AB569: Treatment for Drug Resistant Bacterial Infections
AB569 is a new drug candidate for treating antibiotic resistant bacterial infections, primarily in the lungs and urinary tract. It also has potential to be modified for use in other indications, including adaptation as a topical cream for bacterial skin infections.
AB569 has a mechanism of action that differs from the mechanism of action of antibiotics. AB569 has orphan drug status in the U.S. for the treatment of Pseudomonas aeruginosa infections in the respiratory tracts of patients with cystic fibrosis. AB569 has orphan medicinal product designation in Europe for the treatment of cystic fibrosis.
Respiratory Pseudomonas Aeruginosa Infections
Two deadly diseases, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), are exacerbated by airway bacterial infections that significantly impact the overall quality of patient’s lives. There are approximately 40,000 CF patients and over 14 million individuals diagnosed with COPD in the United States. In both diseases, antibiotic resistant Gram-negative bacteria, such as Pseudomonas aeruginosa (P. aeruginosa), often constitute a significant and problematic cause of the pulmonary exacerbations that result in frequent hospitalizations of these patients.
In particular, the mucoid form of P. aeruginosa is a very challenging infection to treat due to its high resistance to both antibiotics and phagocyte–mediated killing. Once patients present with the mucoid form of P. aeruginosa, their overall lung function precipitously declines resulting in a poor prognosis.
CF patients are predisposed to lung infections due to abnormal mucus production in the lungs and airways. P. aeruginosa infects 40% of CF patients between the ages of 6 and 10 years of age. By the age of 17, the frequency of infection increases to 60% and reaches approximately 70% of all CF patients between the ages of 25 and 34. Thus, there is an urgent clinical need for the development of novel effective treatments in this area.
AB569 constitutes an innovative, bactericidal method to treat mucoid and nonmucoid P. aeruginosa pulmonary infections, as well as other types of bacterial pulmonary infections, that are resistant to traditional antibiotics.
The World Health Organization has declared antibiotic resistance to be one of the biggest threats to global health and development today. According to WHO, while there are new antibiotics currently in development, none are expected to be effective against the most dangerous forms of antibiotic-resistant bacteria. The Company’s AB569 is a non-antibiotic drug that could be a viable alternative or adjunct therapy to current standard of care antibiotics.
Exclusive License with University of Cincinnati on Patents Relating to AB569
In March 2016, the Company entered into an exclusive license agreement with the University of Cincinnati (UC) for the commercial rights to the U.S. patent and patent applications protecting AB569 as an antimicrobial treatment of bacterial infections, including antibiotic resistant infections in the lungs and urinary tract.
Pursuant to the license with UC, the maintenance of issued patents and new patent applications relating to AB569 are being managed by the Company’s patent attorneys in the U.S. at the Company’s expense.
Orphan Drug Designation for AB569 for P. aeruginosa lung infections in Cystic Fibrosis
In November, 2015, Arch Biopartners received Orphan Drug Designation on AB569 from the U.S. Food and Drug Administration for the treatment of P. aeruginosa lung infections in cystic fibrosis (CF) patients.
The Orphan Drug Designation has been granted for the combination of two active ingredients of AB569: sodium nitrite and ethylenediaminetetraacetic acid (EDTA). AB569 is to be administered to patients as a nebulized (inhaled) solution. AB569 was invented at the University of Cincinnati in the lab of Dr. Daniel Hassett.
In pre-clinical studies, Dr. Hassett and his team demonstrated the potency of acidified sodium nitrite and EDTA in killing drug resistant bacteria including Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia under both aerobic and anaerobic planktonic (free-living) and biofilm (surface-attached) conditions. These bacteria are among the most common pathogens to chronically infect the lungs of patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF).
The FDA Office of Orphan Products Development grants Orphan Drug Designation to drugs and biologics to encourage the development of new medicines for the safe and effective treatment of underserved, rare diseases or disorders that affect less than 200,000 patients in the U.S.
The Orphan Drug Designation qualifies Arch for a seven-year term of market exclusivity to sell AB569 in the U.S. following FDA approval of the drug. Additionally, as Arch takes AB569 through the regulatory and human trial process, the Orphan Drug Designation provides an accelerated review and approval process, potential grant funding, tax benefits and an exemption from certain user fees.
Earlier in February 2016, Arch formed an Irish based subsidiary named Arch Bio Ireland Ltd to sponsor and submit an orphan medicinal product application for AB569 to the European Medicines Authority (EMA). In April, 2016, the EMA Committee for Orphan Medicinal Products (COMP) issued a positive opinion recommending AB569 for designation as an orphan medicinal product for the treatment of patients with CF. Final approval from the European Commission for designation of AB569 as an orphan medicinal product in Europe was granted to Arch in early June, 2016.
Medical Advisory Board for AB569
In 2016, Arch management formed a clinical and medical advisory board to support future planning and clinical development of AB569. The advisory board provides guidance and expertise on obtaining regulatory approvals, human trial design and patient enrolment to enable first-in- human trials for AB569 in patients with chronic lung infections.
The members of the clinical and medical advisory board are:
For Cystic Fibrosis (CF):
Dr. Bruce Trapnell, MD, Director, Translational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center (CCHMC), Professor of Medicine and Pediatrics, University of Cincinnati (UC).
Dr. Patricia Joseph, MD, Professor of Medicine and Pediatrics, UC College of Medicine and Director of the Adult CF Center at the UC Medical Center.
For Chronic Obstructive Pulmonary Disease (COPD):
Dr. Ralph J. Panos, MD, Chief of Medicine, Cincinnati Veterans Affairs Medical Center (CVAMC).
Human Trial Plans for AB569
Between 2015 and 2017, the AB569 scientific team successfully completed pre-clinical in vivo and in vitro validation studies. In all studies, AB569 has demonstrated significant efficacy in destroying P. aeruginosa and other antibiotic resistant bacteria. This includes a recent study involving a chronic pulmonary infection model in mice performed at the University of Illinois.
The Arch team believes these results provide the scientific rationale for pursuing a human trial to test the safety and efficacy of AB569 for CF and/or COPD patients whose airways are chronically infected with P. aeruginosa and other types of bacteria.
In April, 2017, Arch announced that the Cincinnati Veterans Affairs Medical Center (CVAMC) will conduct an investigator initiated Phase I human trial to evaluate the safety and pharmacokinetic profile of AB569 as an inhalation drug candidate for treating antibiotic-resistant bacterial infections in the lungs.
Dr. Ralph Panos, Chief of Medicine at CVAMC and world-renowned COPD expert, is the lead investigator of the trial. Arch is funding the study, contributing AB569 clinical inhalation kits and other materials to support the trial. The AB569 inhalation kits were delivered to CVAMC during the month of January 2018 and final preparations are underway to enrol the first patient into the trial.
Clinical investigators at the CVAMC will evaluate single administration of nebulized AB569 in normal participants. The Phase I trial has been designed to determine the pharmacokinetic profile of plasma nitrite and nitrate metabolites, exhaled nitric oxide and circulating hemoglobin after a single inhalation of AB569. In addition, the trial also aims to determine the tolerance of nebulized AB569 in three escalating doses of acidified sodium nitrite and EDTA.
Dr. Hassett’s team has also shown the potential of AB569 to be used for treating drug resistant urinary tract infections and as an effective catheter lock solution to inhibit infection and destroy bacterial biofilms commonly observed in dialysis patients.
The Company’s sponsorship of the human trial application to the Internal Review Board of CVAMC and University of Cincinnati was facilitated through the Cincinnati Education and Research for Veteran’s Foundation.
Manufacturing of AB569 Clinical Inhalation Kits
In support of Arch Biopartners’ GMP manufacturing campaign for AB569, Dalton Pharma Services (Dalton) in Toronto, Canada, provided formulation development, cGMP powder and liquid filling, analytical method development and validation, and quality control release testing.
During August 2016, Arch engaged Catalent Inhalation, a division of Catalent Pharma Solutions (Catalent), to begin the manufacturing process for AB569 in preparation for the first human trials involving patients with antibiotic resistant lung infections.
Catalent Inhalation completed initial stability and formulation studies, which are both important production milestones in preparing a pharmaceutical product for human trials and eventual drug approval by the U.S. Food and Drug Administration and other health authorities.