Twice-yearly inclisiran reduces LDL in ASCVD, FH
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Inclisiran, an investigational cholesterol-lowering therapy, reduced LDL in high-risk patients with atherosclerotic CVD and in those with heterozygous familial hypercholesterolemia, or FH, according to data from the ORION-10 and ORION-9 trials, respectively.
“Inclisiran is a small interfering double-stranded RNA which harnesses natural process of RNA interferences in the liver,” Frederick J. Raal, MBBCh, PhD, FCP(SA), FRCPC, MRCP, professor at University of the Witwatersrand, Johannesburg, said during the presentation.
ORION-10
In this phase 3 trial, twice-yearly injections of inclisiran sodium 300 mg (The Medicines Company) resulted in placebo-adjusted LDL reductions of 58% at 17 months (P < .0001) and time-averaged placebo-adjusted LDL reductions of 56% from month 3 to 18 (P < .0001), R. Scott Wright, MD, professor of medicine and consultant in cardiology at Mayo Clinic in Rochester, said during the presentation.
“Inclisiran potentially offers a novel new treatment for LDL,” Wright said. “Assuming FDA approval, twice-yearly administration coincides with typical twice-year patient visits with health care providers.”
The new data also demonstrate safety, with a profile similar to placebo. The proportion of patients who experienced at least one serious treatment-emergent adverse event was 26.3% in the inclisiran group vs. 22.4% in the placebo group. The incidences of all-cause death (1.4% vs. 1.5%) and new, worsening or recurrent malignancies (3.3% vs. 3.3%) were similar between the inclisiran and placebo groups. There were also no adverse changes in laboratory markers.
Events including reaction, erythema, rash, pruritus and hypersensitivity occurred in 2.6% of patients assigned inclisiran. Events were predominantly mild and none were persistent, Wright said. Halfway through the trial, the injection switched from a vial and syringe to a prefilled syringe; this resulted in numerically lower injection-site pain, he said.
ORION-10 enrolled 1,561 patients with ASCVD and elevated LDL despite maximum tolerated doses of LDL-lowering therapies. Each patient received inclisiran 300 mg administered as a subcutaneous injection initially, again at 3 months and then every 6 months thereafter. Most patients in this study were taking inclisiran or placebo in addition to existing lipid-lowering therapy with a maximally tolerated statin, with or without ezetimibe.
ORION-9
Researchers analyzed data from 482 patients with heterozygous FH who were diagnosed by phenotype or genotype with an LDL greater than 100 mg/dL on a low-fat diet and maximally tolerated statin doses.
Patients were assigned 300 mg of inclisiran subcutaneously every 6 months (n = 242; median age, 56 years; 46% men; baseline LDL, 155 mg/dL) or placebo (n = 240; median age, 56 years; 48% men; baseline LDL, 151 mg/dL) for 18 months. Both treatments were on top of maximally tolerated statins.
A genetic subanalysis of 432 patients was also conducted, during which next-generation sequencing was performed. LDL receptor variants were identified and classified.
The primary effectiveness endpoint was the percent of LDL change vs. placebo at 510 days and an average between 90 and 540 days. Secondary effectiveness endpoints included LDL change over time and changes in PCSK9 and other lipids. Safety and tolerability endpoints were defined as treatment-emergent adverse events and laboratory parameters.
Patients assigned inclisiran had highly significant reductions in LDL compared with placebo at 510 days (difference = –50%; P < .0001) and in a time-averaged analysis between 90 and 540 days (difference = –45%; P < .0001). Robust responses were seen in all genotypes.
“The reduction in those that were found to have an LDL variant was very similar to those with an ApoB variant,” Raal said during the presentation. “Interestingly, the patients that had two variants also had a robust reduction in LDL cholesterol. The single patients with a PCSK9 gain-of-function mutation had a greater than 90% reduction in LDL cholesterol, which is in keeping with the mechanism of action of inclisiran.”
The safety profile of inclisiran was similar to placebo except for adverse events at the injection site, which occurred in 13.3% of patients assigned inclisiran vs. 0% in those assigned placebo. Injection-site reactions were often minor or moderate. There was no evidence of liver, kidney, muscle or platelet toxicity and no difference in serious adverse events in the inclisiran group vs. the placebo group.
“Inclisiran shows potential to address the unmet need of high-risk FH patients,” Raal said during the presentation. – by Katie Kalvaitis and Darlene Dobkowski
- References:
- Raal FJ, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy.
- Wright RS, et al. Late Breaking Science I. Outside the Box: New Approaches to CVD Risk Reduction.
Disclosures: The trials were sponsored by The Medicines Company. Raal reports he received honoraria from Amgen, Sanofi/Regeneron and The Medicines Company. Wright reports he receives honoraria from Boehringer Ingelheim and research support from AstraZeneca and The Medicines Company.
Perspective
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Daniel J. Rader, MD
This trial was generally positive. The LDL reduction was good, and the persistence is good in terms of that, which is not surprising based on other studies with inclisiran, but it’s nice to see in heterozygous FH. It’s nice to see that the efficacy was not only on top of statins, but also in a pretty big subgroup of people on statins plus ezetimibe; this is probably the largest study in which inclisiran has been on top of both statins and ezetimibe. The safety was good. This is going to be a great addition to our armamentarium for patients with FH who really do need PCSK9 inhibition. To be able to administer the therapy once every 6 months like this is going to be a big advantage over having to inject patients every 2 weeks.
It would be interesting to see more about lipoprotein(a) because a lot of our patients with FH have high Lp(a). It’s nice to hear that there is a modest Lp(a) reduction, as the same with the antibodies.
I would really like to see this studied in children. When we think about all of our children, adolescents and young adults with FH who are less than adherent with statin therapy, not that they would come off their statins, but that lack of adherence, so to speak, could be blunted a little bit if they can get one of these injections every 6 months for inclisiran. That’s one of the big issues.
I’m increasingly comfortable with the safety. There’s been so many patients studied now and we have 18-month and 2-year data, but that’s always something we’re going to have to keep an eye on for a new platform: safety.
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Erin D. Michos, MD, MHS, FAHA
We are in a new era of lipid therapy. We used to have nothing available but statins and ezetimibe. Now, there are a number of new agents that have emerged or are on the near horizon, like inclisiran. The twice-a-year dosing is an exciting option to give patients, as compliance with medical therapy is difficult for many. Even with statins, which are inexpensive and effective, studies have shown that there is variable compliance. And, patients who are nonadherent have worse outcomes. I liken this to the flu shot; many people get their flu shot once per year. With this therapy, it's like getting your flu shot twice per year. The data presenting here showing a decrease in LDL by 58% is remarkable. Inclisiran also appears to be safe, based on the data that have been reported thus far. Injectable therapies, as we have seen with the PCSK9 inhibitors, can have some injection-site reactions. In ORION-10, the injection-site reactions were mostly mild and transient. Price is important when it comes to new therapy, so we wait to see what the price of this therapy at this dosing would be. The big thing I'm holding out for is the ORION-4 CV outcomes trial, which will provide information on whether inclisiran reduces CV events. I am a strong believer in the LDL hypothesis, and I think if we can lower LDL, we are going to lower events.
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