Twice-yearly inclisiran cuts LDL in ASCVD patients
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PHILADELPHIA — New data on inclisiran, an investigational cholesterol-lowering therapy in the small-interfering RNA class, demonstrate sustained LDL reductions with twice-yearly dosing in high-risk patients with atherosclerotic CVD.
In the phase 3 ORION-10 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 a presentation at the American Heart Association Scientific Sessions.
“Inclisiran potentially offers a novel new treatment for LDL,” Weight said here. “Assuming FDA approval, twice-yearly administration coincides with typical twice-year patient visits with health care providers.”
The new data also demonstrate safety of inclisiran, with a safety profile similar to that of 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.
As the treatment is delivered by injection, the researchers also evaluated injection site adverse events. 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.
During a discussion of the trial, Karol E. Watson, MD, PhD, FAHA, co-director of the UCLA Program in Preventive Cardiology and Cardiology Today Editorial Board Member, said “there’s a lot of excitement” around inclisran.
“We saw that [inclisiran] was able to lower LDL cholesterol very impressively and very durably. One subcutaneous administration of the 300 mg dose led to over a 50% reduction and four injections over 18 months led to a sustained LDL-lowering effect,” she said.
Watson acknowledged that the impact of infrequent dosing on patient adherence remains unclear.
“I would love to say that most of my patients come to see me twice a year, but they don’t. I don’t know if it’s ‘out of sight, out of mind,’ or if patients will be encouraged to maintain therapy,” she said.
“The effectiveness of statins and other cholesterol-lowering agents absolutely relies on patients taking them correctly and consistently. Finding medications that are both effective and can enhance adherence will improve outcomes. Inclisiran is the first cholesterol-lowering agent in the siRNA class — that opens up a whole host of new and exciting possibilities. Increasing the number and types of effective therapy options that our patients have available to them is good medicine,” Watson 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-10 is the second of three pivotal phase 3 studies of inclisiran. Results of ORION-11 were presented at the European Society of Cardiology Congress in September and the ORION-9 data will be presented later during the AHA Scientific Sessions.
“As with any new therapy, there is always concern about: Is the drug safe? Is it durable? We have a very long phase 3 trial called ORION-4 looking at CV outcomes that will gather additional safety data,” Wright said. “Also, all patients from early ORION trials will enroll in longer-term follow-up, ORION-3, and there will be longer-term follow-up of the ORION-11, ORION-10 and ORION-9 trials, she said.
Regulatory filing is anticipated before the end of 2019 in the U.S. and in the first quarter of 2020 in Europe, Wright said during the press conference. – by Katie Kalvaitis
Reference:
Wright RS. Late Breaking Science I. Outside the Box: New Approaches to CVD Risk Reduction. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Disclosures: Wright reports he receives honoraria from Boehringer Ingelheim and research support from AstraZeneca and The Medicines Company. Watson reports she receives honoraria from Amarin, Amgen, Boehringer Ingelheim and Esperion.
Perspective
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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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