[Updated: 12:55 pm ET 4/19] Vertex Pharmaceuticals isn’t willing to settle for coming up with one great drug for 4 percent of patients with cystic fibrosis. The Cambridge, MA-based company wants to treat a whole lot more children and adults with this deadly genetic disease, and today it offered some more evidence that it’s on track.
The company’s stock (NASDAQ: VRTX) shot up $26.88 a share—a 51 percent gain—in after-hours trading to reach $79.75 at 7:50 pm Eastern time, following Vertex’s report on one of its mid-stage clinical trials.
Investors reacted to news that one of Vertex’s experimental drugs, VX-661, given in combination with its FDA-approved ivacaftor (Kalydeco), was able to help patients with two copies of what’s known as the F508del gene mutation. Anything that helps those patients is a big deal, because F508del patients don’t appear to benefit from ivacaftor alone, and this is the most common genetic abnormality that causes cystic fibrosis. About 30,000 people have the disease in the U.S. and 70,000 have it worldwide. About half of all cystic fibrosis patients have two faulty copies of the F508del gene while about 87 percent are thought to have at least one bad copy of the F508del gene, researchers say.
Before diving into the statistics of what Vertex reported today, here’s some necessary background. Vertex made history a year ago when it won FDA approval of ivacaftor (Kalydeco), which was the first drug that was shown to work by treating the underlying genetic abnormality in CF, rather than just treating the symptoms. Cystic fibrosis, for those unfamiliar, comes from mutations to a gene called CFTR. Those mutations interrupt the transfer of water and salt across cell membranes. When water and salt don’t flow properly, it causes a number of bad things, but most importantly, it leads to the buildup of thick, sticky mucus in the lungs. Patients lose lung capacity, their lungs get infected with various bacteria, and they usually die by their late 30s or early 40s.
While doctors have gotten better at treating the symptoms of CF, Vertex’s ivacaftor is special because it’s the first drug that works by targeting the CFTR protein directly. It helps to prop open these cellular gateways to allow better transport of ions across cell membranes, at least for the 4 percent of patients with the G551d mutation.
The study Vertex reported on today was designed to ask whether VX-661 could help the broader population—F508del patients—by itself, or in combination with ivacaftor (Kalydeco).
Here’s how the study was designed. Vertex randomly assigned 128 patients to get the Vertex combo drugs, or a placebo, and followed them all for 28 days. Patients were assigned to get one of four different doses of VX-661, taken once a day, alongside a fixed dose of ivacaftor taken twice a day. One group of patients got VX-661 alone—and they didn’t see a statistically significant benefit, Vertex said.
Benefit, however, was seen in patients on the combination regimen. Patients on a 100 milligram dose of VX-661 saw a 9 percent relative improvement in their lung function—measured by their capacity for forcing air out of their lungs in one second. Patients on a higher dose, 150 milligrams, also improved, seeing a 7.5 percent improvement in their lung function from their baseline finding. As expected, those on the placebo saw almost zero change in their lung function. When patients went on a 28-day washout period with no more drug, their lung function reverted back to about where it was at the beginning of the study, Vertex said. The benefit seen at the high doses of VX-661 were statistically significant, meaning that even though the study had only a small number of patients, the finding was striking enough that it was unlikely to be the result of chance.
At this point, some readers might wonder, ‘what’s the big deal about a 9 percent improvement?’ It actually is a big deal when evaluating cystic fibrosis patients. For context, I looked back to an interview I did last year with Michael Boyle, a cystic fibrosis expert at Johns Hopkins University in Baltimore, MD. Here’s what he said, although the percentages he’s referring to are in absolute terms, not relative terms.
“Five percent is the magic number, that’s what everybody wants to get to. But 10 percent is a huge effect,” Boyle says. When asked what those numbers mean, he said the outcome can vary depending on how sick a patient is, but it always counts for something important. A person who improves from 20 percent lung function to 30 percent goes from the verge of a lung transplant to having a longer life expectancy. An improvement from 40 percent lung function to 50 percent clearly enables a patient to exercise more. A person going from 50 percent to 60 percent can feel a significant difference when climbing stairs, he said.
While everyone will focus on the percent improvement in lung function, it was only a secondary goal of the study, and the main goal was to assess safety at a variety of doses. Vertex said the combo drug regimen was “well-tolerated” and that the reported adverse events were mostly mild to moderate in severity, and consistent with what patients reported in the placebo group. Vertex plans to discuss the results with regulators, and consider its strategy for verifying the results in the third and final phase of clinical trials normally required for FDA approval of a new drug.
OK, whew, you’re probably thinking that’s a lot of information to process already. But there’s even more context to consider. This new drug candidate, VX-661, is really just one of three different compounds Vertex has designed as a “corrector” of CFTR gene mutations. Last year, Vertex reported similarly encouraging results from a mid-stage clinical trial of another “corrector”—VX-809—in combination with ivacaftor. Those results were compelling enough—showing an improvement in lung function for patients with two copies of the F508del mutation—that Vertex is currently testing the combo in a pivotal clinical trial program that’s recruiting 1,000 patients. Vertex’s scientific hypothesis is that it should be able to help the most patients by pairing a genetic “corrector” drug with a “potentiator” like ivacaftor (Kalydeco), that props open the ion channels on the cell surface, to let water and salts pass through.
Put simply, one drug is supposed to correct the CFTR protein pathway, allowing water and salts to traffic to the cell surface, while another drug props open a channel that enables the stuff to pass through. While Vertex has pushed VX-809 as its most advanced “corrector” drug for cystic fibrosis, VX-661 is next in line, and there’s one more back in the pipeline called VX-983.
VX-661 is from the same chemical class as VX-809, and Vertex’s data says it acts at the same step in the CFTR correction pathway, according to company spokesman Zach Barber. While each drug is different in a chemical sense, they are all striving to reach the same goal, treating patients with F508del mutations.
“Our goal in CF is to help as many patients as possible with combinations of different medicines that act on CFTR,” Barber says. “This could be a dual regimen, like VX-809+ivacaftor, or potentially a future triple regimen, such as two correctors + ivacaftor. Having multiple correctors in development gives us a greater flexibility with how we might be able to combine these compounds to address certain patient populations.”
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