Sustained LDL-c lowering up to 360 days with siRNA directed against PCSK9 in phase 2 study

ACC 2017 Inclisiran, which prevents PCSK9 protein production, resulted in long-term LDL-c lowering after two doses of siRNA, without safety concerns, in the ORION-1 study.

Background

In recent years, major progress has been made in the treatment of atherosclerotic CV disease (ASCVD). PCSK9 inhibition is now a validated target for reduction of LDL-c and ASCVD. A drawback of PCSK9 monoclonal antibody (mAb) therapy may be that it requires 12-26 injections per year. Adherence data with PCSK9 mAbs shows no substantial improvement over statins. This is a problem, as poor adherence and LDL-c variability are associated with poor outcomes. This is most relevant in high risk patients with high LDL-c.

Inclisiran is a novel agent that may address unmet needs. It works via RNA interference (RNAi), and prevents synthesis of PCSK9 protein in the liver. In a Phase I trial, 300 mg inclisiran lowered LDL-c by 50-60% for 84 days (n=69). The ORION-1 study aimed to evaluate optimal dosing regimens in patients with elevated LDL-c and high CV risk. Two dosing regimens were tested, each at three doses of inclisiran: one with a dose of study drug at day 1 and primary evaluation at day 180, and another with a dose at day one and a second dose at day 90, and primary evaluation at day 180. End of study visit was at day 210 and extended follow-up was done at day 360. 483 patients completed the study, out of 501 who were randomised and 497 who were treated.

Main results

• No safety concerns were noted in this trial: the rates of adverse events with inclisiran were similar to the rates with placebo (any treatment emergent adverse events [TEAE]: 70.8% in placebo vs. 75.3% in one-dose regimen, 80.6% vs. 77.2% in two-dose regimen).
• Serious TEAEs were seen at a rate of 4.6% on placebo and 9.1% on inclisiran at one-dose and in 9.7% and 13.0% in the two-dose regimen.
• No injection site reactions were seen on placebo, and in 3.8% of people on the one-dose regimen and 6.5% of the two-dose regimen. These reactions were mild and self-limiting.
• No LFT elevations related to the drug were seen. Transient transaminase increases were infrequent in both groups (0.8% in both treatment groups).
• No differences between treatment groups were seen in incidence of myalgias or CPK enzyme elevations.
• Other relevant safety concerns possibly related to oligo-directed technology were not seen: no thrombocytopenia, no neuropathy, no immunogenicity (no anti-drug antibodies), no pro-inflammatory symptoms or elevated markers (CRP was reduced from end of study as compared to the beginning).
• In the one-dose regimen, rapid PCSK9 knockdown by 70% was seen within 14 days. A slow return to baseline was seen.
• In the two-dose regimen, rapid PCSK9 knockdown by 70% and a further 10% decrease after the second dose at day 90 was seen. This reduction remained more stable over time. Little difference was seen between 200 mg and 300 mg.
• In the one-dose starting regimen, robust sustained LDL-c reductions were seen, with 300 mg being the optimal dose.
• The two-dose starting regimen was the optimal start regime, showing robust, sustained LDL-c reductions. Time averaged reduction in LDL-c was 41%.
• Half of the patients on placebo showed an increase in LDL-c during the study, and the other half a decrease. All patients on inclisiran responded to treatment with an LDL-c reduction (mean 52.6%, max: 80.9%).

Conclusion

Disclosures

Our coverage of ACC.17 is based on the information provided during the congress.

This study was published today in NEJM