Larry Hand

March 18, 2017

WASHINGTON, DC — Treatment with inclisiran (Alnylam Pharmaceuticals/the Medicines Company), which suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis in the liver, can dramatically lower levels of LDL cholesterol and may be suitable for injection every 6 months, suggests a phase 2 randomized trial[x].

Such a dosing schedule would distinguish the potential dyslipidemia agent from the more familiar antibody-based PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), which are injected every few weeks.


Dr Kausik K Ray

The ORION-1 trial was presented here today at the American College of Cardiology (ACC) 2017 Scientific Sessions by Dr Kausik K Ray (Imperial College London, UK), who is also lead author on the trial's publication at about the same time in the New England Journal of Medicine.

An interim analysis from the trial, presented last year and covered by heartwire at the time, also saw that inclisiran injections were associated with long-lasting reductions in both PCSK9 and LDL-C.

ORION-1 is a double-blind, placebo-controlled trial of inclisiran, administered by subcutaneous injection in adults with high LDL-C and at high risk of CVD. LDL-C levels had to be above 70 mg/dL or 100 mg/dL for those with or without a history of atherosclerotic CVD, respectively.

Participants were randomized to one of eight groups: one dose of placebo or 200, 300, or 500 mg of inclisiran on day 1, or two doses of placebo or 100, 200, or 300 mg of inclisiran on day 1 and day 90.

In total, 497 patients received placebo or inclisiran and were included in the efficacy and safety analysis. Most participants (73%) were receiving statins and 31% were receiving ezetimibe at study entry.

In addition to the primary end point of percentage reduction from baseline in LDL-C at day 180, change in PCSK9 levels was also evaluated.

Researchers conducted end-of-trial evaluations on day 210 in some patients. For patients with LDL-C levels that had not returned to within 20% of the starting level, researchers conducted evaluations at day 210 and at follow-up visits every 30 days until day 360 or until LDL levels returned to within 20% of starting level.

Ray presented results for up to day 270.

For the primary end point, the mean reduction from baseline of LDL-C at day 180 was 27.9% to 41.9% after a single dose of inclisiran, compared with a 2.1% increase for placebo (P<0.001).

After two doses of inclisiran, LDL-C levels fell from baseline by 34.2% to 44.1% at day 90 and by 41.1% to 54.6% at day 120. Researchers found that mean reductions in LDL-C levels at day 180 were 35.5% to 52.6% for patients who received two doses of inclisiran.

PCSK9 levels decreased from baseline by a mean of 59.6% to 68.7% over the range of doses (100 to 500 mg) 14 days after one injection of inclisiran, whereas PCSK9 levels increasing by 3.8% with placebo. At 30 days, PCSK9 levels decreased further with inclisiran, to 66.2% to 74.0% below baseline.

The optimal dose of inclisiran turned out to be 300 mg twice.

"With a two-dose starting injection, there's a further decline in PCSK9 [compared with one dose], and this is again maintained through today, day 270, or 9 months," noted Ray.

He said the one-dose time-average reduction in LDL-C was 41.9% at 9 months, with a further improvement of 10% with two doses.

"If you look at day 270, the percentage reduction is very similar to what you observe at day 90, suggesting that might be an optimal time for the next injection, suggesting that a 6-month dosing interval thereafter might be possible," he said. "Importantly, if you look over a 9-month period, the time-average reduction in LDL-C is 50%."

"All patients responded. The optimal dose of 300 mg given twice as a starting regimen appears to allow for a subsequent 6-month dosing interval. All patients appeared to respond, and at 6 months, the mean reduction in LDL-C was 52.6%, with a maximum response of almost 81%," he further explained.

"ORION-1 is a very promising phase 2 trial," panelist Dr Margo Minissian (Cedars Sinai Medical Center, Los Angeles, CA) told heartwire from Medscape.

"It's fantastic that they did not see any antibodies, as noted in prior large studies, and they're going to move forward. I think the adherence question is a wonderful question to see whether 6-month dosing can make a difference for patients."

Also speaking with heartwire, Ray said that inclisiran "is probably the best way to lower PCSK9 because it's easier for the patient. You don't have variability. You take patient compliance out of the equation."

ORION-1 is sponsored by the Medicines Company. Ray reports receiving personal fees from the Medicines Company and grant support from Sanofi and Regeneron. Disclosures for the coauthors are listed in the paper.

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