Could cystic fibrosis drugs be repurposed for treating alcohol‐induced pancreatitis?

Acute pancreatitis (AP) is a sudden and potentially life-threatening inflammatory disease of the pancreas. The global incidence of AP varies significantly by region and aetiology, ranging from approximately 5 to 73 cases per 100,000, and has been increasing, making it a leading cause of gastrointestinal hospitalisations (Tenner et al., 2013). While many cases are mild and resolve spontaneously, about 20% of patients develop more severe forms, with mortality rates reaching up to 30% in the presence of multiple organ dysfunction syndrome or infected pancreatic necrosis. Alcohol consumption is a major risk factor, accounting for approximately 30%–50% of cases. Despite advances in supportive care, no specific pharmacological treatment currently exists, leaving a critical gap in the management of this condition. Pancreatic ductal cells play a key role in maintaining pancreatic health by secreting bicarbonate (HCO3⁻)–rich fluid, which is essential for two main reasons. First, it neutralises gastric acid as it enters the duodenum, creating a suitable pH environment for digestive enzyme activity. Second, it acts as a carrier for digestive enzymes produced by pancreatic acinar cells, safely transporting them to the duodenum. This prevents the premature activation of the enzymes, which could otherwise cause self-damage to the pancreas. At the heart of this process lies the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel which is also present on the luminal membrane of pancreatic ductal cells. CFTR not only provides chloride ions for the Cl⁻/HCO3⁻ exchange via the SLC26A6 transporter but also directly transports bicarbonate. Impaired CFTR function compromises bicarbonate secretion, leading to acidic, viscous pancreatic fluids that can obstruct ducts, cause enzyme buildup and may trigger pancreatitis through premature enzyme activation and autodigestion. Importantly, chronic alcohol consumption disrupts CFTR by impairing its folding, trafficking and reducing its expression at the apical membrane of ductal cells (Maleth et al., 2015). In many ways the CFTR dysfunction caused by alcohol resembles that seen in patients with cystic fibrosis, who are also at risk of pancreatitis due to their CFTR mutations. In the current issue Venglovecz et al. present a promising therapeutic approach by addressing alcohol-induced AP through CFTR modulation with Orkambi (Venglovecz et al., 2024). Originally developed for the treatment of cystic fibrosis, Orkambi combines ivacaftor and lumacaftor to restore CFTR function. Lumacaftor acts as a corrector, improving CFTR folding and ensuring its proper delivery to the cell membrane, thereby preventing the alcohol-induced reduction in CFTR expression within isolated guinea-pig pancreatic ducts. Ivacaftor, as a potentiator, increases the likelihood that CFTR channels remain open, even when alcohol disrupts cellular energy metabolism and reduces ATP availability. This ability to bypass ATP dependency is particularly advantageous, as alcohol-induced mitochondrial damage often results in ATP depletion. Together, these mechanisms ensure continued bicarbonate secretion, preventing the acidic environment that fosters pancreatitis. In a guinea-pig model of alcoholic AP, alcohol exposure significantly impaired CFTR function, reducing bicarbonate secretion, causing ductal damage and increasing inflammation. Treatment with Orkambi, however, successfully restored CFTR expression and activity, which in turn reduced pancreatic necrosis, inflammation and overall disease severity (Venglovecz et al., 2024). These findings are particularly noteworthy, as they offer convincing preclinical evidence that CFTR modulators like Orkambi could be repurposed to treat alcohol-induced AP. Drug repurposing – finding new applications for existing medications – offers several advantages. It reduces development timelines and costs because the safety and efficacy of the drugs have already been established. Furthermore, this approach may extend the market life of existing drugs, providing financial incentives to pharmaceutical companies. The known safety profiles of these drugs also mitigate the risk of unexpected side effects, facilitating regulatory approvals. In conditions like AP where no specific treatments currently exist, drug repurposing could offer a swift and effective solution. Thus, applying CFTR modulation with Orkambi for alcoholic AP could open an exciting new avenue for managing this condition and preventing long-term complications caused by inflammation. Scientific efforts to develop pharmacological treatments for AP have been ongoing, with notable progress made in targeting other mechanisms. For example postulated strategies to inhibit Orai1 or TRPM2 channels focus on pancreatic acinar cells, aiming to prevent cytosolic calcium overload, which triggers the premature activation of digestive enzymes and cell necrosis (Fanczal et al., 2020; Gerasimenko et al., 2013). In contrast, Orkambi targets the pancreatic ductal cells, restoring bicarbonate secretion and addressing the ductal dysfunction that also plays a significant role in the progression of the disease. These therapeutic strategies could potentially complement each other in clinical practice, offering a comprehensive approach by addressing both acinar and ductal cell dysfunction. Looking ahead there is a clear need to extend research into Orkambi's clinical application for treating AP in humans. Future studies should evaluate the drug during AP's inflammatory phase to understand its impact on disease progression and patient outcomes. It could also be of interest to explore whether Orkambi can prevent subsequent episodes after an initial attack, given the high recurrence rate of alcoholic AP. This would confirm not only Orkambi's therapeutic potential but also its preventive capabilities. By restoring bicarbonate secretion and protecting the pancreatic ducts from further damage, Orkambi could play a key role in breaking the cycle of recurrence associated with prolonged alcohol consumption, thus improving patient outcomes and potentially transforming the management of alcoholic AP. As CFTR modulators continue to evolve, they could become essential tools in managing and preventing AP, bringing hope for improved long-term pancreatic health and better overall patient outcomes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The author declares no conflict of interest. P.E.F.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. Narodowe Centrum Nauki (NCN): Pawel E. Ferdek, 2022/46/E/NZ3/00200.