Trends in Cardiovascular Drug Development Speak to Pipeline Problems and Possibilities

Cardiovascular drugs account for a smaller proportion of all medications in the research pipeline than they did 25 years ago, though they are now more likely to target novel biological pathways and to be developed by small- or medium-sized companies instead of by large pharmaceutical companies, according to a new study.

“Given the increasing burden of cardiovascular disease globally, the declining pipeline of new therapies is concerning,” write Thomas J. Hwang, AB (Harvard University, Cambridge, MA), and colleagues in their paper, which was recently published online in JACC: Basic to Translational Science. “Policymakers should focus their efforts on supporting research aimed at improving gaps in the understanding of the pathophysiological bases for cardiovascular disorders, as well as facilitating translational efforts to develop new cardiovascular therapeutics.”

But in an email, senior author Aaron S. Kesselheim, MD, JD (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), seemed more optimistic. “I think the news is good—over time, we’re seeing a greater percentage of new CV drugs in development be innovative, which are the products that are most likely going to have the most important clinical impact,” he told TCTMD. As such, he said, having fewer but more targeted drugs under development is not a bad thing.

Commenting on the study for TCTMD, Clyde Yancy, MD (Northwestern Memorial Hospital, Chicago, IL), cautioned against assuming that the trends observed in the study period spanning 1990 to 2012 would hold up today. “In the last 3 or 4 years we’ve seen really exciting growth in biotech areas, so I think it would be really difficult to assume this is the current status,” he said, noting an increasing shift toward trying to better understand the mechanism of disease and more precisely target therapies.

CV Drugs Make Up a Smaller Slice of the Pie

For their analysis, Hwang et al used a large commercial database to track patterns in the development of cardiovascular drugs—most commonly antihypertensive agents, followed by lipid-lowering and anticoagulant agents—over the 2-decade time span. Between 1990 and 1995, 108 out of 679 phase I trials (16%) dealt with cardiovascular drugs, whereas 125 of 2,366 phase I trials (5%) between 2005 and 2012 were CV drug-related. Phase III trials followed a similar pattern, with the proportion studying cardiovascular drugs dropping from 21% in 1990 to 7% in 2012. By comparison, the researchers point out, the prevalence of cancer drugs in testing increased during that period.

Cardiovascular drugs were as likely as those targeting other conditions to proceed through the various stages of development. Among the 63 CV drugs discontinued in phase III, 44% did so because of inadequate efficacy and 24% due to safety issues.

Novel biological pathways were the focus for half of the CV drugs being tested in phase III trials, with the proportion of novel drugs increasing from 21% in 1990-1991 to 57% in 2012. The proportion of drugs being developed by small or medium instead large companies also grew over time.

Far Less ‘Carpet-bombing’

In an accompanying editorial, Mona Fiuzat, PharmD, Norman Stockbridge, MD, and Robert M. Califf, MD—all of the US Food and Drug Administration—argue on behalf of getting back to the basics.

“Because drug development follows science, continued investment in the basic biology of cardiovascular disease is needed, and because large populations are impacted, attention to improved efficiency of the evidence-generation system will be needed to generate needed sample sizes for definitive trials at a lower cost,” they write. “Finally, involving the full community, including industry, the National Institutes of Health, academic experts, funding agencies, regulators, practitioners, and patients will be an important step in strengthening the science and advancing the field.”

The fact that science is leading the way means that our approach to clinical trials must change, Yancy agreed, calling for greater collaboration. He cited the potential for looking at cardiovascular disease in new ways, such as with mendelian randomization, and treating it with new approaches, such gene silencing via RNA inhibitors. Recent successes include the novel oral anticoagulants and PCSK9 inhibitors, he said.

“These are really exciting moments, but they mean that we won’t have as many products in the pipeline because the science will help us refine our opportunities,” Yancy noted.

Focusing our efforts on therapies most likely to prove successful makes sense, he said. “It takes a lot of effort to do clinical trials. It’s a major contract we make with patients when we recruit them as subjects to participate in a clinical trial. We should be pursuing ideas and using compounds where the yield is high, so that we can exercise the greatest possible respect for a human being’s decision to be subjected to the experiment of a randomized controlled trial.”

What came before is “carpet-bombing,” Yancy commented. “Anything that seemed to have a remote chance of helping cardiovascular disease, we took it under study. Now [not all studies are yet] precision-guided, laser-focused efforts, but we certainly have narrowed the sphere: our targets are more crisp, our interventions are more aligned scientifically, the mechanisms are becoming more apparent, and the likelihood of making real discovery is there.”


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  • Hwang TJ, Lauffenburger JC, Franklin JM, Kesselheim AS. Temporal trends and factors associated with cardiovascular drug development, 1990 to 2012. JACC Basic Transl Sci. 2016;1:301-308.

  • Fiuzat M, Stockbridge N, Califf RM. Resourcing drug development commensurate with its public health importance: the road ahead. JACC Basic Transl Sci. 2016;1:309-312.

  • Hwang reports having been employed by Blackstone and Bain Capital, which has invested in healthcare companies.
  • Kesselheim reports receiving research funding from the Greenwall Foundation, Harvard Program in Therapeutic Science, Laura and John Arnold Foundation, and the FDA Office of Generic Drugs and Division of Health Communication.
  • Fiuzat, Stockbridge, Califf, and Yancy report no relevant conflicts of interest.

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