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  • Periodic Report Summary 2 - PHAGOBURN (Evaluation of phage therapy for the treatment of Escherichia coli and Pseudomonas aeruginosa burn wound infections (Phase I-II clinical trial))

PHAGOBURN Report Summary

Project ID: 601857
Funded under: FP7-HEALTH
Country: France

Periodic Report Summary 2 - PHAGOBURN (Evaluation of phage therapy for the treatment of Escherichia coli and Pseudomonas aeruginosa burn wound infections (Phase I-II clinical trial))

Project Context and Objectives:
Sepsis is a major issue of burn patients and a predominant cause of death. Combined to a global intensive use of antibiotics (ATB), the burn wound pathology put patients at high risk of suffering from multidrug resistant (MDR) infections, notably carried out by two Gram-negative bacteria species: Pseudomonas aeruginosa and Escherichia coli. Furthermore, the last Gram- ATB is more than 20 years old and impeded by spread out exponential resistance. As the number of new antimicrobials under clinical development is low and their introduction to market disappointingly slow, physicians are left with very few alternatives. There is thus a high risk that MDR Gram-negative infections will soon become treatment-deprived pathologies, without any effective therapeutics available.

Consequently, finding innovative ways to counter MDR is becoming an urgent medical need and shall have a broad impact on infected burn wounds, as well as, on other infections due to MDR microorganisms.

In this context, PHAGOBURN is focused on a highly promising alternative to ATB: phage therapy. Natural and exclusively lytic bacteriophages (phages) are viruses that specifically infect and kill bacterial cells during their life cycle. Shortly after their discovery in the beginning of the 20th century, these natural predators of bacteria have been widely used for the treatment of human infectious diseases and referred to as “phage therapy”. They were nonetheless abandoned following the advent of ATB (except in some parts of Eastern Europe, notably Georgia, Russia and Poland).

Nowadays, faced with the constant increase of bacterial resistance to ATB, phage therapy encounters a high renewed interest. However and although phage therapy is currently available in some countries (based on historical use), very few controlled, well-powered and well-designed clinical trials have tested its efficacy and safety. This situation is a clear limiting step and conducting clinical trials to validate the relevance of phages in the treatment of human infectious diseases has thus become utterly important.

In this framework, the main objective of PHAGOBURN is to assess the safety, effectiveness and pharmacodynamics of two therapeutic phage cocktails to treat either E. coli or P. aeruginosa burn wound infections. To this end, the following objectives shall be achieved:

• Validation of a GMP bioproduction process for the production of the two phage cocktails according to current EMA standards regarding drug products;
• Preparation and implementation of a phase I-II multicentric trial involving clinical centres from three European countries (France, Belgium, Switzerland);
• Obtaining evidence of efficacy, safety and local tolerance of the phage cocktails as topical agents for the treatment of E. coli and P. aeruginosa burn wound infections.

In addition, the production process and trial results obtained shall provide basis for an optimisation of current regulatory guidelines, one of the aims of PHAGOBURN being to contribute towards the standardisation of phage therapy at a regulatory level (EMA).
To achieve these objectives, PHAGOBURN Consortium gathers 5 partners from France, Belgium and Switzerland:

• Two French SMEs: Pherecydes Pharma (project initiator and co-coordinator) and Clean Cells (for the GMP bioproduction of drug products);
• Three public partners acting as clinical centres within the project: Percy hospital (French Defence Ministry, co-coordinator of the project), Hospices Cantonaux – CHUV (Switzerland), and the Royal Military Academy – RMA (Belgium) through Queen Astrid Military Hospital, one of its study sites.

Apart from these partners, a number of additional clinical centres (acting as subcontractors) are also greatly involved in PHAGOBURN: Saint-Luc/Saint-Joseph Hospital (France), CHU Nantes (France), CHU Liège (Belgium) and Loverval Hospital (Belgium). CHU Bordeaux (France), CHR Metz thionville (France), Marseille Conception Hospital (France), Toulon Military Hospital (France).

Project Results:
Since the official launch of the project (June 1st 2013), work has been performed in the following Work Packages (WP) towards the achievement of the overall Project objectives:

• WP1 – Bioproduction process of two phage cocktails according to GMP;
• WP2 – Preparation of the phase I-II clinical study;
• WP3 - Implementation of the phase I-II clinical study
• WP4 - Biological samples analysis
• WP6 – Management and Ethics;
• WP7 – Dissemination/exploitation activities.

For each WP, the work performed up to now can be summarised as follow:

• Within WP1, Clean Cells, with a strong support from Pherecydes Pharma, carried out the necessary steps so to finalise and validate both phage cocktails pharmaceutical manufacturing, including, the method and test of Quality Controls. Notably, Clean Cells has now been granted pharmaceutical laboratory status by the French national regulatory authority (ANSM) and the SME also obtained in November 2014 the authorisation to produce the two investigational medicinal products related to the project and which have been released for the clinical trial in July 2015.

• Within WP2, Pherecydes Pharma and the clinical partners (Percy, RMA and CHUV) carried out necessary steps so as to efficiently prepare the phase I-II clinical study. These steps included:
o The finalisation and validation of the clinical protocol
o The completion of all ethical aspects necessary to launch the trial: all requested national authorisations from relevant ethical committees (in France, Belgium and Switzerland) have been obtained by the Consortium;
o The preparation of the Investigation Drug Brochure (IDB) and of all additional necessary documentation (IMPD, Randomisation guide, Data management guide and validation plan)

• Within WP3 and WP4, the clinical trial started in 2015, with the first recruitment occurred on July 22nd, 2015. Several patients have already been included, their biological samples have been analysed.

• Within WP6, work related to management issues was successfully performed so far, including: the preparation and maintenance of the Consortium Agreement, the selection of various subcontractors, the preparation and updates of the Consortium Plan, the preparation and validation of amendments to the Technical Annex, the preparation and organisation of meetings, the overall financial management, and all necessary day-to-day management actions (both administrative and financial).

• Within WP7, work related to dissemination and preparation of exploitation was performed as planned by the whole Consortium. Results achieved so far include:
o The preparation of the Dissemination/Exploitation Plan, updated as relevant during the course of the project;
o The creation of the PHAGOBURN website, regularly updated since the beginning of the project;
o The production and diffusion of several newsletters;
o The participation to several scientific events (national and international);
o The submitting of 3 publications and 4 posters acknowledging the grant;
o The creation of a Phagoburn YouTube channel;
o Numerous press articles, TV and radio broadcasts;
o The creation of a public booklet introducing the clinical trial (almost achieved).

Potential Impact:
Reminder of genuine goals: by the end of PHAGOBURN, the Project shall have enabled obtaining two therapeutic phage products (bacteriophages cocktails) to treat either E. coli or P. aeruginosa burn wound infections, including antibiotics (ATB) resistant strains. The benefit/risk ratio shall be in agreement with the highest standards regulating the evaluation of new therapies in Western countries.

So as to reach this overall final result, several other results shall have been obtained as well in the course of the Project:
• Bioproduction process of both drug products, in compliance with Good Manufacturing Practices (GMP);
• Method and Quality Controls test specific to the phage drug product;
• Proof of efficacy and safety (through the phase I-II clinical study and subsequent analysis performed) according to Good Clinical Practices (GCP).

Obtaining these data shall lead the products to be ready – before the end of the project – for Temporary Authorisation of Use, a first step towards future therapeutic development (after all the necessary work to ultimately obtain market authorisations have been carried out).

Potential impacts and use of these results

Potential impacts of these expected final results can be described both at the level of the Consortium and at the level of society.
First, regarding the Consortium, PHAGOBURN results shall be valued by both SMEs of the Project: Pherecydes Pharma and Clean Cells. Clinical partners i.e. Percy, RMA and CHUV will also benefit from project results through the opportunity to publish non-confidential results in scientific medical journals or to present them during conferences.

As for the two SMEs of the Consortium, the following use of project results has been determined so far:
• Clean Cells will be able to exploit the bioproduction/purification process developed as well as the method and test of quality control to produce bacteriophages. As such, the SME may use these results to produce bacteriophages;
• Pherecydes Pharma will be able to exploit both therapeutic phage products to treat either E. coli or P. aeruginosa burn wound infections (intended targets are therefore hospitals, doctors, etc.). The SME shall also develop new products about bacterial species of interest.

Then, regarding wider socio-economic and societal impacts, PHAGOBURN findings should provide several advantages:
• To patients: availability of effective/safe treatments, with lesser side effects than last rescue antibiotics;
• To medical staff: i) availability of a new therapy to fight bacterial infections, including multidrug resistant ones; ii) reduction of the high mortality rate of such infections; iii) decrease of antibiotics pressure; and iv) regulation of hospital microbial ecology;

On a wider front, the expected final output shall address current significant antibiotics market failure, through providing an efficient alternative to fight increasingly resistant bacteria.

Therefore, such data shall have significant societal impact through bringing to the market a new therapeutic alternative to fight against E. coli and P. aeruginosa infections.

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Stéphane Hatot, (Capitaine)
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