more time is required to show if the ivacaftor/tezacaftor combination is superior to a different combination of ivacaftor and lumacaftor that Vertex brought to market as Orkambi in 2015. “There’s a good chance that it will be,” says Nielson of UCSF, “but we need to have experience with it in the clinical arena.”
“It’s a win,” says Richard Moss, the former director of the Cystic Fibrosis Center at Stanford Medicine. “I think they’re justified in [filing for approval] at this point for it.” (Moss wasn’t involved in the trial, but noted that some of his Stanford colleagues are.)
CF is a genetic disease that causes a steady buildup of thick mucus in the lungs and pancreas. The ensuing health problems, such as bacterial infections, respiratory failure, and difficulty breaking down food, can lead to an early death. The disease affects about 30,000 patients in the U.S. and 70,000 worldwide. CF patients live to a median of 40 years old, according to the nonprofit Cystic Fibrosis Foundation.
For years, treatments only helped with symptoms: Antibiotics, for instance, to help fight bacterial infections, or inhaled drugs to thin the mucus in the lungs. Vertex made history in 2012 when it won FDA approval of ivacaftor—the first therapy to address the molecular malfunction that underlies the disease. It works by restoring the production of a protein, CFTR, which opens up channels that shuttle water and salt across cell membranes. Without CFTR, the channels don’t function properly and mucus builds up in patients’ lungs.
Ivacaftor, however, isn’t a cure, and it is only approved for a roughly 5 percent genetic subset of CF patients. So Vertex has been developing a variety of multi-drug “cocktails” to treat a wider swath of patients—and dominate the CF landscape. These drugs, collectively, are known as CFTR modulators and work in concert with one another by addressing different problems that stifle CFTR function. Lumacaftor, known as a corrector, helps move CFTR to the cell surface, where ivacaftor can make an impact. The ivacaftor-lumacaftor combination is approved for about a third of patients with the disease. Combined, the two drugs generated about $1.7 billion for Vertex in 2016, up from $982 million in 2015, bringing the company after 27 years to the verge of sustainable profitability.
But Orkambi has limitations, including side effects like chest tightness and interactions with other drugs.
“For many patients [the chest tightness] is mild,” says University of South Carolina’s Flume. “But for some people they either cannot tolerate it, or they don’t feel like any appearance of benefit is worth the consistent chest tightness.”
Vertex CEO Leiden says between 20 and 30 percent of patients who start Orkambi discontinue because of respiratory problems. In addition, patients taking the combo tend to see their lung function decline during the first month of treatment. These limitations have affected Orkambi’s uptake. And competition is on the way from AbbVie and Galapagos NV, which are developing their own CF combinations.
The tezacaftor combination might be an alternative for patients who have trouble with or aren’t eligible for Orkambi or ivacaftor alone.
Christian Merlo, a pulmonologist at Johns Hopkins Medicine in Baltimore, MD, calls the new data “encouraging” but wants to see a more detailed breakdown of side effects to determine whether the drug is better than Orkambi, or which of his patients should get which drug.
“It would be tough to say based on those results I would change from Orkambi therapy to the [new] combination,” he says.
Beyond the comparisons of the new combination and Orkambi, however, lie the triple-pill cocktails. Two mid-stage trials are expected to produce data later this year. One adds experimental VX-152 to ivacaftor-tezacaftor, the other adds VX-440. As Leerink analyst Geoffrey Porges wrote recently, their success “hinges on tezacaftor being an effective, well-tolerated, well-behaved foundation for such combinations.”
