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H2020

GLIOMARK Report Summary

Project ID: 673737
Funded under: H2020-EU.3.1.3.

Periodic Reporting for period 2 - 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: 2016-07-01 to 2017-06-30

Summary of the context and overall objectives of the project

Gliomas are recognized as a rare tumor disease 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.
Gliomark will contribute to the goals of the International Rare Disease Research Consortium (IRDiRC), which has set the target of developing 200 new rare disease treatments and diagnostics by the year 2020, and the development of diagnostics for all rare diseases. In support of thiss goal, the SME partners will apply for an orphan diagnostic designation by European Medicines Agency (EMA).
Taken together, the aggregated unique selling point of SPECT in combination with TTF is the first ever and only glioma diagnostic, which assesses a clinically validated glioma biomarker, has high reliability, reproducibility, sensitivity, as well as specificity, which is used to replace an invasive method, is safe, well tolerated, widely available and more affordable.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Significant developments have been made from the beginning of the project (01/07/2015) until the end of the second reporting period (30/06/2017):
• Scientific advice has been given by the Medicines and Healthcare products Regulatory Agency (MHRA) before the finalization of the clinical study protocol.
• Potential clinical trial sites within the EU have been identified by the partners and the CRO and formal qualification procedures have been performed to ensure appropriate sites are included in the Phase II clinical study. Eleven sites have been selected from three European countries.
• The study has received a EudraCT number (2015-005573-21). All relevant formal documents have been collected and submitted to the various regulatory authorities and Ethics committees in the respective countries. All necessary approvals have been obtained.
• Phase II study officially started. Patient recruitment has been completed (Last patient in (LPI) as per revised plan, Jan 2017).
• Phase II study raw data are available (03/05/2017); results analysis is ongoing.
• An amendment to the phase II study is being implemented for the collection of additional follow-up information.
• Preparation of the phase III study is ongoing.

• Orphan designation for tetrofosmin for the diagnosis of Glioma has been granted by the European Commission (14/10/2016).
• A Paediatric Investigation Plan (PIP) has been developed and submitted to European Medicines Agency (EMA).

• Regarding manufacturing of the finished product, necessary pre-formulation studies and most of the pre-validation work related to the analytical development have been performed. Development is fully aligned with all applicable EU guidelines for medicinal products of human use.
• The API pre-validation batch has been delivered to the subcontractor responsible for GMP manufacturing and production activities for the finished radiopharmaceutical kit have been planned.
• Identification of external labs/ service providers to support additional Quality Control requirement (of the radiolabelled product) has been completed.

• The project’s website is being regularly updated (www.gliomark.eu). The site has more than 7.500 visits so far.
• The GLIOMARK project has been published in several national and European newsletters accessible from the general public to highly qualified professionals.
• Consortium partners have actively participated in several international events and conferences.
• Project partners participated in major international trade fairs (BIO-Europe, MEDICA, and BIO_USA) and have established important business contacts to support commercialization activities in the territories of interest.
• The project has also been presented in several conferences in the fields of Oncology, Nuclear Medicine and Neurosurgery with enthusiastic comments from the scientific community.

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 a life-threatening rare disease with poor prognosis. With regards to treatment, in low-grade lesions, radical surgical removal will generally allow functional survival for many years. Adjuvant radiotherapy can delay disease progression and probably increases survival. For high-grade tumours, surgical resection is almost always followed by radiotherapy and adjuvant chemotherapy that are usually given concomitantly. Patients younger than 60 years, with good functional status and gross total tumour resection have a better prognosis, however, the 5-year relative survival rate is still only 17%. With progressing age it further decreases to around 3 % for patients of >65 years.
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) 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.

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