The trial’s design, along with CB-280’s preclinical data, was presented by Joel D. Mermis, MD, of the University of Kansas Medical Center, at the 2020 North American Cystic Fibrosis Conference (NACFC) taking place virtually Oct. 7–23.
CB-280 is a potent suppressor of arginase, an enzyme responsible for converting the amino acid arginine into urea and ornithine, and that is overly active in CF, leading to a shortage of arginine in the lungs. (Amino acids are the building blocks of proteins.)
Since arginine is required for the production of nitric oxide (NO), a naturally occurring gas known to help the lungs resist pathogens by triggering the immune system, arginine deficiency lowers anti-microbial airway resistance and lung function.
By blocking arginase and raising arginine levels, CB-280 is expected to restore NO production, improving lung function and resistance to microbes that cause lung infections, including the bacteria Pseudomonas aeruginosa (P. aeruginosa).
“CB-280 is the first arginase inhibitor to be evaluated for the treatment of cystic fibrosis,” Susan Molineaux, PhD, Calithera’s president and CEO, said in a press release.
“There remains a significant need for investment in and therapeutic innovations for cystic fibrosis, and based on the strong mechanistic rationale, we are optimistic about the potential for arginase inhibition in the treatment of this devastating disease,” Molineaux added.
According to poster data, CB-280 treatment significantly reduced airway resistance (improving lung function) and P. aeruginosa infection in CF mouse models. In addition, a small clinical trial in Canada reported that repeated administration of inhaled arginine to CF patients increased NO production and resulted in a trend toward better lung function.
Calithera has completed a Phase 1 clinical trial assessing the safety, tolerability, and pharmacological profile of CB-280 in healthy volunteers.
The ongoing, dose-escalating Phase 1b study (NCT04279769) will evaluate the therapy’s safety, pharmacokinetics (movement into, through, and out of the body), and pharmacodynamics (effects on the body) in about 32 adults with CF and chronic lung infections caused by P. aeruginosa.
Eligible patients must have moderate-to-mild lung function (percent predicted forced expiratory volume in one second of 40%–90%) and be on stable CF medication for at least 28 days before enrollment, including CFTR modulators. They must also have no history of supplemental oxygen or inhaled NO in the 28 days prior to enrollment, and of smoking or vaping in the past six months.
Enrollment is taking place at 11 clinical sites across the U.S. More information on contacts and locations can be found here.
Participants will be randomly assigned to either one of four doses of CB-280 — 50, 100, 200, or 400 mg; six patients for each dose — or to a matching placebo, given orally twice-a-day for 14 days.
Additional patient groups to test intermediate doses may be added to the trial’s protocol, depending on safety data from planned dose groups.
The study’s main goal is to determine a safe dose range for CB-280, while secondary goals include the therapy’s pharmacokinetics and pharmacodynamics.
As exploratory goals, the trial will also assess changes in airway NO and sweat chloride levels, microbes in sputum (saliva and mucus coughed up from the lungs), biomarkers of arginine, arginase, and NO metabolism, and changes in the respiratory domain of the CF Questionnaire-Revised.
Patient dosing began in July, and Calithera expects to share interim trial data in 2021.
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