Just three decades ago, the average life expectancy of people with cystic fibrosis was around 30 years of age. This has now improved to 50, with some patients living into their 80s. Treatments for cystic fibrosis have also evolved over the years. In fact, a report has revealed that recent advancements in cystic fibrosis research have gradually raised life expectancy, and is predicted to increase by 75% by next year.
People with cystic fibrosis tend to have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene codes for the CFTR protein, which is responsible for regulating the flow of salt in and out of the cells in the body. As a result of the mutation, salt becomes trapped in the cells. Without the flow of salt, cell surfaces become dehydrated. This leads to a thick, sticky mucus that gets coated on the lungs and other parts of the body, making it not only hard for people to breathe but also more prone to infections.
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CFTR modulators change the game for cystic fibrosis patients
One notable breakthrough in recent times has been CFTR modulators. These drugs are designed to get the CFTR proteins to function properly. This way, a proper salt channel is created so that salt can move across cells, and so can water to hydrate the cells. While modulators cannot fully restore chloride flow – a molecule found in salt -, they can improve the flow to a point where patients experience symptom relief.
“Undoubtedly, the most impactful advance in cystic fibrosis treatments has been in CFTR modulators,” said Nadia Shive, trial manager at British biotech Lindus Health. “The treatment has stabilized the disease for many adults, and will continue to transform the face of the disease now that people with cystic fibrosis can start treatment so early in life before the trademark decline in lung function and gastrointestinal health begin.”
The most effective modulator is Trikafta, explained Shive. It is a combination of three modulators, two of which are correctors and one is a potentiator. Correctors help ‘correct’ the shape of the misformed CFTR protein, whereas potentiators hold the gate open for salt to pass through cells.
The drug was approved by the U.S. Food and Drug Administration (FDA) for patients aged 12 and older who have at least one F508del mutation, which is the most common type of cystic fibrosis mutation. It makes up 90% of the cystic fibrosis population.
However, while CFTR modulators are a step up from antibiotics (to treat lung infections) and mucus thinners (to clear mucus from the lungs), these drugs are quite expensive.
Costing more than $300,000 a year in the U.S., calls to revoke Vertex Pharmaceuticals’ Trikafta patent have been made in countries like South Africa, Brazil, India and Ukraine as the drug is inaccessible for patients in low- and middle-income countries. And while the U.K.’s National Institute for Health and Care Excellence (NICE) lauded the drug for its clinical benefit, it stopped short of tagging the drug as ‘cost-effective’ in its latest draft guidance. Some patients across the world also rely on generic drugs manufactured in countries like Argentina where Vertex does not have a patent, according to a report by The Guardian.
Can Enterprise Therapeutics’ drug meet patient needs?
Moreover, there are still unmet needs for patients with cystic fibrosis, particularly those who have mutations different from the ones that CFTR modulators target.
“It’s a priority of the Cystic Fibrosis Foundation and the cystic fibrosis research community to develop similar treatments for this population,” said Shive.
The U.K.’s Enterprise Therapeutics has come up with a treatment to address the needs of this population. Its drug ETD001 inhibits the epithelial sodium channel (ENaC). ENaC regulates the volume of fluid that bathes the airway surface and is critical for the formation of mucus, explained Martin Gosling, chief scientific officer (CSO) of Enterprise Therapeutics.
“Mucus plugs can both directly obstruct the airways and form a nidus for infection, resulting in ongoing respiratory infections and a chronic colonization of the lungs with a range of pathogens. Chronic infection and the associated inflammation drive a vicious cycle of repeated lung injury and repair, resulting in progressive lung damage (bronchiectasis) and airflow limitation with significant morbidity and mortality,” said Gosling. “Inhibiting the function of ENaC improves the hydration of mucus and increases the clearance of the bacteria, viruses and fungi we inhale every day.”
In preclinical studies, ETD001 boosted the clearance of mucus for longer than 12 hours after a single dose. This is linked to the slow absorption of the drug out of the lungs. Moreover, phase 1 studies showed “a pharmacokinetic profile consistent with long lung retention, and no evidence of any of the potential on target side effects associated with systemic ENaC blockade.” Phase 2 trials will begin this month.
Unlike CFTR modulators, which improve hydration in the lungs by enhancing the secretory pathway, ENaC blockers such as ETD001 hinder the absorptive pathway.
“Some classes of mutation in CFTR can result in a failure to synthesize the protein and affected individuals fail to respond to CFTR modulator drugs. Mutations in CFTR also exist where CFTR protein is synthesized but fails to respond to CFTR modulator drugs,” said Gosling. “As such, it (ETD001) has the potential to treat people with cystic fibrosis not currently eligible or receiving benefit from CFTR modulators, and further improve lung function when administered in combination with CFTR modulators.”
Gosling pointed out that although CFTR modulators may be life-changing for many patients, it is not a cure. And while ETD001 isn’t a cure either, administering it in combination with modulators offers the potential to reduce symptoms even further.
Can cystic fibrosis be treated with gene therapy?
Meanwhile, gene therapy research is garnering attention as well. In gene therapy, the correct version of the CFTR gene would be administered to patients. Although the faulty genes would still be present, the new copies would encourage the normal production of CFTR.
American biotech 4D Molecular Therapeutics’ 4D-710 is an inhalable drug that uses the A101 vector for its single-dose delivery. It is currently in phase 1/2 trials. According to a phase 1 exploratory study, CFTR proteins were expressed in 92 to 99% of the cells in the lungs. These results were in line with interim results that were published more recently.
Another gene therapy in the clinic is American biopharma Krystal Biotech’s KB407. A phase 1 trial for the drug began last year.
According to the Novotech report, there have been over 450 studies for cystic fibrosis treatments since 2018. The U.S. and Europe – Germany and the U.K. in particular – are in the lead followed by the Asia Pacific region. But Shive thinks that conducting these studies is not without its difficulties.
Cystic fibrosis clinical trials: not without its challenges
“Historically, some of the biggest challenges included distance from sites (many states have only a handful, if any, specialized cystic fibrosis care centers), disease stability (keeping people healthy enough long enough to enroll in a trial), and treatment burden as many patients already had a regimen that took hours per day and were hesitant or unable to add more. Anecdotally, what I hear now from my former colleagues is that with so many people quite stabilized on modulators, they have less frequency in the clinic, and therefore less connection to the care and research teams,” said Shive.
Besides, Shive believes that along with treatment needs to be fulfilled, there are other issues that accompany a cystic fibrosis diagnosis.
“Adequate treatment for depression and anxiety remains a need in cystic fibrosis,” said Shive. “Interestingly (and concerningly), there is somewhat of a phenomenon of increased worry and strife in adults who are now living or expected to live much longer lives than they knew possible. They made choices – such as not going to college, saving for retirement, or not having children – expecting that they wouldn’t live past their previous life CF expectancy of late 30s.”
Nevertheless, it is a fact that the life expectancy for people with cystic fibrosis has risen, and with more therapeutic studies along the way, this statistic could only improve from here on.
New technologies related to cystic fibrosis:
- Pharmaceutical Composition for the Treatment of Cystic Fibrosis – University of Burgos
- Use of Proteasome Targeting Small Molecules to Mitigate Muscle Wasting – UT Health San Antonio
- Repurposing of Reverse Transcriptase Inhibitors to Alleviate TLR5-mediated Inflammation in Cystic Fibrosis – Cornell University
This article was originally published in November 2021 by Clara Rodríguez Fernández and has since been updated.