2012 Research Annual Report

Just the Beginning

Just the Beginning: Breakthrough Drug for Cystic Fibrosis

Cincinnati Children’s plays an important role in studying combination therapies that could benefit up to 90 percent of CF patients

Breakthrough CF Research Comes To Cincinnati A significant portion of the early research for VX-770 was led by John P. Clancy, MD, who joined Cincinnati Children’s in January 2011 as Research Director, Division of Pulmonary Medicine, and directs CF-related clinical and translational research. Clancy studied CF for 17 years at the University of Alabama-Birmingham. He is part of a novel network of academic and industry investigators who have been collaborating for years to develop CF treatments. “For the right patients, VX-770 is truly a monumental leap. It’s a first-in-class drug, the first therapy that targets the underlying cause of CF,” Clancy says. Here, Clancy leads efforts to build upon Kalydeco’s success. He is involved with tracking the long-term effects of the drug. He also plays important roles in Phase 2 clinical trials to evaluate whether VX-770 in combination with other compounds — VX-809 and VX-661 — can benefit a wider range of CF patients.

When Angela Riddell was growing up, few could tell she had been born with the inherited disease cystic fibrosis (CF).

She was active and mostly healthy, swimming and playing softball in rural Preble County, Ohio. Yet all the while the thick, sticky mucus caused by the disease was taking a toll on her body.

By her early 20s, Riddell’s lung capacity began dropping, eventually falling to 48 percent of normal. Twice a year, sometimes three times, she was hospitalized to battle lung infections, intestinal blockages and pancreatitis. She had lost so much appetite that she often ate only one meal a day.

“It was hard just to get off the couch. I was taking two or three naps a day. I didn’t even want to go outside,” she says.

Now 34, Riddell feels better than she has in years. Her lung capacity has bounced back to 70 percent and she hasn’t needed a hospital stay in more than 18 months.

She owes her remarkable turn-around to participating in a clinical trial of VX-770 — now called Kalydeco. Approved by the FDA just last January, it is the first drug that attacks the underlying causes of CF rather than controlling its downstream symptoms.

Combined Therapy to Help More Patients

Cystic fibrosis affects about 30,000 people in the United States. The disease obstructs the pancreas and prevents the digestive system from absorbing food. It also causes thick, sticky mucus to build up in the lungs, which can lead to life-threatening infections.

All these symptoms occur because people with CF produce defective versions of CFTR, a critical protein needed to form chloride channels that allow salt and fluids to flow correctly through cells.

Kalydeco helps restore this process, but only for patients with the G551D mutation in CFTR, a group that comprises about 4 percent of all CF patients.

Angela Riddell says Kalydeco treatment restored lung capacity so that she can now enjoy time with her daughter, Macy.

Adopting ‘Orphan’ Diseases The development of VX-770 is one result of an unusual “venture philanthropy” arrangement between the drug maker, Vertex Pharmaceuticals, and the Cystic Fibrosis Foundation. The foundation provided key funding to explore a massive library of small-molecule compounds to find the few compounds most likely to affect disrupted CF protein functions. The work involved large amounts of expensive, high-throughput screening analysis. Without such funding, pharmaceutical companies are often reluctant to invest in the basic research needed to attack “orphan” diseases, a large group of diseases that each affect fewer than 200,000 people. Many pediatric diseases fall into the orphan disease category. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development,” FDA Commissioner Margaret Hamburg, MD, said in a press release issued after the drug was approved.

People in this group produce a CFTR protein that fails to open correctly, limiting chloride transport after they reach the cell membrane.

“We believe VX-770 binds to these CFTR proteins and helps open them so that chloride transport is restored,” Clancy says.

However, nearly 90 percent of CF patients have a different mutation — Delta F508. These people produce a misfolded CFTR protein that gets destroyed before it ever reaches the cell membrane.

Previous studies have shown that the VX-809 and VX-661 compounds can help the Delta F508 mutation work better in patients. Yet by themselves, these compounds may not be enough to impact CF symptoms.

Researchers believe that a combined approach can boost the effect. The idea: use VX-809 or VX-661 to help more delta F508 CFTR protein reach the cell membrane, then use VX-770 to help increase its activity and chloride transport.

If successful, this combination therapy would benefit nearly all people with CF, Clancy says.

A Chance to Reach Retirement Age

Clancy says VX-770 represents a potential quantum leap in CF treatment.

“This drug may add decades to life expectancy,” Clancy says. “Living to reach retirement age becomes a real possibility. That hasn’t been the case for most CF patients.”

Angela Riddell says she feels incredibly fortunate that she was part of the VX-770 clinical trial.

“I didn’t think I’d make it to my daughter’s graduation. Now I might be able to see her get married and have children,” she says.