Manufacturing and Formulation Process Development for a Prophylactic Cholera Phage Cocktail

PROJECT SUMMARY The World Health Organization (WHO) estimates that approximately 1.3 billion people globally are at risk for cholera, a severe diarrheal disease caused by the bacterium Vibrio cholerae that is spread through contaminated water sources and substantial secondary person-to-person transmission. In January 2023, the WHO classified the global resurgence of cholera as a grade 3 emergency, its highest internal level. More than 708,200 cases were reported in 30 countries across five WHO regions in 2023, a 50% increase from 2022. The country's case fatality rates have far surpassed the threshold of <1%, reaching 23.8% in the Congo. The sustained upsurge is evident in 2024, disrupting the 2030 disease elimination goals of the WHO Global Taskforce for Cholera Control (GTFCC). Current prevention methods, such as the oral cholera vaccine (OCV) and water, sanitation, and hygiene (WASH) campaigns, require significant investment of resources and time for efficacy, but household contacts of cholera patients often present with cholera symptoms two to three days after the initial patient becomes sick. In addition, the preventive use of antibiotics is not recommended due to widespread resistance for cholera and other pathogens in the same environment. There is a pressing need to develop a targeted clinical intervention to prevent the community spread of cholera using a fast-acting prophylactic treatment. PhagePro aims to fill this gap with its product ProphaLytic-VcTM (PVC). PVC is an orally administered bacteriophage (phage) cocktail comprised of Vibriophages ICP1, ICP2, and ICP3. In this Direct-to-Phase II SBIR proposal, we aim to partner with two Contract Development and Manufacturing Organizations (CDMO), JAFRAL and Serán Bioscience, to scale up manufacturing and formulation of PVC and establish specifications for future clinical trial material production as an orally administered, cold-chain independent, solid dosage form, which are critical characteristics identified by Key Opinion Leaders for an innovative cholera intervention. Stability of PVC in hot and humid environments will enable Ministries of Health to stockpile PVC in-country and distribute to identified cholera hotspots quickly. This mechanism will increase timeliness of the cholera outbreak response, which has been identified as the key factor in controlling an outbreak in both endemic and non-endemic settings. First, PhagePro will collaborate with JAFRAL to establish upstream and downstream manufacturing processes of each PVC phage using 1 liter bioreactor batches based on previously established phage growth parameters. JAFRAL will then perform scaled-up confirmation runs of ICP1, ICP2, and ICP3. At this stage, the individual phages will be in liquid buffers (Drug Substance, DS). Second, PhagePro will collaborate with Serán to finalize excipient formulation and develop a large-scale manufacturing process for enterically coated, encapsulated spray-dried powder in blister packaging (Drug Product, DP). Third, PhagePro will in parallel collaborate with JAFRAL to develop analytical methods for viability and purity, according to prior formal Type C Meeting responses with the U.S. FDA, to optimize growth efficiency, phage viability during processing, and batch purity. Additionally, PhagePro will collaborate with Serán to develop the potency method for PVC, which will be transferred to JAFRAL. Lastly, JAFRAL and Serán will then qualify the developed analytical and potency methods for DS and DP under GMP and establish specifications. Throughout the proposed studies, PhagePro will be responsible for managing this project and act as the final decision maker. At the successful conclusion of the Phase II grant, we will have established scaled-up manufacturing and formulation processes as well as specifications for future clinical trial material production. Future investments and non-dilutive funding will fund clinical surveillance studies, GMP manufacturing for clinical trials, and a first- in-human trial to demonstrate proof-of-clinical-efficacy.