FDA approval yesterday of heart failure drug sacubitril/valsartan (Entresto), previously known as LCZ696, and the pending approval of two PCSK9 inhibitors this summer has reinvigorated the search for further advances in cardiology, experts said. Pharmacologic findings with major impact on clinical practice have otherwise been sparse, noted Milton Packer, MD, chair of clinical sciences at UT Southwestern in Dallas and lead researcher on the PARADIGM-HF trial of LCZ696.”There was a time 10, 15, 20 years ago when cardiovascular drug development was in its heyday with many, many drugs being developed,” he told MedPage Today. “But in the last 5 to 10 years most of the innovation in drug development has moved to other areas — oncology and neuroscience — and many of us began to think that pharmacological innovation and cardiovascular benefit was waning, perhaps dying. “But with LCZ696 and PCSK9s there is energy in the field of cardiovascular medicine.”
There had been no new heart failure drugs for a decade until ivabradine (Corlanor) ended the drought last April.
The excitement was more palpable with LCZ696, called a game-changer for not only reducing heart failure hospitalizations like ivabradine but also preventing heart failure deaths.
In recent years, cardiovascular researchers have often referred to the difficulty in making more than an incremental impact on cardiovascular outcomes now in the era of statins and a plethora of antihypertensives and antithrombotics.
That’s been true in heart failure but is countered by the example of LCZ696 and by advances like the PCSK9 inhibitors, said James Januzzi, MD of Massachusetts General Hospital.
“The approval of LCZ696 illustrates that substantial advances are still possible in the medical field,” he told MedPage Today. “We have seen a substantial change recently in the clinical trial landscape in cardiology. For example, there are several entirely new classes of drugs as well as regenerative therapies being explored for the care of both acute and chronic heart failure, indicating a substantial increase in the confidence in the field.”
The advantage of LCZ696 was still incremental, about 20% atop enalapril in PARADIGM-HF, noted Marrick Kukin, MD, director of the Heart Failure Program at Icahn School of Medicine at Mount Sinai in New York City.
Nevertheless, that’s impressive considering it was in addition to beta-blockers, he told MedPage Today.
“To put that into perspective, the mortality benefit of carvedilol, metoprolol succinate and bisoprolol each were 34% to 35%, but compared to placebo,” he added.
The recent developments should send a signal to industry to renew enthusiasm for research and development in cardiology, said Robert Bonow, MD, director of the Northwestern University Center for Cardiovascular Innovation in Chicago and a past president of the American Heart Association.
These show “that we can and will do more to reduce risk and disability from heart disease, and should reignite the search for new drug targets,” he said.
Mariell Jessup, MD, of the University of Pennsylvania Heart and Vascular Center in Philadelphia and also a past AHA president, agreed and suggested it has already had an effect.
“Already there has been a renewed sense of interest and excitement from many pharmaceutical companies taking another look at heart failure therapy,” she said.
“It would be nice to say this is the summer of blockbusters but if you really look at the field of cardiology in general, there has been steady progress in so many areas almost every year,” she added. “One only has to look at the overall mortality from cardiovascular disease and stroke to realize we have made impressive strides in the disease area.
“I do think it indicates a willingness of the FDA to bring new drugs through the approval process in an accelerated fashion. That feels new to me.”
But optimism about the value of these new drugs aside, there is concern about whether their impact will be felt outside the developed world.
Salim Yuself, DPhil, President of the World Heart Federation said” These two results are important but one wonders whether they will have a major impact on the health of society at large if they are beyond the reach of the vast majority of people who can benefit from it .” Yusef argues that real advances are ones that benefit large populations on a global scale, concluding, “…the major advances which will save lives will come from innovative methods of delivering the care that we know works but don’t implement .So the real advances will come from innovations in health care systems .”
And beyond affordability Clyde Yancy, MD, MSc, a former AHA President, said there was a broader importance to the new drugs which “highlight the importance of science- both basic/translational and clinical- as the foundation of our success in treating cardiovascular disease.”
ancy, Chief of Cardiology at Northwestern University Medical School said “At a time when our landscape is characterized by declining resources to support fundamental research from the NIH; increasing pressure for clinical productivity even at academic medical centers; thin pipelines for new drug development and a frustrated entrepreneurial community beset with cost constraints and regulatory requirements, we now see that somehow, science prevails.”