Novel Cystic Fibrosis Treatments Breathe New Life Into the Therapeutic Space
Inhaled therapies that complement existing CFTR modulators set the stage for next-generation cystic fibrosis treatments.
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Cystic fibrosis (CF) is a multi-organ genetic disease estimated to affect more than 100,000 people globally. The loss-of-function mutation that causes CF results in the production and buildup of thick, sticky mucus in the lungs, pancreas and other organs. Today, advances in therapies and care mean many people with CF (pwCF) can continue to live healthy lives.
CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), which normally transports chloride and bicarbonate. Impaired function has consequences for the hydration and pH of the mucosal environment.
In the lungs, CF can cause a hyper-concentrated mucus gel that is hard to remove. “In health, CFTR drives chloride and fluid secretion into the airway lumen, which hydrates mucus, allowing it to flow and keep the airways clear of pathogens, the system that fails in pwCF,” Dr. Henry Danahay, head of biology at Enterprise Therapeutics, told Technology Networks.
Until the 2010s, care for pwCF focused on slowing lung disease progression with antibiotics, using physiotherapy and/or inhaled drugs to increase mucus clearance and improving nutritional status with pancreatic enzyme replacement or specific diet interventions.
The development of small molecules that partially restore the function of CFTR, known as CFTR modulators, has transformed therapy for many pwCF. CFTR modulators are divided into two types: potentiators and correctors. Potentiators expand the activity of CFTR in the membrane by increasing the probability of the channel being open. On the other hand, correctors are designed to help CFTR form the correct 3D shape to allow it to move to the cell surface.
Ivacaftor was the first CFTR modulator approved by the Food and Drug Administration in 2012. Five CFTR modulators have since been approved for use in people with certain mutations.
“Highly effective CFTR modulators have and continue to be a transformational therapy for the majority of pwCF, providing impressive increases in lung function,” Professor Martin Gosling, chief scientific and operating officer at Enterprise Therapeutics, told Technology Networks.
Despite the transformative effect of these therapies, CFTR modulators are not without their limitations. Most notably, current CFTR modulators are only effective in patients with one of the mutations that an existing drug targets.
“CFTR mutations expressed by ~10% of pwCF are not improved by current CFTR modulators,” said Gosling. In addition, “Not all suitable pwCF either tolerate CFTR modulators (due to side effects) or exhibit a clinically significant improvement in lung function.”
“Even in pwCF who do give a robust response to current CFTR modulators, their annual decline in lung function is higher than in healthy individuals and they do still experience exacerbations,” continued Gosling.
The development of new and potentially more efficacious modulators is ongoing. In addition, drug developers are turning their attention to new drug targets and the possibility of advanced therapies like mRNA and gene therapies.
Overcoming challenges in existing cystic fibrosis treatments
One avenue being explored for treating cystic fibrosis is inhibiting the epithelial sodium channel (ENaC). Enterprise Therapeutics has developed ETD001, a blocker of ENaC aimed at treating people with cystic fibrosis who don’t respond to current therapies. “As ENaC is not mutated in CF, the approach is applicable to all pwCF, unlike current CFTR modulators. This also provides the opportunity for ENaC blockers such as ETD001 to be used in combination with CFTR modulators to deliver enhanced efficacy,” explained Gosling.
ENaC absorbs sodium and, as a result, reduces airway fluid, concentrating the mucus and contributing to mucus plugging in the lungs in pwCF. By inhibiting ENaC function, it is possible to increase mucus hydration by keeping fluid in the airways.
“This premise is supported by human genetics where individuals with a genetic loss of ENaC function (Pseudohypoaldosteronism type 1) have supra-hydrated airways and an accelerated mucociliary clearance (MCC) rate, approximately three times faster than individuals with normal ENaC activity,” Danahay said.
ETD001 has been developed as an inhaled ENaC blocker, designed to have a long duration of action in the lungs. “The therapeutic hypothesis with an inhaled ENaC blocker is to essentially mimic this Pseudohypoaldosterism type 1 effect on airway mucus clearance, to keep the mucus flowing and thereby prevent mucus obstruction and recurrent lung infections,” explained Danahay. “In pre-clinical studies, ETD001 has been shown to accelerate MCC in vivo for at least 16h after a single low dose. Pharmacokinetic data from human studies have shown a profile associated with long lung retention.”
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For an ENaC inhibitor to be successful, the adverse effects that ENaC inhibition can have on the kidneys need to be overcome.
“ENaC blockers were originally developed as diuretics to treat hypertension,” said Danahay. “Blocking ENaC in the kidney leads to reduced sodium and water resorption, increasing urine volume. A consequence of sodium loss (termed ‘natriuresis’) can be elevation of plasma potassium levels (hyperkalaemia), which, if severe, can be potentially life-threatening.”
To overcome this, ETD001 was developed to be delivered at a low dose through inhalation, combined with improved lung retention. “The Phase 1 studies with ETD001 showed no changes in blood potassium levels at doses that are predicted to be far in excess of those required to observe clinical benefit in the lung,” stated Danahay.
The future for cystic fibrosis therapies
ETD001 is undergoing a Phase 2a efficacy study in pwCF unsuitable for taking CFTR modulators, with results expected in the second half of 2025. “A positive study here is expected to trigger additional studies in combination with CFTR modulators and potentially in other muco-obstructive diseases such as chronic bronchitis and bronchiectasis,” said Gosling.
“In addition to ETD001, Enterprise has an earlier program in the portfolio aimed at reducing the number of mucus-producing cells. This is a novel approach to treating respiratory diseases characterized by excess mucus and has the potential to deliver efficacy as both a standalone therapeutic and in combination with ETD001,” continued Gosling.
Other therapies currently in clinical trials include RCT2100, an inhaled gene therapy designed to deliver CFTR mRNA to target cells and instruct them to make a functional version of the CFTR protein. BI 3720931 is a lentiviral vector-based gene therapy designed to insert a functional copy of the CFTR gene into the DNA of airway epithelial cells.
CFTR modulators have brought about transformative changes to CF treatments. However, like many genetic disorders, treating CF is not one strategy that fits all. Despite being a single-gene disorder, there are multiple cystic fibrosis-causing genetic variants, and for many pwCf, there remains a need for improved treatments.
