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The efforts will help researchers identify rare genetic mutations by
scanning large databases of volunteers who agree to have their DNA
sequenced and to provide access to detailed medical records.
It is made possible by the dramatically lower cost of genetic
sequencing - it took government-funded scientists $3 billion and 13
years to sequence the first human genome by 2003. As of last year,
the cost was closer to $1,500 per genome, down from $20,000 five
years ago.
Regeneron Pharmaceuticals Inc, which signed a deal with
Pennsylvania’s Geisinger Health System in January 2014 to sequence
partial genomes of some 250,000 volunteers, is already claiming
discoveries based on the new approach. Company executives told
Reuters they have used data from the first 35,000 volunteers to
confirm the promise of 250 genes on a list of targets for drugs
aimed at common medical conditions, including high levels of
cholesterol and triglycerides.
Regeneron says it has also identified "several dozen" new gene
targets, including a novel gene that plays a role in obesity.
Pfizer Inc, Roche Holding AG and Biogen Inc are working on similar
projects that use DNA and patient health data to find new drug
targets or predict the effects of drugs.
Their investments have been inspired by early successes in cancer
with drugs such as Pfizer's lung cancer treatment Xalkori, which was
approved in 2011 and targets mutations in tumors driving the
disease. More recently, Vertex Pharmaceuticals has changed the
treatment of cystic fibrosis with Kalydeco, which targets the
disease’s underlying genetic cause.
"All of a sudden, it all opened up," as companies recognize the
potential for drugs targeting genetic glitches, Dr. Eric Topol, a
genomics expert at the Scripps Translational Science Institute.
"It's starting to really become a new preferred model for drug
development."
In the past, discovering such genes was a painstaking process, often
involving years of research into isolated populations. In 1991, for
example, researchers discovered a rare mutation in a gene called
Angptl3 that caused very low levels of artery-clogging cholesterol
and triglycerides among families in the remote Italian village of
Campodimele.
It took nearly two more decades and several groups of scientists to
fully understand the potential cardiovascular benefits linked to
mutations in that gene.
Since last autumn, the Regeneron Genetics Center has sequenced the
DNA of more than 35,000 Geisinger patients and is on track to
sequence 100,000 by year end. Already, the company has identified
100 people carrying similar cholesterol-affecting mutations to those
first observed in Campodimele and elsewhere.
“You no longer have to find that one rare family in Italy, because
it's just in the database," said Dr. George Yancopoulos, chief
scientific officer of Regeneron.
PRECISION MEDICINE
Identifying target genes is just a first step, though, and does not
guarantee that a drug can be developed on a genetic lead, or that it
will ultimately be safe and effective enough to be used.
Experts also differ on approach. Regeneron is sequencing exomes, the
protein-making genes that comprise 1 to 2 percent of the genome, a
search that costs roughly $700 per person. Others favor looking at
the whole genome, which costs the $1,500 per person.
Craig Venter, one of the first scientists to sequence the human
genome, believes the whole genome approach will be more meaningful
over time.
"I'd rather have a gold mine with a deep vein of gold and modern
industrial equipment to mine it rather than sitting there with a pan
in a stream looking for gold," he said. "Both will find gold. It's a
question of how much you find."
Even so, the early returns from new "genomic" medicines have
attracted attention from the White House. In January, President
Barack Obama said he would seek $130 million from Congress to gather
genetic data from 1 million volunteers as part of a “precision
medicine” initiative.
Regeneron is lobbying for the Geisinger database to become a
cornerstone of that effort, and proposes creating a consortium of
drugmakers to fund it. In return, Yancopoulos said, the company
hopes to recoup some of its investment.
Dr. Francis Collins, director of the National Institutes of Health,
which is in charge of the precision medicine project, identified
Regeneron among a short list of potential contributors to the 1
million-strong DNA study. Others on the list include Kaiser
Permanente, Mayo Clinic, and the Marshfield Clinic in Wisconsin. A
decision is expected by early fall.
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For drug companies, the lure of a big payoff is strong. Regeneron
and its partner Sanofi are expected to soon win regulatory approval
for a cholesterol-lowering drug that works by blocking the PCSK9
gene. Amgen and Pfizer have developed similar treatments.
Individuals born with non-functioning versions of PCSK9 have very
low cholesterol. The new drugs mimic that effect and are considered
a poster child for treatments that take advantage of glitches in the
genome that prove beneficial to the rare individuals who carry them.
Wall Street analysts project Regeneron/Sanofi's PCSK9 drug will
generate revenues of $4.4 billion by 2019.
MINING THE DATA
Amgen bolstered its search for gene targets by buying Decode
Genetics in late 2012 for $415 million, giving it a database of
complete genetic sequences of 2,636 Icelanders. The community shares
a relatively homogenous genetic profile due to its geographic
isolation, allowing researchers to identify gene variations more
easily.
In March, Amgen reported the discovery of a new mutation that
increases the risk of Alzheimer's and confirmed the role of two
mutations involved in diabetes and atrial fibrillation.
This past January, Roche's Genentech unit tapped Venter's Human
Longevity Inc for a large sequencing project.
Genetic testing company 23andMe announced deals this year with
Genentech and Pfizer. Genentech will have access to 3,000
individuals in 23andMe's community of Parkinson's patients, and
Pfizer will expand an existing collaboration with the company to
study the genetics of lupus.
That same month, Biogen formed a $30 million research alliance to
support the formation of a sequencing center at Columbia University.
"All of the companies are feeling like, 'Oh my gosh. We have to do
something substantial in genomics – yesterday,'" said Dr. David
Goldstein, director of Columbia's Institute for Genomic Medicine.
At the heart of Regeneron’s model is finding rare mutations that
disable normal gene function. So far, it has identified people with
at least one such “loss-of-function” gene that correlates with
nearly all 250 genes on the company's list of drug targets.
That includes essentially every gene previously linked to
triglyceride regulation and several novel candidates, Yancopoulos
said. They have done the same for cholesterol and coronary artery
disease.
Regeneron has also partnered with academic centers studying families
with extreme genetic disorders, collaborations that already have led
to the discovery of a couple of dozen new candidate genes, said Dr.
Aris Baras, who runs Regeneron’s genetics center.
In one case, they are using the Geisinger database to study a rare
gene they believe causes severe obesity in young children. The team
has found milder mutations in the overall population that may cause
an average 10-pound weight gain in adults. That would validate the
role that such genes play in regulating body weight and suggests
that, "if you had a drug it could have a profound effect,"
Yancopoulos said.
"This is why everybody is excited about it," he said.
(Reporting by Julie Steenhuysen; Editing by Michele Gershberg, Sue
Horton and Martin Howell)
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