Final Report Summary - EXALT (Proposal to assess an innovative Immunotherapy, based on a thioredox peptide antigen, in a Phase I Trial for Type-1 Diabetes)
Executive Summary:
The EXALT 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 was to complete a preclinical package and perform a phase I clinical trial in adult newly diagnosed type 1 diabetes (T1D) patients. This clinical study is assessing the safety, the mechanism of action, and preliminary efficacy of an innovative immunotherapeutic technology (also referred to as ImotopeTM) invented by Imcyse.
The ImotopeTM evaluated in the trial is an innovative immunotherapeutic. It consists of a synthetic peptide containing an MHC class II epitope linked to a thioredox motif and is administered with a vaccine adjuvant. 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 diabetic patients.
A preliminary preclinical proof-of-concept study for T1D had been performed by Imcyse in Non-Obese Diabetic (NOD) mice prior to EXALT. Based on these first results, a complete preclinical package was successfully prepared in the scope of the project, using NOD mice as animals of choice. A GMP lot of candidate immunotherapeutic was produced and a thorough toxicology study was run. The phase I study was approved in 7 EU countries, with 24 sites recruiting recent onset T1D patients. A total of 41 patients were sequentially enrolled into one of the three cohorts and allocated to receive IMCY-0098 (the ImotopeTM) or placebo in a 3:1 randomization ratio (meaning that in a group of 4 patients, 3 are treated with the ImotopeTM and one patient receives placebo). The primary objective of the phase I clinical study was (1) to investigate preliminary safety features for a tolerated dose to be explored in further clinical trials. Secondary and more exploratory objectives were (2) to confirm and understand the immune mechanism of action, and (3) to identify signals of clinical and immune activity of potential benefit for the patients. If successful, this experimental approach could lead to a breakthrough in the management of T1D.
At this point in time, the clinical study is still following up patients from the highest dose cohort. Last patient last visit is expected by end of April and full study results will be available in September 2019. No patient drop out has been reported so far and preliminary safety data indicates the product is safe for use in humans.
Project Context and Objectives:
The EXALT program (FP7 EU grant) started off in February 2014. In addition to an extensive preclinical research plan, the final objective of the project is to perform a phase I clinical trial in recent-onset (≤ 6 months) adult diagnosed type 1 diabetes (T1D) patients, using an immunotherapeutic preparation, called ImotopeTM, based on Imcyse technology. The project is being carried out by a consortium of one SME (Imcyse), three academic collaborators (Inserm, HMGU and QMUL) and a Technology Transfer Office (Inserm-Transfert). The project has a duration of 60 months.
Imcyse is a SME located in the province of Liège, at the site of the university hospital Sart Tilman (Belgium). It was founded in 2010 as a spinoff from the KU Leuven. Imcyse is pioneering the development of a new class of active, specific immunotherapeutics: ImotopesTM. An ImotopeTM consists of a short synthetic peptide encompassing an MHC class II epitope of the proinsulin protein flanked by a thiol-disulfide oxidoreductase motif formulated with aluminium hydroxide adjuvant. When presented by MHC class II molecules on antigen-presenting cells (APC), ImotopesTM convert epitope-specific CD4+ T lymphocytes into CD4+ T cells able to induce apoptosis of (1) auto-antigens-loaded APCs present in the pancreas draining lymph nodes, after cognate interaction, and (2) diabetogenic T cells recognising the same as well as alternative epitopes presented by the same APC. The net result of the activity of these cells is the arrest of the ongoing auto-immune response. In addition, these ImotopeTM-activated T cells acquire memory properties. Therefore, the Imcyse technology presents an opportunity to silence the autoimmune reaction at an early stage of the disease in an antigen-specific manner and is expected to provide long term islet β-cell preservation.
T1D is a chronic autoimmune disease, with circulating autoantibodies to islet autoantigens such as insulin, GAD65, IA-2 or ZnT8, in which insulin-producing β-cells located in the pancreatic islets of Langerhans are gradually destroyed by autoreactive T cells, involving CD4 and CD8 T lymphocytes. CD4+ T cells are believed to play a major role in the orchestration of the effector CD8+ T cells responsible of islet β-cell destruction. The pathophysiology of T1D with known islet cell autoantigens and T cell epitopes makes this disease a particularly attractive indication for development of an immunotherapeutic based on Imcyse technology. 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. 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 phase I placebo-controlled, double-blind, dose escalation clinical trial (EudraCT 2016-003514-27; NCT03272269) was initiated in October 2017. The primary objective of the trial is to evaluate the safety of Imcyse’s ImotopeTM IMCY-0098 administered in 3 increasing doses. Study patients (diagnosed ≤6 months with type 1 diabetes) are sequentially enrolled into one of the three cohorts and allocated to receive IMCY-0098 or placebo in a 3:1 randomization ratio. An independent DSMB oversees the conduct of the study to ensure the safety of participating patients.
The secondary objective of the trial is to evaluate the clinical response to IMCY-0098 by assessing disease activity. Clinical measurements like post challenge C-peptide, fasting C-peptide, HbA1c, insulin dose and glycaemic profile will give an idea of the efficacy of the tested ImotopeTM. In addition, some exploratory objectives will evaluate: 1) the impact on autoantibodies against GAD65, IA 2, ZnT8 and insulin and 2) the autoreactive T cell responses specific for autoantigens (proinsulin, GAD65, IGRP) expressed by islet β-cells. Furthermore, an enumeration and characterization of the proinsulin-specific CD4+ T cells induced by IMCY-0098 will be performed.
The data generated during the preclinical research activities in the framework of EXALT (WP2) 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.
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 ImotopeTM as a unique technology for the treatment of a human disease of high medical need, type 1 diabetes. In addition, the success of EXALT will provide a significant contribution to confirm the validity of Imcyse’s platform technology transversally and could enable Imcyse to further develop its pipeline and so provide a key step to a new antigen-specific therapeutic concept for the treatment of multiple immune mediated disorders.
Project Results:
WP2: Pre-formulation, optimisation and process development
The general objectives of this work package were to perform the pre-formulation of the ImotopeTM, the optimisation and development of the manufacturing process for the immunotherapeutic, and the development of process and analyses to the point of readiness for GMP manufacture and release for toxicology analysis.
First, a formulation was optimized for use in humans. The formulation consists of thioredox-peptide and adjuvant. Proinsulin was selected as target antigen. HLA class II-restricted epitopes within its sequence were screened for the design of a modified epitope that would fulfil three main criteria, namely, 1) stable chemical properties, 2) strong binding capacity to DR4 molecule, and 3) best capacity to prime and expand CD4+ T cells with cytolytic properties. Peptide IMCY-0098 was selected. Imcyse has conducted a set of experiments to optimise formulation and composition of the immunotherapeutic. The IMP is a sterile powder (562.5 µg in a vial) to be reconstituted with 2.25 mL of phosphate buffer 50 mM, pH 7.4 containing 500 µg/mL of aluminium hydroxide (alhydrogel 2%) before the administration to the patients. The ratio immunotherapeutic/adjuvant in the final formulation has been fixed to 1/2.
Second, process development through transfer of process from Imcyse to the Contract Manufacturing Organisation (=CMO) was carried out to determine an efficient and robust process for pure peptide manufacture. Bioassay (potency) and analytical assays were developed for purified bulk and final product. Assays were characterised and transferred, to contribute to the regulatory filing and to be ready to release GMP material. Imcyse has developed two tests aiming at determining potency of the peptide: 1) A fluorescence-based assay for the reductase activity of the peptide and 2) an MHC class II binding assay to check the affinity of the peptide with a DRB01*0401 allele. The tests have been set-up and qualified. The potency of the peptide produced by the CMO was tested by Imcyse using both methods.
Third, administration route and schedule have been assessed in preclinical studies for efficacy. For the clinical trial, the following decisions were taken:
• 4 injections in total, with a 2-week interval between each injection;
• A higher initial dose followed by three boost administrations of half the initial dose;
• A 3-step wise increase between cohorts. (Dose cohort 1: 50 µg – followed by 3x 25 µg; Dose cohort 2: 150 µg – followed by 3x 75 µg; Dose cohort 3: 450 µg – followed by 3x 225 µg)
WP3: GMP Campaign, Toxicity and Regulatory Filing
The general objectives of this work package were to manufacture and release a GMP quality batch of ‘IMCY-0098 + adjuvant’, perform required toxicology studies, submit the Clinical Trial Applications (CTAs), obtain scientific advice from an EU national authority on Chemistry Manufacturing and Controls (CMC), toxicology and clinical plans and to obtain regulatory approvals for phase I clinical trial.
The manufacturing of the clinical GMP batches has been performed by the selected subcontractors. Two batches of IMCY-0098 drug product have been produced: AX1-160702 and AX1-170603 – both consisting of over 2000 vials of sterile powder containing 562.5 µg of IMCY-0098 and 10 mg of mannitol. One batch of diluent: AW8-160401 – consisting of over 3000 vials of sterile solution for injection composed of phosphate buffer 50 mM, pH 7.4 containing 500µg/mL of aluminium hydroxide (alhydrogel 2%). One batch of placebo: AX2-160501 – consisting of over 2000 vials of sterile powder containing 10 mg of mannitol. GMP material was characterised and released by a qualified person with the assay methods developed in the previous work package.
Two GLP toxicology studies were performed and completed. First, a repeated dose toxicology and local tolerance study was executed. Second, a test for absence of respiratory distress on GMP batch AX1-160702 was performed. A full report on each of these studies has been written, finalized and signed off by both the contracted CRO and Imcyse. Both toxicology studies confirmed IMCY-0098 was safe in animals.
Before seeking regulatory approval for phase I clinical trial, scientific advice was requested to the Paul Ehrlich Institute (PEI, Germany). Two reasons that led Imcyse to choose the German national authorities were their strong background in immunology and vaccinology; and the reasonable timing to organise a face to face meeting which enabled Imcyse to get a feedback on the toxicology study before its initiation. A briefing document was prepared comprising of questions and company position on CMC, preclinical and clinical topics. It also contained background information, description of the product, summary of the preclinical data and a draft clinical study protocol. The meeting was organised on the 20th of January 2016 after which final minutes were edited by Imcyse and approved by PEI. These minutes were presented to the full consortium at the JSC meeting on 27th of January 2016.
A last task during this work package was to obtain regulatory approval for the trial. The project was initially anticipated to be run with the 3 clinical sites that are partners in the EXALT project (Inserm in France, QMUL in UK and HMGU in Germany). The recruitment rate was anticipated to be between 1-3 patients/per site/per month along the study. When reviewing similar studies performed in the past and their recruitment rate, it became very clear to the team (new team that was not involved in designing the EXALT project) in charge of setting–up the study that it was unrealistic. A recruitment rate of 0.2 pat/site/month in this patient population is what has been observed in similar trials. This is a difference of 5 to 15 times the initial evaluation. In order to remain within reasonable timing and give the project all chances of success, it was decided to increase the number of sites to 20 which was achieved with the addition of 2 countries, namely Belgium and Denmark. Regulatory approval, both by competent national authorities and ethics committees, in these five countries had been obtained by M49.
Because the randomization of early diagnosed patients was very slow in the beginning of the trial, two additional countries, namely Lithuania and Sweden, have been added to increase the recruiting sites to 24. This mitigation plan was necessary to ensure performing the phase I trial within reasonable timelines and respecting the EXALT timeframe as much as possible. The regulatory approvals in Lithuania and Sweden went smooth and swift and were all obtained in Month 52, 4 months only after the back-up plan decision was taken.
WP4: Phase I trial preparation
The general objectives of this work package were to make all the necessary preparations for the phase I trial. More specifically, to prepare the phase I trial protocol and ICF, to contract the participating sites, to develop and finalise the sample collection and SOPs for immune marker assays, to contract the central laboratory and to establish the Data Safety and Monitoring Board (DSMB).
The preparation of the protocol has been initiated with the organization of a working meeting in Paris on 13th of July 2016. The protocol was finalized and signed by the sponsor on 20th of December 2016. This version of the protocol was submitted together with all required documentations to all countries by the end of March 2017 except France. Based on regulatory reviews in the different countries, 2 subsequent versions of the protocol have been developed in order to integrate recommendations and request for changes. The final version of the protocol under which the recruitment of patients has been started is version 1.2 dated 29th of May 2017. This version of the protocol was used for the submission in France performed on 20th of June 2017. The objectives of the phase I clinical study were (1) to investigate preliminary safety features for a tolerated dose, and (2) to evaluate the clinical response to IMCY-0098 by assessing disease activity. Some exploratory objectives will evaluate 1) the impact on autoantibodies against GAD65, IA 2, ZnT8 and insulin and 2) the autoreactive T cell responses specific for autoantigens (proinsulin, GAD65, IGRP) expressed by islet β-cells. Furthermore, an enumeration and characterization of the proinsulin-specific CD4+ T cells induced by IMCY-0098 will be performed.
The ICF that needs to reflect the assessments and treatment schedule described in the protocol was finalized once the protocol was considered to be in the final stage. The final Master ICF used in the different countries to develop the country specific ICF was issued by Imcyse on 9th of February 2017. Here also, a subsequent version was generated to align the Master ICF with the changes made in the protocol and/or specific recommendations from regulatory authorities or ethic committees towards this document. The final version of the Master ICF is version 2.0 dated 6th of June 2017.
Due to the size of the study and the level of complexity (samples logistic, 7 different countries, 24 sites), it was necessary to select a Contract Research Organization (CRO) to run the study. After a thorough screening of potential CRO candidates, 4 of them were invited to present a proposal that they defend in a F2F meeting with Imcyse. The final choice was for INC Research (now called Syneos Health) and an initial service agreement was signed on 14th of Sept 2016 to allow key activities to start without delay. The final contract detailing all activities and timelines was fully executed on 28 Dec 2016. The contracted CRO was in charge of the pre-feasibility and feasibility assessments with the goal to propose a site list to be approved by the Imcyse, contracts with the clinical sites (24 in total), monitoring activities, safety reporting, statistical analysis and ensuring overall quality as well as respect of all applicable legislations.
The final list of sites was a mix of sites identified/proposed by Imcyse and sites identified and proposed by the CRO. Of note, in UK, a newly established network of sites, the T1D UK Consortium, has been selected for the study. This has been possible thanks to the recommendation and input of Professor David Leslies from the QMUL, one of the partners of EXALT, who is also one of the founders of this T1D UK Consortium. 7 sites of the consortium were finally selected for the clinical trial, including QMUL. Despite a slow start in UK due to lengthy regulatory and contractual process, the contribution of the network of sites in UK has been of critical importance to the success of the study.
Clinical Trial Agreement (CTA) templates have been developed by Imcyse and proposed to all selected clinical trial sites by the CRO. The CRO has negotiated, in full collaboration with the sponsor, both legal and financial aspects with each individual site. All tools to support and execute the phase I trial were finalized in collaboration with the CRO and other external providers by the time of submission of the study in the first countries. The main tools are: eCRF, Data management database, laboratory kits and manual, IMP user guidance, Randomization and IMP allocation system, Trial Master File, Freestyle libre system (reader and sensor) material, patient recruitment material.
Two central laboratories have been set-up for the phase I trial. One central lab (MLM) is managed by Imcyse through a logistic partner (ABF Pharmaceutical Services) and is responsible for all safety analyses as well as other non-immune analysis on blood samples from patients enrolled in the study. The second lab is a specialized lab for immune analysis called Caprion Biosciences. Further description on this activity is detailed in the next paragraph.
Immune markers are used to evaluate individual patient response to IMCY-0098. The initial EXALT project was referring to Imcyse and Inserm to perform the immune markers analysis. This matter is extremely complex to implement in large scale and also key to the future of the technology. Therefore, the decision was made to work with a laboratory specialized in this matter for 2 reasons: (i) a systematic tracking of all processes and methodologies including an established and robust Quality Control (QC) process (ii) an increased value of the results for external parties as it is performed independently. When deciding on the exact tests and methodologies to be used, it became very clear that the specialized laboratory had to developed tailored solutions. Although these endpoints are exploratory in the clinical trial protocol, we wanted to at least qualify the processes and methodologies. The qualifications of the different assays are described in the study workplan version 1.0 entitled: “Assay qualification followed by evaluation of immune responses of IMCYSE therapeutic vaccine IMCY-0098 in patients with recent-onset type 1 diabetes” as provided by CRO CAPRION (14th of December 2016). All this set-up has required a considerable effort and resources to properly design the tests that will be crucial to demonstrate, in humans, that the technology is indeed having the mechanism of action described in animal models. The logistics for collection and transportation of the blood samples from clinical sites to the CRO has been organized to guarantee the arrival of the samples at Caprion facilities within 24 hours of their collection on the clinical sites.
To ensure patient safety in the phase I trial, an independent DSMB was set up. The Data Safety Monitoring Board Charter (“Charter”) defines the primary responsibilities of the DSMB, the Committee’s membership, and the timing and purpose of its meetings. The Charter also provides procedures for ensuring confidentiality and recommended methods of communication to be implemented by the DSMB, and an outline of the data reports that will be provided by Syneos Health to the DSMB for review. The DSMB is composed of a Chairman, two members and an unblinded statistician. Consultancy contracts are in place with all members. An interim analysis of the low and middle dose cohort was scheduled to ensure safety before proceeding to subsequent higher dose cohorts.
WP5: Phase I trial conduct
The general objectives of this work packages are to successfully recruit and follow-up patients in the Phase I clinical trial, conduct the pre-specified immune assays, and finally perform data analysis and release a Clinical study Report (CSR).
The very first patient was screened in month 43 but could unfortunately not be randomized. With more sites initiated in September 2017, the first patient was injected month 45. A press release was issued at this moment. The last patient (n=41) was randomized in November 2018 (M58) in the highest dose cohort. The inclusion of sites in Lithuania and Sweden has led to 17.5% of total randomizations in less than 6 months. In total 65 patients have been screened. The study recorded 24 screen failures (37% screen failure rate). This screen failure rate is within the anticipated range (20-40%). However, analysis of the cause of the failures shows that 30% are related to patients who withdrew their consent just before being injected. This is an unusually high rate for this reason and his probably related to the age group (18-30y) and the new onset of their disease.
After confirmation of eligibility, all recruited patients received 4 injections of the immunotherapeutic or placebo (randomisation 3:1 in each dose cohort) and are followed up for 6 months. In total, 8 visits were scheduled per patient. In month 60, all visits were completed for patients in cohort 1 (n=8) and cohort 2 (n=12). Patients in cohort 3 (n=21) completed their visits up to week 12 (6th visit). Last patient last visit is planned for 16th April 2019. So far, no safety issues have been reported and there has been no patient dropped out from the study.
Samples for immune markers analysis are collected 4 times during the study: at week 0, 6, 12 and 24. All analyses are performed on fresh blood within 24 hours after drawing. Very few samples did not make it in time to Caprion Biosciences. A first interim analysis confirms that the used techniques are in place and working. We are not able to discuss results in this final report because the study is still ongoing and all data are still blinded.
Data collection has started following the first patient screening on 23rd of August 2017 and is still ongoing given the last patients of cohort 3 did not finalize the final visit. Study data cleaning is occurring regularly during the study in order to expedite the data analysis after the last patient is out. Specific data extractions and analyses were performed for the DSMB meetings that decided on the dose escalations. A first DSMB meeting was held on 23rd of March 2018. DSMB members gave green light to start enrolment of cohort 2 subjects. Because of a dosage error that occurred in one of the subjects, they recommended to include a witness to the reconstitution and administration process. As this was in fact already implemented in the procedure, a reminder was sent to all sites and a gap analysis was performed on the first subjects included at the different sites. A second DSMB meeting was held on 10th of July 2018. DSMB members gave green light to start enrolment of cohort 3 subjects.
All the relevant clinical data collected from the patients will be merged with the safety laboratories, immune makers and other clinically relevant assays for final analysis. The final study results are expected for September 2019. These results will be communicated to the outside world by means of press release and scientific publications. An additional JSC will be organized to discuss trial results with the EXALT consortium members.
Potential Impact:
Diabetes is a chronic disease that causes a high burden on patients and society. In Europe, 58 million people (aged 20-79 years) are affected, with an estimated rise to 67 million people affected in 2045 (Source: IDF atlas 2017). It is characterised by high levels of blood sugar glucose because the body cannot produce enough insulin (type 1) or is resistant to the circulating insulin (type 2). Insulin is a hormone released by the pancreas, more specifically by the pancreatic β-cells located in the islets of Langerhans. It is responsible for the uptake of glucose from the blood to the body’s cells where glucose is converted into energy. Hyperglycaemia is the main symptom of diabetes. Type I diabetes is caused by an autoimmune reaction towards these β-cells in the pancreas. When the disease is not adequately treated, multiple complications will arise such as neuropathy, nephropathy and cardiovascular disease. When type I diabetes is well controlled, complications can be delayed or prevented. The gold standard to maintain a steady blood sugar glucose level, consists of daily insulin injections. No therapy has been developed so far that is able to stop the autoimmune destruction of the β-cells and thus cure diabetic patients.
Expected results from this first in human trial are multiple. First, results about preliminary safety features should indicate the product is safe for use in humans and a tolerated dose has been identified. So far, no safety issues have been reported and there has been no patient dropped out from the study. These observations are encouraging and strengthen the belief that this first in human trial will meet its primary clinical endpoint. Second, the trial results should allow to gain more insight regarding the innovative mechanism of action of the used Imotope. Thirdly, this study hopefully results in identification of signals of clinical and immune activity of benefit for the patients included in the study.
Consequently, the socio-economic impact of this project could be huge. The success of the project will contribute to the development of a novel therapeutic approach based on ImotopesTM that allows to fight the auto-immune reaction going on in diabetes type I and restore the functionality of the remaining β-cell mass. By consequence, type I diabetes patients who rely on daily insulin for their survival could be no longer dependent on it.
Because ImotopesTM are a platform technology, it will potentially be able to treat other auto-immune disease (e.g. MS, Rheumatoid arthritis, Neuromyelitis Optica...) and a number of allergies. Furthermore, it has the potential to prevent rejections of donor organs or immune reactions towards biotherapeutics. Each of these chronic conditions/graft rejections/anti-drug responses represent a high cost for society. Patients suffer from comorbidities as a consequence of their disease and their quality of life is decreasing as the disease progresses, especially for those patients for which the current symptomatic treatment is not sufficient. The socio-economic impact of this platform technology will translate, on one hand, into prevention of enormous costs at the social security level linked with the treatment of the different diseases and complications. On the other hand, it will facilitate an amelioration of the quality of life of many.
In conclusion, the expectation is to exploit this antigen-specific immune modulation by immunising T1D patients in order to halt disease progression, and also to validate this new technology that could in the long term be applied to other autoimmune diseases. This project would benefit: 1) to patients (better quality of life), 2) to the European economy (decreased cost of the disease), 3) to the scientific knowledge (mechanistic insight), and 4) to the employment at the level of the sponsor/CROs/clinical trial centers (some additional employment to conduct of further trials in Phase II and III and bring this product to the market.)
Dissemination of the EXALT results is ensured through a dedicated work package (WP6). The general objective of this work package is to organize a well-targeted dissemination effort and liaison with key stakeholders, including patient’s organizations, scientific community and the industry, in order to release the full exploitation potential of the immunotherapeutic approach.
Effective use of project results is of great importance and this is particularly true for EXALT that aims to obtain results with high translational value. Several EXALT partners have strong focus and considerable experience in dissemination in terms of clinical application of basic research findings, basic research and clinical research involving SME. Projects results are and will be protected, used and disseminated actively and accurately.
Up to now, dissemination outside the consortium has been carried out by different ways depending on the targeted audience and the nature of the message:
- To all interested individuals: The EXALT website has provided information regarding the project by summarizing the objectives, the status and the people involved.
- To scientists: The EXALT project was presented at the Immunology of Diabetes Society (IDS) congress in London in October 2018 by means of a poster presentation entitled “EXALT-Assessing an innovative immunotherapy, based on a thioredox peptide antigen, in a phase I trial for type-1 diabetes”.
- To the public and media: Different press releases have been published during the conduct of the phase I trial. A first press communication was written at the time of study initiation. A second and a third press releases were prepared at the time of, respectively, the first and last patient inclusions.
Dissemination of project results after end of EXALT
Full results, which will include all clinical data, immunological response data, transcriptomics data and overall data mining, are expected for September 2019. Dissemination of these results will therefore not be happening within the timeframe of EXALT. Results will be submitted for presentation at the annual meeting of the EASD (European Association for the Study of Diabetes) in September 2019. Detailed results will also be published in (an) appropriate journal(s). A first clinical publication is planned that will summarize the trial design and clinical results. A second publication will be discussing more in-depth the transcriptomics and immunological data.
The EXALT consortium has identified key stakeholders and patient associations that will be targeted for the dissemination of the clinical trial results. Furthermore, links have been established between Imcyse and consortium networks like TrialNET on one hand and INNODIA on the other hand, well-known organizations in the diabetes field. TrialNET (based in the US) is an international network of leading academic institutions, physicians, scientists and healthcare teams dedicated to the prevention of type 1 diabetes. They offer risk screening for relatives of people with type 1 diabetes and innovative clinical studies to preserve insulin production. INNODIA (EU IMI consortium) is a global partnership between 26 academic institutions, 4 industrial partners, a small size enterprise and 2 patient organisations, bringing their knowledge and experience together with one common goal: "To fight type 1 diabetes". Experts of both organisations will help to shape and design the phase II trial to be conducted by Imcyse with the current immunotherapeutic.
List of Websites:
http://exalt-fp7.eu/
The EXALT 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 was to complete a preclinical package and perform a phase I clinical trial in adult newly diagnosed type 1 diabetes (T1D) patients. This clinical study is assessing the safety, the mechanism of action, and preliminary efficacy of an innovative immunotherapeutic technology (also referred to as ImotopeTM) invented by Imcyse.
The ImotopeTM evaluated in the trial is an innovative immunotherapeutic. It consists of a synthetic peptide containing an MHC class II epitope linked to a thioredox motif and is administered with a vaccine adjuvant. 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 diabetic patients.
A preliminary preclinical proof-of-concept study for T1D had been performed by Imcyse in Non-Obese Diabetic (NOD) mice prior to EXALT. Based on these first results, a complete preclinical package was successfully prepared in the scope of the project, using NOD mice as animals of choice. A GMP lot of candidate immunotherapeutic was produced and a thorough toxicology study was run. The phase I study was approved in 7 EU countries, with 24 sites recruiting recent onset T1D patients. A total of 41 patients were sequentially enrolled into one of the three cohorts and allocated to receive IMCY-0098 (the ImotopeTM) or placebo in a 3:1 randomization ratio (meaning that in a group of 4 patients, 3 are treated with the ImotopeTM and one patient receives placebo). The primary objective of the phase I clinical study was (1) to investigate preliminary safety features for a tolerated dose to be explored in further clinical trials. Secondary and more exploratory objectives were (2) to confirm and understand the immune mechanism of action, and (3) to identify signals of clinical and immune activity of potential benefit for the patients. If successful, this experimental approach could lead to a breakthrough in the management of T1D.
At this point in time, the clinical study is still following up patients from the highest dose cohort. Last patient last visit is expected by end of April and full study results will be available in September 2019. No patient drop out has been reported so far and preliminary safety data indicates the product is safe for use in humans.
Project Context and Objectives:
The EXALT program (FP7 EU grant) started off in February 2014. In addition to an extensive preclinical research plan, the final objective of the project is to perform a phase I clinical trial in recent-onset (≤ 6 months) adult diagnosed type 1 diabetes (T1D) patients, using an immunotherapeutic preparation, called ImotopeTM, based on Imcyse technology. The project is being carried out by a consortium of one SME (Imcyse), three academic collaborators (Inserm, HMGU and QMUL) and a Technology Transfer Office (Inserm-Transfert). The project has a duration of 60 months.
Imcyse is a SME located in the province of Liège, at the site of the university hospital Sart Tilman (Belgium). It was founded in 2010 as a spinoff from the KU Leuven. Imcyse is pioneering the development of a new class of active, specific immunotherapeutics: ImotopesTM. An ImotopeTM consists of a short synthetic peptide encompassing an MHC class II epitope of the proinsulin protein flanked by a thiol-disulfide oxidoreductase motif formulated with aluminium hydroxide adjuvant. When presented by MHC class II molecules on antigen-presenting cells (APC), ImotopesTM convert epitope-specific CD4+ T lymphocytes into CD4+ T cells able to induce apoptosis of (1) auto-antigens-loaded APCs present in the pancreas draining lymph nodes, after cognate interaction, and (2) diabetogenic T cells recognising the same as well as alternative epitopes presented by the same APC. The net result of the activity of these cells is the arrest of the ongoing auto-immune response. In addition, these ImotopeTM-activated T cells acquire memory properties. Therefore, the Imcyse technology presents an opportunity to silence the autoimmune reaction at an early stage of the disease in an antigen-specific manner and is expected to provide long term islet β-cell preservation.
T1D is a chronic autoimmune disease, with circulating autoantibodies to islet autoantigens such as insulin, GAD65, IA-2 or ZnT8, in which insulin-producing β-cells located in the pancreatic islets of Langerhans are gradually destroyed by autoreactive T cells, involving CD4 and CD8 T lymphocytes. CD4+ T cells are believed to play a major role in the orchestration of the effector CD8+ T cells responsible of islet β-cell destruction. The pathophysiology of T1D with known islet cell autoantigens and T cell epitopes makes this disease a particularly attractive indication for development of an immunotherapeutic based on Imcyse technology. 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. 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 phase I placebo-controlled, double-blind, dose escalation clinical trial (EudraCT 2016-003514-27; NCT03272269) was initiated in October 2017. The primary objective of the trial is to evaluate the safety of Imcyse’s ImotopeTM IMCY-0098 administered in 3 increasing doses. Study patients (diagnosed ≤6 months with type 1 diabetes) are sequentially enrolled into one of the three cohorts and allocated to receive IMCY-0098 or placebo in a 3:1 randomization ratio. An independent DSMB oversees the conduct of the study to ensure the safety of participating patients.
The secondary objective of the trial is to evaluate the clinical response to IMCY-0098 by assessing disease activity. Clinical measurements like post challenge C-peptide, fasting C-peptide, HbA1c, insulin dose and glycaemic profile will give an idea of the efficacy of the tested ImotopeTM. In addition, some exploratory objectives will evaluate: 1) the impact on autoantibodies against GAD65, IA 2, ZnT8 and insulin and 2) the autoreactive T cell responses specific for autoantigens (proinsulin, GAD65, IGRP) expressed by islet β-cells. Furthermore, an enumeration and characterization of the proinsulin-specific CD4+ T cells induced by IMCY-0098 will be performed.
The data generated during the preclinical research activities in the framework of EXALT (WP2) 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.
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 ImotopeTM as a unique technology for the treatment of a human disease of high medical need, type 1 diabetes. In addition, the success of EXALT will provide a significant contribution to confirm the validity of Imcyse’s platform technology transversally and could enable Imcyse to further develop its pipeline and so provide a key step to a new antigen-specific therapeutic concept for the treatment of multiple immune mediated disorders.
Project Results:
WP2: Pre-formulation, optimisation and process development
The general objectives of this work package were to perform the pre-formulation of the ImotopeTM, the optimisation and development of the manufacturing process for the immunotherapeutic, and the development of process and analyses to the point of readiness for GMP manufacture and release for toxicology analysis.
First, a formulation was optimized for use in humans. The formulation consists of thioredox-peptide and adjuvant. Proinsulin was selected as target antigen. HLA class II-restricted epitopes within its sequence were screened for the design of a modified epitope that would fulfil three main criteria, namely, 1) stable chemical properties, 2) strong binding capacity to DR4 molecule, and 3) best capacity to prime and expand CD4+ T cells with cytolytic properties. Peptide IMCY-0098 was selected. Imcyse has conducted a set of experiments to optimise formulation and composition of the immunotherapeutic. The IMP is a sterile powder (562.5 µg in a vial) to be reconstituted with 2.25 mL of phosphate buffer 50 mM, pH 7.4 containing 500 µg/mL of aluminium hydroxide (alhydrogel 2%) before the administration to the patients. The ratio immunotherapeutic/adjuvant in the final formulation has been fixed to 1/2.
Second, process development through transfer of process from Imcyse to the Contract Manufacturing Organisation (=CMO) was carried out to determine an efficient and robust process for pure peptide manufacture. Bioassay (potency) and analytical assays were developed for purified bulk and final product. Assays were characterised and transferred, to contribute to the regulatory filing and to be ready to release GMP material. Imcyse has developed two tests aiming at determining potency of the peptide: 1) A fluorescence-based assay for the reductase activity of the peptide and 2) an MHC class II binding assay to check the affinity of the peptide with a DRB01*0401 allele. The tests have been set-up and qualified. The potency of the peptide produced by the CMO was tested by Imcyse using both methods.
Third, administration route and schedule have been assessed in preclinical studies for efficacy. For the clinical trial, the following decisions were taken:
• 4 injections in total, with a 2-week interval between each injection;
• A higher initial dose followed by three boost administrations of half the initial dose;
• A 3-step wise increase between cohorts. (Dose cohort 1: 50 µg – followed by 3x 25 µg; Dose cohort 2: 150 µg – followed by 3x 75 µg; Dose cohort 3: 450 µg – followed by 3x 225 µg)
WP3: GMP Campaign, Toxicity and Regulatory Filing
The general objectives of this work package were to manufacture and release a GMP quality batch of ‘IMCY-0098 + adjuvant’, perform required toxicology studies, submit the Clinical Trial Applications (CTAs), obtain scientific advice from an EU national authority on Chemistry Manufacturing and Controls (CMC), toxicology and clinical plans and to obtain regulatory approvals for phase I clinical trial.
The manufacturing of the clinical GMP batches has been performed by the selected subcontractors. Two batches of IMCY-0098 drug product have been produced: AX1-160702 and AX1-170603 – both consisting of over 2000 vials of sterile powder containing 562.5 µg of IMCY-0098 and 10 mg of mannitol. One batch of diluent: AW8-160401 – consisting of over 3000 vials of sterile solution for injection composed of phosphate buffer 50 mM, pH 7.4 containing 500µg/mL of aluminium hydroxide (alhydrogel 2%). One batch of placebo: AX2-160501 – consisting of over 2000 vials of sterile powder containing 10 mg of mannitol. GMP material was characterised and released by a qualified person with the assay methods developed in the previous work package.
Two GLP toxicology studies were performed and completed. First, a repeated dose toxicology and local tolerance study was executed. Second, a test for absence of respiratory distress on GMP batch AX1-160702 was performed. A full report on each of these studies has been written, finalized and signed off by both the contracted CRO and Imcyse. Both toxicology studies confirmed IMCY-0098 was safe in animals.
Before seeking regulatory approval for phase I clinical trial, scientific advice was requested to the Paul Ehrlich Institute (PEI, Germany). Two reasons that led Imcyse to choose the German national authorities were their strong background in immunology and vaccinology; and the reasonable timing to organise a face to face meeting which enabled Imcyse to get a feedback on the toxicology study before its initiation. A briefing document was prepared comprising of questions and company position on CMC, preclinical and clinical topics. It also contained background information, description of the product, summary of the preclinical data and a draft clinical study protocol. The meeting was organised on the 20th of January 2016 after which final minutes were edited by Imcyse and approved by PEI. These minutes were presented to the full consortium at the JSC meeting on 27th of January 2016.
A last task during this work package was to obtain regulatory approval for the trial. The project was initially anticipated to be run with the 3 clinical sites that are partners in the EXALT project (Inserm in France, QMUL in UK and HMGU in Germany). The recruitment rate was anticipated to be between 1-3 patients/per site/per month along the study. When reviewing similar studies performed in the past and their recruitment rate, it became very clear to the team (new team that was not involved in designing the EXALT project) in charge of setting–up the study that it was unrealistic. A recruitment rate of 0.2 pat/site/month in this patient population is what has been observed in similar trials. This is a difference of 5 to 15 times the initial evaluation. In order to remain within reasonable timing and give the project all chances of success, it was decided to increase the number of sites to 20 which was achieved with the addition of 2 countries, namely Belgium and Denmark. Regulatory approval, both by competent national authorities and ethics committees, in these five countries had been obtained by M49.
Because the randomization of early diagnosed patients was very slow in the beginning of the trial, two additional countries, namely Lithuania and Sweden, have been added to increase the recruiting sites to 24. This mitigation plan was necessary to ensure performing the phase I trial within reasonable timelines and respecting the EXALT timeframe as much as possible. The regulatory approvals in Lithuania and Sweden went smooth and swift and were all obtained in Month 52, 4 months only after the back-up plan decision was taken.
WP4: Phase I trial preparation
The general objectives of this work package were to make all the necessary preparations for the phase I trial. More specifically, to prepare the phase I trial protocol and ICF, to contract the participating sites, to develop and finalise the sample collection and SOPs for immune marker assays, to contract the central laboratory and to establish the Data Safety and Monitoring Board (DSMB).
The preparation of the protocol has been initiated with the organization of a working meeting in Paris on 13th of July 2016. The protocol was finalized and signed by the sponsor on 20th of December 2016. This version of the protocol was submitted together with all required documentations to all countries by the end of March 2017 except France. Based on regulatory reviews in the different countries, 2 subsequent versions of the protocol have been developed in order to integrate recommendations and request for changes. The final version of the protocol under which the recruitment of patients has been started is version 1.2 dated 29th of May 2017. This version of the protocol was used for the submission in France performed on 20th of June 2017. The objectives of the phase I clinical study were (1) to investigate preliminary safety features for a tolerated dose, and (2) to evaluate the clinical response to IMCY-0098 by assessing disease activity. Some exploratory objectives will evaluate 1) the impact on autoantibodies against GAD65, IA 2, ZnT8 and insulin and 2) the autoreactive T cell responses specific for autoantigens (proinsulin, GAD65, IGRP) expressed by islet β-cells. Furthermore, an enumeration and characterization of the proinsulin-specific CD4+ T cells induced by IMCY-0098 will be performed.
The ICF that needs to reflect the assessments and treatment schedule described in the protocol was finalized once the protocol was considered to be in the final stage. The final Master ICF used in the different countries to develop the country specific ICF was issued by Imcyse on 9th of February 2017. Here also, a subsequent version was generated to align the Master ICF with the changes made in the protocol and/or specific recommendations from regulatory authorities or ethic committees towards this document. The final version of the Master ICF is version 2.0 dated 6th of June 2017.
Due to the size of the study and the level of complexity (samples logistic, 7 different countries, 24 sites), it was necessary to select a Contract Research Organization (CRO) to run the study. After a thorough screening of potential CRO candidates, 4 of them were invited to present a proposal that they defend in a F2F meeting with Imcyse. The final choice was for INC Research (now called Syneos Health) and an initial service agreement was signed on 14th of Sept 2016 to allow key activities to start without delay. The final contract detailing all activities and timelines was fully executed on 28 Dec 2016. The contracted CRO was in charge of the pre-feasibility and feasibility assessments with the goal to propose a site list to be approved by the Imcyse, contracts with the clinical sites (24 in total), monitoring activities, safety reporting, statistical analysis and ensuring overall quality as well as respect of all applicable legislations.
The final list of sites was a mix of sites identified/proposed by Imcyse and sites identified and proposed by the CRO. Of note, in UK, a newly established network of sites, the T1D UK Consortium, has been selected for the study. This has been possible thanks to the recommendation and input of Professor David Leslies from the QMUL, one of the partners of EXALT, who is also one of the founders of this T1D UK Consortium. 7 sites of the consortium were finally selected for the clinical trial, including QMUL. Despite a slow start in UK due to lengthy regulatory and contractual process, the contribution of the network of sites in UK has been of critical importance to the success of the study.
Clinical Trial Agreement (CTA) templates have been developed by Imcyse and proposed to all selected clinical trial sites by the CRO. The CRO has negotiated, in full collaboration with the sponsor, both legal and financial aspects with each individual site. All tools to support and execute the phase I trial were finalized in collaboration with the CRO and other external providers by the time of submission of the study in the first countries. The main tools are: eCRF, Data management database, laboratory kits and manual, IMP user guidance, Randomization and IMP allocation system, Trial Master File, Freestyle libre system (reader and sensor) material, patient recruitment material.
Two central laboratories have been set-up for the phase I trial. One central lab (MLM) is managed by Imcyse through a logistic partner (ABF Pharmaceutical Services) and is responsible for all safety analyses as well as other non-immune analysis on blood samples from patients enrolled in the study. The second lab is a specialized lab for immune analysis called Caprion Biosciences. Further description on this activity is detailed in the next paragraph.
Immune markers are used to evaluate individual patient response to IMCY-0098. The initial EXALT project was referring to Imcyse and Inserm to perform the immune markers analysis. This matter is extremely complex to implement in large scale and also key to the future of the technology. Therefore, the decision was made to work with a laboratory specialized in this matter for 2 reasons: (i) a systematic tracking of all processes and methodologies including an established and robust Quality Control (QC) process (ii) an increased value of the results for external parties as it is performed independently. When deciding on the exact tests and methodologies to be used, it became very clear that the specialized laboratory had to developed tailored solutions. Although these endpoints are exploratory in the clinical trial protocol, we wanted to at least qualify the processes and methodologies. The qualifications of the different assays are described in the study workplan version 1.0 entitled: “Assay qualification followed by evaluation of immune responses of IMCYSE therapeutic vaccine IMCY-0098 in patients with recent-onset type 1 diabetes” as provided by CRO CAPRION (14th of December 2016). All this set-up has required a considerable effort and resources to properly design the tests that will be crucial to demonstrate, in humans, that the technology is indeed having the mechanism of action described in animal models. The logistics for collection and transportation of the blood samples from clinical sites to the CRO has been organized to guarantee the arrival of the samples at Caprion facilities within 24 hours of their collection on the clinical sites.
To ensure patient safety in the phase I trial, an independent DSMB was set up. The Data Safety Monitoring Board Charter (“Charter”) defines the primary responsibilities of the DSMB, the Committee’s membership, and the timing and purpose of its meetings. The Charter also provides procedures for ensuring confidentiality and recommended methods of communication to be implemented by the DSMB, and an outline of the data reports that will be provided by Syneos Health to the DSMB for review. The DSMB is composed of a Chairman, two members and an unblinded statistician. Consultancy contracts are in place with all members. An interim analysis of the low and middle dose cohort was scheduled to ensure safety before proceeding to subsequent higher dose cohorts.
WP5: Phase I trial conduct
The general objectives of this work packages are to successfully recruit and follow-up patients in the Phase I clinical trial, conduct the pre-specified immune assays, and finally perform data analysis and release a Clinical study Report (CSR).
The very first patient was screened in month 43 but could unfortunately not be randomized. With more sites initiated in September 2017, the first patient was injected month 45. A press release was issued at this moment. The last patient (n=41) was randomized in November 2018 (M58) in the highest dose cohort. The inclusion of sites in Lithuania and Sweden has led to 17.5% of total randomizations in less than 6 months. In total 65 patients have been screened. The study recorded 24 screen failures (37% screen failure rate). This screen failure rate is within the anticipated range (20-40%). However, analysis of the cause of the failures shows that 30% are related to patients who withdrew their consent just before being injected. This is an unusually high rate for this reason and his probably related to the age group (18-30y) and the new onset of their disease.
After confirmation of eligibility, all recruited patients received 4 injections of the immunotherapeutic or placebo (randomisation 3:1 in each dose cohort) and are followed up for 6 months. In total, 8 visits were scheduled per patient. In month 60, all visits were completed for patients in cohort 1 (n=8) and cohort 2 (n=12). Patients in cohort 3 (n=21) completed their visits up to week 12 (6th visit). Last patient last visit is planned for 16th April 2019. So far, no safety issues have been reported and there has been no patient dropped out from the study.
Samples for immune markers analysis are collected 4 times during the study: at week 0, 6, 12 and 24. All analyses are performed on fresh blood within 24 hours after drawing. Very few samples did not make it in time to Caprion Biosciences. A first interim analysis confirms that the used techniques are in place and working. We are not able to discuss results in this final report because the study is still ongoing and all data are still blinded.
Data collection has started following the first patient screening on 23rd of August 2017 and is still ongoing given the last patients of cohort 3 did not finalize the final visit. Study data cleaning is occurring regularly during the study in order to expedite the data analysis after the last patient is out. Specific data extractions and analyses were performed for the DSMB meetings that decided on the dose escalations. A first DSMB meeting was held on 23rd of March 2018. DSMB members gave green light to start enrolment of cohort 2 subjects. Because of a dosage error that occurred in one of the subjects, they recommended to include a witness to the reconstitution and administration process. As this was in fact already implemented in the procedure, a reminder was sent to all sites and a gap analysis was performed on the first subjects included at the different sites. A second DSMB meeting was held on 10th of July 2018. DSMB members gave green light to start enrolment of cohort 3 subjects.
All the relevant clinical data collected from the patients will be merged with the safety laboratories, immune makers and other clinically relevant assays for final analysis. The final study results are expected for September 2019. These results will be communicated to the outside world by means of press release and scientific publications. An additional JSC will be organized to discuss trial results with the EXALT consortium members.
Potential Impact:
Diabetes is a chronic disease that causes a high burden on patients and society. In Europe, 58 million people (aged 20-79 years) are affected, with an estimated rise to 67 million people affected in 2045 (Source: IDF atlas 2017). It is characterised by high levels of blood sugar glucose because the body cannot produce enough insulin (type 1) or is resistant to the circulating insulin (type 2). Insulin is a hormone released by the pancreas, more specifically by the pancreatic β-cells located in the islets of Langerhans. It is responsible for the uptake of glucose from the blood to the body’s cells where glucose is converted into energy. Hyperglycaemia is the main symptom of diabetes. Type I diabetes is caused by an autoimmune reaction towards these β-cells in the pancreas. When the disease is not adequately treated, multiple complications will arise such as neuropathy, nephropathy and cardiovascular disease. When type I diabetes is well controlled, complications can be delayed or prevented. The gold standard to maintain a steady blood sugar glucose level, consists of daily insulin injections. No therapy has been developed so far that is able to stop the autoimmune destruction of the β-cells and thus cure diabetic patients.
Expected results from this first in human trial are multiple. First, results about preliminary safety features should indicate the product is safe for use in humans and a tolerated dose has been identified. So far, no safety issues have been reported and there has been no patient dropped out from the study. These observations are encouraging and strengthen the belief that this first in human trial will meet its primary clinical endpoint. Second, the trial results should allow to gain more insight regarding the innovative mechanism of action of the used Imotope. Thirdly, this study hopefully results in identification of signals of clinical and immune activity of benefit for the patients included in the study.
Consequently, the socio-economic impact of this project could be huge. The success of the project will contribute to the development of a novel therapeutic approach based on ImotopesTM that allows to fight the auto-immune reaction going on in diabetes type I and restore the functionality of the remaining β-cell mass. By consequence, type I diabetes patients who rely on daily insulin for their survival could be no longer dependent on it.
Because ImotopesTM are a platform technology, it will potentially be able to treat other auto-immune disease (e.g. MS, Rheumatoid arthritis, Neuromyelitis Optica...) and a number of allergies. Furthermore, it has the potential to prevent rejections of donor organs or immune reactions towards biotherapeutics. Each of these chronic conditions/graft rejections/anti-drug responses represent a high cost for society. Patients suffer from comorbidities as a consequence of their disease and their quality of life is decreasing as the disease progresses, especially for those patients for which the current symptomatic treatment is not sufficient. The socio-economic impact of this platform technology will translate, on one hand, into prevention of enormous costs at the social security level linked with the treatment of the different diseases and complications. On the other hand, it will facilitate an amelioration of the quality of life of many.
In conclusion, the expectation is to exploit this antigen-specific immune modulation by immunising T1D patients in order to halt disease progression, and also to validate this new technology that could in the long term be applied to other autoimmune diseases. This project would benefit: 1) to patients (better quality of life), 2) to the European economy (decreased cost of the disease), 3) to the scientific knowledge (mechanistic insight), and 4) to the employment at the level of the sponsor/CROs/clinical trial centers (some additional employment to conduct of further trials in Phase II and III and bring this product to the market.)
Dissemination of the EXALT results is ensured through a dedicated work package (WP6). The general objective of this work package is to organize a well-targeted dissemination effort and liaison with key stakeholders, including patient’s organizations, scientific community and the industry, in order to release the full exploitation potential of the immunotherapeutic approach.
Effective use of project results is of great importance and this is particularly true for EXALT that aims to obtain results with high translational value. Several EXALT partners have strong focus and considerable experience in dissemination in terms of clinical application of basic research findings, basic research and clinical research involving SME. Projects results are and will be protected, used and disseminated actively and accurately.
Up to now, dissemination outside the consortium has been carried out by different ways depending on the targeted audience and the nature of the message:
- To all interested individuals: The EXALT website has provided information regarding the project by summarizing the objectives, the status and the people involved.
- To scientists: The EXALT project was presented at the Immunology of Diabetes Society (IDS) congress in London in October 2018 by means of a poster presentation entitled “EXALT-Assessing an innovative immunotherapy, based on a thioredox peptide antigen, in a phase I trial for type-1 diabetes”.
- To the public and media: Different press releases have been published during the conduct of the phase I trial. A first press communication was written at the time of study initiation. A second and a third press releases were prepared at the time of, respectively, the first and last patient inclusions.
Dissemination of project results after end of EXALT
Full results, which will include all clinical data, immunological response data, transcriptomics data and overall data mining, are expected for September 2019. Dissemination of these results will therefore not be happening within the timeframe of EXALT. Results will be submitted for presentation at the annual meeting of the EASD (European Association for the Study of Diabetes) in September 2019. Detailed results will also be published in (an) appropriate journal(s). A first clinical publication is planned that will summarize the trial design and clinical results. A second publication will be discussing more in-depth the transcriptomics and immunological data.
The EXALT consortium has identified key stakeholders and patient associations that will be targeted for the dissemination of the clinical trial results. Furthermore, links have been established between Imcyse and consortium networks like TrialNET on one hand and INNODIA on the other hand, well-known organizations in the diabetes field. TrialNET (based in the US) is an international network of leading academic institutions, physicians, scientists and healthcare teams dedicated to the prevention of type 1 diabetes. They offer risk screening for relatives of people with type 1 diabetes and innovative clinical studies to preserve insulin production. INNODIA (EU IMI consortium) is a global partnership between 26 academic institutions, 4 industrial partners, a small size enterprise and 2 patient organisations, bringing their knowledge and experience together with one common goal: "To fight type 1 diabetes". Experts of both organisations will help to shape and design the phase II trial to be conducted by Imcyse with the current immunotherapeutic.
List of Websites:
http://exalt-fp7.eu/