The Medicines Company and Alnylam Pharmaceuticals 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 2 study of inclisiran. Data from ORION-1 were presented today 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 54percent 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 3.2percent of patients), mild or moderate, and transient – in only 2.4percent 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 51percent at Day 60, which were durable to Day 90 (mean 45percent and up to 76percent). 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 59percent at Day 60, which were durable to Day 90 (mean 50percent) and Day 180 (mean 43percent and up to 81percent). Two 300 mg injections of inclisiran – one given on Day 1 and one on Day 90 – achieved a mean LDL-C reduction of 57percent at Day 120, which was durable to Day 180 (mean 52percent and up to 81percent). All differences relative to placebo in these 189 patients were statistically significant (p <0.0001).
“The remarkable strength and consistency of the data from ORION-1 provide compelling support for the medical and commercial potential of inclisiran and drive our decision to move into Phase 3 with what we believe could be a highly-competitive and potentially transformational medicine,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “We will focus our resources on inclisiran for aggressive Phase 3 development to ensure that this promising agent is investigated thoroughly and rapidly in Phase 3, submitted to worldwide regulatory agencies and, if approved, made available to millions of at-risk, often non-adherent, patients worldwide who continue to grapple with the realities and risks of high LDL-C.”
David Kallend, MBBS, Vice President and Global Medical Director of The Medicines Company, added, “These positive results from ORION-1 showed robust and durable knockdown of LDL-C and a very encouraging safety and tolerability profile at this stage of development. The data strengthen our earlier findings in Phase 1 – published recently in the New England Journal of Medicine- that an infrequent, low volume dosing regimen of 2 or 3 injections per year could constitute a highly-differentiated and competitive treatment for patients with hypercholesterolemia. Inclisiran also has the potential to open new care approaches linking the temporal cycle of LDL-C monitoring with counseling and administration of therapy. The ORION-1 data have enabled us to select an optimal dose of 300 mg, and the data presage a quick and efficient transition to Phase 3 development.”
John J.P. Kastelein, M.D., Ph.D., Professor of Medicine and Chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, said, “Elevated LDL-C remains a major risk factor for coronary artery disease, and new therapies are needed for patients who are refractory or intolerant to current approaches for management of their LDL-C levels. PCSK9 therapies have now emerged as a new class of drugs for treatment of hypercholesterolemia, and I believe that these agents have the potential to make a meaningful difference for patients. ORION-1 strengthens prior data with inclisiran, especially the degree and durability of LDL-C lowering effects. If the safety and efficacy of this novel investigational PCSK9 synthesis inhibitor can be confirmed in Phase 3 studies to support approval, it may offer an important treatment option for patients, physicians, and payers.”
John Maraganore, Ph.D., Chief Executive Officer of Alnylam, added, “We are delighted with these data from the ORION development program for inclisiran and thankful for the progress made by investigators and our partner, The Medicines Company. We are very excited to see the rapid progression of the program worldwide and are confident that our RNAi platform provides the opportunity to create new medicines for important diseases such as hypercholesterolemia, which have major unmet medical needs.”
