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Periodic Report Summary 2 - EXALT (Proposal to assess an innovative Immunotherapy, based on a thioredox peptide antigen, in a Phase I Trial for Type-1 Diabetes)

Project Context and Objectives:
The current project is being carried out by a consortium consisting of one SME (ImCyse), and three academic collaborators’ (Inserm, Helmholtz-Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt & Queen Mary and Westfield College - University of London) and a Technology Transfer office (Inserm-Transfert). The objective of EXALT is to complete a preclinical package and perform a phase I clinical trial in adult newly diagnosed with type 1 diabetes (T1D). This clinical study will assess the safety, the mechanism of action, and preliminary efficacy of an innovative immunotherapeutic technology invented by ImCyse.

This immunotherapeutic (ITx) is made up of synthetic peptides and vaccine adjuvant. Although this approach is commonly called a “therapeutic vaccine”, in this report, the experimental product is termed “ITx” or “Thioredox ITx”, which reflects its peculiar and innovative mechanism of action. It is expected to be disease-modifying by stopping the autoimmune-mediated destruction of islet beta cells in the pancreas through an antigen-specific mechanism of action whilst preserving overall immune competence of the patients. A preliminary preclinical proof-of-concept study for T1D had been previously performed by ImCyse in Non-Obese Diabetic (NOD) mice prior EXALT. If successful, this experimental approach could lead to a breakthrough in the management of T1D.

The primary objectives of the phase I clinical study will be (1) to investigate preliminary safety features for a tolerated dose, (2) to confirm and understand the immune mechanism of action, and (3) to identify signals of clinical and immune activity of benefit for the patients.

The second period of EXALT is aiming at:
• refining management tools for advancing the project,
• further strengthening the preclinical package as well as (1) selecting and optimizing the ITx composition suitable for human disease and in general at preparing the development of the manufacturing process, (2) evaluating toxicology/preclinical safety of thioredox ITx, (3) defining biological assays that will be open for use in treated patients and (4) finalizing the clinical trial protocol and ICF. The complete set of preclinical data will be instrumental to initiate the commit to phase I clinical trial.

Project Results:

EXALT project started in February 1, 2014, based on preclinical collaborative work already performed by ImCyse and GSK in the context of their bilateral license and option agreement.

WP1 update
Amendment #2 of GA (1) acknowledging GSK withdrawal, (2) defining INSERM as coordinator of EXALT, (3) allowing INSERM-transfert to accede as a new party was approved by EC. The Consortium Agreement was amended and signed by all partners. At the time of second report submission, the management framework and the governance of EXALT are fully operational.

WP2 update
Following a full project review at the EXALT consortium meeting held in London in January 2016, a series of refined precise criteria were revised by covering the whole preclinical package and the extensive data generated in vivo in mice and in vitro with human cells. The JSC considered MS17 successfully achieved. In brief, the prevention, long-term suppression and treatment of disease with decreased insulitis and preservation of C-peptide have been demonstrated in preclinical models and peptides susceptible to provide the most convincing protection identified. Specific attention to possible toxicity of some peptides after multiple injections, e.g. anaphylaxis, has been considered. Regarding the human ITx peptides composition, from 20 peptides selected based on literature, bioinformatics prediction and biochemical assays, two have been selected as lead candidates based on in vitro cell-based assays using human Peripheral Blood Mononuclear Cells (PBMCs) from
healthy donors and T1D patients. The last round of selection has identified the candidate for the final composition to be developed for the Phase 1 clinical trial of EXALT.

D2.1: Formulation development final report & D2.2: Bioassay and Analytical assay reports are submitted in RP2.

Through this work, peptide solutions have been characterized for in vivo studies, analytical method have been developed, and stability data for peptide bulk material and dosage forms to be used for this project have been generated. Some improvement of peptide on specific features relevant for further clinical development of a human ITx have also been achieved, e.g; stability, adsorption, chemical and biochemical properties for potency.

WP3 update
Preparation of the regulatory strategy for the immunotherapeutic candidate for T1D (WP3) has thus been partially done. The highlights on the outcome of this initiative have been shared with ImCyse and Inserm. GMP formulation of the thioredox ITx has gone through its main step, including contracting a CMO and production of a non-GMP batches upstream of manufacturing of GMP batches, which allowed toxicology studies to start. Advices from EU national competent authorities prior to regulatory submission have been obtained.

WP4 update
The phase 1 trial protocol is almost finalized, taking into account the feedbacks of the IAB of EXALT (Independent Advisory Board) and of the Paul Ehrlich Institute. This trial will allow selecting the dose that will be used in the second confirmation phase in which patients will be recruited to be randomly allocated to either the thioredox ITx in its GMP formulation or a placebo. Beyond test that will allow evaluating the evolution of the residual insulin secretion under treatment as compared to placebo, analysis will be performed to evaluate immune markers that feature the autoimmune response to insulin-secreting cells along the type 1 diabetes process, as well as immune test to evaluate the immune response to the thioredow ITx product used in the study.The first patient is expected to be included in period 3 of EXALT.

WP6 update
Current “background” IP from ImCyse is being strengthened by the data generated in period #1 and #2. The project have a graphical identity and communication tools are almost finalized.

Potential Impact:
T1D is a life-long condition and remains a high burden for the patients and the society. It is still managed by non-curative daily insulin injections to compensate for the lack of endogenous insulin production by the pancreas attacked by an auto-immune process.
Today, the encouraging preclinical results obtained during the period #1 and #2 of EXALT, in terms of potency in mouse models and improvement of the technological development feasibility, have led the consortium members to agree to move forward this project beyond MS17. Ultimately, this unique immunotherapeutic approach, if proven to be successful according to the EXALT plan and criteria, could create an opportunity for developing a disease-modifying medicine with significant added therapeutic value for T1D patients.
The data generated in WP2 activities strengthened the current intellectual property of ImCyse. So far, this project has created the space for synergies between academic and industry sector for scientific, technical, and exchange of best practices for the development of an innovative immunotherapy of T1D. ImCyse has also played an important role in setting the foundation and conditions that should ease the feasibility of industrial development of the therapy if the steps planned in EXALT are successfully achieved by the Consortium.
Today, this collaborative work and EC funding have contributed to provide the means and opportunity for an SME, ImCyse, to set the basis to demonstrate the value of their innovative and unique technology for the treatment of a human disease of high medical need, T1D. In addition, the success of EXALT will provide a significant contribution to confirm the validity of imCyse’s platform technology at large and could enable ImCyse to further develop their pipeline and so provide a key step to a new antigen-specific therapeutic concept for the treatment of multiple immune mediated disorders.

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