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Based on Phase III Data, Vertex Moving Quickly to File for Approval of Cystic Fibrosis Drug Combo

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NEW YORK (GenomeWeb) — Vertex Pharmaceuticals this week released data from two Phase III studies of a combination of its cystic fibrosis drugs lumacaftor and Kalydeco (ivacaftor), showing that the studies have met their primary endpoints of statistically significant improvement in lung function among CF patients ages 12 and older with two copies of the F508del mutation in the CFTR gene.

Based on the data, the company plans "to move as fast as possible to submit applications for approval of this combination regimen in countries around the world," Jeffrey Chodakewitz, senior VP and chief medical officer at Vertex said in a statement.

Vertex has been investigating the two drugs used in the study in homozygous and heterozygous F5508del mutated patients for several years, and moved to Phase III after earlier positive results from a Phase II trial in 2012.

The therapies target two different types of CFTR protein dysfunction caused by different mutations in the CFTR gene. Overall, researchers have found more than 1,800 CFTR mutations involved in CF.

Lumacaftor, previously called VX-809, is a CFTR "corrector," believed to help CFTR proteins reach the cell surface in patients with mutations like F508del that hinder this movement. Kalydeco, is a CFTR "potentiator," and helps keep open CFTR protein channels that other so-called "gating" CFTR mutations have impeded.
Approximately 90 percent of people with CF have at least one copy of the F508del mutation, and about 48 percent have two copies.

Vertex's two Phase III studies, TRAFFIC and TRANSPORT, both included one placebo group and two combination treatment groups evaluating lumacaftor dosed at either 600 mg once daily or 400 mg every 12 hours in combination with Kalydeco dosed at 250 mg on the same schedule.

In the newly released data, researchers reported on 1,108 patients who enrolled and received at least one dose of the combination drug. There were 549 patients in TRAFFIC and 559 patients in TRANSPORT.

According to Vertex, all four combination-treatment arms met their primary endpoint of improvement in homozygous patients' ability to exhale – measured as absolute change from baseline in percent predicted FEV1 – compared to placebo.

The company reported mean absolute improvements in ppFEV1 of between 2.6 and 4.0 percentage points from baseline compared to placebo across the studies, as well as mean relative improvements of 4.3 percent to 6.7 percent.

Vertex also reported data suggesting improvements in a number of other secondary endpoints. Patients who received the combination regimens had statistically significant reductions in the rates of pulmonary exacerbations and statistically significant improvements in body mass index compared to those who received placebo, the company reported.

However, the studies did not find statistically significant changes in patient-reported respiratory symptoms between the treatment and placebo groups.

The company also shared data on the drug combination's safety. According to Vertex, the combination regimens were "generally well tolerated," and adverse events that occurred more frequently in patients who received the combination regimens than those who received placebo were generally respiratory in nature, including dyspnea and abnormal respiration. About four percent of all patients who received combination therapy stopped treatment because of adverse events compared to 1.6 percent of those who received placebo. Seven patients who received combination therapy experienced serious adverse events related to abnormal liver function tests, compared to zero patients who received placebo.

Vertex announced it intends to submit regulatory applications based on these data in the fourth quarter of 2014 in multiple countries for approval of the drug combination for people with CF ages 12 and older who have two copies of the F508del mutation.

The company has also been conducting ongoing Phase II research on the combination of lumacaftor and Kalydeco in patients with only one copy of the F508del mutation. These heterozygous patients represent another 40 percent of all CF cases.

Megan Goulart, a communications officer for Vertex, told PGx Reporter that the company's earlier Phase II research in heterozygous patients failed to show a strong response to combined lumacaftor and Kalydeco.

According to Goulart, the company has since moved to study a different dose, also in Phase II, to see if that might be effective in heterozygous F508del-mutated patients. But, she said, "we don't know that two medicines are going to be enough for those patients."

"We'll know more when we get that data" hopefully in the coming months, she added.

In anticipation that alternative dosing may fail to be effective for heterozygous F508del patients, Goulart said the company is also working on a third class of CFTR-targeted drug, what she called a "next-generation corrector" that would have a different mechanism than both Kalydeco and lumafactor and would be additive to the two.

This compound is still preclinical, but she said Vertex hopes to begin human trials by end of this year or early next year.

The company also researching another first-generation corrector, VX-661, that has a mechanism similar to lumafactor.

Finally, Goulard said Vertex is also planning to start a study in the next few months of ivafactor and lumafactor in children between ages six and 11 who are homozygous for the F508del mutation. This group represents an additional 6,000 patients worldwide who could benefit from the treatment combination in addition to the approximately 22,000 homozygous adolescents and adults globally, she said.

Earlier this year, the company received expanded approval from the US Food and Drug Administration for Kalydeco as a standalone treatment for patients six and older who harbor one of eight mutations in the CFTR gene.

The FDA first approved Kalydeco in late 2012 for the 4 percent of CF patients with at least one copy of the G551D gating mutation. In addition to this mutation, the drug is now approved for CF patients who have the G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D mutations. Vertex has estimated that only about 150 CF patients over six in the US have one of these additional eight mutations.

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