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Periodic Report Summary 1 - OSTEOGROW (Novel Bone Morphogenetic Protein-6 Biocompatible Carrier Device for Bone Regeneration)

Project Context and Objectives:

Within the project we will conduct a regenerative medicine clinical trial of the therapeutic device OSTEOGROW. This novel osteogenic bone device will be used to accelerate and enhance bone repair. It is composed of an autologous carrier and a biologically active recombinant human protein offering a superior therapeutic solution in bone regeneration and more compliant to currently available options. The autologous carrier in OSTEOGROW is actually a whole blood-derived coagulum (WBCD) from the peripheral blood of a patient, which acts as an endogenous biocompatible material. With this carrier significantly less inflammatory reactions and related side effects are noticed than with currently used bone devices.

The bone inducing molecule within OSTEOGROW device is the recombinant human bone morphogenetic protein 6 (rhBMP6) which binds to WBCD components and is more potent than other BMPs in stimulating bone formation according to the results obtained in preclinical animal models. The consortium members will scale-up the production of BMP6 to enter clinical trials on bone regeneration. The indications that will be treated locally with OSTEOGROW are acute radius fractures and high tibial osteotomies to prevent development and progress of osteoarthritis. These conditions are widespread and highly debilitating diseases for which such therapy holds great promise.

Pre-clinical data are available, and the clinical grade recombinant human BMP6 is at the stage of up-scaling the manufacturing process and protein purification. Toxicology studies and the final formulation of OSTEOGROW are currently ongoing. Clinical trials will start in mid-2014 (Month 30 of the project). The work consists of 7 work packages and the general S&T objectives include: finalization of rhBMP6 process development and master cell bank, working cell bank validation and manufacturing by partner Genera Research (GEN) (Zagreb, Croatia) and BMP6 protein validation by partner Vitrology/SGS (VITR) (Dunbartonshire, UK), which includes sterility testing with specific reference to virus contamination and protein quality analyses. Protein stability of GLP batches and toxicology testing will be performed by MediTox (MT) (Prague, Czech Republic) and University of Zagreb School of Medicine (UZSM) (Zagreb, Croatia) project partners. The OSTEOGROW kit with all components for use will be developed by UZSM. An early and late scientific advice will be obtained from the European Medicines Agency (EMA) upon development of clinical protocols and other required documents for monitoring and analyzing clinical study results developed by Paul Regulatory Services (PRS) (Cardiff, UK), Linkoping University (LIU) (Linkoping, Sweden), Smart-Medico (SMED) (Zagreb, Croatia), Medical University of Vienna (MUW) (Wien, Austria), University of Sarajevo Clinical Center (USCC) and Clinical Hospital Centre Sisters of Mercy (KBCSM). Finally, national ethics committee approvals will be obtained for conducting phase I and phase II clinical trials at MUW, USCC and KBCSM.

The SMEs GEN and MT will develop and validate the BMP6 production in their facilities. Consortium members from MUW, USCC, LIU, KBCSM, SMED and PRS will perform, monitor and coordinate clinical trials. OSTEOGROW is expected to find a wide use in human and veterinary medicine.

Project Results:

Since the beginning of the project preclinical grade of rhBMP6 has been manufactured at larger scale for rodent and rabbit toxicology studies. The rhBMP6 production process has been significantly improved by switching to a cell line with high genetic stability in a fully serum free suspension culture in a closed system and adequate production capacity for commercial manufacturing. The pre-master cell bank (pre-MCB) was tested for sterility and stability, with special reference to viral contamination and was approved by Vitrology/SGS (VITR, P10). The developed rhBMP6 purification process is robust, inexpensive and takes only 24-48 hours. The purified rhBMP6 protein was found stable in lyophilized form and is biologically active and free of host cell contaminants and other tested impurities. The scale up process for producing gram quantities of rhBMP6 has been developed and the productivity of the new cell line is stable over several months follow up. For testing of preclinical grade of rhBMP6 several analytical methods and bioassays have been introduced and validated, including liquid chromatography – mass spectrometry, Maldi TOF spectrometry, N-terminal sequencing, isoelectric focusing, protein concentration methods, SDS-PAGE, ELISA, proximity extension assay and custom made C2C12 bioassay enabling sensitive and specific determination of rhBMP6 activity in vitro. Preclinical grade rhBMP6 from two batches has been analyzed and will be compared with the clinical grade material in Month 23 of the project. Biocompatibility studies regarding rhBMP6 have been performed and no issues have been detected. The in vitro safety profile of rhBMP6 has been tested in human tumor cell lines and no cytotoxic effects have been displayed. Highest rhBMP6 concentrations inhibited the proliferation of tested cancer cell lines derived from human lung, liver, breast, prostate and bone. Pharmacokinetic (PK) studies with GLP batches of rhBMP6 showed that the protein is rapidly cleared from the blood after systemic injection in mice and rats. The PK studies of rhBMP6 released form WBCD implanted into the fractured femur demonstrated that only a very small amount was released into the systemic circulation. The final formulation of OSTEOGROW composed of the whole blood coagulum containing rhBMP6 has been determined. Around 90% of rhBMP6 added to the full blood remains in the blood clot bound mainly to its extracellular matrix component.

In vivo this formulation of OSTEOGROW showed significant osteoinductive activity in the rat and mouse model of ectopic bone formation and full absence of inflammation and swelling at the implantation site. The kit for using OSTEOGROW for clinical studies has been designed and the required single components have been all extensively protected by a recently issued patent US 8197840. Selection of the most suitable manufacturers of the kit components is on-going and will be fulfilled by Month 24.

Genera Research obtained SME status (May 2013) from EMA and therefore became eligible for a 90% fee reduction for scientific advice. Work on the Investigational Medicinal Product Dossier (IMPD) and Investigator Brochure (IB) is ongoing. Clinical protocols for Phase I and Phase II studies have been designed and meetings with the clinical partners in the Consortium have been taking place regularly.

Potential Impact:

The expected major result of the OSTEOGROW project is the development of a more efficient osteogenic device, compared to the currently commercially available products, with desirable therapeutic index and minimal side effects. OSTEOGROW addresses this need by the development of strategies involving a novel device which is very safe and does not contain any material from animal origins; does not have allergic/inflammation inducing properties and involves BMP6 with recently proven unique bone forming characteristics as bone growth promoting factor. Studies conducted within OSTEOGROW will enable breakthroughs in translational research directly amenable for clinical applications. All the results are regularly and thoroughly communicated to the scientific and public community through the conferences, publications, press releases, media, web-sites etc.

The prevalence of acute bone fractures in EU, in particular in osteoporotic patients with a high proportion of secondary interventions, is around 6 million which is a high burden for health care insurance agencies. As the population ages, it is predicted that in the EU more than 12 million bone fractures will occur yearly by 2050 . About 50% of postmenopausal women are actually exposed to a bone fracture, which has a life-threatening effect. Classical therapy of bone fractures in osteoporotic patients results with more than 5-11% of non-unions and secondary interventions. Preventing these events can significantly decrease the incidence of failed bone unions and increase the quality of life of millions of patients. Novel therapies to enhance bone formation, to shorten the healing time and prevent non-unions are an urgent medical need.

Currently with no adequate therapy available, healing and present solutions in this therapeutic area rely on expensive and side-effects associated bone devices. OSTEOGROW can bring new insight into application of potentially the most affordable, efficacious and safest therapy for biological bone regeneration. OSTEOGROW is addressing an inexpensive production of new biological entity (rhBMP6) in large quantities and OSTEOGROW is aiming to improve bone repair by utilizing autologous coagulum and minimal quantities of recombinant BMP6, applying them directly on the fracture site, without undesirable effects. In the case that the results obtained in clinical trials prove that OSTEOGROW device is superior and safer to currently used biological bone regeneration procedures, OSTEOGROW will become an affordable new therapeutic solution for the enhancement of bone healing and prevention of bone non-unions. Also, research indicators in the form of new, innovative clinical trial protocols and observations will enter into standardized procedures used by regulatory bodies and enhance the level of orthopedic trauma surgery evidence based medicine.

Furthermore, the Project is enabling further development of participating SMEs, their R&D capacities and contributes to the new Commission’s emphasis, outlined in the Europe 2020 strategy for smart, sustainable and inclusive growth. As the first Croatian biotech, Genera Research (P2) promotes innovation and innovative products supporting better and faster integration of Croatian industrial/biotech sector into EU, leveraging it with European standards and adding value to the EU health research area and industry. Through the partnership within this project, SMEs involved covering the whole drug development process from innovation and production through pre-clinical development to the clinical trials will create a basis for future collaboration in the new innovative product developments. This will largely contribute to the flagship initiative “Innovation Union” of the Europe 2020 strategy, by promoting knowledge partnerships, SME’s access to intellectual property, and their participation in clinical trials.

Of significant importance for OSTEOGROW is also the training of young scientists through not only advanced research but also workshops (‘summer schools’), short but focused exchanged visits and scientific meetings, which will foster the long-term scientific progress in the EU.

OSTEOGROW also aims to actively promote equal opportunities, for example, by encouraging and supporting the participation of women in research and management activities. Indicative of our commitment to this strategy is the participation of 18 female staff member scientists (out of 32) and three female colleagues in the OSTEOGROW Steering Committee, the highest decision-making body of the consortium. Therefore, OSTEOGROW addresses major societal issues.

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