Arginase Inhibitor Cystic Fibrosis

Airway disease in Cystic Fibrosis (CF) has complex pathophysiology and remains an unmet need.

CB-280 is a potent and selective oral inhibitor of arginase. Arginase plays an important role in the pathophysiology of CF airway disease. Sputum from patients with CF has elevated arginase activity leading to diminished arginine levels. Reduced arginine is thought to exacerbate pulmonary disease in CF by impairing the production of nitric oxide, leading to a diminished anti-microbial immune response and impaired airway function. It is known that the airways of patients with CF have lower than normal nitric oxide production, and lower nitric oxide levels directly correlate with worsened lung function and increased colonization with pathogens, including Pseudomonas aeruginosa. Research in CF patients has demonstrated that increasing arginine levels can increase the production of nitric oxide and improve lung function.

Calithera completed a Phase 1 single ascending dose trial to evaluate the safety, tolerability and pharmacokinetic profile of oral CB-280 in healthy volunteers. In July 2020, Calithera initiated a Phase 1b clinical trial (NCT04279769) in adult patients with cystic fibrosis and chronic airway infection. The randomized, double blind, placebo-controlled, dose escalation trial will evaluate multiple ascending doses of CB-280, dosed orally twice daily for 14 days, compared to placebo in up to 32 adult CF patients to determine a safe dose range for CB-280. In October 2020, Calithera presented a trial in progress poster detailing the trial design at the North American Cystic Fibrosis 2020 Virtual Conference. The poster presentation includes preclinical study results which suggest CB-280 significantly improved lung function and reduced Pseudomonas aeruginosa colony-forming units in pre-clinical models. Arginase inhibition with CB-280 resulted in improved central airway resistance in CFTR knockout mice and decreased lung infection in wild type and DeltaF508-CFTR-expressing mice infected with Pseudomonas aeruginosa. In November 2020, Calithera was awarded up to $2.4 million from the Cystic Fibrosis Foundation.