Sustained LDL-c lowering up to 360 days with siRNA directed against PCSK9 in phase 2 study
ORION 1: LDL-C Reduction From 6 to 9 Months Following Single or Second Injection of Inclisiran, a Novel siRNA Compound: Primary Efficacy and Safety Outcomes of the ORION 1 Trial
Presented at ACC.17 by Kausik RayNews - Mar. 16, 2017
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.
- 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%).
This study shows that 300 mg given twice as a starting regimen, then followed by a 6-monthly regimen, seems to be a safe and effective regimen to lower LDL-c. The unique attributes of inclisiran address multiple unmet needs, since LDL-c variability within individuals is practically eliminated by this approach. Furthermore, it reduces injection burden substantially. A sustained effect between infrequent injections is seen. The dosing regimen provides an opportunity to improve patient adherence.
These results may translate into a considerable reduction of CV endpoints, which will be tested in the ORION-4 outcomes study in patients with high risk and average LDL-c of about 130 mg/dL.
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