AHA 2016: Investigational PCSK9 inhibitor safe, effective at 90 days

After 90 days of treatment, patients with atherosclerotic cardiovascular disease who received 300 mg of inclisiran daily had a mean low-density lipoprotein (LDL) cholesterol reduction of approximately 50 percent, according to a pre-specified interim analysis of a phase 2 randomized trial.

Lead researcher Kausik K. Ray, MD, of Imperial College London, presented the results in a late-breaking clinical trials session Nov. 15 at the American Heart Association Scientific Sessions in New Orleans.

In another analysis of the trial, which is known as ORION-1, patients who took inclisiran for at least six months had a significant LDL cholesterol reduction for at least six months. That study was published Nov. 13 in the New England Journal of Medicine.

The Medicines Company and Alnylam Pharmaceuticals, which manufacture inclisiran, funded both studies. The companies announced top-line results of the ORION-1 trial on Oct. 18.

The FDA has not approved inclisiran, which is an injectable proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. So far, the FDA has approved only two PCSK9 inhibitors: alirocumab (Praluent, Regeneron Pharmaceuticals and Sanofi Aventis) and evolocumab (Repatha, Amgen).

The ORION-1 trial included patients who were at least 18 years old and had atherosclerotic cardiovascular disease and an LDL cholesterol level of greater than 70 mg/dL when taking maximally tolerated statins. The patients were randomized to receive an injection of inclisiran or placebo.

As of Oct. 25, which was the date of the pre-specified interim analysis, the researchers had followed up with 497 patients for 90 days and with 189 patients for 180 days. Patients received 100 mg, 200 mg, 300 mg or 500 mg doses.

Among the patients in the 90-day analysis, those who received a 300 mg subcutaneous injection of inclisiran had a mean LDL cholesterol reduction of 51 percent at day 60 and 45 percent at day 90. Patients who received two injections of the 300 mg doses had a mean LDL cholesterol reduction of 57 percent at day 90.

Ray mentioned that there was no significant difference in the 300 mg and 500 mg dose of inclisiran with regards to LDL reduction.

There was also no difference in the groups with regards to treatment-emergent adverse events, which occurred in 54 percent of patients in each group. There was one death, which occurred in a patient who received 500 mg of inclisiran and had a 20-year history of cardiovascular disease and multiple MIs, according to Ray.

Ray added that a single injection of inclisiran reduced PCSK9 by day 15 and achieved a maximal level by day 30, which was sustained through day 90.

Among the patients in the 180-day analysis, those who received a 300 mg subcutaneous injection of inclisiran had a mean LDL cholesterol reduction of 59 percent at day 60; 50 percent at day 90; and 43 percent at 180 days. Patients who received an injection at baseline and day 180 had a mean LDL cholesterol reduction of 57 percent at day 120 and 52 percent at day 180.

“The efficacy, safety and dosing profile inclisiran are likely to ensure significant and durable reductions in LDL cholesterol and thus could potentially impact cardiovascular outcomes,” Ray said during a news conference.

David Kalland, MBBS, vice president and global medical director of The Medicines Company, said in a news release that the company had selected an optimal dose of 300 mg for inclisiran. He added that the company plans on beginning a phase 3 trial to evaluate the drug.

“If the safety and efficacy of this novel investigational PCSK9 synthesis inhibitor can be confirmed in Phase 3 studies to support approval, it may offer an important treatment option for patients, physicians, and payers,” John J.P. Kastelein, MD, PhD, of the University of Amsterdam, said in a news release.