In one of those rare cases of good science translating directly into good medicine, Vertex Pharmaceuticals yesterday unveiled positive results from a Phase III trial of VX-770, a small molecule that treats the underlying defect of cystic fibrosis.
The data “are very fresh, but nonetheless unambiguous and stunningly clear,” Vertex’s CSO Peter Mueller told analysts on a call yesterday. Further, they clear the way for Vertex to file for regulatory approval for VX-770 in the U.S. and Europe in the second half of this year.
Before we get into the details of that data, a quick review of cystic fibrosis. As we described back in 2008, folks with CF have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which carries the recipe for making a protein that shuttles chloride ions from one side of a cell membrane to the other. That faulty gene means that people with CF absorb too much salt and have a hard time secreting it. Without the right balance of hydration, their lungs become dotted with dried-out pockets that get clogged with thick mucus, an environment ripe for bacteria growth. Patients suffer from chronic infections, often with the most pernicious of bugs, and take a panoply of antibiotics and other treatments to manage the symptoms of their disease.
Vertex’s drug is generating excitement because it addresses the underlying cause of the disease. Think of CFTR as a gate that allows chloride ions out of the cell. Depending on the mutation that causes a patient’s CF—there are a handful of genetic malfunctions—that gate might be rusty, and not opening right, or, more commonly, there simply aren’t enough gates. VX-770 is being tested in people with a mutation akin to the former, and works to increase the flow of chloride ions through the gate, thereby restoring the right level of hydration in the lungs.
In the Phase III trial of 161 people, the drug clearly met its primary endpoint of improving lung function. After 48 weeks on the drug, there was a relative improvement in lung function of 16.9% compared to placebo, and the absolute improvement (calculated by dividing the relative improvement by the baseline lung function) of 10.6%. “This improvement in lung function both on an absolute and relative basis is particularly significant since it came on top of the other therapies patients continue to receive,” Vertex’s chief medical officer Robert Kauffman said yesterday.
One of the most striking pieces of information gathered in this trial was the effect on the rate of pulmonary exacerbations, or periods when their disease worsens, Kauffman said. While the ability to improve lung function is critical, for patients the pulmonary exacerbations are what often feel the most disruptive: antibiotics need to be switched, other medications added, and they can even lead to hospitalization. “These exacerbations are a tangible reminder of the disease,” Kauffman noted. The company was surprised to find that despite a relatively short trial, there was a marked decrease in the rate of exacerbations: patients taking VX-770 were 55% less likely to experience an exacerbation than those on placebo.
Analysts were equally excited about the results. The CF franchise could bring in over $500 million, annually, and is under patent protection until at least 2025, Leerink Swann analyst Howard Liang pointed out in a note to investors. Vertex will pay a single-digit royalty on any sales of VX-770 to the Cystic Fibrosis Foundation, which provided substantial funding for the program.
All this good news comes with some caveats. Though promising, the trial was conducted in people with the G551D mutation, which accounts for just 4% of the CF population. Vertex also reported early results from a trial testing the safety and impact on lung function of VX-770 in people with the most common CF mutation, ΔF508. While the safety profile in that patient population was similar to the G551D group, the improvements to lung function were not clinically meaningful.
The problem is that people with two copies of the ΔF508 mutation just don’t have enough of those gates that shuttle chloride ions on the cell surface to begin with. The good news is Vertex is working on a second drug, VX-809, which works to bring more gates to the surface. The idea is to use VX-809 in combination with VX-770 in hopes of achieving the same kind of benefits as in the G551D group. Vertex is now conducting tests of the safety of that combination in patients 18 and older, and hopes to get some sort of a signal on the efficacy of that one-two punch from the trial. Vertex also has in vitro data suggesting there are subsets of patients with other gating mutations that might also directly benefit from VX-770.
On a separate note, the approval of VX-770 would be a great vote of confidence in the venture philanthropy model pioneered by the CF Foundation. This is the kind of program that might never have gotten off the ground without the $75 million in funding the non-profit provided. The CF Foundation gets a royalty on sales of the drug, which it plans to plow back into supporting other CF drug candidates in the pipeline. However, it’ll be interesting to see how the non-profit reacts to what is expected to be a hefty annual price tag on VX-770.
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