Results of inclisiran(ALN-PCSsc) from ORION-1 Phase II trial positive for the treatment of hypercholesterolemia. - The Medicines Company + Alnylam Pharma.

The Medicines Company and Alnylam Pharmaceuticals, Inc.announced positive results from the analysis of Day 90 data for 497 patients, as well as analysis of preliminary Day 180 data for 189 patients, enrolled in the ORION-1 Phase II study of inclisiran. Data from ORION-1 were presented in a Late-Breaking Clinical Trials session at the American Heart Association Scientific Sessions 2016 in New Orleans. Inclisiran (formerly known as PCSK9si or ALN-PCSsc) is an investigational GalNAc-conjugated RNAi therapeutic targeting PCSK9—a genetically validated protein regulator of LDL receptor metabolism—being developed for the treatment of hypercholesterolemia. Inclisiran was generally well tolerated and no material safety issue was observed, including no elevations of liver enzymes considered related to study medication and no neuropathy or change in renal function. Overall incidence of treatment emergent adverse events was 54% both in patients randomized to placebo and in patients randomized to inclisiran, with no differences between inclisiran doses. Injection site reactions (ISRs) with inclisiran were infrequent (observed in 3.2% of patients), mild or moderate, and transient - in only 2.4% of patients, the reported ISR started or was still present 4 or more hours after dosing. Baseline LDL-C was approximately 130 mg/dL among 497 randomized and treated patients. Among these patients, one 300 mg subcutaneous injection of inclisiran achieved mean LDL-C reductions of 51% at Day 60, which were durable to Day 90 (mean 45% and up to 76%). All differences relative to placebo in these 497 patients were statistically significant (p < 0.0001). Among 189 randomized and treated patients who had been followed for 180 days or more by the interim data cut-off date of October 25, 2016, one 300 mg subcutaneous injection of inclisiran achieved mean LDL-C reductions of 59% at Day 60, which were durable to Day 90 (mean 50%) and Day 180 (mean 43% and up to 81%). Two 300 mg injections of inclisiran - one given on Day 1 and one on Day 90 - achieved a mean LDL-C reduction of 57% at Day 120, which was durable to Day 180 (mean 52% and up to 81%). All differences relative to placebo in these 189 patients were statistically significant (p < 0.0001). Comment: ALN-PCSsc uses Alnylam's RNA interference (RNAi) technology to stop the production of PCSK9 rather than block the enzyme's activity. That is switching off synthesis of the protein in the liver via a gene silencing approach rather than binding to it and blocking its interaction with LDL receptors. That accounts for its extended duration of action and the ambition to dose just two or three times a year.