New Novartis Phase II data show LCZ696 may provide clinical benefits in patients with a difficult-to-treat form of heart failure
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New Novartis Phase II data show LCZ696 may provide clinical benefits in patients
with a difficult-to-treat form of heart failure
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* PARAMOUNT study shows LCZ696 reduced a key predictor of morbidity and
mortality in patients with a common form of heart failure called HF-
PEF[1],[2]
* Up to half of the 20 million Europeans and Americans diagnosed with heart
failure have HF-PEF[3]-[5], leading to reduced life expectancy and frequent
hospitalization[4]-[6]
* No therapies are currently approved to reduce morbidity and mortality in
patients with HF-PEF, or heart failure with preserved ejection fraction[5]-
[7]
* Phase III PARADIGM-HF study currently investigating LCZ696 in heart failure
with reduced ejection fraction (HF-REF), the other common form of heart
failure
Basel, August 26, 2012 - Novartis today announced results from the Phase II
PARAMOUNT study showing that the investigational compound LCZ696 is the first
therapy to significantly reduce a key predictor of morbidity and mortality in
patients with a condition called heart failure with preserved ejection fraction
(HF-PEF)[1],[2]. This difficult-to-treat disease affects up to half of the 20
million people with heart failure in Europe and the US [3]-[5]. The data were
presented at the ESC Congress 2012 (European Society of Cardiology) in Munich,
Germany[1], and published simultaneously in The Lancet[2].
The results show that after 12 weeks, LCZ696 met its primary endpoint by
reducing NT-proBNP[*] - a marker of stress on the heart and a predictor of
patient outcomes - significantly more than valsartan[1],[2]. The data also
suggest that LCZ696 may reverse some structural changes to the heart[1],[2] that
occur in patients with heart failure[8].
[*]N-terminal pro-B-type natriuretic peptide
"These Phase II results show that this novel treatment approach has the
potential to reduce stress to the heart and to reduce enlargement of the left
atrium of the heart, which occurs in patients with heart failure," said Dr Scott
Solomon, Professor of Medicine at Harvard University and Director of Noninvasive
Cardiology at Brigham and Women's Hospital in Boston, USA. "So far no treatment
has been shown to reduce morbidity and mortality in patients with HF-PEF. The
favorable effects seen in this study are encouraging, and further testing of
LCZ696 is warranted in this patient population."
Heart failure (HF) is a disease in which the heart is unable to supply enough
blood to meet the body's needs[7],[8]. There are two common types: heart failure
with preserved ejection fraction (HF-PEF) and heart failure with reduced
ejection fraction (HF-REF) [7],[8]. In patients with HF-PEF, the percentage of
blood pumped out of the heart (also called the ejection fraction) remains within
the normal range, but the heart does not relax enough to pump
effectively[5],[7],[9]. This results in structural changes that progressively
weaken the heart leading to a range of debilitating symptoms. Patients with HF-
PEF also commonly have other conditions such as hypertension, diabetes and
atrial fibrillation[7],[8].
"The results of the PARAMOUNT study are promising for patients with HF-PEF as
there is no effective treatment currently available," said Tim Wright, Global
Head of Development, Novartis Pharma. "We believe that thanks to its novel mode
of action and these positive study results, LCZ696 could significantly benefit
people living with chronic heart failure. These results support our commitment
to heart failure patients at every stage of their disease through our ongoing
program of clinical trials."
Heart failure affects an estimated 20 million people in Europe and the US[3],
and kills around half of all patients within five years of diagnosis[10],[11] as
they suffer acute episodes in which their symptoms suddenly become worse and
urgent hospital treatment is needed[5],[7]. Patients suffer fatigue, shortness
of breath and swollen limbs[5],[7],[8], limiting their ability to complete
everyday tasks and placing an ever greater burden on caregivers. Not only does
heart failure have a severe impact on patients, but it also represents a major
economic burden for healthcare providers[12].
LCZ696 is the first in a new class of medicines called angiotensin receptor
neprilysin inhibitors (ARNIs)[13]. It works in a different way to existing heart
failure treatments by inhibiting an enzyme (neprilysin, or NEP) in order to
promote the body's protective mechanisms, and blocking receptors involved in the
narrowing of blood vessels (angiotensin receptors)[13]. LCZ696 therefore acts
simultaneously on two important pathways in the development of the disease[13].
The PARAMOUNT study showed that after 12 weeks of treatment, reduction in NT-
proBNP was 23% greater with LCZ696 than valsartan (p=0.005)[1],[2]. In addition,
there was a greater reduction (p=0.003) in left atrial size (cardiac remodeling)
in LCZ696-treated patients at the end of the 36-week study[1],[2]. This suggests
that LCZ696 could provide an effective treatment for patients with HF-PEF. The
study also showed that LCZ696 had an acceptable safety profile and was well
tolerated in patients with HF-PEF[1],[2].
LCZ696 is one of several compounds being developed by Novartis across the
spectrum of heart failure. In addition to HF-PEF, LCZ696 is also being
investigated for the treatment of heart failure with reduced ejection fraction
(HF-REF) in the Phase III PARADIGM-HF study[14]. A recent Phase II study also
showed that LCZ696 is more effective than valsartan in reducing blood
pressure[15], and a Phase III program has been launched for the first-line
treatment of hypertension in Asia.
PARAMOUNT was an international 36-week, randomized, double-blind, multicenter,
parallel group, active-controlled study to compare the efficacy, safety, and
tolerability profile of LCZ696 with valsartan in patients with HF-PEF[1],[2].
The study consisted of a 12-week core study and a 24-week extension
phase[1],[2]. The study included 301 patients (mean age 71 years) with HF-PEF
(left ventricular ejection fraction >45%)[1],[2]. They all had elevated NT-
proBNP (>400 pg/ml) and at least one of the following symptoms of HF-PEF:
shortness of breath on exertion, shortness of breath when lying flat, episodes
of shortness of breath at night, and swollen ankles[1],[2]. After stopping any
treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin
receptor blocker (ARB), they were randomized to LCZ696 (50 mg twice-daily) or
valsartan (40 mg twice-daily), an ARB indicated for heart failure[1],[2]. Doses
of both drugs were doubled after one week and doubled again after a further week
to a maximum dose of 200 mg and 160 mg twice-daily, respectively[1],[2].
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "could," "currently investigating," "suggest," "may,"
"potential," "encouraging," "promising," "believe," "commitment," "suggests,"
"being investigated," "launched," or similar expressions, or by express or
implied discussions regarding potential marketing submissions or approvals for
LCZ696 or regarding potential future revenues from LCZ696. You should not place
undue reliance on these statements. Such forward-looking statements reflect the
current views of management regarding future events, and involve known and
unknown risks, uncertainties and other factors that may cause actual results
with LCZ696 to be materially different from any future results, performance or
achievements expressed or implied by such statements. There can be no guarantee
that LCZ696 will be submitted or approved for sale in any market, or at any
particular time. Nor can there be any guarantee that LCZ696 will achieve any
particular levels of revenue in the future. In particular, management's
expectations regarding LCZ696 could be affected by, among other things,
unexpected clinical trial results, including unexpected new clinical data and
unexpected additional analysis of existing clinical data; unexpected regulatory
actions or delays or government regulation generally; the company's ability to
obtain or maintain patent or other proprietary intellectual property protection;
competition in general; government, industry and general public pricing
pressures; unexpected manufacturing issues; the impact that the foregoing
factors could have on the values attributed to the Novartis Group's assets and
liabilities as recorded in the Group's consolidated balance sheet, and other
risks and factors referred to in Novartis AG's current Form 20-F on file with
the US Securities and Exchange Commission. Should one or more of these risks or
uncertainties materialize, or should underlying assumptions prove incorrect,
actual results may vary materially from those anticipated, believed, estimated
or expected. Novartis is providing the information in this press release as of
this date and does not undertake any obligation to update any forward-looking
statements contained in this press release as a result of new information,
future events or otherwise.
About Novartis
Novartis provides innovative healthcare solutions that address the evolving
needs of patients and societies. Headquartered in Basel, Switzerland, Novartis
offers a diversified portfolio to best meet these needs: innovative medicines,
eye care, cost-saving generic pharmaceuticals, preventive vaccines and
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only global company with leading positions in these areas. In 2011, the Group
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References
[1] Solomon S. PARAMOUNT: Efficacy and Safety of LCZ696, a First-in-Class
Angiotensin Receptor Neprilysin Inhibitor, in Patients with Heart Failure and
Preserved Ejection Fraction: Primary Results from the PARAMOUNT Study.
Presentation at ESC Congress 2012 (European Society of Cardiology), Munich,
Germany, August 26, 2012.
[2] Solomon S, Zile M, Pieske B, et al. The angiotensin receptor neprilysin
inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2
double-blind randomised controlled trial. www.thelancet.com Published online
August 26, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61227-6.
[3] Metra M, Brutsaert D, Dei Cas L, Gheorghiade M. (2011) ESC Intensive and
Acute Cardiac Care Textbook - acute heart failure: epidemiology, classification,
and pathophysiology. Chapter 49.
[4] Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in patients hospitalised
with heart failure and preserved left ventricular ejection fraction: prevalence,
therapies and outcomes. Circulation. 2012;126:65-75.
[5] Blanche C, Fumeaux T, Polikar R. Heart failure with normal ejection fraction
(HFNEF): is it worth considering? Swiss Med Wkly. 2010;140:66-72.
[6] Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and
outcomes of patients with preserved systolic function hospitalized for heart
failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol.
2007:50:768-777.
[7] McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure 2012: The Task Force
for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the
European Society of Cardiology. Developed in collaboration with the Heart
Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-1847.
[8] Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused Update Incorporated Into
the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in
Adults: A Report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009; 53:e1-90.
[9] Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008.
[10] Loehr LR, Rosamond WD, Chang PP, et al. Heart failure incidence and
survival (from the Atherosclerosis Risk in Communities Study). Am J Cardiol
2008;101:1016-22.
[11] Roger VL, Go AS, Lloyd-Jones DM, et al. Heart Disease and Stroke Statistics
- 2012 Update: A Report from the American Heart Association. Circulation.
2012;125:e2-e220.
[12] O'Connell JB, Bristow MR. Economic impact of heart failure in the United
States: Time for a different approach. J Heart and Lung Trans.
1993:13(4):S107-112.
[13] Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of
LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J
Clin Pharm. 2010;50:401-14.
[14] Clinicaltrials.gov: Prospective comparison of ARNI with ACEI to determine
impact on global mortality and morbidity in patients with heart failure
(PARADIGM-HF) http://clinicaltrials.gov/ct2/show/NCT01035255; Accessed August
2012.
[15] Ruilope LM, Dukat A, Böhm M, et al. Blood-pressure reduction with LCZ696, a
novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a
randomized, double-blind, placebo-controlled, active comparator study. Lancet
2010;375:1255-66.
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Datum: 26.08.2012 - 08:55 Uhr
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