Date: 2017-04-26
Type of
information: Clinical trial authorisation
phase: 3
Announcement: clinical trial authorization
Company: Alnylam Therapeutics (USA - MA) The Medicines Company (USA - NJ)
Product: inclisiran (ALN-PCSsc)
Action
mechanism:
- RNAi/PCSK9 inhibitor. ALN-PCSsc is a subcutaneously administered RNAi therapeutic targeting the gene proprotein convertase subtilisin/kexin type 9 (PCSK9), a target validated by human genetics that is involved in the metabolism of low-density lipoprotein cholesterol (LDL-C, or “bad” cholesterol). This first-in-class investigational medicine acts by turning off PCSK9 synthesis in the liver. Recent pre-clinical results in non-human primate (NHP) studies demonstrated that a single dose of ALN-PCSsc significantly reduced plasma PCSK9 protein by up to 96%, with mean PCSK9 knockdown at nadir of 88% at the top dose. Results also showed lowering of LDL-C of up to 77%, with a mean reduction of 69% at the top dose; these results were observed in the absence of statin co-administration. Knockdown of PCSK9 and lowering of LDL-C were rapid and durable, with maximal effects lasting greater than 90 days and returning to baseline at approximately 160 days. At the top dose of 10 mg/kg, an over 50% reduction in LDL-C was maintained for over 90 days. Moreover, there was sustained and clamped knockdown of PCSK9 and reduction of LDL-C across this entire time period, which contrasts with the cyclical variation in LDL-C observed with monthly dose regimens of anti-PCSK9 monoclonal antibodies (Stein, Curr Opin Lipidol 2013, 24:510–517). All together, these pre-clinical data are supportive of a once-monthly, and possibly once-quarterly, dosing regimen, which could represent a highly competitive target product profile. In addition, four-week GLP toxicology studies evaluating doses administered every other week confirmed that ALN-PCSsc has a wide therapeutic index, with a No Observed Adverse Effect Level (NOAEL) of greater than 250 mg/kg in rats and NHP.
- Alnylam and The Medicines Company are collaborating in the advancement of ALN-PCSsc per the companies’ agreement formed in early 2013. 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. Inclisiran is currently being studied in the ORION-1 Phase 2 study by The Medicines Company.
Disease: atherosclerotic cardiovascular disease (ASCVD, familial hypercholesterolemia (FH),
Therapeutic
area: Cardiovascular diseases
Country: USA
Trial
details:
Latest
news:
- • On April 26, 2017, The Medicines Company and Alnylam Pharmaceuticals announced that The Medicines Company has agreed with the 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 and familial hypercholesterolemia, 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.
Is
general: Yes
