Cardiology Drugs Of The Year: New, Old, And Not-So-Funny

New Drug Of The Year

This was an easy choice. The new drug of the year isLCZ696, the upcoming heart failure drug from Novartis. At the beginning of the year only a few heart failure experts were aware of it, and no one in the heart failure community or on Wall Street had even suggested that it might be a blockbuster. Expectations, if any, were that the drug would join the long string of recent failures of novel cardiovascular drugs, especially since LCZ696 is a chemical cousin to omipatrilat, the Bristol Myers drug which certainly counts as one of the most spectacular drug failures of all time.

Then, on the last day ofMarch, during the American College of Cardiology meeting, Novartis issueda press releasedisclosing that the pivotal phase 3 LCZ696 trial,PARADIGM HF, had been stopped early on the recommendation of theData Monitoring Committee because ofa significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization. The initial announcement garnered onlymodest interest, since by now many observers have learned to be skeptical when a trial is stopped early. Too often the results dont hold up or reflect a statistically significant difference thatmay nottranslate into clinical significance.

But that changed a day later when Milton Packer, the co-principal investigator of the trial, pulled me aside at another ACC session to let me know that, for once (and to its ever-lasting credit)the trial sponsor had actually downplayed the full importance of the result.Packer told me thatthe press release implies that the trial was stopped for the primary endpoint but that was not the case,the trial was stopped for a persuasive effect on cardiovascular mortality alone, and my enthusiasm was based on that very persuasive effect.

It wasthis bit of newsthat prompted initial speculation, by myself (hereandhere) and others, thatLCZ696 might be a big deal. Over the next few months the excitement and anticipation grew.The presentation of the actual results, at the European Society of Cardiology meeting at the end of August, became a major event. Despite a certain amount of pushback from skeptics the general consensus so far is that the trial has held up under fire.It now appears that LCZ696 may be poised to replace ACE inhibitors and ARBs as the goldtandard of treatment for heart failure. Thats a big deal.

Its hard to say just how big LCZ696 will be in the real world. Analysts have now routinely started referring to it as ablockbuster. I think they may well be right, but until PARADIGM HF undergoes thorough scrutiny from the FDA I wont be satisfied. And theres always the danger that some sort of problem could crop up that could kill or wound the drug. One possibility remote but not impossible, based on studies in animals is that the drug might increase the risk of dementia. You can be sure the FDA and others will be looking very hard for signs of problems like these. And remember,it could only takean early signal of a problem like thattoderail or seriously delay drug approval or acceptance. Sales predictions range from $1 or $2 billion a year to as high as $6 billion a year.I try not to predict the future.The past is hard enough to understand.

Speaking of the past. If LCZ is the new drug of the year, thenezetimibe is without doubt the

Old Drug Of The Year LCZ696 represents the future of cardiology.Ezetimibe, by contrast, represents the past, and, in particular,the last decade of controversy, scandal, and gigantic missteps. (Ezetimibe is marketed by Merck as Vytorin and Zetia.) With any luck the final presentation ofIMPROVE-ITat the American Heart Association meeting in November heralded the end of this miserable era. Ive written extensively about IMPROVE-IT (hereandhere) in the past so I wont repeat myself. Suffice it to say thatafter 12 years we know, finally, that ezetimibe works. Sort of. Heres Marilyn Mannssummary:

the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants all patients who had been hospitalized for acute coronary syndrome within the10 days before randomization this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.it is regrettable that we had to wait 12 years after the drugs approval to find out whether it improves outcomes.

Not-So-Funny Drug Of The Year

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Cardiology Drugs Of The Year: New, Old, And Not-So-Funny