advantages genetics could bring to clinical development and decision-making, as
well as the next steps needed to make it a valid tool in this environment, were
underscored in the recent findings of two studies performed by distinct research
groups at Harvard Medical School. The studies analyzed tumor samples from lung
cancer patients who had taken Iressa (gefitinib), a small-molecule targeted cancer
therapy developed by AstraZeneca.
Iressa was approved in the United States in 2003 as a third-line treatment
for lung cancer, based on a Phase II study in which 10% of participants had a
substantial tumor shrinkage response. But in Phase III randomized trials, the
drug caused no survival improvement when added to conventional chemotherapy. So
in a minority of patients, Iressa has a dramatic effect, but in many other cases
its effect is much less or none. Determining when the drug might be the right
one to use has been a difficult task for physicians.
The papers, published in the May issues of Science (2004, 304,
14971500) and The New England Journal of Medicine (2004, 350,
21292139), reported a strong correlation between certain gene mutations
discovered in the kinase domain of Iressas target, the epidermal growth
factor receptor (EGFR), and patient response. The Science study also identified
a cell line, with one of the EGFR gene mutations found in patients, that showed
a dramatic in vitro response to Iressa compared with cell lines without the mutation.
In our study, all of the patients with responses had mutations, and all
of the patients that progressed did not, says William Sellers, assistant
professor of medicine at the Dana-Farber Cancer Institute and one of the lead
authors of the Science paper. On the basis of the results, he is confident
that prescribing Iressa, even as a first-line treatment, is now a much more predictable
In my mind, there is no doubt that if someone has the mutation, they
deserve treatment with Iressa, he says. If I had the mutation, I would
take Iressa alone.
But if you were the FDA, you probably would like to do a clinical trial,
However, the pharmaceutical industry is uncertain about the prospects of performing
trials in which analyzing safety or efficacy is put in the context of genetic
or genomic subgroups or in which patients are initially stratified on the basis
of genetic data. The industry may be even more unsure about the outlook for making
the resulting data available to regulatory agencies and the public.
Despite the enthusiasm researchers have for advancing biomedical technology
and exploring the human genome, there is little willingness to incorporate pharmacogenomics
into clinical trials, says William Evans, St. Jude Childrens Re search
Hospital scientific director.
But signs are emerging that the opportunity for integrating pharmacogenomics,
the science of linking genetic determinants to drug response, into the clinic
The future is arriving, asserts Christopher Webster, director of
regulatory strategy and intelligence at Millennium Pharmaceuticals, a company
founded on the concepts of personalized medicine and pharmacogenomics.
He points to drugs like Genentechs Herceptin (trastuzumab) and ImClone
Systems Erbitux (cetuximab), two monoclonal antibody cancer therapies with
associated FDA-approved tests to measure protein receptor levels predictive of
patient response. Although these tests are immunohistochemical protein assays
and not genetic measurements, they carve out a pathway for the co-development
and co-approval of drug products and assays, an essential aspect of pharmacogenomics-based
By many accounts, overcoming the challenge of carrying out well-designed pharmacogenomics-based
clinical trials and using the information to drive drug development and approval
are at the heart of making personalized medicine a reality.
|Recent studies suggest which patients might
benefit best when taking the anticancer drug Iressa.
Two big reasons industry has been wary of moving ahead too quickly with pharmacogenomics
drug development, says Kurt Jarnagin, vice president of biological sciences and
chemical genomics at Iconix Pharmaceuticals, is regulatory uncertainty and
legal product liability. Essentially, he says, companies are worried about
what the FDA or a trial lawyer might dig out of the data to use against the drug.
This reflects an unknown factor still associated with genomic information.
Whereas the legal issue remains more of a question mark, targeted discussions
ongoing between the FDA and industry since early 2002 have done a lot to flesh
out the regulatory uncertainties.
One product of these interactions is the soon-to-be-released final FDA guidance
document for submitting pharmacogenomics data. A draft version was published in
November 2003. One section of the guidance addresses contexts in which genomics
data, preclinical or clinical, might be required for regulatory review, such as
when assessment of safety, efficacy, or dose in a submitted drug application is
contingent on genetic marker information.
Another component focuses on the types of submissions expected in the nearer
term, that is, voluntarily submitted exploratory pharmacogenomics data not slated
for regulatory decision-making. The voluntary submission concept, Webster says,
came out of calls by industry for a safe harbor, letting companies
submit the data with less concern that it will be put to unintended use and allowing
the agency to get more comfortable working with and analyzing pharmacogenomic
Following the release of the first draft of the guidance in November 2003,
many pharmaceutical and biotechnology companies submitted comments to the FDA
regarding the voluntary submission process and the procedure for validating exploratory
biomarkers. But how forthcoming the firms will be with genomics data still remains
to be seen.
Wyeth has already submitted voluntary genomic data to the FDA, but it was related
to an Alzheimers disease vaccine program that was previously discontinued.
Millennium, Webster says, plans on making a voluntary submission regarding one
of its drugs in development later this year.
Voluntary submissions will provide a mechanism for validating genomic biomarkers
as predictive tools in particular disease contexts. The FDA plans to establish
an Interdisciplinary Pharmacogenomics Review Group to review the voluntary submissions
in relation to each other. And a pharmacogenomics advisory subcommittee will be
formed to assess the aggregate data and determine when a correlation between clinical
outcomes and a genomic marker is convincing enough to drive clinical and regulatory
This will not be a straightforward task, according to several at the helms
of leading clinical research institutions.
In a recent review paper in Nature (2004, 429, 464468),
Evans and St. Jude Hospital colleague Mary Relling, chair of pharmaceutical sciences,
point out some of the challenges of conducting definitive clinical pharmacogenomic
studies. These include the complexity of multiple genes influencing patient response
to a drug or interference in assessing genetic subgroups from nongenetic confounders
like drug interactions, diet, and smoking.
|Mutations in various positions, colored
red, of the epidermal growth factor receptor that were associated with patient
response to Iressa. The L858R missense mutation was also detected in a cell line
that was particularly sensitive to the drug. (Adapted with permission from Paez,
J. G.; et al. Science 2004, 304, 14971500. Copyright
Robert Califf, director of the Duke Clinical Research Institute, noted at an
FDA Science Board meeting in April that the prospect of multivariable genomics
(and burgeoning proteomics) will generate an enormous mathematical problem
in getting meaningful results from clinical trials. He cited replicated clinical
trials that showed a correlation between astrological sign and clinical benefit
from aspirin. This subgroup problem is magnified now that we can measure
multiple biomarkers, he said.
There is not a company on the face of the earth that can do enough experiments
to find out what the array of biomarkers is that predicts a beneficial treatment
over time, or even toxicity, Califf warned.
Both Evans and Relling, as well as Califf, suggest there is a need for large-scale
trials with adequate follow-up, carried out in partnerships between public and
Despite the uphill battle, several companies are clearly taking on the challenge
of incorporating pharmacogenomics into their clinical development programs.
Many firms, for example, are screening for various mutations in CYP450 drug
metabolism enzyme genes such as CYP2D6. This is one of a few genetic classes
that have consensus as validated biomarkers for predicting whether a patient will
have safety or efficacy issues based on over- or undermetabolism of a drug. Roche
Diagnostics November 2003 diagnostic device application submission to the
FDA for its Amplichip CYP450 microarray only signals further efforts in this direction.
Industry is also beginning to broaden its clinical genomics focus.
At a conference entitled Safety Biomarkers that took place in Washington,
DC, in May, Daniel Burns, vice president of discovery genetics at GlaxoSmithKline,
discussed several completed or ongoing GSK clinical trials that involved matching
particular single nucleotide polymorphisms (SNPs) to drug toxicity responses.
One program is for the already marketed HIV drug Ziagen (abacavir). According
to Burns, by using microarray technology to screen large swaths of the genome
of clinical trial participants, GSK has identified SNP markers for abacavir sensitivity,
a side effect that, in situations in which the patient is taken off the drug and
then restarted on it, can be fatal.
Another major pharmaceutical company showing signs of incorporating the pharmacogenomics
model into clinical trials is Pfizer. The company signed an agreement in January
with Perlegen Sciencesa 2000 spin-off of Affymetrix founded to use high-affinity
microarrays to screen clinical trial participants for genetic variationto
find SNPs associated with response to drugs for major depression disorder. Perlegen
also has similar alliances in other disease areas with Pfizer, AstraZeneca, Eli
Lilly, GSK, and Bristol-Myers Squibb.
Like Perlegen, Genaissance Pharmaceuticals is focused on providing services
that allow partner companies to put pharmacogenomics to use in clinical studies
through its HAP technology, which includes a large database of genetic
variation and associated informatics tools.
But Genaissance is also conducting its own clinical trials with the pharmacogenomics
concept at their core. These include the STRENGTH (Statin Response Examined by
Ge netic HAP Markers) study, which was conducted at 65 sites in the United
States to find response markers to the statin class of cholesterol-lowering drugs;
and the CARING (Clozapine and Agranulocytosis Relationships Investigated by Genetics)
trial, designed to determine patients most likely to develop a life-threatening
side effect from the off-patent schizophrenia drug clozapine. Initial results
of the STRENGTH study indicating a specific variant of a gene that controls LDLcholesterol
response to statins were announced in March 2003. The work has attracted major
statin producers, including Bayer and AstraZeneca, wanting to access the companys
By and large, these and other clinical efforts are focused on finding one or
several specific genetic variations associated with drug response. The even more
statistically taxing effort of correlating global gene expression signatures with
response, however, is still predominantly relegated to drug discovery and preclinical
activities. But companies like Iconix, Jarnagin says, which has developed a large
chemogenomics database linking expression data with drug response, are working
to build bridges between this data and improved clinical diagnostics
Back to Iressa
But what about the simpler case of Iressa? The recent Harvard results suggest
a potentially straightforward path relying on a single mutation for predicting
drug response. And the prospects for confirming the results in a clinical trial
are good, Sellers believes. A quick first step, he says, is to go back and analyze
tumor samples from the already completed randomized Phase III trial. One
could very readily ask, by retrospectively analyzing tumors, whether there was
a benefit in the trial to patients with mutations.
|Millenniums Webster, sitting before
a genomic heat map, expressed his confidence in the promise of pharmacogenomics.
This is essentially what AstraZeneca is pursuing now, although the analysis
is not so clear-cut, says company spokeswoman Mary Lynn Carver. Based on
the patients who have received Iressa to date, we dont know enough about
what type of correlation we have, she explains. It looks like we have
a very strong correlation in the dramatic responders. But in one of those trials
[the NEJM study], you had a dramatic responder that did not have a mutation. So
you still have some mysteries. Is there more than one mutation we need to be looking
Carver also points out the approximately 30% of patients in the original Phase
II trial who didnt have dramatic tumor reductions but did maintain stable
disease without substantial progres sion. We dont know if those patients
have the same muta tion, a similar mutation, or anything in common with one another,
AstraZeneca is currently in discussion with both outside and in-house researchers,
Carver stresses, but the company is not ready to say for sure whether this finding
will lead to new trials or discussions with the FDA about new marketing strategies.
|Jarnagin, from Iconix Pharmaceuticals, says
companies are concerned about regulatory uncertainty and legal product liability
when submitting genomic data to the FDA.
Another important factor in a companys decision whether to pursue pharmacogenomics
in later-stage development is the commonly cited concern that identifying a specific
responder group might be bad for business if it limits the drugs market
to only that group. Right after the Iressa results were announced, some analysts
predicted a significant drop in the drugs market size. Whether this consideration
will play a role in AstraZenecas actions on Iressa or in the actions of
Genentech, which, along with OSI Pharmaceuticals and Roche, has completed Phase
III trials, which showed positive results, on another EGFR inhibitor for lung
cancer called Tarceva (erlotinib HCl), remains to be seen.
Often, Millenniums Webster says, the pharmacogenomics isnt going
to be as simple as black and white. You can have a situation where a drug
might bring some benefit to people who dont have the marker but would perhaps
bring much more benefit to people who do have the marker. Therefore, the
economic affects of pursuing this line of research arent necessarily predictable.
(Although, according to IBM Healthcare and Life Sciences Carol Kovac, pursuing
it is the only sustainable option for companies; see Closing
the loop on information, 55 KB PDF.)
Generally, Webster believes pharmacogenomics will not be a downer for drugs
market share. There will still be blockbusters that gross in excess of a
billion dollars, he believes. There will be shifts in the marketplace
and shifts in clinical use, but there will still be blockbusters.
If patients know that they have a much higher likelihood of therapeutic
success with a genomically prescribed drug, they will tend to shift in that direction.