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A Clinical Phase IIB trial with 2OHOA in patients with newly-diagnosed malignant glioma.

Periodic Reporting for period 1 - CLINGLIO (A Clinical Phase IIB trial with 2OHOA in patients with newly-diagnosed malignant glioma.)

Reporting period: 2017-12-01 to 2019-05-31

The CLINGLIO project addresses the clinical unmet need of patients bearing glioma through the advance of novel therapeutic strategies. This project involves a high level of social impact since glioma is the most common brain cancer in adults, representing about 50% of all primary brain tumours. Glioblastoma multiforme (GBM), the most aggressive primary Central Nervous System (CNS) malignancy, accounts for about 2 % of all cancer-related deaths and has a prevalence (grade IV astrocytoma) of less than 0.3 cases/10,000 inhabitants in the EU, which is well below the threshold of orphan diseases (5/10,000 cases). The five-year mortality rate of patients diagnosed with GBM is over 80 %, making this rare disease a serious health problem. Standard of Care (SoC) for GBM consists of surgical resection to the extent feasible, followed by adjuvant radiotherapy (RT) plus Temozolomide (TMZ). Despite SoC, median survival from diagnosis is only 14.6 months.

The CLINGLIO project aims to advance a novel drug (2OHOA) for the treatment of the rare disease GBM towards an initial market entry in Europe. For this purpose, we carry out a well-conducted (demonstrative) clinical trial in patients to evaluate the efficacy of an innovative therapy, based on 2OHOA and SoC in subjects with primary newly diagnosed GBM. In addition, planned CLINGLIO studies with patient samples and glioma cells have the objective to identify new potential biomarkers for predictive (diagnosis and prognosis with threshold biomarkers and omics signatures), pharmacodynamic/pharmacogenomic and stratification (patient treatment assignation) purposes.
The project is divided into seven work packages (WP 1 to 7). WP1 deals with project management and aims to ensure that the project deliverables are met in an integrated and timely manner within the agreed budget, to enable the integration of WP and to promote effective communication among members of the research consortium. LPharma and Praxis through its linked 3rd party Biopraxis are the partners implicated in this WP1. Within this WP the different management bodies were set up and the appropriate supervision and coordination of partners together with the progress into the project was monitored.

WP2 is a basic research package dealing with the molecular mechanism of action of 2OHOA aiming to fully determine the role of a new target gene (sphingomyelin synthase SMS) in carcinogenesis and in the efficacy of 2OHOA treatment. UIB, RFHMO and UNISA are the partners implicated in this WP2. This WP showed the confirmation of the incorporation of 2OHOA in GBM cells, the resolution of the molecular structure of SMS and the finding of the alterations in fat metabolism that occur under 2OHOA treatment. Furthermore, treatment with 2OHOA induces changes in the location of several proteins, critical for cell survival, among the different internal compartments of the cells. All of this suggests that 2OHOA induces a change in cell fate by pushing cells into cell aging.

WP3 is the package for the formulation development and the manufacturing of the drug product for the clinical batches. Praxis, LPharma and SMS are the partners implicated in this WP3. The drug product was produced according good manufacturing practices and in amount to cover the needs of the clinical trial. Simultaneously the analytical methods necessary for the control and assurance of the quality were validated.

WP4 is the phase IIB clinical trial of the 2OHOA in primary newly diagnosed GBM patients. LPharma, SMS and NICR are the partners implicated in this WP4. The consortium is ready to start the recruitment. During the first 18 months of CLINGLIO there was a shift in patient recruitment that might be corrected with an increase in the number of investigational clinical sites. Study is currently progressing through the initiation of implementation/monitoring phase. Clinical study protocol and other required submissions documentations were finalized and presented to the regulatory authorities in IS, IT, FR, SP and UK. Full approvals have been obtained in IS and FR. Final decisions from the other regulatory authorities are expected soon. All in all, the improvement in the protocol is to better align with the SA/PA of the European Medicines Agency (EMA). The protocol is a very ambitious, complex but robust protocol, which covers all the possible scenarios and meets all the requirements and suggestions by the EMA, all in all, increasing the chances to get Conditional Marketing Authorisation (CMA) by the EMA.

WP5 is a basic research package aiming the search and validation of biomarkers in the patients of the phase IIB clinical trial of the 2OHOA in primary newly diagnosed GBM patients. LPharma, UIB and Lipodom are the partners implicated in this WP5 and issued the protocols and a preliminary signature to identify responder patients. Using samples from patients of a previous phase I/IIA clinical trial a preliminar molecular signature was found that might potentially distinguish responder patients.

WP6 is a management package dealing with dissemination, communication, exploitation and marketing strategy. LPharma, UIB, LMBRI and Biopraxis are the partners implicated in this WP6. Significant progress was made in harnessing physician’s perspective of the therapeutic candidates. There are on-going efforts on understanding market economics of the compound and how does that compare with the current medications available. We have determined the payers are different in nature due to different healthcare systems in different countries. The main vehicle of dissemination and interac
The most relevant expected results at the end of the project is demonstrating the efficacy and effectiveness of 2OHOA in the treatment of GBM. Taking into account the absence of adverse events associated to 2OHOA treatment, as observed in the completed Phase I/IIA clinical trial, and the preliminary positive responses observed in some patients, this treatment could provide a significant clinical benefit with respect to the current SoC in GBM patients, improving the life expectancy and the quality of life of patients suffering from this condition worldwide, a remarkable social impact. Further impact is expected on:
- new diagnosis biomarkers and possibly new therapies for patients who do not respond to treatment with 2OHOA.
- growth of SMEs involved in drug development.
- contribution in international cooperation.
- develop a preliminary assessment of the potential economic and public health aspects of the new therapeutic option.
CLINGLIO mid project meeting