Drug Combo Targets Common Cystic Fibrosis Gene Abnormality

Jim Kling

May 18, 2015

DENVER — A new drug combination of the experimental drug lumacaftor and ivacaftor (Kalydeco, Vertex) improves lung function and curbs exacerbations in patients with cystic fibrosis, results of the TRAFFIC and TRANSPORT trials suggest.

The identically designed studies, published online May 17 in the New England Journal of Medicine and discussed at a session here at the American Thoracic Society (ATS) 2015 International Conference, are good news for patients with two copies of a common mutation, which represents some 50% of patients with cystic fibrosis in the United States.

Another 40% of patients carry one copy of the Phe508del mutation.

"We have shown we can take this most common gene abnormality with a really difficult protein product and create a strategy using an orally bioavailable therapy to improve lung function and have a really significant improvement in clinical outcomes," presenter Susanna McColley, MD, from the Cystic Fibrosis Center at the Ann and Robert H. Lurie Children's Hospital of Chicago, Illinois, told Medscape Medical News.

The hypothesis first gained traction when a phase 2 study suggested that the combination could improve clinical outcomes for patients. The new phase 3 TRAFFIC and TRANSPORT trials included 1108 patients.

The researchers randomly assigned people into three groups: high-dose lumacaftor 600 mg daily combined with ivacaftor 250 mg twice daily, low-dose lumacaftor at 400 mg with the ivacaftor at the same 250-mg dose, or placebo.

The primary endpoint of both studies was the change in predicted forced expiratory volume in 1 second (FEV1) from baseline to week 24, calculated by averaging mean change at 16 weeks and mean change at 24 weeks.

Table 1. TRAFFIC and TRANSPORT Pooled Analysis Outcomes

Change in FEV1 Percentage Point Increase 95% Confidence Interval P Value
Lumacaftor 600 mg and Ivacaftor 3.3 2.3 to 4.3 <.001
Lumacaftor 400 mg and Ivacaftor 2.8 1.8 to 3.8 <.001

Both groups also experienced decreases in the rate of pulmonary exacerbations at 48 weeks. Patients receiving the high-dose combination had a rate ratio relative to the placebo of 0.70 (95% confidence interval [CI], 0.56 - 0.87; P = .001), whereas those taking the low-dose combination had a rate ratio of 0.61 (95% CI, 0.49 - 0.76; P < .001).

The improvement in FEV1 was significantly smaller than the benefit ivacaftor typically affords patients on its own. Ivacaftor is already approved by the US Food and Drug Administration for patients with the rare Gly551Asp mutation, which contributes to about 5% of cystic fibrosis cases.

The drug combination's effect was disappointing, Dr McColley acknowledged, and the drugs may be interfering with each other in some way. Other drugs are being developed that could combine more smoothly, she pointed out.

Still, the improvements are important, especially the reduction in exacerbations. "They're a huge driver of that lung function curve," said Dr McColley. "People who have a lot of exacerbations decrease much more rapidly than people who have few. If you can reduce or eliminate exacerbations, the additive effect of that over a year is quite substantial."

Investigators reported an increase in body mass index in both groups compared with placebo. Patients in the high-dose combination experienced a mean increase of 0.28 kg/m2 (95% CI, 0.15 - 0.41 kg/m2; P < .001), and those in the low-dose group also gained weight, with a mean increase of 0.24 kg/m2 (95% CI, 0.11 - 0.37 kg/m2; P < .001).

Table 2. TRAFFIC and TRANSPORT Adverse Events (%)

Adverse Events High-Dose Combination Low-Dose Combination Placebo
Withdrew from trial 3.8 4.6 1.6
Dyspnea 14.9 13.0 7.8
Chest tightness 10.8 8.7 5.9

Compared with the placebo group, the researchers report that more patients in the treatment groups withdrew because of adverse events. There were no differences in liver enzyme elevations between the placebo group and the treatment groups, but there were more serious adverse effects related to liver enzyme elevations in the treatment groups, with seven events.

"To me, the big effect, even though the primary outcome was FEV1, is on exacerbations, because that's what really hurts a patient with cystic fibrosis," session moderator Jeffrey Drazen, MD, from Harvard Medical School and editor of the New England Journal of Medicine, told Medscape Medical News. "If you can cut that down by a third, you've made a big difference."

He added, "I think there will be more steps as we understand the strengths and weaknesses of these drugs and figure out ways to make drugs that work better, with fewer side effects."

Session attendee Marcus Mall, MD, head of the Cystic Fibrosis Center at the University of Heidelberg in Germany, told Medscape Medical News, "We know that the effect could be even better, but this mutation is a particularly difficult one to correct." He added, "It's a very important proof of concept that it's possible to improve the function of this mutation too."

Vertex is seeking approval for a combination of 400 mg lumacaftor and 250 mg ivacaftor twice daily, largely because such a regimen would be the simplest for patients to follow.

"It's pragmatic given that the effect is pretty equivalent for both doses," said Dr McColley. "We hope we'll have something to give patients very soon that can modify their disease."

These studies were funded by Vertex. Dr McColley and Dr Mall have worked as consultants for the company. Dr Drazen has disclosed no relevant financial relationships.

N Engl J Med. Published online May 17, 2015. Full text

American Thoracic Society (ATS) 2015 International Conference. Presented May 17, 2015.

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