The Next Wave: Pharm Exec's 2011 Pipeline Report - Pharmaceutical Executive


The Next Wave: Pharm Exec's 2011 Pipeline Report

Pharmaceutical Executive

Hyperlipidemia: The Anti-CETPs Redux

The crowded cholesterol-control category is the biggest US drug market, with 2010 global sales close to $35 billion, according to IMS Health. A wide array of me-too statins, either generic or soon to be so, already excel at lowering LDL, or "bad" cholesterol, leaving the increase of HDL, or "good" cholesterol, the only low-hanging fruit left in this orchard. Many studies have confirmed that high levels of high-density lipoproteins, which collect the artery-blocking low-density kind and carry them to the liver for expulsion, correlate to low risk of atherosclerosis and heart attack. But in 2006, Pfizer's first-in-class CETP inhibitor flamed out in spectacular Phase III fashion because it increased not only HDL but patient deaths—by 60 percent—mostly due to hormone-induced hypertension.

Most CETP-inhibitor programs were promptly shuttered, but Merck, Roche, and smaller shops quietly persevered, tweaking their molecules to minimize the perceived risk. Last month, Merck snatched the spotlight at the annual heart-association confab with study data showing that patients on a statin and its CETP inhibitor, anacetrapib, had a 40 percent greater reduction in bad cholesterol than the statin-only group. Yet the 'wow' factor was that its good cholesterol soared by 140 percent, while blood pressure and cardiac problems were no different from placebo. Said Christopher Cannon, a cardiologist at Brigham & Women's Hospital and the study's lead researcher: "If what we are seeing now is borne out in larger studies, this could be the next big thing that could benefit hundreds of millions of people."

By contrast, Roche's Phase III anti-CETP contender, dalcetrapib, has demonstrated a weaker lipid punch, lifting HDL by 40 percent and lowering LDL by 15 percent. Other compounds are in the works to treat more serious disease.

Quantity is one thing, quality another. Some skeptics have raised doubts about how well—or even if—drug-produced HDL functions. Whether these high marks translate into clinical benefits—must wait until 2015 at the conclusion of Merck's $150 million, 30,000-person Phase III study. If they do, Merck may have a Lipitor-sized cash cow in its pasture.

Acute Coronary Sydrome: A Risky Business

A new class of anticoagulants is competing to dethrone difficult-to-manage warfarin, long the sole option in the prevention of stroke and other bleeding complications in the 2.5 million US patients with atrial fibrillation. The novel bloodthinners are blockers of direct factor Xa, knocking out a specific enzyme in the coagulation cascade that takes place in veins. Bayer/J&J's Xarelto led the pack after filing data last month showing that in a Phase III trial of more than 14,000 patients, once-daily Xarelto reduced clots by 20 percent compared to warfarin.

Asked for more data by the FDA, Xarelto lost the warfarin-replacement race to Boehringer Ingelheim's oral direct thrombin inhibitor, Pradaxa, which was approved in October. But the $15 billion market is big enough for both new products, plus the late-stage Factor XA inhibitors from Merck/Portola and Daiichi-Sanyko. Post-market studies will shake out the winners and losers. Yet the recent failure of Pfizer/BMS's apixaban in Phase III due to excessive bleeding risk illustrates the tightrope all novel anticlotting drugs must walk between efficacy and safety to get to market.

In the category of antiplatelets, which prevent blood clots in arteries, Plavix has long been king. But when the world's second-best-selling drug goes generic next year, a flood of cheap knockoffs will raise the bar for competitors to gain market share. Proving superiority as well as safety are the keys to the kingdom, and with 30 percent of all patients not responding to Plavix, new options are a must. AstraZeneca's Brilinta got an OK from the FDA's advisory committee last July, but a final decision has been delayed while the agency mulls over the anomaly of its global Phase III trial—the ADP receptor inhibitor proved superior to Plavix in reducing heart attacks, strokes, and deaths everywhere but in the US (the leading theory is that bloodthinning aspirin is used much more widely there than elsewhere).

How brilliant is Brilinta's future? Consider that Lilly's Effient, the latest Plavix rival, has performed so dismally since its 2008 launch. But Brilinta's safety profile far outshines the Lilly drug—at least so far. "Brilinta is likely to succeed where Effient failed," says Wolters Kluwer's analyst Ben Weintraub.

In its ambition to seize control of the cardiovascular space from which some big pharmas have fled, Merck also has a big bet on antiplatelets with its first-in-class Phase III PAR-1 thrombin receptor inhibitor, vorapaxar, whose novel mechanism of action could set it apart from Brilinta, Plavix, and other targeters of ADP receptors. Robert Hazlett, an analyst at BMO Capital Markets, is bullish on the entire Merck cardio franchise, but especially vorapaxar, projecting $5 billion in peak annual sales.


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