Helping Develop a Game-Changing New CF Therapy

The Road to Hope

A game-changing therapy for cystic fibrosis completes thejourney from the laboratory to the bedside with help fromSeattle Children’s.

Ben and Fred Winter

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 trialaren’t told whether the patient is in thestudy group or the control group untilall the data is collected and crunched.

Dr. Ron Gibson and Ben Winterdidn’t need to wait that long. They bothhad a strong suspicion soon after Benjoined a trial for the cystic fibrosis drugivacaftor. It was the only way to explainthe Idaho teen’s stunning improvement.

“You could see the benefits withina few weeks,” says Gibson, who leadsthe Cystic Fibrosis Center at SeattleChildren’s where Ben came to participatein the nationwide study. “The resultswere almost too good to be true.”

In less than three weeks, Ben’sconstant coughing all but vanished.He gained energy, put on weight andsmiled all day because he could finallykeep up with everybody else. A highschooljunior at the time, all he couldthink was, “This is sweet!”

A new pathway opens

Cystic Fibrosis Center

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, Benshowed rapid and lasting improvement,prompting the Food and DrugAdministration to quickly approve thenew medication under the brand nameKalydeco in January 2012. The drug isthe first therapy to treat the underlyingcause of the disease – heralding a newera in cystic fibrosis treatment.

Until Kalydeco, doctors could onlytreat the symptoms of cystic fibrosis (CF), a genetic disease that causesthick mucus to build up in the lungsand other parts of the body. The stickymucus makes it hard to breathe andis a breeding ground for bacteria thatcause chronic lung infections andprogressive lung damage. Fifty years ago, few people born with CF livedpast kindergarten.

Today, improved treatments doa better job of fighting the bacteria.Yet over time, the repeated infectionsstill cause fatal harm. The median lifeexpectancy for someone with cysticfibrosis is the late 30s, but many peoplestill die in their teens and 20s.

Until Kalydeco, doctors could only treatthe symptoms of cystic fibrosis. Now wecan treat the cause.

Kalydeco changes the game.Although the drug only works for the4% of CF patients who have the G551Dgenetic mutation, the science behind itopens new pathways that may lead to acure for all people with CF. The drug’sjourney to development – and howChildren’s contributed – illustrates howvision, commitment and collaborationmove research forward.

Venture philanthropy strategy

Ever since the gene that causes CFwas discovered more than 20 yearsago, hundreds of different mutationshave been identified. Each mutationresults in a unique defect in a proteinthat regulates the flow of salt andwater across the surface of cells. Thedefect causes salt and water to flowsluggishly and create the symptomsof cystic fibrosis.

Although the science was wellunderstood, pharmaceutical andbiotech companies were reluctant toinvest in research and developmentof new therapies because relativelyfew people have the disease (only30,000 people in the U.S.), making the potential market – and profitmargin – too slim to attract theirattention. Frustrated by privateindustry’s lack of interest, Dr. RobertBeall, leader of the Cystic FibrosisFoundation, decided to jump-startprogress with a visionary offer toattract private industry.

In the late 1990s, the CF Foundationdecided to act like a venture capitalfirm, supplying early-stage funding.Equally important, it would create aspecialized clinical trials network – anationwide group of sites that couldeffectively conduct CF drug studies.

“When we began looking forcompanies to get involved, it was crucialto have a network of sites trained andprepared to enroll patients in studies,”Beall says. “Nobody was going to getinvolved in developing new cysticfibrosis therapies without one.”

Beall’s venture philanthropy strategyhas sparked numerous collaborationswith private industry – including theone that led to Kalydeco. In return forfunding and access to a clinical trialsnetwork, Vertex Pharmaceuticalsscreened hundreds of thousands ofchemical compounds, identifiedpromising drugs, conducted trials andultimately produced a life-changingnew therapy.

Making a profound impact

Bonnie Ramsey

Dr. Bonnie Ramsey has
dedicated more than 30 years
to caring for CF patients
and working towardbetter
treatments and cures.
Thanks in large part to her
efforts, both the quality and
length of lifefor people with
CF has improved dramatically.

Beall chose Children’s Dr. BonnieRamsey to design and lead the clinicaltrials network in 1998. The CFFoundation has collaborated withRamsey and other Children’s doctorsto advance cystic fibrosis research andtreatment for decades. Support fromthe CF Foundation helped Ramsey andcolleague Dr. Arnold Smith develop thebreakthrough therapy TOBI, an inhalableform of the antibiotic tobramycin thatis now a standard treatment for lunginfections in patients with CF.

“Nobody has had a more profound impact on improvingcare for cystic fibrosis patients than Bonnie Ramsey.”

Dr. Robert Beall, president and CEO, Cystic Fibrosis Foundation

“Nobody has had a more profoundimpact on improving care for cysticfibrosis patients than Bonnie Ramsey,”says Beall. “She and Seattle Children’shave a long commitment to excellencein cystic fibrosis drug research anddevelopment. Bonnie was the naturalchoice to develop the clinical trialsnetwork.”

Ramsey also led the pivotal phase 3clinical trial for Kalydeco – the finalstudy before the FDA approvedthe drug for use in patients 12 andolder. A separate study led to approvalfor patients ages 6 to 12.

Children’s: a go-to resource

Jill Van Dalfsen

Nearly every research study
involving CF istouched by
the Cystic Fibrosis Therapeutics
Development Network at some
level, says JillVan Dalfsen,
who runs the network’s
day-to-day operations.

Children’s runs the 40-personcoordinating center for the clinical trialsnetwork. Officially known as the Cystic Fibrosis Therapeutics Development Network (CFTDN), the network hasgrown from seven sites in 1999 to 77sites today and remains the go-toresource for all CF research. “Nearlyevery study involving cystic fibrosiscomes through the coordinating centerat some level,” says Jill Van Dalfsen,who leads the center’s day-to-dayoperations.

In some cases, the coordinatingcenter manages trials. In others, itconsults with study sponsors to designprocedures, develop outcome measuresand search the network’s patientregistry for clinical sites with eligibletrial candidates.

The CFTDN grew dramatically in thelast five years as Kalydeco and otherpotential therapies reached advancedstages of development, requiring moreand more study participants. “No singlesite can enroll more than a handfulof patients because CF is such a raredisease and the study criteria arevery selective,” says Van Dalfsen. Ben,for example, was the only participantin Kalydeco’s phase 3 trial enrolledat Children’s. The University ofWashington trial site enrolled fourpeople under the leadership ofDr. Moira Aitken.

The coordinating center and Ramseyconsulted with the CF Foundation andVertex to design the procedures for theivacaftor studies and identify suitablestudy sites and patients. “We alreadyhave the infrastructure in place so wecan help move research forward muchfaster than if a study team works ontheir own,” Van Dalfsen says.

The next step

Bonnie Ramsey ship

Dr. Bonnie Ramsey received
an unusual honor this summer:
a huge petroleum barge was
christenedwith her name. “All
of the strides they’ve made in
cystic fibrosis because of her
commitment anddedication is
very inspirational to us. She
gives hope to families,” says
Harley Franco, of HarleyMarine
Services, Inc., the company
that owns the barge.

Kalydeco is now being tested aloneand in combination with other potentialdrugs to treat additional CF mutations – including the Delta F508 mutationthat is found in nearly 90% of all cysticfibrosis patients in the U.S. Final studyresults are expected this summer.In addition, Children’s physicianDr. Margaret Rosenfeld is studyingwhether a liquid version of Kalydecois safe in children ages 2 to 5 with theG551D mutation.

“I never thought we’d make this muchprogress in my lifetime.”

Dr. Bonnie Ramsey

By revealing a pathway to treat thecause of cystic fibrosis, Kalydeco isa rewarding turning point in the longand challenging fight against CF. “The day Vertex came to Children’sto announce the final study data tothe clinical trials network, people whoworked on the trials had tears in theireyes,” recalls Beall.

No one was more gratified thanRamsey. “I never thought we’d makethis much progress in my lifetime,”she says.