Amgen scores a victory for PCSK9, halving cardio risks after one year

A new generation of cardiovascular drugs has proved itself capable of lowering bad cholesterol across dozens of Phase III trials, but many physicians are holding out to see whether doing so can meaningfully improve patients' lives. In an early peek at some long-term data, one such injected therapy from Amgen halved the risk of major cardiovascular problems after one year of treatment, bolstering the case for the whole class of drugs.

In a study presented at the American College of Cardiology meeting, patients taking Amgen's ($AMGN) evolocumab were about half as likely to die, suffer a heart attack, endure a stroke or be hospitalized compared with those taking a standard regimen of statins. The trial was a one-year extension study enrolling roughly 4,500 patients who had already participated in an evolocumab trial, re-randomizing them to receive Amgen's drug plus standard of care or standard of care alone. In the end, the rate of cardio events was 2.1% for the statin group and just 0.95% for those taking evolocumab. The study was simultaneously published in The New England Journal of Medicine.

Evolocumab works by blocking the protein PCSK9 and thus helping the body clear LDL, or bad, cholesterol from the blood. The antibody is expected to win FDA approval by Aug. 27, trailing Sanofi ($SNY) and Regeneron's ($REGN) alirocumab, which, thanks to some regulatory opportunism, is likely to hit the market a month or so before. Pfizer ($PFE) is in third place, working through Phase III with its bococizumab. Analysts say each treatment could bring in more than $3 billion a year at its peak, but such lofty projections hinge on each company demonstrating that lowering bad cholesterol can improve cardio outcomes.

As for Amgen's antibody, these latest results help make the case for evolocumab as a potential life-saver for high-risk patients, lead investigator Marc Sabatine said, but the extension study is just a taste of what's to come from an ongoing, 27,500-patient outcomes trial, which won't be ready for analysis until 2017.

"We won't have any definitive answers until this larger trial we are doing is complete, but these data now give us a sense for the potential clinical benefit of these drugs," Sabatine, a senior cardiologist at Brigham and Women's Hospital, said in a statement. "We know from previous research that evolocumab lowers LDL cholesterol, but these data offer support for their potential to reduce major adverse cardiovascular events in our patients."

That said, the early results have a strong readthrough for the whole PCSK9 class. In the extension study, evolocumab lowered LDL by a whopping 61% from baseline, taking them from 120 milligrams per deciliter, not far from the U.S. average, down to 48 milligrams per deciliter on average. That profound reduction in LDL might be why researchers saw such a marked reduction in cardio events so quickly, Sabatine said, which is good news for companies making PCSK9 treatments.

"It suggests that if we can drive a patient's LDL cholesterol down a large amount to a very low level, we may start to see a benefit sooner than would be expected with a more modest intervention," Sabatine said.

Meanwhile, Sanofi and Regeneron were at ACC with positive data of their own. In a 2,341-patient study also published in the NEJM, alirocumab lowered bad cholesterol by 62% over statins at 24 weeks, meeting its primary endpoint, and maintained a 56% reduction after 18 months of treatment.

Furthermore, the rate of cardiac events was 3.3% for the statin group and just 1.7% for those on alirocumab. However, the small number of cardio events observed in the trial make it less than ideal for determining alirocumab's long-term effects, Sanofi and Regeneron note, and the pair are awaiting results of their own longitudinal outcomes study, which will wrap up in 2017.

Combined, the evolocumab and alirocumab studies "whet our appetites for further results that show cardiovascular benefit and documented safety, even at substantially lower LDL cholesterol ranges than achieved before," cardiologists Neil Stone and Donald Lloyd-Jones wrote in an NEJM editorial accompanying the two studies.

"However, it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary endpoint analysis and safety assessment, are available," the pair wrote. "... Much work remains to be done, but PCSK9 inhibitors appear on track to become important arrows in our quiver for targeting reduction of cardiovascular events among higher-risk patients when statins are not enough."

On the safety side, while both studies found the drugs to be generally well tolerated, neither dispelled concerns about neurocognitive side effects that have haunted the PCSK9 development process. The evolocumab study charted a slight increase in so-called fuzzy thinking in the treatment group, affecting .9% of patients compared to placebo's .3%, while alirocumab had the same effect on 1.2% versus .5% on statins. The FDA flagged such side effects last year, asking each company in the PCSK9 field to keep a close eye on how their drugs affected cognition and stirring fears that the new treatments be hampered by safety concerns. Amgen and Sanofi and Regeneron have all said they don't believe it to be a serious issue, but each has included cognitive measurements in its outcomes study, and, much like with efficacy, the issue is unlikely to go away until those major trials are complete.

In the meantime, the two leading PCSK9 factions are preparing for a near-term fight to differentiate themselves as they march toward the market. Express Scripts ($ESRX), the pharmacy benefit manager that successfully spurred a price war among competing hepatitis C therapies last year, has identified PCSK9 blockers as its next target, figuring it can squeeze some savings by pitting fairly comparable drugs against one another. None of the companies has explicitly discussed expected pricing for the injected therapies, but it's sure to be contentious topic come July.

But, for the teams behind each medicine, their coming debut is a long-in-the-making payoff after years of work, Sanofi PCSK9 head Jay Edelberg said.

"Praluent for us is really the opportunity to deliver on PCSK9 and to get patients to LDL levels that they previously couldn't get to," he said. "We can't wait to get this to our patients."

- get the evolocumab results (PDF)
- here's the alirocumab data
- read the NEJM editorial

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