On May 12, 2015, the Pulmonary-Allergy Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) will hold a hearing to discuss Vertex Pharmaceuticals’ new drug application for approval of the lumacaftor/ivacaftor combination therapy for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation.
The results of a phase 3 clinical trial with lumacaftor and ivacaftor showed statistically significant improvements in lung function and other markers. Sue Landgraf, CFRI’s executive director, will address the committee during oral presentations from the public, advocating for FDA approval of the combination therapy.
To read the FDA’s announcement of the hearing, click here.
HERE’S A SNAPSHOT OF THE SUMMARY OF THIS COMBINATION DRUG THERAPY TO DATE:
Participants in the Phase 3 trials who received the combination treatment showed significant improvements in lung function and other important health measures, compared with those on placebo, and these gains were sustained throughout the 24-week trials.
Both trials tested the same two doses of lumacaftor in combination with ivacaftor. All groups of participants receiving the treatment achieved the trials’ primary endpoint goal of a mean absolute improvement in lung function (measured by FEV1), with a range of 2.6 – 4 percentage point improvement across the groups.
Those taking the combination treatment also had significant improvements in multiple secondary endpoints, including a mean relative improvement in FEV1 between 4.3 and 6.7 percent; improved weight gain; and significant reductions in the rate of pulmonary exacerbations and associated hospitalizations and IV antibiotic use.
The two six-month Phase 3 clinical trials studied the combination treatment in people with two copies of the F508del mutation ages 12 and older. In total, more than 1,100 study volunteers participated at nearly 200 clinical trial sites in North America, Europe and Australia.
Both trials tested the same two doses of lumacaftor in combination with ivacaftor. Participants were monitored and given laboratory tests and surveys to measure lung function, body weight and body mass index, hospitalization rates and overall health and quality of life.
The trials were “double-blinded:” neither the participants nor the trial researchers knew which groups received the drug combination and which group received placebo.
Most Phase 3 trials are about one year long. However, the combination trials were completed in about half the time typically required for a Phase 3 trial, following the FDA’s awarding the potential combination treatment “Breakthrough Therapy Designation,” intended to speed the development of select potential therapies that treat life-threatening diseases or conditions.
The drug combination must be tested in people under age 12 to determine its safety and efficacy in this patient group. Vertex plans to conduct a clinical trial of the combination treatment in people with CF with two copies of the F508del mutation ages 6 to 11 in the first half of 2015.
The potential combination treatment targets a more complex problem in CF than Ivacaftor targets.
Ivacaftor has been approved for people ages 6 and older with the G551D mutation and several closely related mutations. In people with these mutations, the CFTR protein is at its proper place at the cell surface but does not function normally. Instead, it acts like a locked gate. Only one drug is needed to help increase CFTR activity and unlock that gate, allowing the normal flow of salt and fluids that helps thin the thick mucus that builds up in the lungs of people with CF.
In people with the most common CF mutation, F508del, a series of problems prevents the CFTR protein from taking its correct shape and reaching its proper place on the cell surface. Addressing these problems requires a multi-pronged approach that takes place in different parts of the cell. Lumacaftor is designed to help move the defective CFTR protein to the cell surface, while ivacaftor improves its function once it is there.
The combination treatment is not a cure for CF. However, based on the results from the Phase 3 trials in people with two copies of the F508del mutation ages 12 and older, the two drugs in combination have been shown to significantly improve lung function and other important measures of the disease.
The Phase 3 results further validate findings from other late-stage studies that have demonstrated it is possible for an oral drug to improve key symptoms of CF by addressing the defective CFTR protein caused by mutations in the CF gene.
What is the current status of Vertex’s FDA approval application as it stands now?
On Nov. 5, 2014, Vertex Pharmaceuticals Inc. submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of the combination of ivacaftor (Kalydeco™) and the potential therapy lumacaftor (VX-809). The potential combination drug is designed for people with cystic fibrosis ages 12 and older who have two copies of the most common mutation of cystic fibrosis, F508del.
Results from Phase 3 trials of the combination drug showed that people with two copies of the F508del mutation ages 12 and older who received the treatment had significant improvements in lung function and other key measures of the disease.
Both ivacaftor and lumacaftor are designed to treat the underlying cause of CF — a defective protein, called CFTR, caused by mutations in the CF gene.
Vertex has requested a priority review of the combination drug, which, if granted, could shorten the FDA review timeframe from approximately 12 months to 8 months.