Project update

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.

At Leibniz-Institut DSMZ GmbH, phage screening was successfully completed. Since the beginning of the project, it has been the basis for all subsequent steps of the project and has led to a selection of promising phage species, which in combination show a comparatively high bacterial host coverage of Pseudomonas aeruginosa strains.

Detailed investigation of many different phages with regard to their efficiency in destroying the host bacteria and many other aspects finally narrowed the circle of possible candidates for further processing by ITEM. Basically, it was desired that the phages would complement each other significantly in their bacterial coverage in order to increase the final coverage percentage of patient strains in the clinical application. On the other hand, it was desired that the phages overlap in their bacterial coverage so that more than one phage can effectively attack patient strains as often as possible.

Such forward-looking considerations and, in addition, the greatest possible genetic and morphological diversity of phage contribute significantly to the efficiency of the final phage product and are based on the biology of the individual phage. Therefore, phages for clinical application must be comprehensively investigated and compared, always with the aim of successful high purification. Consequently, they must also produce high titres, be stable in the event of slight temperature or pH fluctuations, remain stable in the planned application form, etc.

The fact that these factors are present in many phages is due to the fortunate circumstance of evolution: Phages are the most common living units on earth, ensure the continuous turnover of one third of the global bacterial mass and live as a regulatory force in our own microbiome. In the meantime, different phages have been selected as candidates and were handed over to ITEM for reproduction.

During the further course of the project, Leibniz Institute DSMZ GmbH will continue to work on the characterisation of these phages in order to learn more about the phages with regard to their effectiveness as phage “cocktails” in comparison to the effect of antibiotics or about their effectiveness in artificial biofilms or artificial sputum medium.

Immediately after receipt of the phages, the multi-stage, complex sequence of production steps for the propagation and purification of these candidates began at the Fraunhofer Institute ITEM. At the moment, the research group is trying to optimize the purification process.

At a recent meeting of the project participants in Berlin, the toxicological programme of the pre-clinic was coordinated. The aim is to ensure that, as far as possible, future project phases are harmonised between the partners at an early stage and adapted to regulatory requirements, so that the preclinical development work can be tackled in a timely manner as soon as phage material is available from ITEM.