Thursday, April 27, 2017
The Medicines Company and Alnylam Pharmaceuticals, Inc.today announced that The Medicines Company has agreed with the U.S. Food and Drug Administration (FDA) on plans for the Phase III clinical program for inclisiran, which is designed to support the submission of a New Drug Application (NDA). The Company has received final, End-of-Phase II meeting minutes from the FDA.
The Phase III program will comprise clinical trials in subjects with atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia (FH), and will collectively enroll approximately 3,000 subjects randomized to treatment with inclisiran (1,500) or placebo (1,500).
The primary endpoint for all pivotal trials will be LDL-C change from baseline.Subjects will be studied for 18 months. The dose of inclisiran will be 300 mg given subcutaneously on day-1, day-90 and then every six months thereafter. Subjects will receive a total of four doses of inclisiran during the 18-month study period.
Although not part of the first NDA, The Medicines Company will also perform a cardiovascular outcomes trial in approximately 14,000 subjects with ASCVD and/or risk equivalents, such as diabetes, to determine the effects of LDL-C lowering with inclisiran on cardiovascular outcomes. The design of the outcomes trial has also been agreed with the FDA and the primary efficacy endpoint of the trial will be a composite of coronary heart disease death, non-fatal myocardial infarction and fatal and non-fatal ischemic stroke. These endpoints have been demonstrated to be modifiable in previous, similar outcomes trials. The duration of the outcomes trial will be long enough to accumulate a sufficient number of events to provide overwhelming statistical power to ascertain treatment group differences and maximize the clinical effect size associated with LDL-C lowering. Assuming success, results of the outcomes trial will be submitted to the FDA as a supplemental NDA.
“We are grateful to the FDA for its expertise, advice and support. Cardiovascular disease is a serious threat to the health of Americans, and it is clear that the FDA is committed to facilitating the development and approval of effective and safe drugs to address this important public health problem,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “Based on data from our Phase II ORION-1 study and the previous Phase I study – both published in The New England Journal of Medicine – we are confident that inclisiran reduces LDL-C meaningfully. We have also been highly encouraged by the safety data in these prior studies. Furthermore, inclisiran’s highly-differentiated dosing schedule has the potential to transform the burden placed on millions of patients who so badly need to lower LDL-C levels. We anticipate completing the LDL-C lowering program quickly and expect to submit an NDA for ASCVD and FH at or around the end of 2019. We believe our agreement with the FDA on the Phase III clinical development program for inclisiran is highly favorable and adds significantly to inclisiran’s strategic value.”
Dr. Meanwell added, “Although not required for the NDA, we will also perform an aggressive cardiovascular outcomes trial in high-risk subjects with ASCVD and/or risk-equivalents, such as diabetes. We believe that positive outcomes data, with primary outcome clinical effects greater than those reported for anti-PCSK9 monoclonal antibodies, will drive a high level of competitiveness in the worldwide market – which we expect to become very large.”
“The Medicines Company’s agreement with the FDA supports a clear path forward for further inclisiran development and regulatory review. Indeed, we’re pleased with the excellent progress made by our colleagues at The Medicines Company to advance this potential, innovative medicine to patients in need, and we intend to fully support them in their efforts,” said John M. Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Moreover, we believe the planned development path for inclisiran positions this promising potential medicine to contribute meaningfully to our Alnylam 2020 goals.”
