Merck & Co. Inc. tipped its hand a week earlier in SEC paperwork regarding what the outcome of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) might mean for the pharma firm's bottom line, but the world had to wait until Monday morning to find out how the experiment could help or hinder developers of anti-cholesterol protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

For them, too, the news was good. "It hit!" enthused ISI Group analyst Mark Schoenebaum wrote in an alert to investors, after Merck disclosed first word that the primary endpoint had been reached. At the American Heart Association (AHA) Scientific Sessions in Chicago, Whitehouse Station, N.J.-based Merck unveiled results from IMPROVE-IT. The trial, testing Merck's Vytorin (ezetimibe/simvastatin) to determine whether it's better than simvastatin (Zocor, Merck & Co. Inc.) alone in preventing cardiovascular (CV) trouble, met its primary endpoint.

Some investors worried that the doubled pill wouldn't show enough benefit. Other IMPROVE-IT watchers wanted to see whether the notion that the knockdown of low-density lipoprotein cholesterol (LDL-C) would hold up as a biomarker for CV outcomes – an important idea for developers of the more-potent, late-stage PCSK9 therapies.

The results were positive for Merck "but go beyond by suggesting that LDL lowering with drugs other than statins provides a cardiovascular benefit (a reaffirming of the LDL hypothesis that was beginning to be questioned) and that LDL levels should possibly be driven lower than guidelines have recommended (below 70 mg/dl)," Schoenebaum wrote. "Today's results add the first real data point to our understanding of the relationship between LDL reduction and outcomes at very low LDL levels."

IMPROVE-IT, which included 18,144 high-risk patients presenting with acute coronary syndromes, met its primary and all secondary composite efficacy endpoints. Patients who took Vytorin to lower their LDL-C showed significantly fewer major CV events (as measured by a composite of cardiovascular death, non-fatal myocardial infarction [MI], non-fatal stroke, re-hospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization) than those given simvastatin alone.

Patients were followed for an average of six years. The trial ended after there were 5,250 primary endpoint events (CV death, MI, hospital admission for unstable angina, coronary revascularization more than a month after randomization, or stroke).

Because high-risk patients treated with statins, including those on treatment with low levels of LDL-C, are still at more CV risk, Merck wanted to find out with IMPROVE-IT whether dropping LDL-C to well under 70 mg/dL by adding ezetimibe to a statin further reduced CV events. The study found that, at seven years, 32.7 percent of patients taking Vytorin experienced a primary-endpoint event compared to 34.7 percent of patients taking simvastatin alone (hazard ratio of 0.936, p = 0.016). Based on the LDL-C range compared in the study's treatment arms (at one year, a mean LDL-C of 53 mg/dL vs. 70 mg/dL, respectively), the 6.4 percent relative risk reduction observed in the Vytorin arm of IMPROVE-IT was consistent with the treatment effect that had been projected based on prior studies of statins.

PCSK9 MESAGE 'SIMPLE'

Merck said it will submit the data from IMPROVE-IT to the FDA in mid-2015 to support a new indication for reduction of major CV events for Vytorin and Zetia, which now are given for use with a healthy diet to reduce LDL-C in hyperlipidemia patients.

Meanwhile, analysts covering the PSCK9 players were sorting out what the news might mean for candidates in that space.

Thousand Oaks, Calif.-based Amgen Inc. has evolocumab, and Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y. (with Paris-based partner Sanofi SA) is advancing alirocumab. Newer to the game is Pfizer Inc., of New York, with RN316, which entered a phase III program last fall. Amgen and Regeneron/Sanofi are the opponents to watch, and likely would first compete in high-risk cardiovascular patients with uncontrolled LDL, in heterozygous hypercholesterolemia (HeFH), and in statin-intolerant patients. (See BioWorld Today, April 1, 2014.)

Deutsche Bank analyst Robyn Karnauskas sounded more subdued but no less encouraged by the Merck data. "Given that IMPROVE-IT showed a positive link between greater LDL-c lowering and better CV outcomes, we see this as a positive for PCSK9s as they lower LDL-c more than statins, and thus should produce greater risk reduction for long-term CV events," she wrote in a research report.

RBC Capital Markets analyst Michael Yee, covering Amgen, noted that his firm has "continuously stated we think PCSK-9 will get approved in August 2015 based on robust LDL lowering effects, and very clean safety as an antibody [no off-target effects]. We think buy-side expectations on launch are low because of a view that patients won't want to 'inject' for a disease they don't really feel [high cholesterol]," wrote Yee in a research report, pointing out the "huge market opportunity" of as much as $5 billion worldwide.

Adnan Butt, Yee's colleague at RBC, covers Regeneron. "The [IMPROVE-IT] trial not working could have added complexity to the messaging around alirocumab and other anti-PCSK9s," Butt noted, but with the favorable data, "the message for patients and doctors remains simple, i.e., the lower the LDL-C, the better the outcomes for patients long term."

Because of the hefty revenues to be made in the cholesterol space, such firms as Ann Arbor, Mich.-based Esperion Therapeutics Inc. also are in the running. The firm has ETC-1002, which in phase IIb trials as monotherapy lowered LDL-cholesterol by up to 40 percent, and by almost 50 percent in combination with ezetimibe (Zetia, Merck & Co. Inc.) and over 50 percent when paired with atorvastatin (Lipitor, Pfizer Inc.) Tim Mayleben, CEO of Esperion, hailed Merck's latest results, noting that they "confirm the LDL-C-lowering hypothesis, and predicting that his company's candidate may also "play a very important role" for patients with hypercholesterolemia, including those who can't tolerate statins, "a patient population with a very high level of unmet medical need." (See BioWorld Today, Oct. 3, 2014.)

Merck, in a 10-Q filing with the SEC about a week ago, disclosed that "the company [had] been unblinded to the results from the IMPROVE-IT trial" and "has determined that the Zetia and Vytorin intangible assets are not impaired," but did not provide further details and held off until the AHA meeting.

Shares of Merck (NYSE:MRK) closed Monday at $59.46, up 39 cents. Regeneron (NASDAQ:REGN) ended at $399.65, up $4.45, with Sanofi (NSYE:SNY) at $47.54, up 86 cents, and Pfizer (NYSE:PFE) at $30.32., down 2 cents.