Project update

Completion of phage production, preparation of the clinical trial

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.

Completion of work at ITEM, start of preclinical testing

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.

Progress report of Fraunhofer ITEM

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.

Update of Leibniz-Institut DSMZ GmbH and Fraunhofer ITEM

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.

Phage-lab, (C) Chr. Rohde

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.

Evaluating…. (C) Chr. Rohde

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.

Coordination with the regulatory authorities

The long-term perspective of the joint project Phage4Cure is the approval of bacteriophages for the treatment of bacterial infections. Although bacteriophages have been used as therapy for more than one hundred years, there are many different aspects to be considered when compared with traditional drugs. Until now, drug approval procedures have been based on classical chemical and biotechnological substances and can therefore not simply be translated to phages. In order to pave the way for the approval of phage therapy, the project members aim to discuss the necessary steps regularly with the regulatory authorities. Already at the end of September 2017, the Paul Ehrlich Institute (PEI) hosted a meeting in Langen near Frankfurt. In February 2018 the first meeting took place at the Federal Institute for Drugs and Medical Devices (BfArM) in Bonn. Meanwhile, the responsibility of the authorities has been clarified: the BfArM will be in charge.

The project team visiting the BfArM (Febr. 2018) F.l.t.r.: Prof. Dasenbrock (ITEM), Dr. Rohde (DSMZ), Dr. Hüser (CRO), Dr. Roß (ITEM), Dr. Hertrampf (CRO), Fr. Lehmann (CRO), Dr. Ziehr (ITEM), Prof. Witzenrath (Charité)
The project team visiting the PEI (Sept. 2017) F.l.t.r.: Dr. Rohde (DSMZ), Dr. Uhle (CRO), Dr. Hertrampf (CRO), Dr. Seitz (ITEM), Prof. Witzenrath (Charité), Prof. Dasenbrock (ITEM), Dr. Ziehr (ITEM), Dr. Roß (ITEM), Dr. Hüser (CRO).