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Three-Drug Combination Improves Lung Function in Most Common Genetic Form of Cystic Fibrosis

A phase three clinical trial that the University of Texas (UT) Southwestern Medical Center participated in has determined that a three-drug combination improved lung function and reduced symptoms in cystic fibrosis (CF) patients who have a single copy of the most common genetic mutation for the disease. Earlier this month, the Food and Drug Administration approved the therapy based on the results of this international study, published online on October 31, 2019 and in the November 7, 2019 issue of the New England Journal of Medicine. The article is titled “Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.” A companion investigation, appearing simultaneously in The Lancet, reported on people with one or two copies of the mutation. The Lancet article, published online on October 31, 2019 and in the November 23, 2019 issue, is titled “Efficacy and Safety of the Elexacaftor Plus Tezacaftor Plus Ivacaftor Combination Regimen in People with Cystic Fibrosis Homozygous for the F508del Mutation: A Double-Blind, Randomised, Phase 3 Trial.” A commentary article (“Entering the Era of Highly Effective CFTR Modulator Therapy”) also appears in The Lancet. Raksha Jain (photo), MD, Associate Professor of Internal Medicine at UT Southwestern Medical Center, is corresponding author of the NEJM article and an investigator on The Lancet study. Dr. Jain presented both studies at the North American Cystic Fibrosis Conference 2019 in Nashville October 31 to November 2. CF is a chronic, progressive, and frequently fatal genetic disease that affects the respiratory and digestive systems in children and young adults. The sweat glands and the reproductive system are usually also involved. Individuals with CF have a shortened lifespan. “Although there are over a thousand different disease-causing mutations, nearly 90 percent of people with cystic fibrosis have at least one copy of the most common mutation, the Phe508del CFTR allele,” Dr. Jain said. An estimated 80,000 people worldwide are affected by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, she said. People inherit a gene from each parent that encodes the CFTR protein. CF is an example of a recessive disease. That means a person must have a mutation in both copies of the CFTR gene to have CF. If someone has a mutation in only one copy of the CFTR gene and the other copy is normal, he or she does not have CF and is a CF carrier.

“This three-drug combination was highly effective in people with cystic fibrosis who inherited the Phe508del CFTR mutation, improving health outcomes and symptoms,” said Dr. Jain, referring to the NEJM study on those with one mutated copy of the gene.

In the clinical trial conducted at 115 sites in 13 countries from June 2018 to April 2019, 403 patients of ages 12 and older were randomized to receive either elexacaftor-tezacaftor-ivacaftor combined therapy or a placebo. The trial was co-sponsored by Vertex Pharmaceuticals.

Lung function was measured at 4 and 24 weeks. Compared with patients receiving a placebo, lung function in the treatment group was significantly improved at four weeks and sustained through week 24. In addition, lung flare-ups, or increases in symptoms, were 63 percent lower in the treatment group. Study participants also answered questionnaires regarding their quality of life and respiratory symptoms – with those in the treatment group reporting higher scores in these areas.

Excessive amounts of salt via sweating is a hallmark of cystic fibrosis. The treatment group had a lower concentration of salt in their sweat than the placebo group, which demonstrates how this therapy in targeting the underlying cause of the disease, Dr. Rain added.

Adverse events leading to discontinuation occurred in 1 percent of those receiving the drug combination. Although the therapy was generally safe and well-tolerated, long-term studies are needed to further understand potential side effects, Dr. Jain said.

“The CF community is working hard to find highly effective therapies for people who are not eligible for this treatment because they don’t have the appropriate gene mutation,” said Dr. Jain, a Dedman Family Scholar in Clinical Care and Director of the UTSW Adult Cystic Fibrosis Center.

UTSW received funding from Vertex. Other sites received funding from the National Institutes of Health.

Dr. Jain, who has worked on clinical trials with Vertex for eight years, reports advisory board and consulting fees from the company.

[Press release] [NEJM abstract] [The Lancet abstract] [The Lancet commentary] [Vertex Pharmaceuticals]