Vertex’s New CF Drug – tezacaftor

Is Vertex’s New CF Drug Unprecedented? Incremental? Expensive? Maybe All Three

Article written by Matthew Herper, and published in Forbes Magazine on March 29, 2017.

Shares in Boston’s Vertex Pharmaceuticals are up 22% to $109 after the biotechnology company released data on an experimental combination pill to treat cystic fibrosis, a genetic disease that shortens patients’ lives by affecting their lungs and digestive systems. That gives the biotech a market capitalization of $27 billion.

“To me, this is really unprecedented innovation,” says Jeffrey Leiden, Vertex’s chief executive. Vertex has had 10 positive late-stage trials in cystic fibrosis in five years, and if approved this new medicine will be the third it has brought to market. “To me, that’s an amazing story. It’s one of the things I’m proudest of about the company.”

Doctors unconnected with Vertex give use a more muted word to describe the new drug, tezacaftor: incremental, a small step along the path of coming up with a treatment for all the patients with the many different genetic mutations that can cause cystic fibrosis.

“This one may be a tiny bit better,” says Brian O’Sullivan, a pediatric pulmonologist at Dartmouth-Hitchcock in Manchester, New Hampshire. “It’s not dramatically better. I do think there are fewer drug-drug interactions, which I think is a real plus. And there may be fewer discontinuations. It’s a little hard to tell from this study.”

Look at the numbers: compared to Orkambi, Vertex’s existing cystic fibrosis combo pill, the new pill containing tezacaftor is only slightly better. In patients who have two copies of a genetic variant called F508del–the people for whom Orkambi is approved–the Vertex studies released last night show an increase in FEV1, a measure of lung capacity, of more than 4%. For Orkambi, the number was less than 3%. The new drug may be better, but it’s hard to say for certain comparing across studies. (Both tevacaftor and Orkambi are given as single-pill combinations that also contain Vertex’s original CF drug, Kalydeco.)

One hope is that the new drug will have fewer side effects. Up to a third of the patients who started Orkambi outside of clinical trials have stopped because of wheezing and difficulty breathing. The new drug doesn’t seem to have that side effect, but we won’t know for sure until it is approved and more widely used. A bigger impact was seen when the tevacaftor and Kalydeco were used in patients who had one F508del mutation and one barely functioning CF gene. Their lung function increased 4.7% on Kalydeco alone, and 6.8% on the tevacaftor-Kalydeco combination.

“With personalized medicine, most of the advances will come incrementally like this, instead of one drug to conquer everybody,” Mark Wylam, director of the cystic fibrosis center at the Mayo Clinic in Rochester, Minn., says. “The hope is down the road we’ll have a drug for everybody.”

Vertex’s efforts in cystic fibrosis have been an attempt to extend a breakthrough. Kalydeco, approved in 2012, increases FEV1 by 10% in patients whose CF is caused by a mutation called g551d. That’s a big increase in lung function. But only 5% of the 70,000 people with CF worldwide have this mutation. So Vertex has been trying to develop new drugs to make Kalydeco work in patients with other mutations. Orkambi was the first. The company’s goal is to get to a three-drug combination, and part of the reason for analyst excitement about tevacaftor is that it seems as if it will be a better ingredient for that cocktail.

“As new three-drug combinations come out both by Vertex and other people that want to develop therapies, this looks like a much more solid base because of the interaction profile,” says Steve Rowe, director of the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama, Birmingham. Companies including Galapagos, which is partnered with the drug giant AbbVie, Flatley Discovery Laboratory, and Bayer are looking at their own add-on CF drugs. Vertex’s has four candidates for a three-drug combo in trials. “It’s not a question of if we’re really going to see a transformation of this disease,” says David Altshuler, the companies chief scientific officer. “It’s a question of when.”

One question that’s unavoidable: how much will this cost? Kalydeco entered the market with a list price of $300,000 per patient per year. Orkambi, despite being less effective, lists at $259,000 per year. O’Sullivan has previously criticized the Orkambi price; he declined to do so now, preferring to focus on the science and the drugs’ clinical benefits for the moment.

The Vertex data came out at the same time that two new drugs were approved: Dupixent, an eczema treatment from Sanofi and Regeneron, and Ocrevus, a multiple sclerosis treatment from Roche. In both cases, the companies chose to price below what analysts would have expected based on existing medicines. Could Vertex do the same with tevacaftor?

Leiden said it was too early to talk about pricing. Last year, Vertex had cystic fibrosis revenue of $1.68 billion, up 70% from 2015; $703 million came from Kalydeco, and $980 million from Orkambi. Leiden says the price of the combo pill of tevacaftor and Kalydeco will be based on three factors: the value of the drug to patients; the amount Vertex has invested; and the amount that will still need to be required to get a triple-drug therapy that will work for most CF patients. “That’s going to require a lot more investment as we think about pricing we’ll take all three of those into account,” Leiden says.