An Unknown Majesty in Cardiovascular Medicine

20. February 2015
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What happens when a drug candidate in cardiovascular medicine is prematurely terminated? What if the drug responses vary across genetic profiles? Thanks to the researchers at the Montreal Heart Institute, we have now witnessed a world’s first in cardiovascular medicine.

On September 17, 1971, LIFE magazine published an article, “The Tragic Record of Heart Transplants,” an excerpt from a new book at the time, “Hearts” by Thomas Thompson. The article and the book detail the pioneering work and tragic record of surgeons in the 1960s seeking to perform the world’s first human-to-human heart transplant. Thompson penned that the heart “is a peculiar, particular organ, not only a pump, but a creature of some internal, unknown majesty – its depths not fully divined by a hundred thousand microscopic slides and tissue examinations.” While Aristotle long considered the heart to be “the seat of thought, reason and emotion,” it wasn’t until 17th century physician William Harvey recognized the heart as “the sovereign of everything within them…from which all power proceeds” that the true function of the heart received its justified scientific recognition.

The rise of precision medicine

Today, we recognize the concept of precision medicine, which emerged from a 2010 National Academy of Sciences report co-authored by University of California, San Francisco (UCSF) Chancellor Susan Desmond-Hellmann, MD, MPH, and Charles Sawyers, MD, of Memorial Sloan-Kettering Cancer Center. The concept of precision medicine is to “transform medical care worldwide by integrating the wealth of data emerging from both the human genome and research on the molecular basis of disease, with information from patients’ health records and environmental data.” While scientists in many clinical areas are at the vanguard of processing massive volumes of clinical, epidemiological, and molecular big data into actionable insights, today we must laud the pioneering work in precision medicine of cardiovascular researchers uncovering “the unknown majesty” locked within a specific genetic variant.

Patient benefit by means of the help of dalcetrapib

Researchers at the Montreal Heart Institute, led by Drs. Jean-Claude Tardif and Marie-Pierre Dubé, have truly achieved a world’s first – that patients with cardiovascular disease and the appropriate genetic background can benefit greatly when treated with the cholesteryl ester transfer protein (CETP) inhibitor known as dalcetrapib. Their research demonstrated correlated polymorphisms in the ADCY9 gene impact the effect of dalcetrapib on atherosclerotic outcomes. These findings were published in a recent article in the prestigious journal, Circulation: Cardiovascular Genetics. With a reduction of 39% in combined clinical outcomes including heart attacks, strokes, unstable angina, coronary revascularizations and cardiovascular deaths, patients also benefit from a reduction in the amount of atherosclerosis (thickened walls) in their vessels.

The researchers conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism (SNP) was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10-8), with eight polymorphisms providing P<10-6 in this gene.

“We used state-of-the-art genetic and statistical techniques to demonstrate that the effect of the patient’s genetic profile was only observed in those treated with dalcetrapib and not placebo. We want to provide patients with additional personalized cardiovascular therapies in the years to come, for more efficacious and safer medicines”, commented Marie-Pierre Dubé PhD, director of the Beaulieu-Saucier Pharmacogenomics Center at the Montreal Heart Institute and professor of medicine at the University of Montreal.

Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared to placebo (HR=0.61; 95%CI 0.41, 0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten SNPs in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r2=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10-8; HR=0.67, 95%CI 0.58, 0.78).

Hope for patients with cardiovascular diseases

“These results will lead to a genetics-guided clinical study in patients with the appropriate genetic background to allow review by health regulatory agencies and to provide personalized therapy with dalcetrapib. It also offers great hope for precision treatments for patients with cardiovascular diseases and for curbing atherosclerosis, the first cause of mortality in the world” said lead investigator Jean-Claude Tardif MD, director of the Research Center at the Montreal Heart Institute and professor of medicine at the University of Montreal.

It should be noted that not too long ago that CETP inhibition was considered a promising treatment approach for patients with dyslipidemia. This emerging class of drugs generated tremendous excitement in the medical community due to the fact that treatment options for patients with decreased HDL were, and remain, extremely limited. The excitement abated in 2006, however, when Pfizer halted the development program of its CETP inhibitor, torcetrapib, in the “interest of patient safety.” Dalcetrapib, which was studied as part of the dal-HEART global development programme, which involved six clinical trials: dal-OUTCOMES, dal-OUTCOMES 2, dal-PLAQUE 2, dal-ACUTE, dal-PLAQUE (completed) and dal-VESSEL (completed), had its dal-OUTCOMES trial and all the studies in the dal-HEART programme terminated in 2012 by Roche due to “due to a lack of clinically meaningful efficacy.”

Obama’s support for precision medicine

While this notable discovery from the researchers at the Montreal Heart Institute may reignite the development of innovative medicines like dalcetrapib, it certainly may pave the way for a new era in cardiovascular medicine with precision medicine. A number of world leaders including United States President Barack Obama recognize this promise and are hoping to accelerate the development of precision medicine. President Obama has recently inaugurated a new initiative focused on this concept. In a statement that would make William Harvey proud, President Obama said, “Precision medicine gives us one of the greatest opportunities for new medical breakthroughs that we have ever seen.” It appears that in the future, at least in the clinical area of cardiovascular, it will be precision medicine “from which all power proceeds”.

 

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Physician

In view of the above, many of the drugs that were introduced; and later withdrawn for safety concerns; need to be re-evaluated, if real progress is to be made on these basis.
-Parimal

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