Inclisiran’s Safety Data Suggest Game-Changing Potential In PCSK9 Market

The Medicines Co. followed up its 26 August top-line readout for the Phase III ORION-11 trial of inclisiran with a full dataset that shows the short-interfering RNA (siRNA) therapy can offer LDL cholesterol-lowering capability similar to on-market PCSK9 inhibitors with twice-yearly dosing and a safety and tolerability profile similar to placebo.

Presenting the data at the European Society of Cardiology meeting on 2 September, The Medicines Co. asserted that inclisiran can be a market-disrupting LDL-C therapy that will address needs for therapeutic adherence and convenience.

The data “increase our confidence and excitement in the substantial possibility for inclisiran to fundamentally reshape the landscape of cardiovascular care like never before,” CEO Mark Timney said. “It's the first and only LDL-C therapy that would be administered by a health care professional twice yearly. We believe that inclisiran is a game-changer that solves two critical unmet needs – additional LDL-C lowering and poor adherence – which will get many more patients to goal.”

On 26 August, the New Jersey company announced inclisiran met all primary and secondary endpoints in ORION-11, which was the first of three pivotal studies expected to read out during this quarter, but observers wanted more detail on the magnitude of its LDL-lowering effect and its safety profile.

The Medicines Co. hopes to position inclisiran, which silences production of the PCSK9 enzyme, as a more-convenient alternative to approved PCSK9 inhibitors.
Amgen Inc.’s Repatha (evelocumab) and Sanofi/Regeneron Pharmaceuticals Inc.’s Praluent (alirocumab) are given once or twice a month versus inclisiran's twice-yearly administration. (Also see "The Medicines Co. CEO Timney On Selling Inclisiran And Why Big Pharma Is Still Interested In CV Disease " - Scrip, 29 Apr, 2019.)

SVB Leerink analyst Joseph Schwartz called the ORION-11 data “better than expected” in a 2 September note and said they partially de-risk the upcoming Phase III ORION-9 and ORION-10 studies. ORION-9 tests the candidate in heterozygous familial hypercholesterolemia, while ORION-10 and ORION-11 are in the atherosclerotic cardiovascular disease (ASCVD) setting.

In a 1,617-patient study that randomized patients to 4mg, 8mg or 12mg of inclisiran twice-yearly or placebo, the 12mg dose yielded a placebo-adjusted mean reduction in LDL-C of 54% from baseline (p<0.0001) at 17 months (510 days) and a time-averaged placebo-adjusted LDL reduction of 51% from days 90 through 540 of treatment (p<0.0001). The study was designed to dose patients on day one and day 90 and then every six months after that.

Analysts previously said the drug would need to at least replicate the 51% LDL reduction seen in Phase II to stand a strong chance competing against Repatha and Praluent. Jefferies analyst Biren Amin pointed out in a 2 September note that those antibody therapies posted 56% and 47% LDL-lowering efficacy in their Phase III programs, respectively.

“With unrivaled convenience, clean safety and comparable efficacy to approved PCSK9 antibodies, ORION-11 data reinforces inclisiran as a potential front-runner in the PCSK9 space, in our view,” wrote Leerink’s Schwartz.

On safety, inclisiran was numerically superior on several measures compared to placebo. Serious treatment-emergent adverse events occurred in 22.5% of control-arm subjects and 22.3% of patients receiving study drug. Rates of death (1.9% versus 1.7%) and malignancies (2.5% versus 2%) also were higher among those who received placebo. Liver and renal function tests favored inclisiran over placebo as well.

ORION-11 tried to give an early indication of cardiovascular outcomes, although The Medicines Co. conceded that significantly more data would be needed before inclusion in labeling would be possible. The company noted that 87% of trial subjects had established cardiovascular disease, and the rest were high-risk patients for whom prevention was being sought. Ninety-five percent of patients were on high-intensity statin therapy, and the baseline LDL level was more than 100mg/dL.

The rate of fatal and non-fatal heart attack was lower in patients who received inclisiran (1.2%) than placebo (2.7%), as was the rate of fatal and non-fatal strokes (0.2% for treated patients, 1% for control).

Kausik Ray of Imperial College London, lead clinical investigator for the ORION-11 study, told a 2 September investor call that those are the primary endpoints being investigated in the 15,000-patient ORION-4 cardiovascular outcomes study of inclisiran, expected to yield data in 2022.

“Although not powered for statistics, we believe this early peek at outcomes data is encouraging for long-term trial ORION-4 and may improve physician uptake ahead of full outcomes results,” Schwartz said. Jefferies’ Amin called the cardiovascular data “encouraging," suggesting success for ORION-4, which is enrolling patients with similar characteristics to ORION-11.

One notable safety and tolerability difference between the study drug and placebo was injection-site reactions, seen in 4.7% of those who received inclisiran, but just 0.5% of control-arm subjects. However, “the majority were mild, none were severe and none were persistent,” Ray told the call.

Amin said the use of a 22-gauge needle and the volume of drug administered may be the cause for the injection-site reactions, and may lead to more in-office administration of inclisiran. “Typically, 22-gauge needles are associated with intramuscular injections or subcutaneous vaccine shots, and we think doctors and patients will prefer in-office use,” he said.

A potential benefit here is that since doctors administer the medicine, they can be assured of therapeutic adherence. Morgan Stanley analyst David Leibowitz noted on 3 September that The Medicines Co. believes roughly two-thirds of patients receiving first-line LDL-reducing therapy are not adherent after one year.

Ray emphasized the vast difference for patients between taking 365 tablets a year or getting up to 26 injections, compared to twice-annual injections that would coincide neatly with scheduled doctor visits.