Periodic Reporting for period 4 - GLIOMARK (Validation of blood-brain-barrier permeability as a glioma biomarker by means of the radiotracer 99mTc-tetrofosmin and single-photon emission computer tomography) Reporting period: 2018-07-01 to 2021-12-31 Summary of the context and overall objectives of the project Gliomas are rare tumours with poor prognosis. Currently used imaging techniques such as computer tomography (CT) or magnetic resonance (MR) are often not able to accurately distinguish gliomas from other diseases or lesions. Positron emission tomography (PET) has high diagnostic accuracy, however, is costly and not widely available. As a result, final confirmation of diagnosis and grading of brain tumours can only be achieved with an invasive brain biopsy. The GLIOMARK project aims at providing an easy-to-use, non-invasive method for the differential diagnosis and grading of brain tumours using Single-photon emission computed tomography (SPECT). SPECT is widely available but is currently not used for diagnosing and staging Gliomas due to lack of appropriate and validated diagnostic procedures. More specifically, the objective of GLIOMARK is to clinically validate the permeability of the blood brain barrier (BBB) as an in vivo biomarker for the diagnosis and grading of gliomas. Based on research undertaken by the group of Andreas Fotopoulos, professor of nuclear medicine at the University Hospital of Ioannina, Greece, this will be accomplished by means of the radiotracer 99mTc-tetrofosmin (TTF) and SPECT. TTF has been used for a long time in diagnosis of heart diseases and considered safe. The ultimate output of GLIOMARK will be a diagnostic kit, containing tetrofosmin, used for SPECT brain imaging which leads to avoidance of patient-burdening brain biopsies. This shall be achieved by (1) conducting a clinical phase II, (2) conducting a clinical phase III and (3) developing and producing clinical grade TTF. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Major scientific and technological achievements have been accomplished during the project’s lifetime:• Orphan designation for tetrofosmin for the diagnosis of Glioma has been granted.• Regarding manufacturing of the finished product, development is fully aligned with all applicable EU guidelines for medicinal products of human use.• The phase II clinical study encompassing six European sites has been successful completed; results encourage the conduct of a phase III (both primary and secondary end-points have been met).• The quality and robustness of the phase II study's results have been confirmed from the positive feedback received from a Scientific Advice meeting with the MHRA.• Active substance (API) has been successfully developed and its GMP manufacturing process and analytical methods have been validated.• Formulation development of the finished product has been completed, medium scale batches have been produced and clinical scale batches for phase III trial could be produced anytime. The quality control of our product vs. the originator's is successful.• A Scientific Advice for the Phase III study design from the MHRA has been obtained (April 2018). The outcome of the meeting was positive.• To pursue further activities in continuation of GLIOMARK (conduct the phase III trial and perform research on radiotherapies) the company ALBEGA Medical GmbH was founded. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Gliomas, the most frequent primary brain tumours, are life-threatening rare tumours with poor prognosis. Currently, CT and MRI are necessary to identify brain lesions in general. Limitations of these methods are that MRI and CT are often not able to detect low-grade gliomas or distinguish glioma from other tumours or other pathologies. Moreover, MRI and CT are not able to grade the glioma stage. To date, glioma confirmation and grading still have to happen during brain surgery with biopsies and histopathology. However, reliable, fast, differential diagnosis with high sensitivity and specificity and glioma grading are of utmost importance since they have immediate impact on patient management and the type of therapy: the earlier the disease is diagnosed, the more likely is a longer survival.In consequence, there is a significant unmet medical need for a fast, reliable method to perform differential diagnosis of glioma with high sensitivity as well as specificity, which is widely available and economically viable at the same time.End-users of the final diagnostic product (currently under development, clinical phase III in preparation) used for the imaging technique in combination with SPECT, will be patients with glioma and patients with reliably excluded glioma. Both can be guided to different therapies for their particular suffering without prior brain biopsy. Further, beneficiaries and buyers will be hospitals and ambulatory centres specialized on brain tumour diagnostics and potentially treatment. Although the results of the Phase II study were positive, these results need to be confirmed in the larger Phase III study. Until this has been completed and the results have been analysed, the full impact of this project cannot be properly assessed. GLIOMARK project logo
