REG - AstraZeneca PLC - Forxiga CHMP opinion for symptomatic chronic HF

AstraZenecaAnnouncement

19/12/2022 07:00

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RNS Number : 0759K  AstraZeneca PLC  19 December 2022

19 December 2022 7:00 GMT

 

Forxiga recommended for approval in the EU by CHMP

for symptomatic chronic heart failure

 

If approved, Forxiga will be the first heart failure therapy indicated across
the full ejection fraction range with proven mortality reduction

 

AstraZeneca's Forxiga (dapagliflozin) has been recommended for approval in the
European Union (EU) to extend the indication for heart failure with reduced
ejection fraction (HFrEF) to cover patients across the full spectrum of left
ventricular ejection fraction (LVEF) including HF with mildly reduced and
preserved ejection fraction (HFmrEF, HFpEF).

 

The Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency based its positive opinion on results from the DELIVER Phase
III trial, published in The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa2206286) (1) and results from a
pre-specified, patient level, pooled analysis of the DAPA-HF and DELIVER Phase
III trials published in Nature Medicine
(https://www.nature.com/articles/s41591-022-01971-4) (2). The pooled analysis
showed Forxiga to be the first HF medication to demonstrate mortality benefit
across the full ejection fraction range(3).

 

HF is a life-threatening chronic disease in which the heart cannot pump enough
blood around the body(4), affecting 15 million people in the EU(5). Patients
with HFmrEF or HFpEF experience an especially high burden of symptoms and
physical limitations, and a poor quality of life, which is why improving
health status is a key goal of management(6).

 

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D,
AstraZeneca, said: "Forxiga has already transformed the standard of care for
millions of people in the EU living with heart failure. If approved for this
new, broader indication for heart failure with mildly reduced or preserved
ejection fraction, more patients will be able to benefit from this
well-tolerated and guideline-directed treatment. As a leader in cardiorenal
disease, AstraZeneca is committed to expanding heart failure treatment
options, changing the way we treat this complex disease to improve patient
outcomes."

 

The CHMP recommendation states Forxiga is indicated in adults for the
treatment of symptomatic chronic HF.

 

Results from the DELIVER Phase III trial in patients with HFpEF and HFmrEF
showed that Forxiga reduced the composite outcome of cardiovascular (CV) death
or worsening of HF by 18% (16.4% in the dapagliflozin group and 19.5% in the
placebo group [p<0.001, absolute risk reduction  ARR  3.1%] over a median
follow-up of 2.3 years)(1). The treatment effect was consistent across the
LVEF range, without evidence of attenuation of effect by LVEF(1).
Additionally, the pre-specified, patient level, pooled analysis of the DELIVER
and DAPA-HF Phase III trials demonstrated that Forxiga reduced the risk of CV
death by 14% (p=0.01, ARR 1.5%), death from any cause by 10% (p=0.03, ARR
1.5%), and total (first and repeat) hospitalisation for HF (hHF) by 29%
(p<0.001, ARR 6%) over the median follow-up of 22 months(2).

Forxiga (known as Farxiga in the US) is approved for the treatment of patients
with HFrEF in more than 100 countries around the world including the US, the
EU, China and Japan. It was most recently approved in Great Britain and Turkey
to extend the HF indication to include patients across the full spectrum of
left ventricular ejection fraction. The HF indication extension application is
currently under review in the US and other countries.

Notes

HF
HF is a chronic, long-term condition that worsens over time(7). It affects
nearly 64 million people globally(8) and is associated with substantial
morbidity and mortality(9). Chronic HF is the leading cause of hospitalisation
for those over the age of 65 and represents a significant clinical and
economic burden(10). There are several types of HF often defined by LVEF, a
measurement of the percentage of blood leaving the heart each time it
contracts, including: HFrEF (LVEF less than or equal to 40%), HFmrEF (LVEF
41-49%) and HFpEF (LVEF greater than or equal to 50%)(11). Approximately half
of all HF patients have HFmrEF or HFpEF, with few therapeutic options
available(11,12).

 

DAPA-HF
DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure)
was an international, multi-centre, parallel-group, randomised, double-blinded
Phase III trial in 4,744 patients with HFrEF, with and without type-2 diabetes
(T2D), designed to evaluate the effect of Forxiga 10mg, compared with
placebo, given once daily in addition to standard of care (SoC). The primary
composite endpoint was time to the first occurrence of a worsening HF event
(hospitalisation or equivalent event, i.e. an urgent HF visit), or CV death.
The median duration of follow-up was 18.2 months. Key secondary endpoints
included the total number of hHF (including repeat admissions) and CV deaths,
change from baseline to 8 months in the total symptom score on the Kansas City
Cardiomyopathy Questionnaire (KCCQ)(13).

DELIVER
DELIVER was an international, randomised, double-blind, parallel-group,
placebo-controlled, event-driven Phase III trial designed to evaluate the
efficacy of Forxiga, compared with placebo, in the treatment of HF patients
with LVEF greater than 40%, with or without T2D. Forxiga was given once
daily in addition to background therapy (regional SoC for all comorbidities,
including diabetes and hypertension, with the exception of concomitant use of
a sodium-glucose cotransporter 2 (SGLT2) inhibitor)(14).( )DELIVER is the
largest clinical trial to date in HF patients with LVEF above 40%, with 6,263
randomised patients(14).

The primary composite endpoint was the time to first occurrence of CV death,
hHF or an urgent HF visit. Key secondary endpoints include the total number of
HF events (hHF or urgent HF visit) and CV death, change from baseline in the
total symptom score of the KCCQ at eight months, time to the occurrence of CV
death and time to the occurrence of death from any cause(14).

Forxiga

Forxiga (dapagliflozin) is a first-in-class, oral, once-daily SGLT2
inhibitor. Research has shown Forxiga's efficacy in preventing and delaying
cardiorenal disease, while also protecting the organs - important findings
given the underlying links between the heart, kidneys and pancreas(13,15,16).
Damage to one of these organs can cause the other organs to fail, contributing
to leading causes of death worldwide, including T2D, HF and chronic kidney
disease (CKD) (4,8,17,18).

Forxiga is approved in adults and children aged 10 years and above for the
treatment of insufficiently controlled T2D mellitus as an adjunct to diet and
exercise. Forxiga is also approved for the treatment of HFrEF in adults and
the treatment of CKD in adults based on the findings of the DAPA-HF and
DAPA-CKD Phase III trials.

AstraZeneca in CVRM

Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms
one of AstraZeneca's main 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 (http://www.astrazeneca.com/) and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

Contacts
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.

References

 

1.   Solomon S, et al. Dapagliflozin in Heart Failure with Mildly Reduced or
Preserved Ejection Fraction. N Engl J Med. 2022;387:1089-1098.

2.   Jhund P, et al. Dapagliflozin and outcomes across the range of ejection
fraction in patients with heart failure: a patient-level pooled analysis of
DAPA-HF and DELIVER. Nature Medicine. 2022;28:1956-1964.

3.   AstraZeneca Press Release  Internet . New data show Farxiga
significantly lowers the risk of cardiovascular death in patients with heart
failure [cited 2022 Nov 23]. Available from:
https://www.astrazeneca.com/media-centre/press-releases/2022/farxiga-lowers-risk-cv-death-heart-failure.html
(https://www.astrazeneca.com/media-centre/press-releases/2022/farxiga-lowers-risk-cv-death-heart-failure.html)
.

4.   Mayo Clinic  Internet . Heart failure [cited 2022 Nov 23]. Available
from:
https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142
(https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142)
.

5.   Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of
acute and chronic heart failure 2008: the Task Force for the Diagnosis and
Treatment of Acute and Chronic Heart Failure 2008 of the European Society of
Cardiology. Developed in collaboration with the Heart Failure Association of
the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine
(ESICM). Eur Heart J 2008; 29:2388-2442.

6.   Warraich HJ, et al. Physical function, frailty, cognition, depression,
and quality of life in hospitalized adults ≥60 years with acute
decompensated heart failure with preserved versus reduced ejection fraction.
Circ Heart Fail. 2018;11:e005254.

7.   Cleveland Clinic  Internet . Heart failure [cited 2022 Nov 23].
Available
from: https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure
(https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure)
.

8.   Vos T, et al. Global, regional, and national incidence, prevalence, and
years lived with disability for 328 diseases and injuries for 195 countries,
1990-2016: A systematic analysis for the Global Burden of Disease Study
2016. Lancet. 2017;390(10100):1211-59.

9.   Mozaffarian D, et al. Heart disease and stroke statistics-2016
update. Circulation. 2016;133(4):e38-360.

10.  Azad N, et al. Management of chronic heart failure in the older
population. J Geriatr Cardiol. 2014;11(4):329-37.

11.  Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of
Heart Failure: A report of the American College of Cardiology/American Heart
Association Joint Committee on Clinical Practice Guidelines. J Am Coll
Cardiol. 2022;79(17):e263-421.

12.  Dunlay SM, et al. Epidemiology of heart failure with preserved ejection
fraction. Nat Rev Cardiol 2017;14(10):591-602.

13.  McMurray JJV, et al. Dapagliflozin in patients with heart failure and
reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.

14.  Solomon SD, et al. Dapagliflozin in heart failure with preserved and
mildly reduced ejection fraction: rationale and design of the DELIVER
trial. Eur J Heart Fail. 2021;23(7):1217-25.

15.  Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney
disease. N Engl J Med. 2020;383(15):1436-46.

16.  Wiviott SD, et al. for the DECLARE-TIMI 58 Investigators. Dapagliflozin
and cardiovascular outcomes in type-2 diabetes [article and supplementary
appendix]. N Engl J Med. 2019;380(4):347-57.

17.  Centers for Disease Control and Prevention (CDC)  Internet . A snapshot:
Diabetes in the United States [cited 2022 Nov 23]. Available
from: https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes.html
(https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes.html)
.

18.  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 Internet . Heart disease & kidney disease [cited 2022 Nov 23]. Available
from: https://www.niddk.nih.gov/health-information/kidney-disease/heart-disease
(https://www.niddk.nih.gov/health-information/kidney-disease/heart-disease) .

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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