Inclisiran (siRNA) for the Treatment of Hypercholesterolemia: PDUFA Date Set as December 2020

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Highlights of Inclisiran Program

- Inclisiran, an investigational cholesterol-lowering therapy, was added to the pipeline from the Novartis acquisition of The Medicines Company. 
- Inclisiran recently received a positive CHMP opinion and recommendation for marketing authorization in Europe and is under review by the US Food and Drug Administration
- 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 categories
- Expected Approvals by End of 2020 or H1 2021



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.

Inclisiran (ALN-PCSsc) is a long-acting, subcutaneously delivered, synthetic siRNA directed against PCSK9 that is conjugated to triantennary N-acetylgalactosamine carbohydrates. Its twice-yearly dosing by subcutaneous injection may integrate seamlessly into a patient’s healthcare routine.

Regulatory Status
US Food and Drug Administration
The NDA for commercialization of inclisiran is under review by the FDA. The PDUFA date is set as 26 December 2020. 

European Market Application
Inclisiran recently received a positive CHMP opinion and recommendation for marketing authorization in Europe.

Clinical Study Update for Inclisiran

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
  • 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 HeFH (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. 
  • The pooled analyses assessed inclisiran's efficacy for lowering LDL-C, as well as safety and tolerability, across age ranges and by gender.

Impact of gender on the efficacy of inclisiran vs placebo:
  • 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%, respectively
  • Across both analyses, inclisiran was reported to be well-tolerated, irrespective of age or gender. Injection site reactions (ISRs) were more frequent in female vs male patients and in the <65 population vs elder patients; all ISRs were transient and mild or moderate in terms of severity.
Reference 
https://www.novartis.com/news/media-releases/novartis-announces-nejm-publication-three-pivotal-trials-showing-durable-and-potent-efficacy-inclisiran-investigational-first-class-sirna-cholesterol-lowering

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