August 2017

The Pharmacogenetics of Cardiovascular
Disease Therapy
Researchers at the Montreal Heart Institute used the Infinium® HumanOmni2.5Exome BeadChip toidentify responder genotypes in a failed cholesterol drug trial.
Introduction
The success rate of late-stage clinical trials is estimated to be
25–50%1. Could a reason that so many drugs fail be that theirefficacy varies across genetic profiles? That’s what Marie-Pierre
Dubé, PhD and her colleagues at the Montreal Health Institute (MHI)
have set out to determine. As the director of the Beaulieu-Saucier
Pharmacogenomics Centre at MHI, Dr. Dubé collaborates withpharmaceutical companies to look for the genetic determinants thatmodulate the efficacy and safety of cardiovascular therapeutics.
Dr. Dubé and her team, along with Jean-Claude Tardif, MD, focused
their first study on dalcetrapib, a cholesterol-lowering drug candidatethat failed to reduce cardiovascular adverse events in subjects who
received it in Phase 3 clinical studies. The MHI team investigatedthe pharmacogenomics of subject response using the Infinium
HumanOmni2.5Exome BeadChip. They analyze DNA samples
collected as part of the dalcetrapib clinical trials program and identified
the genotypes of responders and nonresponders2.
iCommunity spoke with Dr. Dubé about her pharmacogenomics
studies and how Illumina technologies are making them possible.
Q: What sparked your interest in pharmacogenomics?
Marie-Pierre Dubé (MPD): I became fascinated by the analyticalaspect of genetics as an undergraduate student at McGill University
and later focused my PhD studies on developing new statistical
approaches to genetics. During my post doc in public health, I
became more interested in population approaches and epidemiology.
A subsequent job at a biotech company gave me experience working
with extreme phenotypes for drug discovery. That has really defined
my current interest in pharmacogenomics, the study of an individual’s
unique genetic response to medications.

more as a valuable tool to identify efficacy factors. We’re now seeing
drugs launched with companion diagnostics that were developed basedon pharmacogenomic data. For example, we’re seeing the integration ofcompanion diagnostics for genotype-dependent therapeutics in treatingbreast and lung cancer.
Q: What recent technologies are making pharmacogenomics possible?
MPD: The genomic tools available today have really advanced thefield of pharmacogenomics. Illumina has been a strong player in thefield and its arrays and sequencing systems are enabling population
approaches to genomics. In this case, those tools are enabling
efficient analysis of data from very large clinical trials.
Q: What is dalcetrapib and what was it developed to treat?
MPD: Dalcetrapib is a cholesterylester transfer protein (CETP) inhibitor
developed by Roche. It raises HDL cholesterol, which people sometimes
refer to as ‘good cholesterol.’ A large body of epidemiological evidence
supports the idea that higher HDL cholesterol is better for you; it
prevents cardiovascular disease in general and myocardial infarction
specifically. In May 2012, Roche ended its dal-OUTCOMES dalcetrapib
clinical trial program because an interim analysis showed that it did not
significantly reduce cardiovascular adverse events in the nearly 8000
people who received the drug, although it successfully increased HDLcholesterol by approximately 30%.
Dalcetrapib was the second CETP inhibitor to fail in clinical trials
despite initial excitement that raising HDL-cholesterol levels would
translate into a reduction in clinical cardiac events. This caused somein the cardiovascular disease community to believe that raising HDL
was the wrong approach for reducing cardiovascular events.

Q: What are the genetics behind drug response?
MPD: There are 2 genomic aspects of drug response. One of themhas to do with the pharmacodynamics, changes in efficacy related
to drug target or phenotypic aspects. The other is pharmacokinetics,
which has to do with how a drug is transformed, absorbed,metabolized, and excreted. Genetic variations in proteins directly
or indirectly involved in any of those processes could modulate
drug response.
Q: How has the field of pharmacogenomics changed over thepast decade?
MPD: There was a lot of hype about pharmacogenomics 15 years ago
and it’s been slow to deliver on its promise. Pharmacogenomics was firstused to identify genetic factors of adverse response, but there has beena major shift in the field recently. Today genetics is being seen more andFor Research Use Only. Not for use in diagnostic procedures.

Dr. Marie-Pierre Dubé is Director of the Beaulieu-Saucier
Pharmacogenomics Centre at the Montreal Health Institute.

August 2017
Q. What prompted you to focus on the pharmacogenomicof dalcetrapib?
MPD: We focused on the pharmacogenomics of dalcetrapib
because we still believed that raising HDL was a good approach.
We wondered whether there could be a genetic subgroup thatwould benefit from the drug and decided to reanalyze the datato look at the pharmacogenomics.

“We worked with theHumanOmni2.5Exome
BeadChip in the past and werepleased with its quality and fast
turnaround time.”
Q: What were the objectives of your pharmacogenomics analyses?
MPD: Our primary objective was to determine whether there wasa group of subjects in the treatment arm that did benefit fromdalcetrapib. The end point was a reduction in cardiovascular events,
such as coronary heart disease death, resuscitated cardiac arrest,
nonfatal MI, nonfatal stroke, and unstable angina, or revascularization
while on treatment. The secondary objective was to identify if there
were genetic factors that put certain subjects at risk of a recurrent
cardiovascular event, regardless of the treatment arm in which they
were enrolled.
Genetic data had not been systematically collected from everyonein the trial, but about 6000 dal-OUTCOMES participants agreed
to participate in a Roche research program where DNA samples
were taken. These samples made it possible to perform genomewide association studies (GWAS) to see if there was a genetic basis
behind subject response to dalcetrapib. In performing the follow-on
dalcetrapib study for Roche, we also were given subject data fromdal-PLAQUE-2, an imaging trial to show whether dalcetrapib alteredatherosclerosis as measured by carotid intima-media thickness (IMT).
This provided supporting evidence to the GWAS results.
Q: Why did you choose the HumanOmni2.5Exome BeadChip foryour analyses?
MPD: We worked with the HumanOmni2.5Exome BeadChip in thepast and were pleased with its quality and fast turnaround time. We
thought it offered great potential in answering our primary researchquestion, because it includes markers from the HumanOmni2.5 andHumanExome BeadChips and therefore provides information oncommon, rare, and exonic SNP variants. We liked the fact that when
we identified a GWAS hit in a region, we’d also had the exome datato determine if there was a coding variant that could be involved in
the signal.
Q: What were the results of your study?
MPD: The data from GWAS with the HumanOmni2.5Exome BeadChip
showed a strong association between the effects of dalcetrapib andADCY9 (adenylate cyclase 9) on chromosome 16, particularly for a
specific genetic variant (rs1967309). We would never have discovered
this gene using a candidate gene study.

For Research Use Only. Not for use in diagnostic procedures.

ADCY9 was not the drug target; however, it’s a gene that makes
sense at the physiological level. When we stratified genotypes inthe dalcetrapib arm of the dal-OUTCOMES trial, subjects that werehomozygous for the rs1967309 AA allele had a 39% reduction in
cardiovascular events or urgent coronary revascularization comparedwith placebo. In contrast, participants who were homozygous for
the GG variation had a 27% increased risk of cardiovascular eventsor revascularization. We then evaluated samples from the dalPLAQUE-2 study. Again, individuals homozygous for the protective
AA allele showed a significant reduction in IMT when treated withdalcetrapib. In contrast, subjects with a wild-type genotype showedcoronary atherosclerosis progression. Subjects with the protective
genotype made up approximately 20% of the participants in the dalOUTCOMES study. We were excited to identify a variant that could be avaluable biomarker.
Q: Have the results from this study triggered further clinical studiesof dalcetrapib?
MPD: This fundamental genomics work will lead to a genetics-guided
Phase 3 clinical study of dalcetrapib in subjects with the genetic
profile associated with a positive response to dalcetrapib. A positive
outcome in this Phase 3 clinical trial could result in a personalized
cardiovascular therapy.

“The data from GWAS with theHumanOmni2.5Exome BeadChip
showed a strong association
between the effects of dalcetrapiband ADCY9, particularly fora specific genetic variant(rs1967309). We would never
have discovered this gene usinga candidate gene study.”
Q: Could this pharmacogenomics approach be valuable inresuscitating other failed cardiovascular drug candidates?
MPD: I believe that the same approach can be used to analyze data
retrospectively from other drugs that showed potential, but ultimately
failed in clinical trials. AstraZeneca has recently entrusted our teamwith its cardiovascular and metabolic disease biobank. It has 80,000
samples and data from 99 clinical trials of 10 different drugs. We’llbe analyzing those Phase 2 through Phase 4 clinical trial data with
the new Infinium Multi-Ethnic Genotyping Array (MEGA), looking fordifferences in drug response across the populations. We’ll also look at
optimization of the subject profile, genotyping of the diseases in those
populations, and metaanalyses across different clinical trial phases.
Q: Do you think pharmacogenomics will change the way drug trials
are conducted?
MPD: I’m inspired by the success we had with dalcetrapib and with thepotential that pharmacogenomics is finally offering. Pharmacogenomics
relies on a combination of large clinical trial data and efficient genomicAugust 2017
approaches to identify variants and potential biomarkers. In the end,
patients and clinicians need to recognize the value and the potential ofpharmacogenomics information to improve health care. I think eventuallypeople will want drug response information included in their medical
records, so that attending physicians will know if they are allergic,
sensitive, or nonresponders to certain drugs. But the only way to identify
responders and nonresponders is through pharmacogenomic studies.
I’m hoping that increasing numbers of people will participate in studies
that support personalized medicine and precision management oftherapeutics. It might be a slow process, but there is finally real hopefor it to become a reality.

“We’ll be analyzing this Phase
2 through Phase 4 (dalcetrapib)
clinical trial data with the new
Infinium Multi-Ethnic Genotyping
Array (MEGA), looking fordifferences in drug response
across the populations.”
References1.

2.

Grainger D. Why Too Many Clinical Trials Fail – And A Simple Solution
That Could Increase Returns On Pharma R&D. Forbes. January 29, 2015.
www.forbes.com/sites/davidgrainger/2015/01/29/why-too-many-clinicaltrials-fail-and-a-simple-solution-that-could-increase-returns-on-pharmard/. Accessed July 8, 2015.
Tardif JC, Rhéaume E, Lemieux Perreault LP, et al. Pharmacogenomic
determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc
Genet. 2015;8(2):372–382.

Learn more about the Illumina products
mentioned in this article:••••

HumanOmni2.5Exome BeadChip, www.illumina.com/products/
humanomni25exome-8.html.
Infinitum Multi-Ethnic Genotyping Array (MEGA), www.genomeweb.
com/microarrays-multiplexing/illumina-collaborators-design-multiethnic-genotyping-array-empower-gwas
HumanOmni2.5 Beadchip, www.illumina.com/products/humanomni25-8_beadchip_kits.html.
HumanExome BeadChip, www.illumina.com/products/infinium_
humanexome_beadchip_kit.html.

For Research Use Only. Not for use in diagnostic procedures.

August 2017

Illumina • 1.800.809.4566 toll-free (US) • +1.858.202.4566 tel • techsupport@illumina.com • www.illumina.com
For Research Use Only. Not for use in diagnostic procedures.
© 2017 Illumina, Inc. All rights reserved. Illumina, Infinium, and the pumpkin orange color are trademarks of Illumina, Inc. and/or its affiliate(s)in the U.S. and/or other countries. Pub. No. 1070-2015-001 Current as of 12 May 2017