Safety and Efficacy of Inclisiran in Patients With ASCVD and Elevated LDL Cholesterol - Results From the Phase 3 ORION-10 Trial

Presented during the AHA Scientific Sessions 2019 by R. Scott Wright (Mayo Clinic, Rochester, MN) .

Introduction and methods

LDL-c lowering is the most effective intervention to change the course of ASCVD yet substantial residual risk remains despite aggressive treatment with statins and other agents. Secondary prevention are founded on lifestyle modification and statin treatment. Ezetimibe and monoclonal antibodies directed at PCSK9 are adjunctive strategies to reduce LDL-c and clinical events, according to various treatment guidelines.

Inclisiran represents another therapeutic strategy to lower LDL-c. It is a small interfering double-stranded RNA, that harnesses the natural process of RNA interference and inhibits production of PCSK9 in hepatocytes. It is specifically distributed to the liver through a GalNAc conjugation.

Phase I-II studies of inclisiran identified a twice yearly dose potential and 300 mg was the dose that was considered most promising. The purpose of ORION-10 was to assess efficacy and safety of inclisiran 300 mg compared to placebo in a high risk population of ASCVD subjects during a follow-up of 18 months. To this end, 1561 patients were randomized to inclisiran 300 mg or placebo, on top of maximally tolerated statins, and observed for 18 months. Patients assigned to inclisiran received injections at visit 1/day 1, at visit 3/day 90, at visit 5/day 270 and at visit 7/day 450. The primary efficacy endpoint was % LDL-c change vs. placebo at day 510 and the average over days 90-540.

Main results

• Highly significant lowering of LDL-c with inclisiran relative to placebo was seen at day 510 (Mean -58%, P<0.00001). The time-averaged LDL-c lowering in days 90-540 was -56% (P<0.00001).
• Inclisiran showed a durable and potent LDL-c lowering effects in ITT analyses.
• Almost all patients showed an LDL-c lowering response to inclisiran.
• Adverse event profile of inclisiran was similar to that of placebo.
• Injection site adverse events were infrequent (2.6% vs 0.9% with placebo), mostly mild (1.7%) and transient.
• Injection site pain was reported in 2.1% vs. 0.4%. During the trial, the protocol was switched from a vial+syringe procedure to a pre-filled syringe, which lowered injection-site pain to 1.0% vs. 0.1%.
• There was no evidence of liver, kidney, muscle or platelet toxicity.
• There were no differences in serious adverse events: 22.4% of patients on inclisiran and 26.3% of those on placebo had at least one serious TEAE. 2.2% and 2.4%, respectively, had TEAEs leading to drug discontinuation.
• The prespecified exploratory CV endpoint occurred in 7.4% of patients on inclisiran and in 10.2% of patients on placebo (CV death: 0.9% vs. 0.6% and fatal or non-fatal MI or stroke: 4.1% vs. 3.3).

Conclusion

Results of ORION-10 showed that inclisiran achieved durable and potent LDL-C reduction with twice yearly injection in ASCVD patients on appropriate lipid lowering therapies over 18 months of follow-up with a safety profile similar to placebo in a high risk cardiovascular population.

Discussion

Discussant Karol Watson summarized the lessons we learned from ORION-10, in that inclisiran lowers LDL-c impressively and durably, with four subcutaneous injections over 18 months.

She also pointed out what we still do not know, for instance the effect of other lipid parameters such as HDL-c, triglycerides and Lp(a). Also, we need to know whether inclisiran will be safe and effective over longer term follow-up. Are there relevant inter-individual differences in the response to inclisiran? Moreover, while the presenter said that the two injections per year coincide with twice yearly check-ups, Watson noted that she wished that her patients would come twice a year, but many do not. So, it remains to be seen what impact infrequent dosing has on patient adherence.

The biggest question that still needs answering is of course whether the treatment will lead to improved clinical outcomes, and how this effect on clinical outcomes compares to the effect of statin treatment.

Inclisiran is the first cholesterol-lowering agent in the siRNA class. By being effective and potentially improving treatment adherence, it is an interesting new treatment option.

- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -

Watch the video about the ORION-10 results