The Hospices Civils de Lyon (HCL) has become the first healthcare institution in Europe — and the first public institution worldwide — to receive authorization to manufacture pharmaceutical-grade raw materials for therapeutic bacteriophages. The approval granted by the French National Agency for Medicines and Health Products Safety (ANSM) allows Lyon University Hospital to produce Good Manufacturing Practice (GMP)-compliant therapeutic phages for use in clinical trials and patient care.

“This is the first time a public institution has received this type of authorization anywhere in the world,” said Frédéric Laurent, PharmD, PhD, head of the HCL Therapeutic Phage Laboratory (LPT) and coordinator of PHAG-ONE, and leads THERAPHAGE — both supported France’s 2030 initiative.

Phage Therapy Returns to the Forefront

Bacteriophages, or phages, are viruses that infect bacteria. First described in the early 20th century by French Canadian microbiologist Félix d’Hérelle, they attracted considerable interest in Europe and the US before falling out of favor with the introduction of antibiotics. The global rise in antimicrobial resistance has renewed interest in phage therapy.

In 2016, researchers at the Institut Pasteur in Paris, France, and UCLouvain in Louvain-la-Neuve, Belgium, identified the genetic and metabolic mechanisms underlying the therapeutic action of the bacteriophage PAK_P3, which shows potential for treating bacterial infections.

Since 2017, researchers from HCL in Lyon, France, have worked to re-establish phage therapy as a regulated therapeutic approach. That year, the HCL integrated microbiology laboratories within the Institut des Agents Infectieux at the Hôpital de la Croix-Rousse campus and launched the PHAGEinLYON program to pioneer regulated, pharmaceutical-grade bacteriophage therapy against multidrug-resistant bacterial infections.

The multidisciplinary program brings together microbiologists, clinicians, pharmacists, and researchers to develop a public phage therapy program that meets current scientific and regulatory standards in France.

First European Authorization

The newly granted ANSM authorization permits HCL to manufacture pharmaceutical-grade therapeutic phages in compliance with GMP requirements.

According to the ANSM, HCL has received two authorizations for its therapeutic phage production project. One covers the production of a phage suspension, an intermediate active substance, at the LPT at Croix Rousse Hospital. The other covers purification of the phage suspension into a therapeutic phage active substance at the FRIPHARM platform, a hospital-university unit for pharmaceutical fabrication, research, and innovation located within the pharmacy department of Édouard Herriot Hospital in France. Both manufacturing processes must comply with GMP standards for active pharmaceutical ingredients and may be inspected by ANSM to verify compliance.

Speaking with Medscape’s French edition, Laurent said, “We are delighted to receive these authorizations, which recognize years of scientific, clinical, and regulatory development,” “Our objective is to establish public sector production of therapeutic phages.”

“When I began working on phages in 2012, we were using those produced by a startup, Pherecydes Pharma initially focusing on Staphylococcus aureus infections because the HCL is home to both the National Reference Center for Staphylococci and the Regional Reference Center for Complex Bone and Joint Infections, the collaboration made perfect sense. We worked with them to identify the best phages for this indication,” he said.

One of the first patients treated had a chronic S aureus infection involving a knee prosthesis after years of unsuccessful antibiotic therapy. Transfemoral amputation was the only remaining treatment option before the patient received intra-articular phage therapy. One month later, the patient was discharged after walking independently.

Since 2017, approximately 100 patients have received therapeutic phages through compassionate use programs.

“These are patients who have exhausted all available treatment options and have no therapeutic alternative,” Laurent said. “Although the numbers remain relatively small, they continue to increase every year.”

Building a Public Manufacturing Platform

Alongside patient care, HCL has developed its own manufacturing platform to produce therapeutic phages that meet pharmaceutical quality standards in a hospital setting.

In 2021, HCL and Claude Bernard University Lyon 1 launched the PHAG ONE Project, selected under France’s Priority Research Programme on Antimicrobial Resistance as part of the France 2030 investment plan funded by French National Research Agency and Inserm. The initiative aims to establish a sustainable public manufacturing system for therapeutic phages.

Laurent explained that the manufacturing process begins with the isolation of phages from wastewater. The most promising candidates are selected and multiplied using bacterial production strains, producing concentrated phage lysates containing approximately 100 billion phages/mL.

These intermediates are then transferred to the Fripharm platform, where they are purified to remove impurities before being formulated into pharmaceutical grade preparations that can be stored for several years at 4 °C.

National Public Health Priority

HCL previously held authorization to prepare individualized hospital formulations from pharmaceutical grade phages. The new authorization expands its capacity to manufacture active pharmaceutical ingredients.

“With this hospital produced preparations, we will be able to conduct clinical trials while continuing compassionate use treatment,” Laurent said.

He also highlighted broader public health implications.

“This is a matter of national sovereignty because antimicrobial resistance is becoming a major public health challenge,” he said. “It is also a question of financial sustainability because our objective is to manufacture these products at cost.”

The laboratory currently manufactures batches of approximately 500 vials and performs more than 25 in-house quality control tests. Although manufacturing costs remain difficult to estimate because of public funding, Laurent expects economies of scale to reduce costs as production expands. The short-term goal is to establish a national production center capable of supplying therapeutic phages throughout France.

Safety and Future Clinical Trials

According to Laurent, therapeutic phages have shown excellent safety profiles.

“Phages infect only bacteria and cannot infect human cells,” he said. “Unlike antibiotics, they also preserve the normal gut microbiota because they target only the specific bacterial species for which they are selected.”

Among the approximately 100 patients treated with HCL, no significant adverse effects have been reported.

For Laurent, the remaining challenge is logistical. “Selecting the right phage requires a phagogram, the phage equivalent of an antibiotic susceptibility test. However, the process has not yet been automated, and only two or three laboratories in France are currently able to perform it,” he said.

Planned Clinical Trials

At present, the phages produced target only S aureus. “They will be used to treat bone and joint, pulmonary, vascular, and ophthalmic infections. With phages, treatment is guided by the infecting bacterium rather than the disease itself. We are going to conduct clinical trials because we want to practice evidence-based medicine,” Laurent said.

Clinical evidence remains limited because phage therapy has largely been used on a compassionate use basis, and randomized clinical trials are still lacking. “We currently have two clinical trials in preparation: The University Hospital Health Research - RHU THERAPhage programme, for bone and joint infections and a second trial evaluating phage therapy for vascular graft infections,” he said.

Laurent believes that the next step now depends on national policy. “If France wants to establish a public production system for therapeutic phages, it must provide HCL with the resources to do so. Production at a cost the healthcare system can sustain can only be achieved through a public sector model,” he said.

This story was translated from Medscape’s French edition.