LDL lowered, sustained with inclisiran injection in phase 2 study

NEW ORLEANS — Inhibition of PCSK9 synthesis via RNA interference with the investigational therapy inclisiran yielded significant reductions in LDL that were sustained out to 180 days, according to new data from the ORION-1 trial presented at the American Heart Association Scientific Sessions.

Researchers for the phase 2, double blind, randomized, controlled, dose-finding trial compared six different subcutaneous dosing regimens of inclisiran (Alnylam Pharmaceuticals/The Medicines Company) — 100 mg, 200 mg, 300 mg or 500 mg — compared with placebo. Those enrolled had atherosclerotic CVD (ASCVD) and LDL > 70 mg/dL or high risk for ASCVD and LDL > 100 mg/dL despite maximally tolerated therapy.

The long-acting agent is being developed for the treatment of hypercholesterolemia as a less-expensive alternative, with the potential for sustained suppression of hepatic PCSK9 production with fewer injections.

Kausik K. Ray, MD, MPhil, from Imperial College, London, reported results of a planned interim analysis of 90-day data for 497 patients and preliminary data for 189 patients at 180 days. The primary endpoint was percent change in LDL from baseline to 180 days.

Baseline LDL was approximately 130 mg/dL among 497 randomized and treated patients. In this group, one 300-mg subcutaneous injection of inclisiran achieved mean LDL reductions of 51% at 60 days, which were durable out to 90 days. All differences relative to placebo in these 497 patients were significant (P < .0001), according to a company press release.

Among 189 randomized and treated patients who had been followed for 180 days or more by the interim data cut-off point on Oct. 25, 2016, one 300-mg subcutaneous injection of inclisiran achieved mean LDL reductions of 59% at 60 days, which were durable out to 90 days (mean, 50%) and durable to 180 days. Two 300-mg injections of inclisiran, given on the first and 90th days, achieved a mean LDL reduction of 57% at 120 days, which persisted at 180 days. All differences vs. placebo in these 189 patients were significant (P < .0001), according to the release. In ORION-1, inclisiran injection was generally well tolerated. The researchers reported no material safety issues, including liver enzyme elevations, neuropathy or change in renal function. The overall incidence of treatment-emergent adverse events was 54% in both groups, and no difference between inclisiran doses was observed. The most common treatment-emergent adverse events (> 2%) were myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea and dizziness, according to the results.

Injection-site reactions with inclisiran were infrequent (3.2%), Ray said.

Patients in this study were in their early 60s, overweight, mostly white and mostly male. The majority of patients presented with ASCVD and were receiving lipid-lowering or statin therapy.

These data come on the heels of phase 1 data published this month in The New England Journal of Medicine.

“The potential for biannual or triannual dosing is affirmed,” Ray said during a press conference. “The results of ORION-1 support the start of a phase 3 trial. The efficacy, safety and dosing profile of inclisiran are likely to ensure significant and durable reductions in LDL and thus potentially impact CV outcomes.”

Reference:

Ray K, et al. LBCT.03 – Insights from New Therapeutic Trials for Lipids. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Disclosure: Ray reports receiving research grants from Merck Sharpe & Dohme, Pfizer, Regeneron and Sanofi; honoraria from AbbVie, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cipla, Kowa Pharmaceuticals, Pfizer, Sanofi and Takeda; and consulting and/or serving on advisory boards for AbbVie, Amgen, AstraZeneca, Cerenis, Ionis, Regeneron, Resverlogix, Sanofi and The Medicines Company.