3-drug treatment could be a breakthrough in cystic fibrosis

By Amy Norton
HealthDay Reporter

THURSDAY, OCTOBER 18, 2018 (HealthDay News) – In what researchers call a "breakthrough," two preliminary trials have shown that one or the other of two treatment regimens for triple therapy could potentially benefit 90 % of people with cystic fibrosis.

Trials were short-lived and showed that drug combinations improved lung function in adult patients for four weeks. But experts have been optimistic about the results of larger, longer-term trials already under way.

What's more exciting, they said, is that the three-drug approach could offer new options to almost every patient with cystic fibrosis.

"This is not a cure for cystic fibrosis," said Dr. Steven Rowe, who led one of the trials. "But that could change the game."

CF is a genetic disease that causes persistent lung infections. Over time, extensive lung lesions cause respiratory failure. At one time, children with CF usually died before school age. But with improved treatments, the typical life expectancy is now about 40 years old, according to the Cystic Fibrosis Foundation.

Cystic fibrosis is caused by various mutations of a gene called CFTR. In recent years, drugs targeting the underlying genes have become available. Known as CFTR modulators, they have been reported as a major breakthrough in the treatment of the disease.

However, they only work well for a small number of people with certain mutations of the CFTR gene, explained Rowe, director of the Cystic Fibrosis Research Center at the University of Alabama in Birmingham.

The most common mutation that causes cystic fibrosis is called F508del – and it has proven more difficult to fight, says Rowe.

About half of people with CF carry two copies of the mutation (inherited from each parent). For them, the combination of two existing CFTR modulators can relieve breathing problems – but the overall effects are only "modest," Rowe said.

Next come the 30% of CF patients who only own one copy of the F508del, as well as another defect called "minimal function" mutation. For them, existing CFTR modulators do not work at all.

The two new trials focused on these two groups of patients. The results are published on October 18th. New England Journal of Medicine, to coincide with the researchers' presentation at a North American meeting on cystic fibrosis in Denver.

The Rowe team has tested a combination of two available CFTR modulators – tezakaftor and ivakaftor – and an experimental one, called VX-659. The other trial was using the same existing drugs, as well as a new, similar drug called VX-445.

The Rowe team randomly assigned 54 adults with cystic fibrosis to follow the three-drug regimen or to be part of a control group. In the comparison group, patients with a F508del mutation took a placebo, while patients with two copies of the mutation took tezakaftor and ivakaftor alone.

The trial showed that triple therapy improved lung function in patients with both types of mutations after four weeks. Their performance in a test called FEV1 increased by 13 percentage points on average – what Rowe described as a "steep improvement".

The other test had almost identical results.

It's the first time, says Rowe, that CFTR modulator treatment "pushes the needle" in patients with a F508del mutation.

An editorial published with the studies indicates that they "represent a major breakthrough".

Now the questions are whether improved lung function can be maintained and whether drugs prevent exacerbations of symptoms and other complications, wrote Dr. Fernando Holguin of the University of Colorado, Aurora.

The Cystic Fibrosis Foundation helped fund this work by providing a grant to Vertex Pharmaceuticals, Inc., which is developing both experimental drugs.

"The ability of these potential drugs to treat individuals carrying a single F508del mutation means that more people than ever before could benefit," said Dr. Michael Boyle, executive vice president of therapeutic products at the foundation. "It's a very exciting news for our community."

Rowe agreed that there remained important questions about three-drug regimens. The first is, how do they work for younger patients?

Patients younger than 12 years old are included in the larger trials underway, Rowe said.

Until now, the treatments seem safe. Most of the side effects seen in clinical trials lasting four weeks were "mild to moderate," the researchers said.

If the experimental drugs are finally approved, there will be a real world price problem.

Vertex currently markets the combination of tezakaftor and ivakaftor under the name Symdeko – at a list price of $ 292,000 per year.

In the United States, more than 30,000 people have cystic fibrosis, according to the foundation.

More information

For an overview of cystic fibrosis, visit the Cystic Fibrosis Foundation.

SOURCES: Steven Rowe, M.D., M.S.P.H., Director, Gregory Fleming James Center for Research on Cystic Fibrosis, University of Alabama, Birmingham; Michael Boyle, M.D., Executive Vice President, Therapeutics, Cystic Fibrosis Foundation, Bethesda, Md .; October 18, 2018, New England Journal of Medicine