Date: 2014-11-17
Type of
information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the American Heart Association (AHA) Scientific Sessions 2014
Company: Alnylam Pharmaceuticals (USA - MA)
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)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.
Disease: hypercholesterolemia
Therapeutic
area: Cardiovascular diseases - Metabolic diseases
Country:
Trial
details:
Latest
news:
- • On November 17, 2014, Alnylam Pharmaceuticals announced that it has presented new pre-clinical data from its investigational RNAi therapeutic programs toward genetically validated targets in development for the treatment of cardiovascular metabolic diseases, including: ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia. These new data are being presented at the American Heart Association (AHA) Scientific Sessions 2014 in a poster presentation titled “Development of Monthly to Quarterly Subcutaneous Administration of RNAi Therapeutics Targeting the Metabolic Disease Genes PCSK9, ApoC3 and ANGPTL3.” Among other data, Alnylam presented new pre-clinical multi-dose data in non-human primates (NHPs) with over six months of dosing for ALN-PCSsc showing robust and clamped knockdown of PCSK9 of up to 92% and reductions in LDL-C of up to 77% with a once-monthly subcutaneous dosing regimen. Recently, Alnylam filed and received approval for a Clinical Trial Application (CTA) for ALN-PCSsc, and now expects to start the Phase 1 trial before year’s end with initial clinical data expected in mid-2015.
Is
general: Yes
