QLD Orkambi trial shows really positive results

Screen Shot 2015-05-18 at 8.22.50 pmQueensland researchers may have discovered a game-changing treatment for children suffering from cystic fibrosis.

The Queensland Children’s Medical Research Institute has released results from world-first clinical trials of a new treatment that combined two existing drugs, lumacaftor and ivacaftor.

Neither had shown significant clinical outcomes when used alone, but QCMRI interim director Claire Wainwright said the combination treatment had resulted in up to 39 per cent fewer lung infections.

“Cystic fibrosis is the most common life-threatening genetic condition affecting children in Australia, so these results are incredibly exciting,” Professor Wainwright said.

“As well as the 30-39 per cent reduction in lung infections, our trial participants reported a decrease in events requiring hospitalisation or use of IV antibiotics.

“Results like this mean our novel treatment is a potential game changer for the way we treat CF and other genetic disorders in the future.”

Cystic fibrosis sufferers have abnormally thick mucus linings in the lungs, which clog air passages and result in repeated infections and blockages.

It affects the respiratory, digestive and reproductive systems and usually leads to a shortened life expectancy, around 37 years on average.

“Research into novel treatments like the one we trialled is essential to improve the quality of life for CF patients,” Professor Wainwright said.
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“There is still no cure for CF but with treatments like this proving successful, our research could have positive outcomes for CF patients not just here in Australia but internationally for years to come.”

More than 1100 children under the age of 12 participated in the six-month study, which involved two randomised, double-blind, phase 3 clinical trials.

Senior researcher Scott Bell said 187 hospitals in Australia, Europe and the United States collaborated in the trials.

“Nine CF centres in Australia have been involved in the study and patients have been eagerly awaiting the results,” Professor Bell said.

“More than 1000 patients in Australia have the potential to benefit from the treatment in the future.”

The Food and Drug Administration will make a decision on the treatment in July, after which it will be assessed by the Therapeutic Goods Administration to determine market availability and costs.

Source: Beaudeserttimes.com.au


Lumacaftor/Ivacaftor Combo Helps Common CF Mutation

Phase III trial finds drug combo boosts forced expiratory volume in homozygous DF508del cystic fibrosis patients

  • This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Note that this pair of randomized trials of lumacaftor and ivacaftor in combination improved lung function in patients with cystic fibrosis.
  • These results have led to a recommendation for approval by the FDA.

DENVER — Combination of approved cystic fibrosis drug, ivacaftor (Kalydeco), and experimental drug, lumacaftor, improved forced expiratory volume in patients with common gene mutation, researchers reported.

In two, phase III randomized, controlled, multi-center trials including over 1,000 cystic fibrosis patients with the Phe508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, found the drug delivered in two different dose combinations improved predicted forced expiratory volume by 2.6% to 4.0% compared to a placebo without drastic increases in serious adverse events (4.2% versus 1.6%), Claire E. Wainwright, MBBS, MD, of Lady Cilento Children’s Hospital in Queensland, Australia, and colleagues, presented at the American Thoracic Society annual meeting.

These findings were also reported in the New England Journal of Medicine.

The drug, which is being developed by Vertex and will be marketed under the brand name Orkambi, was recommended for approval by an FDA advisory committee last week.

Phe508del mutation in CFTR is the big target for CF patients, Pamela B. Davis, MD, PhD, Dean of the School of Medicine at Case Western Reserve University, wrote in the New England Journal of Medicine.

Roughly half of cystic fibrosis patients in the U.S. are homozygous for this mutation, and more than 90% have at least one allele, she wrote.

Ivacaftor is generally used for patients with the Gly551Asp mutation. It works on the fraction of time that the CFTR channel is open, the “open probability,” of the mutant protein, but it doesn’t work on patients who are homozygous for the Phe508del mutation, Davis added. Lumacaftor improves the processing of the mutant CFTR by prolonging its residence at the cell surface, but it doesn’t improve the open probability.

“The combination of lumacaftor and ivacaftor produced significant improvements in lung function and weight gain, as well as significant amelioration of respiratory symptoms and pulmonary exacerbations,” Davis wrote. “However, the extent of improvement was not as great as that produced by ivacaftor alone in the treatment of patients with the Gly551Asp mutation.”

Davis compared the forced expiratory volume improvements seen in the trials to those seen with inhaled DNase, and even slightly less than those seen with inhaled tobramycin. Davis does note that neither inhalants address the basic defect in the protein the way ivacaftor does.

Davis proposed that the combination of ivacaftor and lumacaftor create a need for higher doses of ivacaftor, as lumacaftor is a strong CYP3A inducer and ivacaftor is a sensitive CYP3A substrate and weak inhibitor, as the combination can cause problems with other cystic fibrosis drugs that the patient might need to take.

In light of these complexities, Davis suggested a tailored dose would probably work better than the fixed doses used in the trials. She also mentioned two laboratory studies demonstrating prolonged exposure to the combination eventually interfered with lumacaftor’s mechanisms by reducing the protein release from the endoplasmic reticulum, thereby reducing the chloride transport activity originally seen in the combination.


Wainwright’s team conducted two phase III, randomized, controlled trials to test the effects of combining lumacaftor, a CFTR corrector, and ivacaftor, a CFTR potentiator. The trials were know as TRAFFIC and TRANSPORT. All patients were at least 12 years old, and were homozygous for the Phe508del CFTR mutation.

Both trials were double-blinded, and dose-identical. For 24 weeks, 1,108 patients, across 187 centers, either received either 600 mg of lumacaftor once a day with 250 mg of ivacaftor every 12 hours, 400 mg of lumacaftor every 12 hours with 250 mg of ivacaftor every 12 hours, or a placebo.

Patients were assigned to each group on a 1:1:1 ratio, and allowed to remain on their pre-study medications. Controls were matched for age, gender, and pulmonary function.

Changes in forced expiratory volume were measured at baseline. The mean of which was 61% of the predicted value.

At 24 weeks, the mean absolute improvement in the predicted forced expiratory volume ranged from 2.6% to 4.0% (P<0.001). The improvements in mean relative treatment difference ranged from 4.3% to 6.7% (P<0.001).

Compared to the placebo group, pulmonary exacerbations were 30% lower in the 600mg/day of lumacaftor group (P=0.001) and 39% lower in the 400mg/12-hours of lumacaftor group (P<0.001).

Improvements in forced expiratory volume were seen as early as day 15 on the therapy across treatment arms.

Relative improvements in percentage of predicted forced expiratory volume of 5% or higher were reported by 39% to 46% in the treatment arms versus 22% in the placebo group (odds ratio 2.9 for 600 mg/day and 2.2 for 400 mg/12-hours). That of 10% or higher were found among 24% to 27% of those in the treatment arms compared to 13% in the placebo group.

The researchers also reported clinically meaningful reductions in the rates of protocol-defined pulmonary exacerbations in both treatment arms compared to placebo: rate ratio 0.57 to 0.72 (P<0.001 to P=0.05). However, these rate ratios didn’t reach significance in the testing hierarchy.

After 24 weeks on the therapy, slight weight gains were noted in the treatment groups, 1.23 kg and 1.57 kg, on average. The researchers estimated that either better caloric absorption, possibly due to normalized intestinal pH, or lower energy expenditure from improvements in symptoms explained this result.

CFQ-R scores, though improved in the 600 mg/day of lumacaftor group, did not meet the criteria for clinical difference of 4 points.

Serious Adverse Events

Serious adverse events were reported among 28.6% of those in the placebo arm, and 17.3% to 22.8% of patients in the pooled treatment arms. The most common event was infective pulmonary exacerbations, which comprised 24.1% of SAEs in the placebo group, and 13% in the combined treatment arms.

Drop out rates were 4.2% for those in the combined treatment groups, and 1.6% in the placebo group. Elevated creatine kinase levels occurred in 4 patients, hemoptysis in 3, bronchospasm in 2, dyspnea in 2, pulmonary exacerbations in 2, and rash in 2 patients. No deaths were reported.

Seven patients in the treatment arms, and none in the placebo group, experienced abnormal liver function.

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