The first-in-human study PHAGE4CURE-001 investigated, for the first time in humans, the inhalable mixture of three different bacteriophages against Pseudomonas aeruginosa in the lungs which had been manufactured before by Fraunhofer ITEM in accordance with GMP criteria. The study was conducted from September 2023 to May 2025 at the research facility of Charité Research Organisation GmbH.

Study participants were randomly assigned to receive either the phage agent or a placebo. Eighteen healthy volunteers completed the first part of the study—13 participants received a single or three inhalations of the phage agent, while 5 participants received the placebo. In the second part, 6 healthy volunteers received inhalations three times daily over 10 days (4 participants received the phage agent, 2 received the placebo). In the third part of the study, a total of 26 patients whose lungs are chronically colonized with Pseudomonas aeruginosa received the phage agent (20) or placebo (6) three times daily over 10 days.

During and after the inhalation treatment, regular examinations were conducted and samples were collected, such as blood, urine, and sputum samples, lung function tests, vital signs, and ECG. This was done to monitor the participants’ well-being and to gain insights into the effect of the active ingredient.

Results

The phage-based drug was generally well tolerated. No serious adverse events occurred, and none of the reported symptoms were attributed to the phage-based drug. Phages were not detectable in the blood but could be detected in sputum at doses of 10 billion active phages or higher; this suggests that they reach the airways and lungs. Clear evidence of efficacy has not yet emerged in this early-stage study. Since only a small number of patients participated and Phase 1 studies primarily assess safety and tolerability, further studies are necessary to reliably evaluate efficacy.

Several exploratory parameters are currently being further evaluated. These include, among other things, analysis of the Pseudomonas aeruginosa burden, investigations of the lung microbiome, and determination of the BIMs frequency. The latter describes how frequently bacterial mutants occur that are resistant to the phages used, thereby providing important clues about potential resistance development. These additional analyses are intended to help more accurately classify the biological effects of phage treatment. In parallel, the Phage4Cure team is preparing a scientific publication in which the study’s results will be presented in detail.

The project “Phage4Cure” is about to enter the home stretch: recently, the German Federal Institute for Drugs and Medical Devices (BfArM) and the responsible ethics committee approved the clinical trial that has been planned since the beginning of the project. In this upcoming first-in-man study, the phage compounds produced by the project partners will be tested in humans for the first time – in addition, this is also the first study in Germany in which bacteriophages are administered as part of a clinical drug trial.

The study is being conducted at the Charité in Berlin by Charité Research Organisation GmbH. First, it will be investigated in healthy volunteers how the human body reacts to the administration of phages: like it is known from asthma patients, the phages are inhaled into the lungs using an inhaler. It will then be studied how the immune system reacts to the phages and how long the phages remain in the lung tissue.

If this first phase of the study is positive (i.e., for example, no severe side effects occur in the volunteers), the phage compound will be tested on patients in the next step. The active ingredient is a mixture of three phages (the so-called “phage cocktail”), which were selected because they are specifically effective against the bacterium Pseudomonas aeroginosa. A sputum sample will be tested from patients suffering from chronic colonization with this bacterium. This is to determine whether these patient bacteria are sensitive to the phage cocktail. The patients can participate in the study and will be treated with the phage cocktail only, if it is proven by the lab results, that the phage cocktail could be effective (further inclusion and exclusion criteria apply).

The aim of the testing in patients is not therapeutic treatment or even a cure, but will also serve to assess the safety, tolerability and dose finding of a phage therapy. If this first-in-man study is successful overall (the evaluation will take about one year), further studies are intended (and then hopefully with therapeutic approaches).

The study is expected to start in mid-September 2023. Interested subjects should register on the portal of the Charité Research Organisation GmbH, patients directly on the register page for patients. You will find further information about the upcoming study there as well.

Using the phages selected by the DSMZ, the Fraunhofer-ITEM’s Pharmaceutical Biotechnology Unit is developing manufacturing processes for the phages that, as active pharmaceutical ingredients, will be the active ingredients of a drug to be administered by inhalation. The aim is to achieve a largely generic phage production technology that will later allow adaptation to the production of newly added phages by adjusting only a small number of parameters.

In the meantime, the Phage4Cure phages have been produced in the required quantities as active ingredients and delivered to the project partners for preclinical studies on pharmacology and toxicology issues. For the first clinical application study scheduled in 2022, the same phages were produced once again as active ingredients and additionally as phage test drugs, but this time in pharmaceutical quality under the specifications of the quality assurance system GMP (“Good Manufacturing Practice”).

At the moment, the project focus is on the evaluation and documentation of the preclinical studies as well as the preparation of the extensive documentation for the application for the clinical trial – this is being done in close coordination between Charité, Charité Research Organisation GmbH and the regulatory authorities. The first clinical application study is expected to start in late summer 2022.

The department of Pharmaceutical Biotechnology at Fraunhofer-ITEM (Prof. Dr. Holger Ziehr) develops production processes for active phage ingredients from the phages which have been selected by DSMZ, which will be the active components (active ingredients) of the drug to be administered by inhalation. The aim is to develop a generic phage manufacturing platform that allows the production of new phages in pharmaceutical quality by adjusting only a few parameters. This process is now nearly completed.
In the meantime, selected phages have been produced in the intended scale and quality as active pharmaceutical ingredients, subsequently filled in vials under sterile conditions and handed over to the project partners ITEM in Hannover and Charité in Berlin, where preclinical studies on pharmacological and toxicological issues have already started.
Work at ITEM is increasingly focusing on questions of galenic development (i.e. the composition of the dosage form) and the associated stability and durability of the phages in the test drug. The production of the investigational drug to be used in the clinical study is scheduled for 2021.

The pharmaceutical biotechnology department at Franhofer-ITEM (Prof. Dr. Holger Ziehr) is manufacturing the components of an inhalative preparation from the phages selected by the DSMZ in accordance with the specifications of the GMP quality assurance system. The necessary process development on production scale is now well advanced. The aim is to create a manufacturing platform that allows new phages to be produced in pharmaceutical quality by adapting only a few parameters.

To date, the selected phages have been produced at Fraunhofer ITEM in the planned scale and quality of pharmaceutical active ingredients. The feasibility of the platform approach is becoming increasingly apparent. The focus of the work is now increasingly on questions of galenic development (i.e. the type of preparation) and thus on the stability and shelf life of the phage both as an active ingredient and as a test drug.