AP-PA02
AP-PA02 is a therapeutic phage cocktail that targets the pathogen P. aeruginosa, to treat serious respiratory infections, with an emphasis on patients with cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis (NCFB).
AP-PA02 is one example of the novel product candidates to emerge from Armata’s robust research and development capabilities. Phages that comprise AP-PA02 were selected with desired attributes for a product candidate targeting P. aeruginosa lung infections. AP-PA02 is comprised of a cocktail of natural P. aeruginosa phages originating from distinct families and subfamilies, targeting multiple receptor classes, functioning with compatibility and cooperativity, and further characterized by being highly potent and having a broad host range. Preclinical highlights of AP-PA02 include:
- Significantly reduced P. aeruginosa biofilm mass in vitro;
- Persistence of active phage particles in the lung;
- Limited systemic and off-target organ distribution;
- Decreased mortality in a murine model of acute P. aeruginosa lung infection;
- Components are stable in relevant biological fluids, such as sputum;
- Not antagonistic with standard of care antibiotics; and
- Active in the presence of other CF therapies.
AP-PA02 is developed as a sterile liquid formulation, suitable for delivery by inhalation. Clinical trial material of AP-PA02 is manufactured under cGMP at Armata’s production facility in California.
Clinical Development of AP-PA02 in Cystic Fibrosis: Completed Phase 1b/2a “SWARM-P.a.” Study
In October 2020, Armata received FDA clearance for its IND to initiate the “SWARM-P.a.” study – a Phase 1b/2a, multicenter, double-blind, randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial to evaluate the safety, tolerability and phage recovery profile of AP-PA02 administered by inhalation in subjects with cystic fibrosis and chronic pulmonary Pseudomonas aeruginosa infection. Primary Endpoints (SAD and MAD) included incidence and severity of treatment-emergent, adverse events. Secondary Endpoints (MAD) included changes in P. aeruginosa colony-forming units. We looked at clinical parameters as a part of exploratory endpoints for the SAD and MAD cohorts. The SWARM-P.a. study was supported by a $5 million Therapeutics Development Award from the Cystic Fibrosis Foundation.
In the first quarter of 2023, Armata announced positive topline results from the completed “SWARM-P.a.” study. Data indicate that AP-PA02 was well-tolerated with a treatment emergent adverse event profile similar to placebo. Pharmacokinetics findings confirm that AP-PA02 can be effectively delivered to the lungs through nebulization with minimal systemic exposure, with single ascending doses and multiple ascending doses resulting in a proportional increase in exposure as measured in induced sputum. AP-PA02 exposures were generally consistent across subjects. Additionally, bacterial levels of P. aeruginosa in the sputum measured at several timepoints suggest improvement in bacterial load reduction for subjects treated with AP-PA02 at the end of treatment as compared to placebo after ten days of dosing. In addition, a correlation was seen between increasing phage dose (higher AP-PA02 exposures) and reduction in the bacterial load, supporting the biologic plausibility of a bacterial specific mechanism of action and creating the opportunity for phage as a therapeutic alternative to inhaled antibiotics. Following the promising Phase 1b/2a results of favorable safety and tolerability profile and plausible mechanism of action, an additional confirmatory Phase 2 trial was initiated in non-cystic fibrosis Bronchiectasis (NCFB) patients with similar chronic pulmonary disease with infections due to P. aeruginosa.
Clinical Development of AP-PA02 in Non-Cystic Fibrosis Bronchiectasis: Phase 2 “Tailwind” Study
With positive outcomes from the first clinical study, SWARM-P.a., we initiated a follow-on Phase 2 study investigating the efficacy of AP-PA02 in NCFB patients chronically infected with P. aeruginosa. Screening P. aeruginosa isolates from people diagnosed with NCFB revealed that the five-phage AP-PA02 cocktail offers broad coverage and robust potency in this indication as well.
On February 22, 2022, Armata announced that it had received approval from the FDA to proceed with the IND application for inhaled AP-PA02, in a second indication, NCFB. The “Tailwind” study is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety, phage kinetics, and efficacy of inhaled AP-PA02 phage therapeutic in subjects with NCFB and chronic pulmonary P. aeruginosa infection. The trial design included two cohorts in order to analyze AP-PA02 as monotherapy as well as AP-PA02 in combination with inhaled antibiotics. One cohort enrolled subjects not on chronic inhaled antibiotics, randomized to receive either inhaled AP-PA02 or placebo. The other cohort enrolled subjects on chronic inhaled antibiotics, randomized to receive either inhaled AP-PA02 plus their chronic inhaled antibiotic or placebo plus their chronic inhaled antibiotic. The aim of the study is to define a safe dose and dosing duration with promising biologic correlation in anticipation for a definitive Phase 3 trial. In July 2024, we announced completion of enrollment of the Phase 2 Tailwind Study. We anticipate topline data from the Tailwind study by the end of 2024, followed by potential initiation of a pivotal bronchiectasis trial in 2025 in which we plan to evaluate inhaled AP-PA02 as an alternative to inhaled antibiotics in chronic pulmonary P. aeruginosa infections in subjects with NCFB. As there are no FDA approved anti-infective treatments for NCFB, a definitive pivotal placebo-controlled trial is plausible, providing a pathway to commercialization for chronic pulmonary diseases with concurrent chronic bacterial infection, pending positive clinical trial results.
Target Market and Medical Need
P. aeruginosa is consistently recognized by the CDC, and other public health agencies, as among the most dangerousand difficult-to-treat pathogens associated with significant impacts on health, quality of life, and economic burden.
P. aeruginosa is particularly problematic for CF patients given that their already compromised immune system leads to chronic infections. CF affects over 40,000 people in the U.S. (105,000 people worldwide) with approximately 1,000 new diagnoses per year. Outcomes for people with CF have improved significantly in recent years through early screening, the development and use of CFTR modulators, and other therapies. However, people with CF still suffer significant morbidity and mortality due to pulmonary infection with P. aeruginosa. Chronic P. aeruginosa infections occur in 45% of CF patients by age 40, and are strongly associated with worsening lung function, frequent pulmonary exacerbations, and increased mortality. Regular standard-of-care antibiotics treatments often fail to completely eradicate the pathogen, and the problem is further complicated by rising rates of antibiotic resistance due to a growing number of multidrug-resistant isolates emerging, particularly with long term use. Hence the need for more effective therapies, ideally with a different mechanism of action compared to traditional antibiotics, for the treatment of chronic P. aeruginosa infection. GlobalData projects that total antibiotic sales in the CF market will exceed $900 million in the U.S. in 2030.
NCFB is a chronic respiratory disease affecting more than 100,000 people in the U.S. and 200,000 people in Europe, characterized by recurrent respiratory infections that lead to a vicious cycle of impaired mucociliary clearance, chronic infection, bronchial inflammation, and progressive lung function loss. P. aeruginosa is the most prevalent pathogen responsible for these recurrent infections. It is found in approximately 30% of cases and is associated with enhanced disease progression, including poorer lung function and lower quality of life, more frequent exacerbations, increased hospitalizations, and higher mortality. NCFB patients frequently become chronically colonized with multidrug-resistant strains of P. aeruginosa because of the need for repeated courses of antibiotic treatment. There are currently no approved inhaled antibiotics for the treatment of NCFB patients with chronic P. aeruginosa respiratory infection.
AP-PA03
Representing the different physiology of acute pneumonia lung infections as compared to chronic CF and NCFB respiratory infections, a novel cocktail is in development for the clinical indication of acute hospitalized pneumonia. Armata has deployed its extensive P. aeruginosa clinical isolate collection and phage library to identify a candidate phage cocktail, AP-PA03. Hospital-acquired pneumonia and ventilated-associated pneumonia is one of the most common causes of death among all hospital‐acquired infections, with approximately 300,000 hospitalizations each year in the U.S. due to Pseudomonas. Infection with Pseudomonas results in mortality rates ranging as high as 35‐50%, drives considerable healthcare costs, and accounts for around 50% of all intensive care unit antibiotics.
