Medicines Co. (MDCO), Alnylam Pharma (ALNY) Announce Publication of Significant ALN-PCSsc Phase 1 Data in LDL-C, PCSK9

November 14, 2016 6:43 AM EST

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and The Medicines Company (Nasdaq: MDCO) announced that results from the Phase 1 study of inclisiran (in-CLEE-si-ran), the recommended International Nonproprietary Name (INN) for ALN-PCSsc, were published in The New England Journal of Medicine (NEJM). Inclisiran is an investigational RNAi therapeutic targeting PCSK9 – a genetically validated protein regulator of LDL receptor metabolism – being developed for the treatment of hypercholesterolemia. The paper can be found online here.

Results from the study showed doses ≥300 mg (single or multiple doses) significantly reduced PCSK9 and LDL cholesterol for at least 6 months. Moreover, inclisiran was found to be generally well tolerated.

"The published findings from our Phase 1 trial with inclisiran add to the clinical evidence supporting PCSK9 as a therapeutic target for significantly lowering LDL cholesterol, as well as the ability of RNAi therapeutic candidates to inhibit synthesis of liver-derived target proteins in a potent and durable manner,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. “We believe that inclisiran represents an innovative and differentiated approach for the treatment of hypercholesterolemia.”

Inclisiran is currently being studied in the ORION-1 Phase 2 study by The Medicines Company. With more than 500 patients enrolled, ORION-1 is the largest study of a GalNAc-siRNA conjugate to date. The Medicines Company recently announced positive top-line results from the day 90 interim analysis of the Phase 2 study demonstrating significant and durable LDL-C reduction that validates the potential for a triannual or biannual dosing regimen. Top-line results also showed that inclisiran was generally well tolerated, with no evidence of drug-related elevations of liver enzymes, neuropathy adverse events, or changes in renal function. The Medicines Company plans to present complete interim results from the ongoing study in a Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions on November 15, 2016.

“We look forward to presenting the interim results of the ORION-1 Phase 2 data at AHA this week including Day 90 follow-up results for all 501 patients and a preliminary analysis of Day 180 follow-up for up to 200 patients,” said David Kallend, MBBS, Vice President and Global Medical Director at The Medicines Company. “Based on the strong results from the Phase 1 study, we hope to further elucidate the hypothesis of triannual or biannual dosing of inclisiran with the ORION-1 results.”

The NEJM publication highlights key results from the Phase 1 clinical trial of inclisiran, including safety and pharmacodynamic measures (PCSK9, LDL cholesterol, exploratory lipid parameters).

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;
  • All observed adverse events (AEs) were mild or moderate in severity;
  • There was one Grade 3 GGT elevation considered related to statin therapy.

The lead development responsibility for inclisiran transitioned from Alnylam to The Medicines Company in August 2015. The two companies are now working to advance inclisiran in the ORION development program, a comprehensive global clinical development plan designed to support regulatory approval and market access worldwide.

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