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Injectable inclisiran (siRNA) as 3rd anti-PCSK9 behind mAbs Repatha and Praluent

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/27/2021

The drug, dubbed MEDI5884, is designed to neutralize a circulating enzyme called endothelial lipase. The protein regulates HDL in the blood by breaking down lipids called phospholipids. Previous studies have found increased endothelial lipase levels in people with obesity and coronary artery disease.

In monkeys, blocking endothelial lipase with MEDI5884 increased plasma HDL-C in a dose-dependent manner, the AZ team reported in a study published in Science Translational Medicine. At the highest dose tested, researchers recorded a roughly twofold increase in HDL-C within two weeks. The effect lasted throughout the two-month study.

RELATED: Regeneron’s Evkeeza, carrying big price tag, wins FDA approval in ultra-rare cholesterol disease

The AZ team also tested the drug in a small group of healthy volunteers in a phase 1 study. The treatment increased HDL-C—though to a lesser extent than it had in the monkeys—without causing any major side effects, the researchers said. The drug also increased the size and number of HDL particles.

Oddly, the researchers also observed a concurrent increase in bad cholesterol in both monkeys and humans. So they decided to combine MEDI5884 with an anti-PCSK9 antibody drug. The FDA has approved two PCSK9 inhibitors to lower LDL-C and reduce CV risks: Sanofi and Regeneron’s Praluent and Amgen’s Repatha.

In monkeys pretreated with a PCSK9 inhibitor, MEDI5884 raised HDL-C to a similar degree while the magnitude of the increase in LDL-C was reduced, according to the team.

PCSK9 drugs once carried megablockbuster potential thanks to their strong LDL-lowering effects, but neither Praluent nor Repatha has lived up to expectations. Payer pressure and an ongoing price war haven’t helped either player in the market.

The AZ team suggested combining endothelial lipase inhibition with a PCSK9 blockade could enhance the efficacy of each component. “[I]t is intriguing to consider dual inhibition of EL and PCSK9 and the potential for synergy that may arise from combined action of the two complementary mechanisms, both targeting different aspects of [reverse cholesterol transport],” the scientists wrote in the study.

SOURCE

https://www.fiercebiotech.com/research/combination-astrazeneca-s-booster-good-cholesterol-and-pcsk9-inhibition-shows-promise-for?mkt_tok=Mjk0LU1RRi0wNTYAAAF8sqquETWOW6kv9ecI1ikHVxrB3MWy4NubkNVJKoZOj4sPNcjIYQiDqfMjH6GAiU0bTgxkNFh_lPioA6TvQOFf_kjQSRvue6JVXWUKGDW1qltaaE4&mrkid=993697

Next stop, filing for approval. The Medicines Company has said it plans to submit inclisiran for FDA review by the end of 2019 and EMA review in the first quarter of 2020. If the drug’s approved it’ll be the third anti-PCSK9 behind mAbs Repatha and Praluent, and could try to compete on price to gain market share.

The company’s been very careful not to disclose its pricing plans for inclisiran, said ORION-10 principal investigator Dr. Scott Wright, professor and cardiologist at the Mayo Clinic. But, Wright said, The Medicines Co. and other companies he advises on clinical trial design “have learned the lesson from the sponsors of the monoclonal antibodies [against PCSK9], they’re not going to come in and price a drug that’s out of proportion to what the market will bear.” 

Because the anti-PCSK9 mAbs were initially priced beyond what patients and insurers were willing to pay, “now most of the physicians that I meet have a resistance to using them just because they’re fearful about the pre-approval process” with insurers, said Wright. “They’re much easier to get approved and paid for today than they’ve ever been, but that message is not out in the medical community yet.”

SOURCE

From: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Reply-To: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Date: Monday, November 18, 2019 at 2:59 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Interim look at Amarin data, an inclisiran update, & Philly’s giant heart