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Helping Develop a Game-Changing New CF Therapy

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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 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 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

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, 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

Bonnie Ramsey

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

Jill Van Dalfsen

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

Bonnie Ramsey ship

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.

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