Phase1 Trial Supports PCSK9-Inhibitor Inclisiran For Reducing LDL Cholesterol Interview with:

Kevin Fitzgerald, Ph.D. Alnylam Pharmaceuticals Cambridge, MA 02142

Dr. Kevin Fitzgerald

Kevin Fitzgerald, Ph.D.
Alnylam Pharmaceuticals
Cambridge, MA 02142 What is the background for this study?

Response: Inclisiran (ALN-PCSsc) is a subcutaneously administered RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia. The Phase 1 trial of inclisiran was conducted in the U.K. as a randomized, single-blind, placebo controlled, single ascending-and multi-dose, subcutaneous dose-escalation study in 69 volunteer subjects with elevated baseline LDL-C (≥ 100 mg/dL). The primary objective of the study was to evaluate the safety, side effect profile, and pharmacodynamics effects of inclisiran. What are the main findings?

Response: In the single-ascending-dose (SAD) phase, pharmacodynamic measures showed:
• Doses ≥300 mg reduced PCSK9 at day 84 (up to a least-squares mean (LSM) reduction of 74.5%);
• Doses ≥100 mg reduced LDL cholesterol at day 84 (up to a LSM reduction of 50.6%);
• Reductions in PCSK9 and LDL cholesterol were maintained at day 180 with little variation over the 6-month period for doses ≥300 mg.
In the multiple-dose (MD) phase, pharmacodynamic measures showed:
• Reduced PCSK9 (up to a LSM reduction of 83.8%) and LDL cholesterol (up to a LSM reduction of 59.7%) at day 84;
• Levels of PCSK9 and LDL cholesterol remained reduced in all the inclisiran cohorts at day 196.

Safety and side effect profile evaluations showed inclisiran was generally well tolerated following single and multiple subcutaneous dose administration. No serious adverse events (SAEs) or discontinuations due to AEs were reported and all observed adverse events (AEs) were mild or moderate in severity. There was one Grade 3 GGT elevation considered related to statin therapy. What should readers take away from your report?

Response: Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving adequate LDL-C levels with currently available therapies such as statins.

Agents which block PCSK9 are proving to be promising treatment alternatives for lowering LDL, yet the two agents currently available have a short duration of effect, requiring one to two doses a month. The Phase 1 study of inclisiran supports quarterly or bi-annual dosing, something that may be transformative for patients who require long-term treatment to control their cholesterol levels. What recommendations do you have for future research as a result of this study?

Response: The findings from the Phase 1 trial add to the clinical evidence supporting PCSK9 as a therapeutic target for significantly lowering LDL cholesterol. It also demonstrates the ability of RNAi therapeutic candidates to inhibit synthesis of liver-derived target proteins in a potent and durable way. Based on the positive results of this study, inclisran is now in phase 2 clinical trials. The development leadership of ALN-PCSsc has transitioned from Alnylam to The Medicines Company. We jointly established the ORION™ Development Program, which is a comprehensive global clinical development plan designed to support inclisiran regulatory approval and market access worldwide. Is there anything else you would like to add?

Response: The Medicines Company will be presenting interim results of the ORION-1 Phase 2 study on Tuesday, November 15 at the American Heart Association Scientific Sessions. The data will include Day 90 follow-up results for all 501 patients and a preliminary analysis of Day 180 follow-up for up to 200 patients. We hope the findings further demonstrate the possibility of triannual or biannual dosing of inclisiran. Thank you for your contribution to the community.

Disclosure: Study supported by:
Alnylam Pharmaceuticals and the Medicines Company.


A Highly Durable RNAi Therapeutic Inhibitor of PCSK9
Kevin Fitzgerald, Ph.D., Suellen White, B.S.N., Anna Borodovsky, Ph.D., Brian R. Bettencourt, Ph.D., Andrew Strahs, Ph.D., Valerie Clausen, Ph.D., Peter Wijngaard, Ph.D., Jay D. Horton, M.D., Jorg Taubel, M.D., Ashley Brooks, M.B., Ch.B., Chamikara Fernando, M.B., B.S., Robert S. Kauffman, M.D., Ph.D., David Kallend, M.D., Akshay Vaishnaw, M.D., and Amy Simon, M.D.
November 13, 2016DOI: 10.1056/NEJMoa1609243

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on November 14, 2016 by Marie Benz MD FAAD

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