Novartis new analysis shows high consistency in lowering LDL-C in individual response with investigational inclisiran

• Pooled data from Phase III ORION-10 and -11 showed highly consistent efficacy, tolerability and safety profile over 17 months on twice-yearly subcutaneous dosing in 2,300 patients (of which 1,164 were on inclisiran) ¹
  
• New post-hoc analysis demonstrates 99% of patients treated with inclisiran showed placebo-adjusted reduction in low-density lipoprotein cholesterol (LDL-C) of ≥30% with a mean reduction of 54.1% from baseline (observed values)²
  
• 88% of inclisiran-treated patients achieved LDL-C placebo-adjusted reduction of at least 50% at any time point during the study (observed values)²
  
• Inclisiran is currently under review by the FDA and the EMA for the treatment of primary hyperlipidemia (including Heterozygous Familial Hypercholesterolemia) in adults who have elevated LDL-C while being on a maximally tolerated dose of statin therapy

Basel, August 30, 2020 — Novartis today announced results from a post-hoc analysis of pooled data from the Phase III ORION-10 and -11 trials evaluating the individual responses of patients on low-density lipoprotein cholesterol (LDL-C) reduction with inclisiran, a first-in-class investigational treatment for hyperlipidemia in adults. This new analysis of inclisiran showed a highly consistent effect, with a safety and tolerability profile similar to placebo, on a twice-yearly dosing schedule after an initial dose and one 3 months later, across individual patients with atherosclerotic cardiovascular disease (ASCVD) or risk equivalents over 17 months of treatment.

Presented at the ESC Congress 2020, the annual meeting of the European Society of Cardiology, the analysis evaluated the efficacy and tolerability of inclisiran on top of a maximally tolerated dose of statins, in two studies of more than 2,300 patients (of which 1,164 were on inclisiran) from the Phase III trials. Results demonstrated a low inter-individual variability, with 99% of inclisiran-treated patients showing a placebo-adjusted ≥30% reduction of their LDL-C levels with a mean reduction of 54.1% from baseline (observed values)^2­ .

“This analysis confirms that as a small interfering RNA (siRNA), inclisiran provides a remarkably consistent treatment profile. Nearly all patients from these trials achieved clinically meaningful reductions of their LDL-C levels over the 17 month period, and inclisiran had a safety and tolerability profile similar to placebo,” said ORION-11 principal investigator Kausik Ray, M.D., Professor of Public Health, Consultant Cardiologist, Imperial College London. “These efficacy and safety results showcase the promise of inclisiran as a therapy for those ASCVD patients who cannot reach their LDL-C goals.”

An LDL-C reduction of at least 50% was reached by 88.4% of patients at any time point in the study (observed values). After 17 months, 66.4% of the inclisiran group had a reduction in LDL-C of at least 50% as compared to 2.5% from the placebo group (observed values) ². Overall, inclisiran was well-tolerated with a safety profile similar to placebo. All patients were on twice-yearly dosing, following an initial dose and one 3 months later.

“There remains an urgent need for innovative LDL-C-lowering therapies for patients not reaching their LDL-C target goals with current standard of care. This analysis reinforced our view of inclisiran’s therapeutic value and its potential as the first cholesterol-lowering siRNA,” said David Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development, Novartis. “With a unique twice-yearly dosing, if approved, inclisiran may fit seamlessly into patients’ regular healthcare visits and help us reimagine treatment for ASCVD.”

Inclisiran is currently under review by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of primary hyperlipidemia (including Heterozygous Familial Hypercholesterolemia) in adults who have elevated LDL-C while being on a maximally tolerated dose of statin therapy.

About the ORION-10 and -11 Phase III LDL-C Lowering Studies
ORION-10 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 by a healthcare professional in an initial dose, again at 3 months, and then every 6 months thereafter in 1,561 participants with atherosclerotic cardiovascular disease (ASCVD) and elevated low-density lipoprotein cholesterol (LDL-C), despite a maximum tolerated dose of LDL-C-lowering therapies (e.g. a statin 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 (observed values). The study was conducted at 145 sites in the United States¹.

ORION-11 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 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 a maximum 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 (observed values). The international study was conducted at 70 sites in seven countries¹.

About ASCVD
Atherosclerosis corresponds to the accumulation of lipids over time – mainly 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 stroke³. Atherosclerotic Cardiovascular Disease (ASCVD) accounts for over 85% of all cardiovascular disease deaths⁴. ASCVD is the primary cause of death in the EU and its burden in the US is greater than that from any other chronic diseases^5,6.

About Inclisiran
Inclisiran, an investigational cholesterol-lowering treatment, was added to the pipeline from the Novartis acquisition of The Medicines Company. Inclisiran will potentially be the first and only LDL-C-lowering small-interfering RNA (siRNA) treatment. It is intended to be administered by a healthcare professional by subcutaneous injection with an initial dose, again at 3 months 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 on the sense strand with triantennary N-acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran increases 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. Data from each of the Phase III studies was recently published online, ahead of print, in The New England Journal of Medicine. A cardiovascular outcomes trial, ORION-4, is ongoing.

In the Phase III trials, 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, dyspnea, 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^1,7.

Novartis has obtained global rights to develop, manufacture and commercialize inclisiran under a license and collaboration agreement with Alnylam Pharmaceuticals.

About Novartis in Cardiovascular-Renal-Metabolism
Bending the curve of life requires addressing some of society’s biggest public health concerns. Novartis has an established and expanding presence in diseases covering the heart, kidney and metabolic system. In addition to essential treatment Entresto^® (sacubitril/valsartan), Novartis has a growing pipeline of potentially first-in-class molecules addressing cardiovascular, metabolic and renal diseases.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. 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 is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 109,000 people of more than 140 nationalities work at Novartis around the world. Find out more at
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References
1.    Ray K, Wright R, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. New England Journal of Medicine. 2020;382:1507-1519.
2.    R. Scott Wright, ORION-10 and ORION-11, Interindividual variability in LDL C reductions with inclisiran. Data presented at the ESC Congress 2020, August 29 - September 1.
3.    Goldstein J, Brown M. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161–172.
4.    WHO Cardiovascular diseases (CVDs) (https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) ; accessed June 30, 2020).
5.    Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, et al. Heart disease and stroke Statistics-2012 update. Circulation. 2012;125(1):e2–e220.
6.    Kim H, Kim S, Han S, Rane PP, Fox KM, Qian Y, and Suh SH. Prevalence and incidence of atherosclerotic cardiovascular disease and its risk factors in Korea: a nationwide population-based study. BMC Public Health. 2019;19:1112.
7.    Raal F, Kallend D, Ray K, al. Inclisiran for the Treatment of Heterozygous Familial HypercholesterolemiaNew England Journal of Medicine. 2020;382(16):1520-1530.

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