Community Research and Development Information Service - CORDIS

FP7

DAVIAD Report Summary

Project ID: 602779
Funded under: FP7-HEALTH
Country: Belgium

Periodic Report Summary 2 - DAVIAD (The development of a novel therapeutic vaccine for the selective treatment of the autoimmune disorder, Graves’ disease.)

Project Context and Objectives:
The aim of the DAVIAD project is to develop a therapeutic vaccine for Graves’ disease (GD) that has a better safety and efficacy profile than current treatments.

Autoimmune diseases arise as a consequence of an abnormal immune response to self-antigens (or autoantigens). These proteins are normally not recognised as ‘dangerous’ (so called immune ‘tolerance). Autoimmunity is a common feature that can be identified in all individuals whether or not they have disease. However, disease is normally prevented by various central and peripheral mechanisms that lead to a deletion or regulation of the auto-reactive cells (lymphocytes). Autoimmune disease can therefore be seen as a breakdown in self-tolerance resulting in a hypersensitive response to a specific auto-antigen. The aim of a vaccine for an autoimmune disease is to dampen down or desensitise the individual to the auto-antigen(s). In particular, GD results in the overproduction of thyroid hormones (hyperthyroidism), which is caused by T and B cells being auto-reactive to the primary auto-antigen, the thyroid stimulating hormone receptor (TSHR).

A disease modifying vaccine for GD will address a serious unmet need and potentially offer a therapy that can change the way this disease is treated, offering better quality of life for sufferers and reducing burden on health services. DAVIAD will provide evidence of safety and clinical proof of principle of a novel auto-antigen specific peptide-based therapeutic vaccine to treat GD, a chronic condition currently with limited therapy for GD patients targeted to the root-cause of the disease in the immune system, therefore “immune disease-specific”, in contrast to other immunosuppressive drugs.

The core objectives of DAVIAD are to:
• Undertake final preclinical characterisation of candidate peptides to be used in the tolerogenic vaccine for GD in a First in Man study.
• Manufacture a drug product for toxicology and clinical testing.
• Conduct a set of pre-clinical toxicity studies to confirm the safety of the lead peptides to progress into clinical development.
• Obtain Regulatory Authority and Ethics Committee approval of a European Clinical Trial Authorisation (CTA) application.
• Conduct a Phase I/IIa clinical trial in patients to provide safety, initial efficacy and pharmacodynamic data.
• Expand the intellectual property protection to include the peptides and products selected using the Apitope platform under DAVIAD, providing an opportunity for commercialisation.
• Disseminate the outcomes of the project to audiences across the EU and beyond and develop plans for the exploitation of the project results for the benefit of EU society, with economic and health impacts.
DAVIAD will provide evidence of safety and clinical proof of principle of a novel auto-antigen specific peptide-based therapeutic vaccine to treat GD, a chronic condition currently with limited therapy for GD patients targeted to the root-cause of the disease in the immune system, therefore “immune disease-specific”, in contrast to other immuno-suppressive drugs.

Project Results:
In Period 2 of the project the DAVIAD consortium has made significant progress in the technical development of the vaccine such that the pre-clinical, analytical and regulatory activities have all been completed within the reporting period to enable the clinical trial of the vaccine to be initiated within the current review period.

In WP2 (CMC) the formulation and manufacturing process for small scale production of GMP drug product ATX-GD-59 for toxicity studies has been completed. Stability studies are well under way with no concerns identified to date. In addition, the drug has been packaged and released to the clinic by a qualified person, for use at approved clinical centres in the ATX-GD-59-001 clinical trial (WP5).

Repeat dose toxicity and cardiovascular studies (WP3) in Sprague Dawley rats have been completed with no adverse effects reported.

Regulatory applications (WP4) for the Phase I clinical trial have been completed in UK, Belgium and Germany. Regulatory approval was obtained for Belgium and the UK, however Germany would not issue an approval without significant additional pre-clinical work, amendments to the study design and the clinical trial application.

ATX-GD-59-001 clinical trial (WP5) has received approval to open six clinical sites in the UK. The protocols have been written and accepted following some amendments requested by competent authorities. The trial has now commenced and screening and recruiting subjects in the UK is in progress.

In WP6 (Clinical Analysis Method Development) the methodology for the antidrug antibody (ADA) has been validated and implemented for screening and monitoring ADA during the ATX-GD-59-001 clinical trial. The design of flow cytometry antibody panels which will be used to test the frequency and function of peptide-specific regulatory and effector T cell subsets has been completed to test PBMC samples from patients enrolled in the immunotherapy trial in order to test for biomarkers of treatment efficacy. The assay is now ready for the clinical trial samples predicted to be analysed in Q1 2017.

A procedure was also established and implemented for the collection and transportation of subject samples from the clinical centres.

In WP7 progress has continued in the dissemination of the project.

Potential Impact:
The project will produce the following impacts:

Health Impacts:

GD is a chronic autoimmune disease especially in the more severe forms such as GO including sight threatening GO and paediatric GD. Patients can experience a wide range of symptoms and suffer major impairment in most areas of health-related quality of life (HRQL). There are currently around 12,000 children diagnosed with GD in Europe and the US. Living with GD creates substantial impacts especially for GO patients on whom there is a severe impact on quality of life – physical, emotional and social functioning. As the disease progresses dependency on family and community services increases creating a further set of psychological issues for carers. A novel and effective vaccine strategy will have a major impact for patients, society and public health systems.

The long-term benefits of DAVIAD will greatly assist the EU in its research efforts in the field of vaccines for its citizens. The health impacts arising from this new vaccine will assist in improving the health conditions of both the patients suffering from these diseases and their carers who otherwise may become isolated or overwhelmed as patients are often demanding of attention. The health of family caregivers is a high priority as, without them, the cost of professional home care would increase dramatically.

The long term benefits of DAVIAD will greatly assist the EU in its research efforts in the field of vaccine for its citizens. The realistic aim of the project is to prove the therapeutic peptides’ effect on chronic autoimmune conditions in a target patient population. This will maximise the chances of detecting a relevant clinical proof-ofprinciple during the project and lead to the opportunity for members of the consortium to invest the remaining funds that would be required to make the vaccine publicly available as a treatment that would benefit both society and individual patients.

The health impacts arising from this new vaccine are not restricted to reducing the number of patients suffering from these diseases, but also improving the health conditions of the carers. Carers, particularly family carers, may become isolated or overwhelmed as patients are often demanding of attention. Evidence of high levels of distress and depression amongst carers can be seen in many studies of service users and in community surveys. There can also be adverse impacts on their physical health e.g. through stress impacts. The health of family caregivers is a high priority as, without them, the cost of professional care at home would increase by at least two-fold. Therefore DAVIAD will also contribute to the health condition of the family members of patients.

Economic Impacts:

GD imposes significant economic cost on the health and social services organisations across EU27. The current pharmacologic treatment for GO and paediatric GD is largely palliative rather than curative and has limited efficacy. Specific treatment of GO includes immunosuppression and orbital surgery. Long-term non-specific immunosuppression can be associated with disruption of natural immunity with significant adverse effects such as increased incidences of osteoporosis, liver failure, glaucoma’s and other less severe impacts on daily health.

Despite the financial burden there is a limited amount of data available on the economic impact of these diseases. A study undertaken to assess the economic effects of Thyroid disorder-related morbidity in Germany estimated the annual cost for meditherapy of thyroid disorders (mainly iodine deficiency goitre and hypothyroidism) to average €100 million.

Given the pressure throughout the EU and worldwide on the growing health budget requirements, therapeutics that can modify the course of diseases or avoid long-term treatment of patients are sought by governmental authorities. The cost-benefit balance of a therapy for auto-immune diseases, which will be developed by the DAVIAD project, is in favour of a new therapeutic when compared with the existing treatments of continuous and long-term non-specific suppression of the immune system. Significant saving in the costs associated with GD is likely if the therapeutic peptides being developed by the DAVIAD project achieve the anticipated levels of efficacy. Whilst the project does not underestimate the challenges included in taking the therapy to market following a successful completion of the DAVIAD project, the potential economic benefits that would arise from the
outcomes of the projects, taken forward into the commercialisation, could be significant once the product is launched, in the EU alone.

Employment and EU competitiveness

The DAVIAD project will make a serious contribution to society by providing a new and better therapy to smaller unfavourable patient populations. To date, research by the DAVIAD project has not identified any company aiming to treat the underlying cause of GD through specific T-lymphocyte immune modulation. Successful completion of the DAVIAD project and future exploitation of results is expected to generate a first product market approval in 2023/2024.

Estimates based on projections by DAVIAD, taking a conservative approach, calculate that the outcome could be the generation of a billion Euro revenues over a 10 year sales period. As well as creating jobs, DAVIAD will reduce the number of working days lost to GD and the current side effects of therapy suffered by patients. For the EU biopharmaceutical sector, the project provides groundwork for further scientific collaborations and implementation of other R&D initiatives for suitable treatments of autoimmune and allergic diseases. It is proposed that subject to satisfactory results relating to safety, clinical and immune activities observed in this phase I/IIa trial, further late phase development and preparation for commercialisation of this treatment will be initiated leading to growth and profit potential.

Successful implementation of the DAVIAD project would place the European pharmaceutical industry with an edge over its competitors. There is extensive evidence from pre-clinical and clinical trial data that SIT with short peptides is an efficacious method of inducing immune tolerance and alleviating clinical symptoms. Sight threatening GO and paediatric GD orphan diseases have small patient populations but high unmet needs which will be addressed by the DAVIAD project.

The innovative approach of DAVIAD provides new hope for GD patients, their families and caregivers and health practitioners. For the EU biopharmaceutical sector, the project will provide a new ground work for developments in the further scientific collaborations and enforcement of other R&D initiatives for suitable treatments of autoimmune and allergic diseases. This is crucial for European pharmaceutical companies to maintain their competitive advantage and retain the best talent within Europe. Therefore, the project potentially contributes to the development of a new competitive advantage, new periods of growth and new employment opportunities.

List of Websites:
www.daviad.eu

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Life Sciences
Record Number: 197167 / Last updated on: 2017-04-13