With New Data, Medicines Co. Takes Long-Lasting Heart Drug to Phase 3

Xconomy New York — 

The Medicines Co. and Alnylam Pharmaceuticals released new data today supporting a potentially longer lasting alternative to the widely hyped wave of cholesterol-fighting drugs that hit the market in 2015. But it’ll take more clinical testing, and likely several years, before the drug’s potential and commercial viability are proven.

Today at the American Heart Association’s scientific sessions in New Orleans, Medicines Co. (NASDAQ: MDCO), of Parsippany, NJ, and Cambridge, MA-based Alnylam (NASDAQ: ALNY) provided the latest interim look at a roughly 500-patient, placebo controlled Phase 2 study of an RNA-based drug, inclisiran, meant to lower cholesterol levels. The data, the companies said, reinforced earlier studies showing a single dose of inclisiran might reduce significant amounts of the notorious low-density lipoprotein cholesterol (LDL-C) and suggest patients might only have to take it only two or three times a year. Based on the findings, Medicines Co.—which licensed the drug from Alnylam in 2013—will advance inclisiran into Phase 3 trials.

In October, Medicines Co. said after 90 days of follow-up for all patients, the drug led to “significant and durable” reductions in LDL-C without any material safety problems. Today, the company is providing some more details, as well as preliminary numbers on the trial’s main outcome measure—LDL-C reductions in patients who have had at least 180 days of follow-up. More data is being provided at today’s presentation at AHA.

According to Kausik Ray, an investigator in the inclisiran studies and a professor at Imperial College London’s school of public health, so far 21 patients have been followed for at least 180 days after a single 300 mg injection of inclisiran, and 28 have gotten two 300 mg injections of inclisiran 90 days apart.

A single 300 mg injection of inclisiran helped lower the first group’s LDL-C by an average of 59 percent after 60 days, an average of 50 percent after 90 days, and an average of 43 percent after 180 days, compared to patients’ levels at the outset. Those who got two 300 mg injections of inclisiran saw their LDL-C lowered by an average of 57 percent after 120 days, and 52 percent after 180 days. Cholesterol levels for patients on placebo stayed steady throughout the study. The 300 mg dose will be the one Medicines Co. uses in further testing.

No new safety issues cropped up—there were side effects in 54 percent of patients on drug and placebo, though the companies didn’t provide specifics. Mild or moderate injection-site reactions occurred in 3.2 percent of patients.

“This [drug] might give us a strategy whereby two or three injections a year administered by a healthcare professional maintains a 50 percent reduction in LDL cholesterol, which would be remarkable,” said Ray.

These numbers will have to be replicated in longer, larger studies—and more information from additional patients in this Phase 2 trial will likely come next year.

But even if inclisiran does in fact succeed, will it be commercially viable? In 2015, Amgen (NASDAQ: AMGN) and Regeneron Pharmaceuticals (NASDAQ: REGN) won FDA approval of two drugs, evolocumab (Repatha) and alirocumab (Praluent) that were hailed as a big step forward in the treatment of heart disease. Both drugs are engineered antibodies that block a protein, PCSK9, that interferes with the body’s ability clear LDL-C from the bloodstream.

Cholesterol-lowering drugs like atorvastatin (Lipitor), known as “statins,” have been among the best selling drugs of all time. Yet many patients can’t tolerate or don’t respond to statins, and even despite their widespread use, heart disease remains a leading cause of death in the U.S., according to the Centers for Disease Control and Prevention. The anti-PCSK9 drugs’ striking ability to reduce LDL-C in clinical trials led many analysts to hail these drugs as the next big step in cardiovascular care and forecast multi-billion dollar sales. The two drugs were approved for high-risk patients who can’t lower their cholesterol levels with statins or other means. About 9 million Americans fit those criteria.

But the uptake of anti-PCSK9 drugs has been disappointingly slow—partly because of pushback to their high price tags, and partly they haven’t yet proven whether they can actually reduce the likelihood of heart attacks and strokes. The two drugs are each priced at about $14,000 per patient, per year, while statins, many of which are available in generic form, can be prescribed at a fraction of that cost. Anti-PCSK9 drugs, like statins, must be taken chronically, so cost is an ongoing concern, and some insurers have been demanding more proof before covering them. That’s why, combined, the two drugs generated only about $80 million worldwide during their last reported quarters. And it’s also why Pfizer (NYSE: PFE) scrapped development of another PCSK9-blocking drug, bococizumab, that was in Phase 3 testing earlier this month.

“The totality of clinical information now available for bococizumab, taken together with the evolving treatment and market landscape for lipid-lowering agents, indicates that bococizumab is not likely to provide value to patients, physicians, or shareholders,” Pfizer said at the time.

Two massive outcomes studies from Amgen and Regeneron are expected to produce data showing whether the two PCSK9 blockers on the market do, in fact, lead to better health outcomes. Success or failure in these huge studies—each including more than 10,000 patients—could mean the difference of billions of dollars in revenue for each company.

It’s in this complex environment that inclisiran will try to differentiate itself. Alirocumab and evolocumab are antibodies that bind to PCSK9 in the blood and block its activity. Inclisiran is a drug that uses RNA interference—a method of stopping genes from producing disease-causing proteins—to prevent the liver from making PCSK9 in the first place. The proposed benefit of inclisiran is convenience: Alirocumab and evolocumab have to be administered once or twice a month, while inclisiran could potentially be injected just two or three times a year. A small, shorter Phase 1 study, published earlier this week in the New England Journal of Medicine, showed that average LDL-C reductions for a single 300 mg dose of inclisiran were about 50 percent after four to six months. Though there are many caveats to comparing drugs across trials, inclisiran investigator Ray says inclisiran’s effectiveness is “in the same ballpark” as the approved antibody drugs.

Ray says that reducing the number of injections inclisiran could ultimately make for better control over patients’ cholesterol levels, though. “The more complicated a drug regimen is the less compliant [patients] are over time,” he says. Inclisiran could be like a flu shot. “You go to the doctor, and the nurse gives you the injection and you go away and you’re fine [for] six months.”

Not everyone is convinced that doctors would jump at the chance to switch patients off of antibody drugs for inclisiran, even if its safety and effectiveness hold up in longer, larger studies. Ethan Weiss, a cardiologist and associate professor at UCSF, who isn’t involved with Medicines Co., says that doctors might hesitate given that RNAi is a relatively new drugmaking method with—as of yet—no approved therapies. Antibody drugs are much more established, and Amgen and Regeneron’s drugs will have been on the market for several years if and when inclisiran gets there.

“If you’ve got a once a month dosing regimen are you really that much better off with a once every six months? What are you getting for that?” says Weiss. “As a doctor, and even if I were a patient looking at these therapies to take, I’d ask myself: Is it worth all the unknowns when there’s a readily available alternative therapy that is really well studied?”

That’s the case Medicines Co. hopes to build for physicians, patients, and payers over the next few years.