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Q&A: Success of triple therapy in cystic fibrosis
Two studies — one published in The New England Journal of Medicine and one published in The Lancet — have shown the promise of combination therapy with elexacaftor, tezacaftor and ivacaftor in certain patients with cystic fibrosis. Although the treatment was studied in two different patient populations, the findings from both studies highlight the therapeutic benefits of this triple therapy.
In the NEJM study, elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) improved lung function and pulmonary exacerbations in patients aged 12 years and older with cystic fibrosis with Phe508del-minimal function genotypes who did not previously respond to cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy.
In The Lancet study, elexacaftor/tezacaftor/ivacaftor, as compared with tezacaftor plus ivacaftor alone, also improved lung function, respiratory-related quality of life and sweat chloride concentrations in patients aged 12 years and older with cystic fibrosis homozygous for the F508del mutation.
Raksha Jain, MD, MS, associate professor of medicine in pulmonary and critical care at the University of Texas Southwestern Medical Center and researcher for the study published in NEJM, discussed the findings as well as other important issues related to caring for patients with cystic fibrosis.
Question: How does your study compare with previous studies?
Jain: In some ways, these results are transformative in that this is a study that’s potentially going to impact a much larger number of people. These results are similar to what we have seen with the use of ivacaftor in people with cystic fibrosis who have certain genes but maybe even greater.
Q: Were any of the results surprising to you?
Jain: They were very similar to the phase 2 study results, so while we are excited, I do not think they were different than what we would have expected based on the phase 2 results.
Q: What were the strengths and limitations of the study?
Jain: Its major strength is that it is a well-designed, randomized, double-blind, placebo interventional trial, which is the gold standard for a clinical trial, and it was conducted in a population that did not previously have a modulator therapy available. In terms of limitations, as with all studies, we were unable to include the entire population. Overall, though, it was fairly well done.
Q: Which findings do you think may be most important?
Jain: One is the very positive impact we see on lung function, which tends to be a very good marker of health in cystic fibrosis. Second, the decline in sweat chloride is significant because that really points to this therapy treating the underlying cause of cystic fibrosis. Third, the treatment’s impact on the symptoms per the questionnaire is noteworthy because it shows that people felt better, which is important. Additionally, there was a decrease in exacerbations that should be beneficial and help improve patients’ quality of life as well because it should mean that people get sick less often.
Q: How do the findings from your study complement those published in The Lancet ?
Jain: There were similarities in the beneficial impact of the treatment on lung function, quality of life and decrease in sweat chloride, so the results are fairly compatible. People who have two copies of the F508del mutation did have modulators available to them, but people who have a single copy of this F508del mutation previously had no modulator therapy available, and per the results of this trial, they may experience a notable improvement in their health with the use of these agents.
Q: What would you like to see studied further?
Jain: Evaluation of the long-term benefits and long-term side effects is key. They are always important to track, and I believe they will be tracked. Also, we would ideally like to be able to help patients who are not eligible for this therapy by providing research and resources to focus on that population who is in need of something to help them as well.
Q: Are there any other issues or topics related to cystic fibrosis that warrant more attention?
Jain: I think treating the extrapulmonary aspects of cystic fibrosis is becoming important. For so long, we focused on improving lung health because that is a major cause or morbidity and mortality in cystic fibrosis. Now, that is improving and although there is not a cure, people are living longer and healthier lives. We need to spent additional effort understanding all the complications of cystic fibrosis that occur outside the lungs and develop therapies, treatment and care for those other extrapulmonary complications. I think that will be the next big area of interest.
Also, now that patients with cystic fibrosis are living longer, we need a lot of re-education for physicians who care for adults. Many physicians trained in an era where cystic fibrosis was a disease for pediatricians, and it was not highlighted in the training for internists and internal medicine subspecialists. We need to keep up with the fact that these patients are going to be seeking care from different types of subspecialists who may not be used to seeing people with cystic fibrosis. I do think we’re going to have to disseminate a lot of education about the illness.
Q: Do you have a take-home message?
Jain: This is a true step in the progress of targeting therapy at a genetic condition. Hopefully, this provides hope for many people who also care for and have other genetic diseases. Maybe this can serve as a model for other illnesses in trying to find therapies for those as well. – by Melissa Foster
For more information:
Raksha Jain, MD, MS, can be reached at raskha.jain@utsouthwestern.edu.
Disclosure: Jain reports she has served as a consultant and as an advisory board member for Vertex Pharmaceuticals.