PHAGE4DAIR: A €14.9 Million Horizon Europe Trial Evaluating Phage Therapy for Staphylococcus aureus Prosthetic Joint Infections

Prosthetic joint infections (PJIs) remain among the most devastating complications following hip and knee replacement surgery. Although relatively uncommon, these infections are associated with prolonged hospitalization, repeated surgical interventions, substantial healthcare costs and, in many cases, permanent functional impairment. Staphylococcus aureus is one of the leading pathogens responsible for acute prosthetic joint infections, owing to its remarkable ability to form biofilms on implant surfaces and develop resistance to multiple antibiotics. Once established, these biofilms create highly structured bacterial communities protected by an extracellular matrix that dramatically reduces antibiotic penetration and shields bacteria from host immune responses, making eradication particularly challenging.

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Current management of acute prosthetic joint infections often relies on the DAIR procedure—Debridement, Antibiotics and Implant Retention—which aims to preserve the implant while surgically removing infected tissue and administering prolonged antibiotic therapy. Although this conservative approach avoids complete prosthesis replacement and its associated morbidity, failure rates remain high, particularly in infections involving antibiotic-resistant Staphylococcus aureus. The need for innovative adjunctive therapies capable of improving clinical outcomes while preserving implanted prostheses has therefore become increasingly urgent.

To address this challenge, the European Union has invested €14,869,038.73 in PHAGE4DAIR (Phage Therapy for Arthroplasty Infections using Local and Conservative Surgery), one of the three flagship projects selected under the Horizon Europe programme dedicated to evaluating bacteriophage therapy against antibiotic-resistant bacterial infections. Coordinated by the Canadian biotechnology company Qeen Biotechnologies, the project officially began on 1 June 2026 and will continue until May 2031.

PHAGE4DAIR is designed as a multicenter, randomized, double-blind, placebo-controlled adaptive Phase I/II clinical trial evaluating the safety and preliminary efficacy of a Good Manufacturing Practice (GMP)-produced bacteriophage cocktail composed of five carefully selected lytic phages targeting Staphylococcus aureus. Unlike personalized phage therapy approaches, PHAGE4DAIR investigates a standardized fixed phage cocktail intended to provide immediate availability for clinical use while facilitating future regulatory approval and commercial deployment.

Patients enrolled in the study will present with confirmed acute Staphylococcus aureus prosthetic joint infections requiring DAIR surgery. During the procedure, the investigational phage cocktail will be administered directly into the infected surgical site while additional intravenous administration will complement conventional antibiotic therapy. This dual local and systemic delivery strategy is designed to maximize phage exposure at the implant surface while simultaneously targeting disseminated bacterial populations. Clinical efficacy will be evaluated through co-primary endpoints assessing both treatment safety and clinical cure three months after completion of antibiotic therapy.

One of the major scientific innovations of PHAGE4DAIR is its seamless Bayesian adaptive trial design. Rather than relying on a rigid conventional protocol, Bayesian methodology allows predefined modifications of dose selection, treatment allocation and statistical analyses as evidence accumulates throughout the study. This adaptive framework has the potential to accelerate clinical development while improving the efficiency of early-phase evaluation and optimizing future Phase III trial design.

The project extends well beyond clinical efficacy. Investigators will generate comprehensive pharmacokinetic and pharmacodynamic data describing how therapeutic phages distribute throughout the body, interact with bacterial populations and respond to host immunity. Detailed microbiological analyses will monitor bacterial clearance, phage persistence, resistance development and biofilm disruption, while immunological studies will evaluate host immune responses following repeated phage exposure. Together, these complementary datasets are expected to provide one of the most comprehensive clinical evaluations of phage therapy ever performed in orthopaedic infections.

An important advantage of  PHAGE4DAIR is that its investigational five-phage cocktail is already being developed under an Investigational New Drug (IND) application in the United States for related indications. This existing regulatory experience facilitates alignment between North American and European regulatory pathways and may accelerate future international development of standardized phage therapeutics. Throughout the project, the consortium will work closely with the European Medicines Agency to establish a regulatory framework capable of supporting future marketing authorization and large-scale clinical implementation.

PHAGE4DAIR also incorporates a comprehensive exploitation and dissemination strategy aimed at ensuring rapid translation from clinical research to healthcare practice. Alongside scientific publications and stakeholder engagement, the project will develop manufacturing, regulatory and commercialization pathways intended to support future Phase III clinical development and eventual routine use of bacteriophage therapy in orthopaedic surgery.

The international consortium brings together twenty academic institutions, university hospitals, biotechnology companies and clinical research organizations from Europe and North America. Coordination is provided by Qeen Biotechnologies in Canada, supported by major Canadian partners including the Ottawa Hospital Research Institute, the University of Calgary, Unity Health Toronto and the University of Alberta. European clinical expertise is contributed by Hospices Civils de Lyon, Université Claude Bernard Lyon 1 and Centre Hospitalier Universitaire de Nice in France; Charité – Universitätsmedizin Berlin in Germany; Aristotle University of Thessaloniki in Greece; University Medical Center Groningen in the Netherlands; the Medical University of Vienna in Austria; and an extensive United Kingdom network comprising University College London, University College London Hospitals NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, Royal National Orthopaedic Hospital NHS Trust, University Hospitals Birmingham NHS Foundation Trust, the University of Exeter and Centre for Process Innovation. Additional expertise is provided by Mayo Clinic in the United States, while several professional societies—including the Bone and Joint Infection Society, the European Hip Society, the Canadian Arthroplasty Society and Acıbadem University in Türkiye—participate as associated partners supporting dissemination and clinical implementation.

By combining advanced clinical trial methodology, GMP phage manufacturing, standardized regulatory development and multidisciplinary translational research, PHAGE4DAIR aims to establish whether bacteriophage therapy can improve the management of one of the most difficult orthopaedic infections encountered in modern medicine. If successful, the project could significantly reduce treatment failure following DAIR procedures, preserve prosthetic implants that would otherwise require replacement, decrease prolonged antibiotic exposure and generate the robust clinical evidence needed to support regulatory approval of standardized phage therapeutics for prosthetic joint infections.

Together with REPhRAME and P-PEAKS UTI, PHAGE4DAIR represents one of the largest coordinated international efforts ever undertaken to establish bacteriophage therapy as an evidence-based treatment for antibiotic-resistant bacterial infections.

Source :

European Commission – CORDIS. PHAGE4DAIR (Grant Agreement No. 101287116). DOI: https://doi.org/10.3030/101287116