Tests suggest limits to Vertex’s cystic fibrosis treatment

A Vertex employee at the company’s headquarters on the South Boston waterfront.
A Vertex employee at the company’s headquarters on the South Boston waterfront.(Dina Rudick/Globe Staff)

Investors and patients were exuberant last month when Vertex Pharmaceuticals released results from clinical trials showing that cystic fibrosis patients’ lung function improved on an experimental two-drug regimen. But on Wednesday, two independent teams of scientists published studies showing that the medications interfere with each other, at least when they are administered to human cells in a laboratory dish.

The studies published in the journal Science Translational Medicine raise fundamental questions about how the drugs work in patients and also suggest that a different strategy might be more effective. Questions about the mechanism of the medicine might be largely academic if the benefits to patients are deemed sufficient for approval by regulators, but several outside scientists said that the findings might help guide the future development of an improved approach.


“It may explain partially why we haven’t seen as big an improvement as we’d hoped in the combination therapy,” said Dr. Brian P. O’Sullivan, a professor of pediatrics at the University of Massachusetts Medical School in Worcester.

The data were first presented at a scientific conference last year and came as both a surprise and disappointment to both teams of scientists. Vertex has said it plans to submit the combination therapy for approval by the US Food and Drug Administration before the end of the year.

“While these and other preclinical experiments represent interesting cell biology that can inform our research efforts, what doctors and patients care about -- and what we’re focused on -- is the benefit the combination has on people with CF,” said Vertex spokesman Zach Barber.

Investors seemed to discount the studies published Wednesday. Vertex shares edged up 40 cents to $98.14, a gain of 0.4 percent on the Nasdaq stock exchange.

“The clinical data show the combination has an effect in humans,” said Mark Schoenebaum, biotechnology analyst for investment strategy firm ISI Group in New York. “Humans trump test tubes. No one disputes that Vertex will endeavor to improve upon the efficacy results they have already generated.


“In the end, it’s a very common sense issue,” he added. “There is no reason – no reason – that a CF patient with the appropriate mutations would not want access to this drug combination.”

Last month, Vertex released data from two late-stage clinical trials involving 1,110 people with cystic fibrosis showing that the experimental drug lumacaftor in combination with the already-approved drug ivacaftor improved lung function, as measured by the volume of air that patients could exhale, by between 2.6 and 4 percent. The study also found some weight gain and reduced complications that resulted in hospitalizations.

While physicians and patients were excited by those results and the stock price soared 40 percent, the improvement in the volume of air exhaled was significantly less than when ivacaftor alone was given to patients with a different genetic defect responsible for a small subset of cystic fibrosis cases. The improvement is also less than the initial gains patients experienced in studies of several treatments that only target the symptoms of the disease, O’Sullivan said.

In cystic fibrosis, a protein that is normally found on the surface of cells, where it acts as a gateway to secrete chloride, malfunctions, causing the buildup of sticky mucus in the lungs, the intestines, and other organs. There are more than 2,000 known DNA mutations that can cause cystic fibrosis, but the most common one causes the protein, called CFTR, to be misfolded. That prevents it from making it to the surface of the cell.


Scientists have developed a class of experimental drugs called “correctors ” -- including lumacaftor, one component of the treatment in the clinical trial -- which fix the protein so that it can sit on the cell surface. Alone, those drugs don’t help very much, so scientists have tried pairing them with ivacaftor, a “potentiator” that helps the gateway function more effectively. Ivacaftor was approved by the FDA in 2012 for patients with the unusual cystic fibrosis mutation.

Martina Gentzsch, an assistant professor of cell biology and physiology at the University of North Carolina at Chapel Hill who led one of the new studies, said that she launched her experiment because she thought the initial study by company scientists showing the benefit of the drug combination in a dish measured it in a way that wasn’t very analogous to how patients would receive the medications. First, the corrector was administered to cells, and then those cells got an acute dose of the potentiator. Most patients, she thought, would take a combination pill.

“We performed the experiment in the way that it should have been performed. We added the two [drugs] at the same time, which mimics what you would do as a patient. The correcting effect was no longer visible; there was a strong inhibition,” Gentzsch said. “It is not the magic bullet right now.”


Gergely Lukacs, a professor of physiology at McGill University in Montreal, said he was surprised and disappointed when he did a similar experiment and found the corrected protein seemed to be easily destabilized by the potentiator. And the effect wasn’t simply due to how that one corrector drug works; the same destabilizing happened with another experimental corrector drug from Vertex called VX-661.

Lukacs noted an important caveat was that it was impossible to tell from these studies whether the same interference effect will occur in the human body, but he said the results suggest that studies should examine whether the combination drug is working as people thought by taking measurements that indicate the CFTR protein’s function.

The pair of studies suggests that while many researchers had been focused on the need to find drugs that more effectively “correct” the mutation, in fact there may be a need for a different drug that opens the cell’s gateway without destabilizing the fragile, corrected protein.

“It’s difficult to reconcile these results” of cells grown in a dish with the results in patients, said Chris Penland, vice president of research for the Cystic Fibrosis Foundation, which provided funding to both research teams. The foundation also has funded the development of Vertex’s experimental drugs and has an agreement with the company that allows it to share royalties if drugs are approved.

“I think that in the end the clinical trial results will trump all, and if you can’t demonstrate activity in cultured cells and yet there is a clinical benefit, you have to go with the clinical benefit,” Penland said.


Several doctors said that they hope the new therapy will be approved, but that the new evidence suggests the Vertex combination is not likely to be the final therapy for cystic fibrosis patients.

“We have more to go and it’s a worthy pursuit for another few years, to get the most out of this concept,” said Dr. John Clancy, professor of pediatric pulmonary medicine at Cincinnati Children’s Hospital Medical Center. “What it tells me is we can do better.”

Carolyn Y. Johnson can be reached at Follow her on Twitter @carolynyjohnson.