Meeting News

ORION-3: Inclisiran safely reduces LDL by more than 50%

John J. Kastelein
John J. Kastelein

MIAMI — Inclisiran injections administered twice per year safely reduced LDL by at least 50% out to 3 years, according to a late-breaking clinical trial presented at the National Lipid Association Scientific Sessions.

“That actually translates into what is in my eyes as a clinician a totally new therapy that you only have to inject twice a year, and there is absolutely nothing like this,” John J. Kastelein, MD, PhD, professor of medicine and strategic chair of genetics of cardiovascular disease, department of vascular medicine at the Academic Medical Center of the University of Amsterdam, told Cardiology Today. “Most of the monoclonals you have to inject every 2 weeks, and that’s 26 injections per year.”

Open - label extension study

In this phase 2 open-label extension study, researchers analyzed data from patients who completed the ORION-1 study and were previously treated with any dose of inclisiran (The Medicines Company).

As Cardiology Today previously reported, the phase 2 ORION-1 study found that inclisiran was associated with reduced LDL and PCSK9.

“The idea was that all these therapies that lower LDL cholesterol are basically lifelong therapies, so it’s imperative to understand what the long-term performance of your compound is and especially what the long-term safety is,” Kastelein said in an interview. “ORION-3 gives us a very good opportunity to do that.”

Patients were treated with 300 mg inclisiran sodium twice per year (n = 290) or 140 mg evolocumab (Repatha, Amgen) every 2 weeks for 1 year followed by 300 mg inclisiran sodium on day 360, day 450 and every 6 months after that (n = 92).

Results in this analysis included patients assigned inclisiran only, with future analyses including both patient groups, according to the abstract.

The primary endpoint was the mean percent change in LDL from the baseline value during the ORION-1 study, which was measured at day 210 for patients treated with inclisiran only. Safety and efficacy were also assessed over 3 years of treatment.

At day 210, LDL was reduced by a mean of 51% and PCSK9 levels were lowered by a mean of 77%.

Safety profile

Inclisiran injections administered twice per year safely reduced LDL by at least 50% out to 3 years, according to a late-breaking clinical trial presented at the National Lipid Association Scientific Sessions.
Source: Adobe Stock

During at least 3 years of follow-up, there were no changes in the overall safety profile and no laboratory test abnormalities associated with the treatment including liver function tests.

Each injection of inclisiran every 6 months was linked to an LDL reduction of at least 50% independent of the number of doses and the level of the dose given during the ORION-1 trial.

“Based on everything that we’ve seen in this research, we can tell the patient what LDL he will achieve and what percentage of LDL reduction he will achieve with that,” Kastelein said in an interview. “Taking it one step further, we can also quite reliably predict what kind of percent of reduction in MACE events, meaning what is his reduction in the risk for heart attack and stroke. It gives us a lot of handles on our discussions with the patient, which is also extremely nice because patients like some kind of certainty and they like to be informed of what’s happening with them. This research and this drug makes that all possible.”

Researchers are currently working on their next steps for this treatment.

“What is coming next is to finish all of the phase 3 trials so that the sponsor can go to the FDA and submit for market authorization in the U.S. and the rest of the world,” Kastelein told Cardiology Today.

“The strong data from ORION-3 bolster our confidence in inclisiran’s robust therapeutic profile which offers a vastly different value proposition compared to any other LDL-C-lowering option,” Mark Timney, chief executive officer of The Medicines Company, said in a press release from the company. “We truly believe that inclisiran could be a game-changer in cardiovascular care, providing simplicity and confidence to the treating physician and the treated patient that LDL cholesterol is lowered.” – by Darlene Dobkowski

Reference:

Kastelein JJ, et al. Late Breakers. Presented at: National Lipid Association Scientific Sessions; May 16-19, 2019; Miami.

Disclosures: The study was funded by The Medicines Company. Kastelein reports he received research grant support and has been an adviser for The Medicines Company. Timney is an employee of The Medicines Company.

John J. Kastelein
John J. Kastelein

MIAMI — Inclisiran injections administered twice per year safely reduced LDL by at least 50% out to 3 years, according to a late-breaking clinical trial presented at the National Lipid Association Scientific Sessions.

“That actually translates into what is in my eyes as a clinician a totally new therapy that you only have to inject twice a year, and there is absolutely nothing like this,” John J. Kastelein, MD, PhD, professor of medicine and strategic chair of genetics of cardiovascular disease, department of vascular medicine at the Academic Medical Center of the University of Amsterdam, told Cardiology Today. “Most of the monoclonals you have to inject every 2 weeks, and that’s 26 injections per year.”

Open - label extension study

In this phase 2 open-label extension study, researchers analyzed data from patients who completed the ORION-1 study and were previously treated with any dose of inclisiran (The Medicines Company).

As Cardiology Today previously reported, the phase 2 ORION-1 study found that inclisiran was associated with reduced LDL and PCSK9.

“The idea was that all these therapies that lower LDL cholesterol are basically lifelong therapies, so it’s imperative to understand what the long-term performance of your compound is and especially what the long-term safety is,” Kastelein said in an interview. “ORION-3 gives us a very good opportunity to do that.”

Patients were treated with 300 mg inclisiran sodium twice per year (n = 290) or 140 mg evolocumab (Repatha, Amgen) every 2 weeks for 1 year followed by 300 mg inclisiran sodium on day 360, day 450 and every 6 months after that (n = 92).

Results in this analysis included patients assigned inclisiran only, with future analyses including both patient groups, according to the abstract.

The primary endpoint was the mean percent change in LDL from the baseline value during the ORION-1 study, which was measured at day 210 for patients treated with inclisiran only. Safety and efficacy were also assessed over 3 years of treatment.

At day 210, LDL was reduced by a mean of 51% and PCSK9 levels were lowered by a mean of 77%.

Safety profile

Inclisiran injections administered twice per year safely reduced LDL by at least 50% out to 3 years, according to a late-breaking clinical trial presented at the National Lipid Association Scientific Sessions.
Source: Adobe Stock

During at least 3 years of follow-up, there were no changes in the overall safety profile and no laboratory test abnormalities associated with the treatment including liver function tests.

Each injection of inclisiran every 6 months was linked to an LDL reduction of at least 50% independent of the number of doses and the level of the dose given during the ORION-1 trial.

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“Based on everything that we’ve seen in this research, we can tell the patient what LDL he will achieve and what percentage of LDL reduction he will achieve with that,” Kastelein said in an interview. “Taking it one step further, we can also quite reliably predict what kind of percent of reduction in MACE events, meaning what is his reduction in the risk for heart attack and stroke. It gives us a lot of handles on our discussions with the patient, which is also extremely nice because patients like some kind of certainty and they like to be informed of what’s happening with them. This research and this drug makes that all possible.”

Researchers are currently working on their next steps for this treatment.

“What is coming next is to finish all of the phase 3 trials so that the sponsor can go to the FDA and submit for market authorization in the U.S. and the rest of the world,” Kastelein told Cardiology Today.

“The strong data from ORION-3 bolster our confidence in inclisiran’s robust therapeutic profile which offers a vastly different value proposition compared to any other LDL-C-lowering option,” Mark Timney, chief executive officer of The Medicines Company, said in a press release from the company. “We truly believe that inclisiran could be a game-changer in cardiovascular care, providing simplicity and confidence to the treating physician and the treated patient that LDL cholesterol is lowered.” – by Darlene Dobkowski

Reference:

Kastelein JJ, et al. Late Breakers. Presented at: National Lipid Association Scientific Sessions; May 16-19, 2019; Miami.

Disclosures: The study was funded by The Medicines Company. Kastelein reports he received research grant support and has been an adviser for The Medicines Company. Timney is an employee of The Medicines Company.

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