Personalized medicine comes to cystic fibrosis

Ivacaftor targets G551D mutation with success

A phase III study of an experimental, targeted cystic fibrosis (CF) treatment shows sustained lung function improvement for patients with CF with a certain mutation, according to a report published in November in the New England Journal of Medicine [Ramsey et al., 2011].

The experimental drug ivacaftor, also known as VX-770, is the first personalized treatment for CF. It targets an underlying genetic cause of CF, the G551D-CFTR mutation, not just its symptoms. About 4–5% of patients with CF have at least one such mutation.

Ivacaftor produced substantial lung function improvement in patients with CF age 12 and older after two weeks. It sustained this improvement through the 48 weeks of the study. Ivacaftor produced a 10.6 percentage point improvement in forced expiratory volume in one second (FEV1) over placebo at 24 weeks, reported by Bonnie Ramsey, MD, Director of the Center for Clinical and Translational Research at Seattle Children's Research Institute, and colleagues [Ramsey et al., 2011].

“This research is truly a paradigm for promise we have all anticipated with sequencing of the human genome and the advent of an era of personalized medicine,” Dr. Ramsey says. “It is a very important first step and like all 'breakthroughs' in medicine it brings excitement but also more challenges as we need to find equally efficacious therapies for the remaining 95% of patients with CR”

Dawn Kalmar, a spokesperson for Vertex Pharmaceuticals, said the company is seeking Food and Drug Administration approval of the drug, which it plans to market as Kalydeco.

Ivacaftor Gets Good Results

In the double-blind, placebo-controlled trial, researchers randomly assigned 84 patients to receive 150 mg of ivacaftor every 12 hours and 83 to receive a placebo for 48 weeks.

The patients who received ivacaftor were 55% less likely to have a pulmonary exacerbation than were placebo patients. The patients on ivacaftor also scored 8.6 points higher than did placebo subjects on a questionnaire about how CF symptoms affect quality of life.

Ivacaftor patients also gained an average of 2.7 kg more weight than placebo patients. Sweat chloride concentration, a measure of CFTR activity, was 48.1 moll per liter less for ivacaftor patients than their placebo counterparts. The groups had similar incidences of adverse effects, but ivacaftor patients suffered fewer serious ones, 24% versus 42% for placebo patients.

Unanswered Questions

In an editorial accompanying the paper, Pamela B. Davis, MD, PhD, of Case Western Reserve School of Medicine points to key questions about ivacaftor. Chief among these is whether the drug is safe for infants and children or for long-term use. She noted that other unknowns include whether the drug activates other CFTR alleles that reach the cell surface and if ivacaftor is effective after permanent structural damage to airways [Davis, 2011].

According to Kalmar, Vertex is conducting an open label study that looks at longer-term use of ivacaftor's effect on FEV1. The company plans to complete a phase II study of a pediatric formulation of ivacaftor in children ages 2 though 5 this year, Kalmar adds. It also plans to begin studying the drug in people with certain gating mutations other than G551D and in mutations that result in some residual function of the defective CFTR protein on the cell surface.

At the Annual North American Cystic Conference in November, Richard Ahrens, MD, of the University of Iowa reported that his evaluation of ivacaftor in 52 children with G551D mutations ages 6 to 11 found those who received the drug improved FEV1 12.5 percentage points compared with baseline. The placebo improved FEV by only 0.04 percentage points. Through 48 weeks, children treated with the drug had a mean improvement in lung function of 10% of predicted FEV1, compared to placebo, and a relative mean improvement of 15.1% from baseline.

Other Drugs

Some experts emphasize the need for treatment that targets multiple mutations. That's because while ivacaftor increases the function of defective CFTR proteins by increasing gating activity, or ability to transport ions across the cell membrane, most CF patients need to improve CFTR function by increasing the trafficking, or movement, of CFTR to the cell surface.

“G551D presented an opportunity to use a natural mutation that had completed most of the steps to channel activation, so that the potentiator drug, VX770, only had to work on one of the final steps,” Dr. Ramsey says.

The 90% of CF patients with the most common CF mutation, delta F508, will need at least one other drug to ensure proper folding and trafficking of the CFTR protein to the cell surface.

To this end, Vertex has begun studying ivacaftor and VX-809, a CFTR corrector, in about 100 people with at least one F508 deletion. The study is expected to evaluate multiple dose levels of VX-809, and will look primarily at safety and tol-erability, as well as the drug combination's effect on lung function, according to Vertex.

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Ivacaftor produced substantial lung function improvement in patients with CF age 12 and older.

Vertex also plans to begin Phase 2 development of VX-661, another CFTR corrector, in the first quarter of 2012. The company expects to evaluate VX-661 first as a single therapy, followed by dosing of VX-661 in combination with ivacaftor in people with two copies of the F508del mutation.

In addition, PTC Therapeutics announced in September the start of a phase III trial of ataluran, also called PTC 124, which targets nonsense mutations in both CF and Duchenne/Becker muscular dystrophy. In CF, ataluren overrides the premature stop signal so that a functional protein can be formed.

In the meantime, Robert Beall, PhD, President and CEO of the Cystic Fibrosis Foundation, says he is excited about Dr. Ramsey's research, which he calls “an amazing proof of concept,” adding that the study “marks an important and exciting milestone for the cystic fibrosis community, and it confirms that we are one step closer to finding a cure for the disease.” He predicts that ivacaftor “will be the poster child of personalized medicine.”