Aridis Meets Primary and Secondary Endpoints in Phase 2a Study of AR-501 in Cystic Fibrosis Patients

Rare Daily Staff

Aridis Pharmaceuticals said its experimental therapeutic AR-501 met the primary and secondary endpoints of safety and pharmacokinetics in a phase 2a study of the inhaled aerosol in cystic fibrosis patients with confirmed Pseudomonas aeruginosa bacterial and other potential infections.

The study was conducted with funding support from the Cystic Fibrosis Foundation. AR-501 is being developed as a once-per-week inhaled dosing regimen that is self-administered using a commercially available nebulizer device.

Cystic fibrosis (CF) is a genetic disorder that is caused by genetic changes in the CFTR gene and inheritance is autosomal recessive. It causes mucus to build up and damage organs in the body, particularly the lungs and pancreas. Cystic fibrosis patients often suffer from severe, persistent secondary bacterial lung infections due to their underlying lung disease which results in an immune-compromised state.

AR-501 is an inhaled formulation of gallium citrate that is being developed to treat chronic lung infections in cystic fibrosis patients. It is a non-antibiotic, broad acting antimicrobial with a mechanism of action involving interference with iron acquisition in microbes and disruption of microbial iron-dependent metabolic pathways distinct from current antibiotics. AR-501 acts as an iron analog and is believed to disrupt multiple iron dependent pathways in microbes, leading to growth inhibition. AR-501 has antimicrobial activities against a number of gram-negative and gram-positive bacteria, including antibiotic resistant strains. Preclinical efficacy and safety data have demonstrated that AR-501 works synergistically with multiple antibiotics, is effective against antibiotic resistant strains, and has a low intrinsic resistance profile.

The randomized, double-blind, placebo-controlled phase 2a study of AR-501 was primarily designed as a safety and PK trial in clinically stable cystic fibrosis subjects and due to the heterogeneity of concurrent medicine use (CFTR channel modulators and antibiotics) in the study subjects; exploratory objectives, such as microbiological burden of P. aeruginosa and lung function (FEV1), were not established in this study.

The study enrolled 42 adults, ages 18–80, with cystic fibrosis (CF) and confirmed P. aeruginosa bacterial colonization to evaluate the safety and pharmacological properties of three weekly doses of AR-501 administered as a liquid aerosol at low, mid, and high dose levels. Dose related increase in blood serum level of gallium was observed, reaching 0.6ug/mL AR-501 after the third inhaled dose at day 14 for the high dose cohort. Sputum levels of gallium, a surrogate for level in lung fluids, were well over 50 ug/mL, which is greater than 50-fold required to inhibit P. aeruginosa.

Three weekly inhaled doses of AR-501 at 6.4mg, 20mg, and 40mg dose levels were well tolerated in CF patients. No drug related serious adverse events (SAEs) were observed. The majority of treatment emergent adverse events (TEAEs) were respiratory in nature and mostly mild to moderate in severity.

CF patients achieved high uptake of AR-501 in the respiratory tract, as measured by sputum concentrations, at levels that were more than 50-fold higher than required for inhibition of the target bacteria P. aeruginosa. Inhaled delivery achieved more than 10-fold higher respiratory uptake of gallium (AR-501) than past clinical studies of intravenous (IV) gallium which resulted in lung function improvement and P. aeruginosa reduction.

” The high drug level achieved in the lungs along with low systemic exposure from inhaled delivery effectively overcome the limitations of conventional intravenous delivery, and provide a strong basis for a large efficacy study in CF and other lung infections,” said Hasan Jafri, chief medical officer at Aridis.

“The attractive safety profile of AR-501, combined with the recent results from our AR-301 mAb phase 3 program in older adults with ventilator associated pneumonia provide Aridis with two promising first-in-class, novel anti-infectives,” said Aridis’ CEO Vu Truong. Truong said the company will discuss with regulators a plan for the definitive next study for each program to support the filing of a license application.

An independent data and safety monitoring board consisting of CF physicians has reviewed the safety data and authorized the escalation to the 80 mg (highest) dose cohort. Aridis received approval by the FDA and support from the CF Foundation to continue the study with the 80mg cohort to explore the drug candidate’s potential at a higher dose. Data from the highest cohort are expected in the second half of 2023.

AR-501 has received Orphan Drug designation in the United States and in Europe, Fast Track and Qualified Infectious Diseases Product designations from the FDA as a potential treatment of CF-related lung infections.

Photo: Aridis’ CEO Vu Truong