Inhibition of PCSK9 synthesis with investigational RNAi compound halves LDL-c up to 90 days
Inhibition Of PCSK9 Synthesis Via RNA Interference: 90 Day Data From Orion-1-a Multi-centre Phase-2 Randomized Controlled Trial (ORION 1)Presented at the AHA Scientific Sessions 2016 by: Kausik K. Ray, MBChB, M.D., M.Phil., FRCP, Imperial College London, London, United Kingdom
PCSK9 synthesis can be inhibited by RNA interference (RNAi) with inclisiran, which lowers LDL-c significantly, up to 57% with two doses of 300 mg, as was seen in the ORION-I phase II study. These observations support the start of a phase III trial with this investigational compound.
Inclisiran is a double stranded oligonucleotide that targets PCSK9 synthesis under investigation for LDL-c lowering. While antibodies directed against PCSK9 have been demonstrated to be effective at lowering LDL-c levels with or without statins, they require 12-24 subcutaneous (s.c.) injections per year (totalling ~2-5 grams). RNAi is a highly efficient approach to inhibit PCSK9 synthesis in the liver and in a phase I study 300 mg inclisiran lowered LDL-c by about 50% for 4-6 months (n=69).
RNAi works at the level of translation; by specifically degrading PCSK9 mRNA, production of PCSK9 protein is prevented. The ORION I study was a dosage selection study (100 mg, 200 mg, 300 mg and 500 mg evaluated), with percent change in LDL-c from baseline to day 180 as primary endpoint.
The current results represent a pre-specified interim analysis (endpoints up to 90 days, which is a secondary endpoint in the overall study). Inclisiran was tested in patients with high CV risk and elevated LDL-c (>70 mg/dL if with ASCVD, or LDL-c >100 mg/dL in case of primary prevention). At the follow-up cut-off date for the interim analysis, 497 patients had been followed for 90 days, and 189 to 180 days.
Treatment emergent adverse events (TEAE) up until day 90 were seen to a similar extent in placebo-treated patients (n=127, 69 events, 54%) and in the pooled group of inclisiran doses (n=370, 198 events, 54%). Most common TEAEs (>2%) were myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhoea and dizziness. Occurrence of TEAEs did not seem to increase with increasing dose of inclisiran. Very few inclisiran-treated patients showed ALT >3x ULN (0.3%), AST >3x ULN (0.3%), ALP >2x ULN (0.8%) or CK >5x ULN (0.6%) (all never observed on placebo). Myalgia was noted in 5.7% of inclisiran-treated patients and in 4.6% of placebo-treated patients.
Injection-site reactions (erythema, pruritus, rash or reaction) were observed any time in 3.2% of patients (1.1%, 0.3%, 0% and 1.9% respectively), and 2.4% were observed within 4 hours.
PCSK9 levels declined rapidly, in a dose dependent manner, and remained decreased until day 90. LDL-c levels decreased up to about 50% at day 30, and the reduction was maintained until day 90. Reductions of up to 30% in total cholesterol was seen after 90 days with one dose of inclisiran, about 10% lowering of triglycerides with the middle doses, non-HDL-c decreased by up to 42%, apoB by up to 40% and Lp(a) by up to 23%. HDL-c increased with up to 9% over 90 days.
When comparing one dose of 300 mg with repeating a dose at day 90, and follow-up until 180 days, the second dose gave a slight additional reduction in LDL-c, whereas after the single dose a slight loss of the LDL-c reduction was seen between day 90 and 180. Individual patient response to the two doses varied from -26.5 mg/dL to -122 mg/dL (mean: -64.9 mg/dL, median: -64 mg/dL).
Thus, the well-tolerated inclisiran showed reductions in LDL-c of up to 57% (with two doses of 300mg), that lasted at least 90 days. The potential for biannual or triannual dosing is affirmed. These results support the start of a phase III trial. The efficacy, safety and dosing profile of inclisiran are likely to ensure significant and durable reductions in LDL-c and may thus impact CV outcomes.
- Our reporting is based on the information provided during the AHA congress –