The Road to Hope
A game-changing therapy for cystic fibrosis completes the
journey from the laboratory to the bedside with help from
Seattle Children’s.
Ben Winter, with his dad Fred Winter, traveled from Idaho several times a year to participate in the clinical trial studying Kalydeco, the first medicine to address the cause of cystic fibrosis rather than the symptoms. Ben’s health improved dramatically within just three weeks of starting the new drug.
Doctors and patients in a drug trial
aren’t told whether the patient is in the
study group or the control group until
all the data is collected and crunched.
Dr. Ron Gibson and Ben Winter
didn’t need to wait that long. They both
had a strong suspicion soon after Ben
joined a trial for the cystic fibrosis drug
ivacaftor. It was the only way to explain
the Idaho teen’s stunning improvement.
“You could see the benefits within
a few weeks,” says Gibson, who leads
the Cystic Fibrosis Center at Seattle
Children’s where Ben came to participate
in the nationwide study. “The results
were almost too good to be true.”
In less than three weeks, Ben’s
constant coughing all but vanished.
He gained energy, put on weight and
smiled all day because he could finally
keep up with everybody else. A highschool
junior at the time, all he could
think was, “This is sweet!”
A new pathway opens
Dr. Ron Gibson, left, leads the Cystic Fibrosis Center at Seattle Children’s. Alan Genatossio, RN,
and Sharon McNamara, MN, provide hands-on care for many of the patients who participate in
the CF studies.
Like many patients in the study, Ben
showed rapid and lasting improvement,
prompting the Food and Drug
Administration to quickly approve the
new medication under the brand name
Kalydeco in January 2012. The drug is
the first therapy to treat the underlying
cause of the disease – heralding a new
era in cystic fibrosis treatment.
Until Kalydeco, doctors could only
treat the symptoms of cystic fibrosis
(CF), a genetic disease that causes
thick mucus to build up in the lungs
and other parts of the body. The sticky
mucus makes it hard to breathe and
is a breeding ground for bacteria that
cause chronic lung infections and
progressive lung damage. Fifty years ago, few people born with CF lived
past kindergarten.
Today, improved treatments do
a better job of fighting the bacteria.
Yet over time, the repeated infections
still cause fatal harm. The median life
expectancy for someone with cystic
fibrosis is the late 30s, but many people
still die in their teens and 20s.
Until Kalydeco, doctors could only treat
the symptoms of cystic fibrosis. Now we
can treat the cause.
Kalydeco changes the game.
Although the drug only works for the
4% of CF patients who have the G551D
genetic mutation, the science behind it
opens new pathways that may lead to a
cure for all people with CF. The drug’s
journey to development – and how
Children’s contributed – illustrates how
vision, commitment and collaboration
move research forward.
Venture philanthropy strategy
Ever since the gene that causes CF
was discovered more than 20 years
ago, hundreds of different mutations
have been identified. Each mutation
results in a unique defect in a protein
that regulates the flow of salt and
water across the surface of cells. The
defect causes salt and water to flow
sluggishly and create the symptoms
of cystic fibrosis.
Although the science was well
understood, pharmaceutical and
biotech companies were reluctant to
invest in research and development
of new therapies because relatively
few people have the disease (only
30,000 people in the U.S.), making the potential market – and profit
margin – too slim to attract their
attention. Frustrated by private
industry’s lack of interest, Dr. Robert
Beall, leader of the Cystic Fibrosis
Foundation, decided to jump-start
progress with a visionary offer to
attract private industry.
In the late 1990s, the CF Foundation
decided to act like a venture capital
firm, supplying early-stage funding.
Equally important, it would create a
specialized clinical trials network – a
nationwide group of sites that could
effectively conduct CF drug studies.
“When we began looking for
companies to get involved, it was crucial
to have a network of sites trained and
prepared to enroll patients in studies,”
Beall says. “Nobody was going to get
involved in developing new cystic
fibrosis therapies without one.”
Beall’s venture philanthropy strategy
has sparked numerous collaborations
with private industry – including the
one that led to Kalydeco. In return for
funding and access to a clinical trials
network, Vertex Pharmaceuticals
screened hundreds of thousands of
chemical compounds, identified
promising drugs, conducted trials and
ultimately produced a life-changing
new therapy.
Making a profound impact
Dr. Bonnie Ramsey has dedicated more than 30 years to caring for CF patients and working toward
better treatments and cures. Thanks in large part to her efforts, both the quality and length of life
for people with CF has improved dramatically.
Beall chose Children’s Dr. BonnieRamsey to design and lead the clinical
trials network in 1998. The CF
Foundation has collaborated with
Ramsey and other Children’s doctors
to advance cystic fibrosis research and
treatment for decades. Support from
the CF Foundation helped Ramsey and
colleague Dr. Arnold Smith develop the
breakthrough therapy TOBI, an inhalable
form of the antibiotic tobramycin that
is now a standard treatment for lung
infections in patients with CF.
“Nobody has had a more profound impact on improving
care for cystic fibrosis patients than Bonnie Ramsey.”
Dr. Robert Beall, president and CEO, Cystic Fibrosis Foundation
“Nobody has had a more profound
impact on improving care for cystic
fibrosis patients than Bonnie Ramsey,”
says Beall. “She and Seattle Children’s
have a long commitment to excellence
in cystic fibrosis drug research and
development. Bonnie was the natural
choice to develop the clinical trials
network.”
Ramsey also led the pivotal phase 3
clinical trial for Kalydeco – the final
study before the FDA approved
the drug for use in patients 12 and
older. A separate study led to approval
for patients ages 6 to 12.
Children’s: a go-to resource
Nearly every research study involving CF is
touched by the Cystic Fibrosis Therapeutics
Development Network at some level, says Jill
Van Dalfsen, who runs the network’s day-to-day
operations.
Children’s runs the 40-person
coordinating center for the clinical trials
network. Officially known as the Cystic Fibrosis Therapeutics Development Network (CFTDN), the network has
grown from seven sites in 1999 to 77
sites today and remains the go-to
resource for all CF research. “Nearly
every study involving cystic fibrosis
comes through the coordinating center
at some level,” says Jill Van Dalfsen,
who leads the center’s day-to-day
operations.
In some cases, the coordinating
center manages trials. In others, it
consults with study sponsors to design
procedures, develop outcome measures
and search the network’s patient
registry for clinical sites with eligible
trial candidates.
The CFTDN grew dramatically in the
last five years as Kalydeco and other
potential therapies reached advanced
stages of development, requiring more
and more study participants. “No single
site can enroll more than a handful
of patients because CF is such a rare
disease and the study criteria are
very selective,” says Van Dalfsen. Ben,
for example, was the only participant
in Kalydeco’s phase 3 trial enrolled
at Children’s. The University of
Washington trial site enrolled four
people under the leadership of
Dr. Moira Aitken.
The coordinating center and Ramsey
consulted with the CF Foundation and
Vertex to design the procedures for the
ivacaftor studies and identify suitable
study sites and patients. “We already
have the infrastructure in place so we
can help move research forward much
faster than if a study team works on
their own,” Van Dalfsen says.
The next step
Dr. Bonnie Ramsey received an unusual honor this summer: a huge petroleum barge was christened
with her name. “All of the strides they’ve made in cystic fibrosis because of her commitment and
dedication is very inspirational to us. She gives hope to families,” says Harley Franco, of Harley
Marine Services, Inc., the company that owns the barge.
Kalydeco is now being tested alone
and in combination with other potential
drugs to treat additional CF mutations – including the Delta F508 mutation
that is found in nearly 90% of all cystic
fibrosis patients in the U.S. Final study
results are expected this summer.
In addition, Children’s physician
Dr. Margaret Rosenfeld is studying
whether a liquid version of Kalydeco
is safe in children ages 2 to 5 with the
G551D mutation.
“I never thought we’d make this much
progress in my lifetime.”
Dr. Bonnie Ramsey
By revealing a pathway to treat the
cause of cystic fibrosis, Kalydeco is
a rewarding turning point in the long
and challenging fight against CF.
“The day Vertex came to Children’s
to announce the final study data to
the clinical trials network, people who
worked on the trials had tears in their
eyes,” recalls Beall.
No one was more gratified than
Ramsey. “I never thought we’d make
this much progress in my lifetime,”
she says.