Press Release: Novartis announces NEJM publication of three pivotal trials showing durable and potent efficacy of inclisiran, an investigational first-in-cla...

-- Inclisiran, an investigational medicine, showed durable and potent

reduction of low-density lipoprotein cholesterol (LDL-C) in patients with

atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents

and heterozygous familial hypercholesterolemia (HeFH)1,2

-- Inclisiran reduced LDL-C at 17 months by 52% in patients with ASCVD

(ORION-10), 50% for ASCVD and ASCVD risk equivalents (ORION-11) and by

50% in HeFH patients (ORION-9); all of whom had elevated LDL-C levels

despite maximally tolerated lipid-lowering therapy1,2

-- Inclisiran's novel siRNA mechanism of action could potentially enable a

unique twice-yearly subcutaneous dosing regimen administered by a

healthcare provider

-- Inclisiran is currently under review by the U.S. Food and Drug

Administration and European Medicines Agency for use in adults with ASCVD

or HeFH who have elevated LDL-C while being on a maximum tolerated dose

of a lipid-lowering therapy

Basel, March 18, 2020 -- Novartis announced today the publication of

three pivotal Phase III clinical trials for inclisiran, a potential

first-in-class small interfering RNA (siRNA) investigational agent for

hyperlipidemia in adults. The findings were published in two online

articles ahead of print in The New England Journal of Medicine. The

primary endpoints were achieved in all three trials. Namely, percentage

change in LDL-C from baseline to 17 months and time-adjusted percentage

change in LDL-C from baseline from 3 through 18 months. This

demonstrates that after two starter doses, twice-yearly subcutaneous

dosing with inclisiran resulted in durable and potent LDL-C reductions

versus placebo. Inclisiran was well-tolerated with a safety profile

similar to placebo(1, 2).

Hyperlipidemia refers to the high level of lipids (fats, cholesterol,

triglycerides), such as LDL-C, found in the blood that are either

acquired or a result of genetic disorders(3). The length of time a

person has elevated LDL-C levels, is understood to be causal to ASCVD,

which can lead to a cardiovascular event such as a heart attack or

stroke(4,5). LDL-C is the most readily modifiable risk factor for

ASCVD(6-11). People who are on lipid-lowering therapies often do not

reach optimal LDL-C levels, leaving them at increased risk for

significant morbidity and mortality associated with this

condition(12,13). Approximately 40 million patients in the US have been

diagnosed with atherosclerotic cardiovascular disease (ASCVD) or

familial hypercholesterolemia (FH) and are at risk of a cardiovascular

event(14).

ORION 10 and 11

One article reported the results from the ORION-10 and -11 studies,

which evaluated the use of inclisiran in addition to maximally tolerated

lipid-lowering therapies in patients with ASCVD (ORION-10) or ASCVD and

ASCVD risk equivalents (ORION-11) through 18 months.

In ORION-10 and -11, at 17 months inclisiran resulted in

placebo-adjusted LDL-C reduction of 52% and 50% respectively and

time-adjusted reduction from 3 through 18 months of 54% and 49%

respectively(1).

Treatment-emergent adverse events were generally similar between the

inclisiran and placebo groups.

"Inclisiran and its twice-yearly dosing schedule in three large trials

consistently delivered potent and sustained cholesterol-lowering and was

generally well tolerated," said Kausik Ray, M.D., ORION-11 principal

investigator, Imperial Centre for Cardiovascular Disease Prevention,

Department of Primary Care and Public Health, Deputy Director of

Imperial Clinical Trials Unit, Imperial College, London. "These data

provide support for this groundbreaking approach to reducing LDL-C in

patients who are not achieving LDL-C treatment goals with the current

standard of care."

"Elevated LDL-C is an important modifiable risk factor for

cardiovascular events for millions of people, particularly those with

ASCVD," said ORION-10 principal investigator R. Scott Wright, M.D.,

Professor of Medicine, Consultant in Cardiology, Mayo Clinic in

Rochester, Minnesota. "The data from ORION-10 shows that inclisiran

results in significant and sustained reductions in LDL-C over a

six-month period with a safety profile similar to placebo."

ORION 9

A separate article on ORION-9 highlighted results of treatment with

inclisiran in HeFH, a rare hereditary disease that causes high levels of

LDL-C and leads to early onset of ASCVD. In this study, inclisiran

reduced LDL-C by 50%* at 17 months with a time-adjusted reduction of 45%

from 3 through 18 months, compared to placebo. There was a robust

reduction of LDL-C with all FH genotypes(2).

Treatment-emergent adverse events were similar between inclisiran and

placebo(2).

"Familial hypercholesterolemia remains a difficult condition to treat

but the potential addition of inclisiran gives hope to many FH patients

to help meet and maintain guideline-recommended LDL-C levels with two

injections of inclisiran per year," said Frederick Raal, M.D.,

University of the Witwatersrand, Department of Medicine, University of

the Witwatersrand Kallend, South Africa.

In all three Phase III trials patients received inclisiran or placebo in

addition to maximally tolerated lipid-lowering therapy. The twice-yearly

dosing regimen, which followed two starter doses, was administered

subcutaneoulsy by a healthcare provider.

"There are over 50 million secondary prevention patients worldwide with

atherosclerotic cardiovascular disease or familial hypercholesterolemia

on current standard of care who don't achieve their desired LDL-C goal

and remain at increased risk of cardiovascular events," said Marcia

Kayath, M.D., Global Head of Medical Affairs and Chief Medical Officer,

Global Pharmaceutical Division, Novartis. "With inclisiran's unique

twice-yearly dosing, we're reimagining what potent and durable control

of LDL-C looks like for patients and physicians with the potential to

improve adherence and keep patients' cholesterol levels low over the

long term."

Inclisiran is currently under review by the U.S. Food and Drug

Administration and European Medicines Agency for use in adults with

ASCVD or HeFH who have elevated LDL-C while being on a maximum tolerated

dose of a lipid-lowering therapy. If approved, inclisiran will be the

first and only cholesterol-lowering treatment in the siRNA class.

*Observed percentage, analysis for imputed values of missing numbers

also performed.

About the ORION Phase III LDL-C lowering studies

ORION-9 was a pivotal Phase III, placebo-controlled, double-blind,

randomized study to evaluate the efficacy, safety and tolerability of

inclisiran sodium 300 mg administered subcutaneously in 482 patients

with clinical or genetic evidence of heterozygous familial

hypercholesterolemia (HeFH) and elevated LDL-C, despite maximum

tolerated dose of statin, with or without other lipid-modifying therapy,

and who required additional LDL-C reduction(2). Inclisiran was

administered in two starter doses and then every 6 months thereafter.

ORION-10 was a pivotal Phase 3, placebo-controlled, double-blind,

randomized study to evaluate the efficacy, safety and tolerability of

inclisiran sodium 300 mg administered subcutaneously by a healthcare

professional in an initial dose, again at 3 months, and then every 6

months thereafter in 1,561 participants with ASCVD and elevated LDL-C,

despite maximum tolerated dose of LDL-C-lowering therapies (e.g., a

statin or ezetimibe). The study was conducted at 145 sites in the United

States(1).

ORION-11 was a pivotal Phase 3, placebo-controlled, double-blind,

randomized study to evaluate the efficacy, safety, and tolerability of

inclisiran sodium 300 mg administered administered subcutaneously by a

healthcare professional in an initial dose, again at 3 months, and then

every 6 months thereafter in 1,617 patients with ASCVD or ASCVD-risk

equivalents and elevated LDL-C despite maximum tolerated dose of statin

therapy (with or without ezetimibe(6) The international study was

conducted at 70 sites in seven countries(1).

About inclisiran

Inclisiran, an investigational cholesterol-lowering therapy, was added

to the pipeline from the Novartis acquisition of The Medicines Company.

Inclisiran will potentially be the first and only LDL-C lowering siRNA

medicine. It is intended to be administered by a healthcare professional

with 2 starter doses and then every 6 months thereafter. Its

twice-yearly dosing by subcutaneous injection may integrate seamlessly

into a patient's healthcare routine. As a siRNA, inclisiran is thought

to harness the body's natural process of clearing LDL-C from the

bloodstream. Inclisiran is a double-stranded siRNA, conjugated with

GalNAc allowing for targeted uptake by hepatocytes. In hepatocytes,

inclisiran silences PCSK9 expression, increasing LDL-C receptor

recycling and expression on the hepatocyte cell surface, thereby

increasing LDL-C uptake by hepatocytes and lowering LDL-C levels in the

circulation.A cardiovascular outcomes study, ORION-4, is ongoing.

In the Phase III studies, inclisiran was reported to be well-tolerated

with a safety profile similar to placebo. The most common adverse

reactions reported (>=3% of patients treated with inclisiran and

occurring more frequently than placebo) were, diabetes mellitus,

hypertension, nasopharyngitis, arthralgia, back pain, dypspnea,

bronchitis and upper respiratory tract infection. Adverse events at the

injection site were more frequent with inclisiran than placebo and were

generally mild and none were severe or persistent(1.2).

Novartis has obtained global rights to develop, manufacture and

commercialize inclisiran under a license and collaboration agreement

with Alnylam Pharmaceuticals.

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