Press Release: New Novartis analyses for investigational inclisiran demonstrate consistently effective and sustained LDL-C reduction at month 17 regardless o...

-- Pooled data analyses from Phase III ORION-9, -10 and -11 showed that

inclisiran consistently reduced low-density lipoprotein cholesterol

(LDL-C) by approximately 51% in both male and female adult patients and

in three age categories1,2

-- Sustained LDL-C reduction with inclisiran was observed regardless of age

or gender differences1,2 with two doses a year, after an initial dose and

then again at three months; the overall trial dosing schedule was at

months 1, 3 and then every 6 months up to month 17

-- LDL-C is the most readily modifiable risk factor for atherosclerotic

cardiovascular disease (ASCVD), yet despite widespread statin use 80% of

high-risk patients do not reach guideline-recommended LDL-C targets3,4

-- Inclisiran recently received a positive CHMP opinion and recommendation

for marketing authorization in Europe and is under review by the U.S.

Food and Drug Administration

The digital press release with multimedia content can be accessed here:

https://novartis.gcs-web.com/New-Novartis-analyses-for-investigational-inclisiran-demonstrate-consistently-effective-and-sustained-LDL-C-reduction-at-month-17-regardless-of-age-and-gender

Basel, November 13, 2020 -- Novartis today announced results from two

pooled post-hoc analyses of Phase III ORION-9, -10 and -11 trials,

evaluating the impact of age and gender on the efficacy and safety of

inclisiran, an investigational and potential first-in-class small

interfering RNA (siRNA) for hyperlipidemia in adults with

atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial

hypercholesterolemia (HeFH). The data showed that at month 17,

inclisiran was well-tolerated and provided effective and sustained

reduction in low-density lipoprotein cholesterol (LDL-C) when used in

addition to other lipid lowering therapies regardless of patients' age

and gender(1,2). During the trials, inclisiran was administered at

months 1, 3 and then every 6 months up to month 17. Results were

presented at the virtual American Heart Association Scientific Sessions

2020.

"High LDL-C and other risk factors for ASCVD, as well as the potential

for treatment side effects, may increase with age and differ by gender,"

said Kausik Ray, MD, ORION-11 trial principal investigator, Professor of

Public Health at Imperial College London and Honorary Consultant

Cardiologist at the Imperial College NHS Trust. "These data are

important as they show that inclisiran, as a siRNA, has the potential to

provide consistent efficacy and tolerability despite the

cholesterol-lowering treatment challenges posed by age and gender with

two doses a year after the initial dosing regimen on day 1 and month 3."

In post-hoc analyses of the pooled results from the ORION Phase III

trials in more than 3,600 patients, treatment with inclisiran delivered

similar LDL-C reductions of approximately 51% from baseline for both

women and men (50.6% vs 50.6% respectively) compared to placebo(1).

Results from a second pooled analysis showed that inclisiran-treated

patients in three age categories all achieved similar LDL-C reductions

of approximately 51% (-51.3% <65 years; -49.9% >=65 years to <75 years;

-51.0% >=75 years)(2). In both analyses, inclisiran was

well-tolerated(1,2).

"Whether you look at it from an age or a gender perspective, inclisiran

analyses continue to show consistency with effective and sustained LDL-C

reduction lasting over the dosing interval," said David Soergel, MD,

Global Head of Cardiovascular, Renal and Metabolic Drug Development,

Novartis. "As we move forward in our journey to reimagine treatment for

ASCVD, these data analyses reinforce the potential of inclisiran as a

first-in-class siRNA treatment to transform LDL-C management with two

doses a year, following the initial dose and another dose at three

months, and a positive tolerability profile."

On Friday, October 16, 2020, the Committee for Medicinal Products for

Human Use of the European Medicines Agency adopted a positive opinion

and recommended granting marketing authorization for inclisiran.

Novartis is anticipating a final regulatory decision in Europe in

December 2020 and is under review by the US Food and Drug

Administration.

About the Pooled Post-Hoc Analyses from Phase III ORION-9, -10 and -11

trials: Age and Gender

The pooled analyses include data from inclisiran's ORION-9, -10 and -11

trials, which were multicenter, double-blind, randomized,

placebo-controlled,18-month studies evaluating inclisiran in patients

with heterozygous familial hypercholesterolemia (ORION-9), ASCVD

(ORION-10) and ASCVD or ASCVD risk equivalents (ORION-11) on statin

therapy who required additional LDL-C lowering. The primary endpoints

for these studies were percentage change in LDL-C from baseline to 17

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

between 3 months and up to 18 months. The primary endpoints were

achieved in all three studies(5-7).

The pooled analyses assessed inclisiran's efficacy for lowering LDL-C,

as well as safety and tolerability, across age ranges and by gender(1,2)

.

Impact of age on the efficacy of inclisiran versus placebo (<65 years;

>=65 years to <75 years; >=75 years)(2) :

-- Percentage change between inclisiran and placebo in LDL-C at month 17 was

similar across all ages: -51.3% (<65 years), -49.9% (>=65 years to <75

years), -51.0% (>=75 years)

-- Time-adjusted percentage LDL-C change between inclisiran and placebo at

month 18 was similar across all ages: -49.6% (<65 years), -51.5% (>=65

years to <75 years), -50.8% (>=75 years)

Impact of gender on the efficacy of inclisiran versus placebo(1) :

-- Percentage change between inclisiran and placebo in LDL-C at month 17 was

consistent across women and men at -50.6% and -50.6% respectively

-- Time-adjusted LDL-C change between inclisiran and placebo at month 18 was

consistent across women and men at -50.5% and -50.6%

Across both analyses, inclisiran was reported to be well-tolerated

irrespective of age or gender. Injection site reactions (ISR) were more

frequent in female versus male patients and in the <65 population versus

elder patients, all ISRs were transient and mild or moderate in terms of

severity.

About the ORION Phase III Low-density Lipoprotein Cholesterol

(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 salt 300 mg, equivalent to 284 mg of inclisiran,

administered subcutaneously by a healthcare professional starting it at

an initial dose(5). Inclisiran was then administered again at 3 months

and then every 6 months thereafter in 482 participants with clinical or

genetic evidence of heterozygous familial hypercholesterolemia and

elevated LDL-C, despite a maximally tolerated dose of LDL-C-lowering

therapies (e.g. a statin or ezetimibe). For the primary endpoints of

ORION-9, inclisiran delivered mean placebo-adjusted percentage change in

LDL-C reductions of 48% (P<.0001) at 17 months and demonstrated

time-adjusted percentage change in LDL-C reductions of 44% (P<.0001)

from 3 through 18 months. The international study was conducted at 46

sites in eight countries(5).

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

randomized study to evaluate the efficacy, safety and tolerability of

inclisiran sodium salt 300 mg, equivalent to 284 mg of inclisiran,

administered subcutaneously by a healthcare professional starting it at

an initial dose(6). Inclisiran was then administered again at 3 months

and then every 6 months thereafter in 1,561 participants with

atherosclerotic cardiovascular disease (ASCVD) and elevated LDL-C,

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

statin and/or ezetimibe). For the primary endpoints of ORION-10,

inclisiran delivered mean placebo-adjusted percentage change in LDL-C

reductions of 52% (P<.0001) at 17 months and demonstrated time-adjusted

percentage change in LDL-C reductions of 54% (P<.0001) from 3 through 18

months. The study was conducted at 145 sites in the United States(6,7).

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

randomized study to evaluate the efficacy, safety and tolerability of

inclisiran sodium salt 300 mg, equivalent to 284 mg of inclisiran,

administered subcutaneously by a healthcare professional starting it at

an initial dose(6). Inclisiran was then administered 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 a maximally tolerated

dose of statin therapy (with or without ezetimibe). For the primary

endpoints of ORION-11, inclisiran delivered placebo-adjusted change in

LDL-C reductions of 50% (P<.0001) at 17 months and demonstrated

time-adjusted LDL-C reductions of 49% (P<.0001) from 3 through 18

months. The international study was conducted at 70 sites in seven

countries(6,7).

About Atherosclerotic Cardiovascular Disease (ASCVD)

Atherosclerosis corresponds to the accumulation of lipids over time

mainly low-density lipoprotein cholesterol (LDL-C) in the inner lining

of the arteries. Unexpected rupture of the atherosclerotic plaque can

cause an atherosclerotic cardiovascular event such as a heart attack or

stroke(8,9). ASCVD accounts for over 85% of all cardiovascular disease

deaths(10). ASCVD is the primary cause of death in the European Union

and its burden in the United States is greater than that from any other

chronic diseases(11,12). ASCVD risk equivalent corresponds to

conditions that confer a similar risk for a ASCVD event (e.g. diabetes,

heterozygous familial hypercholesterolemia)(6,13).

About Inclisiran

If approved, inclisiran (KJX839) would be the first and only therapy to

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