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FAQs about Combined Ivacaftor (Kalydeco™) & Lumacaftor (VX-809) Phase 3 Clinical Trials

On June 24, 2014, Vertex Pharmaceuticals Inc. released results from its Phase 3 clinical trials of ivacaftor (Kalydeco™) in combination with another potential therapy, lumacaftor (VX-809), in people with the most common mutation of cystic fibrosis, F508del.

Results 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 plans to submit a New Drug Application (NDA) by the end of 2014 to the U.S. Food and Drug Administration (FDA) for review, with potential approval in 2015 of the combination treatment for people with two copies of the F508del mutation ages 12 and older.


What were the results of the ivacaftor and lumacaftor Phase 3 clinical trials?

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. 

For more information on the results, see the Vertex press release.

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When will this drug combination be available?

Based on the Phase 3 trial results, Vertex plans to submit a New Drug Application (NDA) by the end of 2014 to the FDA for review, with potential approval in 2015 of the combination treatment for people with two copies of the F508del mutation of CF ages 12 and older.

Generally, the FDA’s review takes between 6 and 12 months to be sure important questions about safety and efficacy regarding use of the drug have been thoroughly addressed.

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How did the Phase 3 trials of the drug combination work?

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.

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Can people with CF who are very ill get the drug combination immediately?

It is not yet known whether the drug combination will be available to any individual with CF prior to its potential approval. We are pleased, however, that Vertex is exploring options for an expanded access (sometimes called compassionate use) program for those with two copies of F508del who could safely benefit from the combination therapy during the FDA review period.

The CF Foundation will continue to monitor this situation and inform the CF community as we know more about this expanded access program.

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Will the combination treatment be available to people with CF who are younger than 12 years of age?

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 study of the combination treatment in people with CF with two copies of the F508del mutation ages 6 to 11 in the coming months.

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Why weren’t the results from the Phase 3 combination trials as good as the results from studies of ivacaftor alone in people with G551D?

The potential combination treatment targets a more complex problem in CF than what 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. 

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Is this drug combination a cure for CF?

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.

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What will the drug combination cost?

It is not yet known what the cost of the potential drug combination will be. The drug manufacturer, Vertex, will set the price if the FDA approves the treatment. The CF Foundation is not involved in setting the cost of any drug; however, we will strenuously advocate that the best interests of people with CF and their families be foremost in mind during this process.

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What is the difference between ivacaftor and lumacaftor? How do the two drugs work together?

Both ivacaftor and lumacaftor are designed to address the underlying cause of CF and improve key clinical measures of the disease. 

In people with the most common CF mutation, F508del, a series of problems prevents the CFTR protein from achieving the correct shape and reaching the cell surface, where it is needed to help regulate the flow of salt and fluids in and out of the cells of the lungs and other organs. Lumacaftor is designed to help move the defective CFTR protein to its proper place at the cell surface. Ivacaftor increases the activity of the protein once it is there, allowing a normal flow of salt and fluids, which helps thin the thick mucus that builds up in the lungs of people with CF.

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How many people with CF have the F508del mutation?

About 50 percent of people with CF in the United States have two copies of the F508del gene mutation. About 40 percent of people with CF in the United States have at least one copy of the F508del mutation.

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Will the ivacaftor and lumacaftor combination therapy help people who have only one copy of the F508del mutation?

It is too early to know. In an earlier Phase 2 trial of the combination therapy, participants with one copy of the F508del mutation showed some improvement in lung function, compared with those on placebo. However, these improvements were smaller than those seen in people with two copies of F508del.

Vertex is currently conducting an additional eight-week Phase 2 study of the combination therapy in people with one copy of F508del. Results of this study are expected in the coming months.

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For people with one copy of F508del, what other clinical trials are in progress for drugs to treat the underlying cause of CF?

Vertex plans additional combination studies of ivacaftor and another potential compound, VX-661, that will include people with a single copy of the F508del mutation.

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For people with two copies of F508del, what other clinical trials are in progress for drugs to treat the underlying cause of CF?

In addition to studies of ivacaftor in combination with lumacaftor, Vertex is conducting a Phase 2 trial of ivacaftor coupled with another potential compound, VX-661, in people with two copies of the F508del mutation.

Results from an earlier Phase 2 trial showed a significant improvement in lung function among those who took the combination treatment, compared with those who received a placebo. The study evaluated four different doses of VX-661 combined with ivacaftor; participants who received the highest doses of VX-661 had the greatest improvement in lung function.

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For people with rare CF mutations, what clinical trials are underway?

Vertex is studying ivacaftor when taken as a stand-alone drug in more patient groups, including: 

  • People ages 6 and older who have the R117H mutation and certain other mutations that result in residual CFTR function at the cell surface.

  • Children 2 to 5 with at least one of the following mutations of CF: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. (The FDA has approved ivacaftor as a single drug for people ages 6 and older with these mutations.)

PTC Therapeutics Inc. plans to begin a Phase 3 trial to test the potential drug ataluren in people with nonsense mutations — representing about 10 percent of the CF population.

Results from an earlier Phase 3 trial indicated that the use of inhaled aminoglycosides (a group of antibiotics that includes TOBI®) may have interfered with the effect of ataluren. The new trial will evaluate ataluren in people with nonsense mutations who are not receiving aminoglycosides.

In addition to these clinical trials underway, the CF Foundation continues to pursue the development of more potential compounds that target the basic defect in CF. These efforts include research programs with leading pharmaceutical companies — including Pfizer, Genzyme as well as Vertex — to identify the next generation of compounds that could move swiftly into clinical trials and benefit more people with CF, including those with rare mutations.

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What was the CF Foundation’s role in the development of ivacaftor and lumacaftor?

Ivacaftor and lumacaftor were discovered by Vertex in collaboration with the CF Foundation, which provided substantial clinical and financial support in the development process, including approximately $75 million in research funding. The Foundation has since committed another $75 million with Vertex for the discovery of additional CF drugs.

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How can I find out which CF mutations I or my child have?

If you do not know what your or your child's two CF mutations are, contact your CF doctor or care center.

The Cystic Fibrosis Foundation’s Mutation Analysis Program (MAP) offers free and confidential genetic testing to patients with a confirmed diagnosis of cystic fibrosis. MAP provides genotyping for cystic fibrosis patients who have not yet been tested, or who have been tested previously but still have one or more unknown mutations.

To learn more about MAP, talk with your CF doctor or care center.

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Where can I find more information about clinical trials in general?

To learn more about cystic fibrosis clinical trials, click here.

Updated 6/24/2014

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