CLINGLIO

The CLINGLIO activities are organised in six Work packages (WPs) to ensure the success of the project, thanks to the strong interdisciplinary interactions among all partners and WPs.

WP1. Project management (Laminar Pharma and Praxis).

To ensure the proper scientific, technical, legal and administrative management of the project, properly optimising the application of the resources, in order to support the Participants to achieve CLINGLIO objectives, reach the project milestones in a proper time/ manner and guarantee the presentation of the deliverables.

WP2. Molecular mechanism of action of 2OHOA (UIB, UNISA and RFHMO).

A deep understanding of the anticancer mechanism of action of 2OHOA is necessary to design an optimum clinical development plan and,ultimately, to obtain approval from regulatory agencies. These studies will be based on various complementary research lines:

(i) investigation of the drug's molecular target, sphingomyelin synthase (SMS).

Since expression of SMS is associated with the patients' median survival, an important part of the study will be focused on how the two main SMS forms (SMS1 and SMS2) are regulated in different glioma (and other tumour) cell lines, by using several tumour cell lines and a control non-tumour cell line.

Determination of SMS 3D structure is key to know the structure of catalytic and regulatory sites and better understand how to modulate the enzyme's activity. For this purpose, we will apply novel molecular docking techniquesto clarify the SMS regions responsible for the interaction with 2OHOA. Along with docking studies, we will perform a full molecular dynamics study to explore the enzyme behaviour upon interaction with 2OHOA and other natural and synthetic fatty acids.

(ii) investigation of the cellular proliferation switch SMSs are key enzymes in the regulation of the raft-prone lipid SM and the nonraft- and nonlamellar-prone lipid PE. The ratio between these two lipids is critical for the type and abundance of amphitropic signalling proteins in the membrane, whose cell localization greatly depends on the membrane lipid structure. For this reason, we will evaluate the type and abundance of membrane signalling peripheral proteins to determine how this lipid proliferation switch operates.

(iii) investigation of the molecular basis of the response to 2OHOA treatment 2OHOA is a modified fatty acid that cannot be metabolised via beta-oxidation and itaccumulates 4-fold faster in cancer than normal cells. Therefore, one of the purposes of this project is to investigate the impact of 2OHOA treatments in cancer cell energetics, by carrying out analysis of the metabolomic effect of 2OHOA.

WP3. New sustainabledrug formulation development and manufacturing of clinical batches (Praxis, LPHARMA, SMS).

For the previous clinical trial, 2OHOA was formulated as a solid, stable powder stored in amber glass bottles of 200 mlto produce a suspension in water for oral administration. Because of environmental and economic reasons, for the current clinical study we will investigate and develop oral suspension sachets, ensuring the completion of all required quality and stability development of the Drug Product, Quality Control, Quality Assurance, DMF and release of the batches.

WP4. Phase IIB study of 2OHOA in newly diagnosed malignant glioma patients (LPHARMA, UNEW, FINCB, RMH, SMS, RFHMO, IGR).

A randomized, double-blind, placebo-controlled, 2 parallel arms (1:1 ratio), adjuvant trial to assess the efficacy and safety of 2-hydroxyoleic acid (2- OHOA) versus placebo in patients with newly diagnosed GBM IDH wildtype. In all arms, patients will receive the SoC and will be randomized to receive either placebo (Arm A), or a dose of 12 g/day 2-OHOA (Arm B). The primary endpoints of the study are PFS and OS. The first part of the study is planned to enrol 140 patients, 70 patients per arm. After 45 events for PFS are observed, a formal interim analysis will be performed Based on this, the IDMC will make recommendations regarding: the sample size and the continuation of the trial overall. Depending on the results observed at interim, IDMC will recommend to continue as it was planned or to increase the total number of events both for PFS and OS by up to 50% and also the total sample size will also be increased to up to 210 patients.

WP5. Study and validation of biomarkers in patients (LPHARMA, UIB, Lipodom).

The current diagnosis tool for glioma is based on MRI (expensive) plus histopathological biopsy analysis (invasive and not always viable). Following the need to search more affordable biomarkers and to determine the presence of several exploratory biomarkers involved in 2OHOA's mechanism of action, blood samples and/or biopsies will be analysed. These studies will be useful for diagnosis, prognosis and evaluation of the response to treatment. We will study the DNA/RNA sequence mutations (molecular signature) as well as the lipidomic profile in plasma samples from glioma patients before and after treatment. The presence of specific lipid species and their levels will be considered to evaluate their potential use in GBM diagnosis, prognosis and potential response to treatment.

WP6. Dissemination, communication, training and marketing strategy (all participants).

Dissemination and external communication activities will be a strategic process to raise awareness of CLINGLIO, its objectives, partnership, activities and intended impacts at different levels, from reputable researches to general public, in an effort to do research for and in society.

General dissemination actions will include:

A website

An annual open symposium and international meetings

Communication actions targeting general media, scholars and professionals[/Li2]

Patient associations will be engaged with the project from the beginning.

Free open access to all publications generated within the project will be granted through gold open access schemes, and will be available in the project website.

Training activities will be organised to sustain or create opportunities for researchers to improve their skills, and to spread 2OHOA knowledge in Clinical communities.

Regarding the placing on the market of 2OHOA, significant knowledge and expertise in evaluating and coordinating regulatory agencies, healthcare systems, payers, service providers and physicians community is required. The severity of glioma, lack of effective therapies, and its 'orphan drug' status, could qualify 2OHOA to obtain conditional approval after the phase IIB trial proposed in this project, which justifies the need of a detailed marketing and commercialisation plan for 2OHOA for the treatment of glioma in Europe and other markets. Market access strategy in all major markets, pricing and reimbursement and a broad international health economics analysis will be developed in order to define a clear policy to exploit the results of the CLINGLIO project.

A detailed Business Plan will be implemented, together with an update of the already developed market study, including: identification of key exploitable results, Intellectual Property Rights management, market assessment (size, volume, distribution), constitution of an exploitation team, detailed financial projections, detailed cost evaluation for product manufacture, marketing costs and foreseen revenue, commercialisation roadmap and risk assessment. This business plan will be supported by a detailed Exploitation Plan in order to catch all the exploitable items to be transferred to markets or to be serve as a basis for future R&D efforts. Exploitation will be understood in a wide manner at different levels, as exploitation interest will differ between industrial and academic partners, but in a full complementary way.

WP7. Ethics requirements.

The objective of this work package is to ensure compliance with the ethics requirements set out by the European Commission. CLINGLIO Ethics Board will provide with the protocols submitted for evaluation as well as with copies of ethics and regulatory approvals. Copies of ethics and regulatory approvals for the research with humans will be procured together with the protocols submitted for approval.

OVERVIEW

At a glance:

Project plan: