referenced assessments to quantify
muscle weakness, muscle stretch reflexes, sensory loss, and autonomic
impairment(1). The secondary endpoint was change from baseline in the Norfolk
QoL-DN score versus external placebo group at week 35(2,5). The Norfolk QoL-DN
is a patient-reported questionnaire capturing neuropathy-related QoL(11).

 

Eplontersen

Eplontersen is a 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(2,4-6).

 

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 (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical
company that focuses on the discovery, development, and commercialisation 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 astrazeneca.com (https://www.astrazeneca.com/) and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

References

1.   Dyck PJB, et al. Development of measures of polyneuropathy impairment
in hATTR amyloidosis: from NIS to mNIS +7. J Neurol Sci. 2019;405:116424.

2.   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.

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.   ClinicalTrials.gov  Internet . CARDIO-TTRansform: A Study to Evaluate
the Efficacy and Safety of Eplontersen (Formerly Known as, IONIS-TTR-LRx and
AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid
Cardiomyopathy (ATTR CM) [cited 18 June 2022]. Available from:
https://clinicaltrials.gov/ct2/show/NCT04136171
(https://clinicaltrials.gov/ct2/show/NCT04136171) .

5.   ClinicalTrials.gov  Internet . NEURO-TTRansform: A Study to Evaluate
the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884,
IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Hereditary
Transthyretin-Mediated Amyloid Polyneuropathy [cited 18 June 2022]. Available
from: https://clinicaltrials.gov/ct2/show/NCT04136184
(https://clinicaltrials.gov/ct2/show/NCT04136184) .

6.   Viney N, et al. Ligand conjugated antisense oligonucleotide for the
treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC
Heart Failure. 2020;8(1):652-661.

7.   Gertz M, et al. Avoiding misdiagnosis: expert consensus recommendations
for the suspicion and diagnosis of transthyretin amyloidosis for the general
practitioner. BMC Fam Pract. 220;21(1):198.

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;16:7.

9.   Lauppe RE, et al. Nationwide prevalence and characteristics of
transthyretin amyloid cardiomyopathy in Sweden. Open Heart. 2021;8(2):e001755.

10.  Ionis Pharmaceuticals, Inc.,  Internet . Annual Report, 2022 [cited 18
June 2022]. Available from:
https://ir.ionispharma.com/static-files/285deeed-625c-4d5b-beff-8490f93622ce
(https://ir.ionispharma.com/static-files/285deeed-625c-4d5b-beff-8490f93622ce)
.

11.  Vinik EJ, et al. Norfolk QOL-DN: validation of a patient reported
outcome measure in transthyretin familial amyloid polyneuropathy. J Peripher
Nerv Syst. 2014;19(2):104-114.

 

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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