Final Report Summary - DAVIAD (The development of a novel therapeutic vaccine for the selective treatment of the autoimmune disorder, Graves’ disease.)
Executive Summary:
Graves’ disease is an autoimmune disease characterised by antibodies targeting the Thyroid Stimulating Hormone Receptor (TSHR) resulting in hyperthyroidism and multiple organ damage. The ideal therapy for an autoimmune disease would switch off the abnormal response to the target and reinstate immune tolerance but, importantly, without altering any other component of the immune system. This is exactly the concept that the peptide vaccine in the DAVIAD programme aimed to deliver.
The development of a disease modifying vaccine for Grave’s Disease (GD) addresses a serious unmet need and presents a potential first innovative therapy for patients in over sixty years. The potential to offer a disease modifying therapy able to change the way in which this disease is treated offers a new hope for a better quality of life to patients and reduces the burden of care for families and health services alike.
The DAVIAD project successfully resulted in the manufacture GMP grade ATX-GD-59 and completion of pharmacodynamic and toxicology studies in order to progress the therapeutic vaccine into a Phase I/IIa clinical trial. In the clinical trial, he vaccine was proven to be safe and well tolerated. Furthermore, the improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for hyperthyroid GD. These data together with all of the other work completed to reach this outcome, reflect a successful consortium approach to this project and position the therapeutic vaccine, ATX-GD-59, for further clinical development and commercialisation.
The outcomes of the project were widely disseminated to audiences across the EU and beyond through publications in peer reviewed journals and conferences. A wide-ranging exploitation plan for ATX-GD-59 is now being implemented by the project co-ordinator.
Project Context and Objectives:
The aim of the DAVIAD project was 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 were 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 was targeted to 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:
Period One – M1 – M18
During this period the DAVIAD consortium developed plans to streamline the activities in the work packages, initiated research to further evaluate properties of the selected peptides; transferred technologies between consortium partners; finalised protocols and performed dosing and pilot experiments.
Several expert service providers were evaluated for their suitability to manufacture the GMP API (active pharmaceutical ingredient) and GMP IMP (investigational medicinal product) and to execute GLP compliant toxicity studies.
Additional preclinical data generated during this period supported the removal of one of the three peptides from the vaccine and the development of the optimised product ATX-GD-59. As this was a significant change in the product, a number of performed tasks had to be repeated including confirmation of activity in pre-clinical models (Work Package 1 (WP1)) manufacture of the technical and GMP batches of IMP and the toxicology programme. The need to repeat these tasks introduced an unavoidable delay to the submission of the CTA application.
In WP1 two animal models using HLA-transgenic mice were evaluated for TSHR-specific T and B cell responses and increased thyroid hormone levels to support optimal vaccine dose finding and co-medication. Investigations focused on a standard TSHR/CFA immunisation model and an adenoviral driven TSHR expression (AdV-TSHR) model in the HLA-DR transgenic strains. A revised design of the AdV-TSHR model was selected and the model validated using known current medications. The drug interactions between ATX-GD-459 and methimazole; and ATX-GD-459 and propranolol were then analysed in co-medication studies.
In WP1 the characterisation of the shortlisted peptides in short term human PBMC assays was also performed and peptides 4K-G, 5D-K and 9B-N were initially selected for inclusion in the IMP prior to obtaining the additional preclinical data indicated above.
All WP2 activities initiated in the period were successfully completed. These activities included vendor selection; manufacture of non-GMP API and IMP; manufacture of GMP grade API and IMP; analytical method development and validation and stability studies. All of the activities were completed as planned with all manufactured products meeting specification.
During this period, it was confirmed that a variety of potential toxicology strains in both mice and rats, possessed both MHC class II molecules and T cell receptors capable of recognising and eliciting responses to the peptides selected under WP1. Ultimately, the Sprague Dawley (SD) rat was chosen as the strain for toxicity studies and the planned toxicity studies were completed by the selected vendor; Aptuit. No findings of toxicological significance were reported.
Following discussions with the European Medicines Agency, the consortium concluded that it was unlikely that the planned application for EU Orphan Medicinal Product Designation would be successful. As the vaccine could potentially be used in the treatment of all GD patients and not just those with the highest unmet medical need (paediatric GD or sight threatening orbitopathy), the indication would not meet the prevalence criterion for orphan designation in the EU. The consortium agreed to focus on submitting an application for US Orphan Drug Designation based on ATX-GD-59, where it may be possible to get designation for subtypes of a disease. The consortium also held a successful Scientific Advice meeting with MHRA in November 2014. The MHRA agreed with the consortium position on all questions raised in particular plans for toxicity and clinical studies within WP4.
The consortium agreed the proposed clinical study design and the 12 clinical sites across 3 countries (UK, Germany and Belgium) were selected following the successful completion of a comprehensive feasibility study.
The DAVIAD website was launched in April 2014. A download section was included in the public part of the website to upload documents such as the DAVIAD poster and brochure, as well as other documents intended to inform the general public about the project. An event schedule was added to inform the general audience of upcoming conferences to which the consortium members will participate. News items relating to activities performed by the consortium, such as the initiation of preclinical development for ATX-GD-459, were disseminated through press releases. For example, the initiation of preclinical development for ATX-GD-459 was disseminated in a press release on 21st June 2014. News items were also posted on the DAVIAD project website (www.daviad.eu ) and consortium members’ websites, as well as the LinkedIn social platform. The British Thyroid Foundation’s involvement in DAVIAD was reported in the society newsletter issues 85 and 87.
Significant results achieved within this period include:
Work Package 1 - Candidates:
• Decision taken on the preferred animal model
• The efficacy of the drug, methyl-prednisolone, was demonstrated in the AdV-TSHR model. This validates the model as immunological driven and an appropriate model for ATX-GD-459 evaluation.
• One of the clinically used medications, methimazole (active component in carbamizole), used to reduce hyperthyroidism in patients, has been tested in the mouse disease model. The results show the drug is active in reducing the plasma T4 in the HLA-DR transgenic mice in a dose dependent manner but did not show any impact or alteration of the T cell or B cell immunological response.
• In co-medication experiments in the AdV-TSHR model, neither methimazole or propranolol (beta-adrenergic blocker) interfered with ATX-GD-459 T cell tolerance induction.
• Prophylactic treatment with ATX-GD-459 in the AdV-TSHR model – efficacy was demonstrated by suppression of the T cell dependent B cell produced anti-TSHR IgG antibodies by approximately 60-80% compared to controls. A further analysis of the quality of the TSHR-specific B cell response revealed the IgG subclass IgG2b was reduced compared with controls.
• The recognition of the peptides in ATX-GD-459 by T cells from GD patients was confirmed and supports the clinical development of the cocktail. The frequency of peptide specific T cell proliferation was summarised as follows:
o for 5D-K1 : 5 out of 20 patients tested (25%)
o for 4K-G: 6 out of 20 patients tested (30%)
o for 9B-N: 9 out of 24 patients tested (38%)
The requirement of 5% patients recognising each peptide was well met and supported the cocktail for clinical development.
• All generated data was compiled into reports.
Work Package 2 - CMC:
• Task 2.1 6 peptides each of 1g of non GMP technical batch were manufactured and released in 2 lots.
• A 1000 vial technical batch of ATX-GD-459 was manufactured and released
• The provisional specifications for the GMP grade batches of 5D-K1, 4K-G and 9B-N were established
• Task 2.2 HPLC methods were developed for API and IMP and validated
• Task 2.3 the forced degradation studies, were completed. (Results)
• Task 2.4 GMP peptide manufacture, was completed (Results – release of peptides). Certificates of Analysis were made available (D2.1)
• The IMP formulation was decided upon (Task 2.5)
• Provisional specifications for GMP ready API were established, indicative stability study initiated and provisional data shared with the MHRA
Work Package 3 - Toxicology:
• The scientific protocols for the toxicology studies were agreed and written.
• The validity of the key assay platform to be used for toxicology species selection was demonstrated.
• The SD rat was chosen as the strain to proceed with for toxicity studies.
• MHRA accepted both the choice of SD rat as a relevant species; and the design of the toxicology programme and in particular DAVIAD’s proposal to use a single species.
• Aptuit (Italy) was chosen as a vendor to complete Tasks 3.3 and 3.4 and the contracts signed.
• The toxicology studies were executed by Aptuit.
• An unexpected antibody response to 4K-G was observed in the high dose treated SD rats.
Work Package 4 - Regulatory:
• A decision was made to submit an orphan drug designation (ODD) application in the US once the results from WP1 were available. The ODD application will be based on ATX-GD-59 and not as originally envisaged ATX-GD-459
• An Informal meeting held with the EMA/COMP advised against submission of an EU application for Orphan medicinal product designation (OMPD).
• A scientific advice procedure was completed at MHRA (O4.1). Based on the advice received, no further engagement with regulatory agencies was envisaged prior to submission of the CTA.
Work Package 5 – Clinical Trial:
• The Feasibility study was completed and report finalised.
• Clinical study sites selected.
Work Package 6 – Clinical Analysis Method Development:
• Identification of Kahaly Laboratory to perform TSHR antibody analysis on clinical samples
Work Package 7 – Dissemination & Exploitation:
• The DAVIAD website was launched
• A first press release was prepared and distributed worldwide.
• A leaflet, poster and the press release were disseminated to the general public
• Apitope’s approach was published and presented at international conferences
• News about the DAVIAD programme reached patients via publications from the consortium and also via the British Thyroid Foundation newsletters.
Work Package 8 – Consortium Management and Reporting to the EC:
• Management Boards were set up and working initiated.
• Project Meetings were held as scheduled.
• Restricted Access Partner online area was created for document sharing and populated.
• A PCT patent application was filed for the initial GD patent application.
• A UK patent application was filed on the 24th of December 2014 to protect the cocktail and use of ATX-GD-459 peptides
• GSK terminated its participation in the consortium due to a change in strategic focus. The preparation of an amendment to the Grant Agreement was initiated to reflect this change and also the addition of various third parties.
Period Two – M19 – M36
During this period of the project the DAVIAD consortium made significant progress in the technical development of the vaccine such that the pre-clinical, analytical and regulatory activities were all completed to enable the clinical trial of the vaccine to be initiated.
In WP2 (CMC) the formulation and manufacturing process for small scale production of GMP drug product ATX-GD-59 for toxicity studies was completed. Stability studies were initiated with no concerns identified. In addition, the drug was 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 were also completed with no adverse effects reported.
Regulatory applications (WP4) for the Phase I clinical trial were 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) received approval to open six clinical sites in the UK. The protocols were written and accepted following some amendments requested by competent authorities. The trial was therefore started with screening and recruiting of subjects in the UK.
In WP6 (Clinical Analysis Method Development) the methodology for the antidrug antibody (ADA) was validated and implemented for screening and monitoring ADA during the ATX-GD-59-001 clinical trial. The design of flow cytometry antibody panels for use in testing the frequency and function of peptide-specific regulatory and effector T cell subsets was completed to test PBMC samples from patients enrolled in the trial in order to test for biomarkers of treatment efficacy. The assay was reported 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.
Significant results achieved within this period include:
Work Package 2 - CMC:
• Task 2.1 6 peptides each of 1g of non GMP technical batch were manufactured and released in 2 lots.
• A 1000 vial technical batch of ATX-GD-459 and ATX-GD-59 was manufactured and released.
• The provisional specifications for the GMP grade batches of API and IMP were established.
• Task 2.2 HPLC methods were developed for API and IMP and validated.
• Task 2.3 the forced degradation studies, were completed. (Results)
• Task 2.4 GMP peptide manufacture, was completed (Results – release of peptides). Certificates of Analysis were made available (D2.1)
• The IMP formulation was decided upon (Task 2.5)
• 2-year stability studies on the API peptides were completed and both peptides were within specification.
• 1-year indicative stability studies on the IMP formulation were completed. GMP stability studies reported as on-going and remained within specification. The 18- month timepoint was reported as June 2017.
• ATX-GD-59 was packaged and released to the clinic by a qualified person for use at approved clinical centres in the ATX-GD-59-001 clinical trial.
• A 2-year expiry date was applied to the packaged IMP.
Work Package 3 – Toxicology
• The scientific protocols for the toxicology studies were agreed and written.
• The validity of the key assay platform to be used for toxicology species selection was demonstrated.
• The SD rat was chosen as the relevant species for toxicity studies.
• MHRA accepted both the choice of SD rat as a relevant species; and the design of the toxicology programme and in particular DAVIAD’s proposal to use a single species.
• An unexpected antibody response to 4K-G was observed in the high dose treated SD rats and a new formulation (ATX-GD-59) omitting 4K-G was tested.
• The NOAEL (No observed adverse event level) for the revised formulation of ATX-GD-59 was considered to be above 1mg/kg.
Work Package 4 – Regulatory
• A decision was made to submit an ODD application in the US once the results from WP5 were available. The ODD application will be based on ATX-GD-59 and not as originally envisaged ATX-GD-459
• An Informal meeting held with the EMA/COMP advised against submission of an EU application for OMPD
• A scientific advice procedure was completed at MHRA (O4.1). Based on the advice received, no further engagement with regulatory agencies was considered necessary prior to submission of the CTA.
Work Package 5 – Clinical Trial
• Clinical Study Protocol, version 1.0 was signed 15 Jan 2016
• UK National Regulatory application to the MHRA submitted 19 Feb 2016
• German National Regulatory application to BfArM submitted 7 Mar 2016
• UK EC application to MREC submitted 8 Mar 2016
• Internal Team Kick-Off Meeting was held 9 Mar 2016
• Clinical Study Protocol, version 2.0 signed 5 Apr 2016
• UK MHRA approval received 20 Apr 2016
• Clinical Study Protocol, version 3.0 signed 17 May 2016
• Belgium National Regulatory application to famhp and EC Application to Saint Luc submitted 30 May 2016
• UK MREC approval received 6 Jun 2016
• UK HRA application submitted 10 Jun 2016
• Investigator Meeting held 13 Jun 2016
• Belgium famhp approval received 20 Jul 2016
• UK HRA approval received 26 Jul 2016
• First site initiated 5 August 2016
• First patient first screened 27 Sep 2016
• First patient first dose 18 October 2016
• No safety issues related to the study drug or procedures reported.
Work Package 6 – Clinical Analysis Method Development
• ADA assay was established, validated and routinely used for the ATX-GD-59-001 clinical trial.
• PBMC Assay panels were finalised – included proliferation, cell surface markers and cytokine measurement.
• PBMC T cell proliferation assay was validated.
Work Package 7 – Dissemination & Exploitation
• A significant second press release regarding initiation of patient enrolment was prepared and distributed worldwide.
• The clinical trial was published on the worldwide register clinicaltrials.gov
• The potential new therapeutic for GD was presented at many international conferences
• The basis for the measurement of biomarkers and efficacy (WP6) was also introduced at various specialist conferences
• News about the DAVIAD programme reached patients via publications and especially the active patient group, the British Thyroid Foundation via its newsletters and the NHS.
• The PCT patent application was filed for the peptide cocktail
Work Package 8 – Consortium Management & Reporting to the EC
• Changes to the project consortium as identified in the Period 1 report were implemented in the early part of Period 2 by means of a contract amendment.
Period Three – M37 – M55
Work in this period concentrated on the tasks remaining in the three outstanding technical work packages, WP2 – CMC, WP5, Clinical Trial, WP6 Clinical Analysis, together with the ongoing activities in WP7 – Dissemination & Exploitation and WP8 Consortium Management & Reporting to the EC.
In WP5 (Clinical Trial), the central set of activities in this period, the clinical trial was conducted at 8 sites. The Clinical Trial was implemented in accordance with all current global the DAVIAD consortium partners’ Standard Operating Procedures (SOP) to ensure that the delivery and quality of all aspects of studies adhere with ICH GCP guidelines and the guidelines of the UK where the clinical trial activities were performed. In terms of recruitment, 7 sites recruited at least 1 patient into the study prior to the completion of screening on 16 Jun 2018 and the last subject first visit recruitment was on 19th July 2017.
A number of recruitment initiatives were employed by the DAVIAD consortium team to maximise the number of subjects recruited into the clinical protocol. These included the following initiatives which commenced before 1st December 2016 and continued after that date as follows:
• Addition of patient identification centres (PIC sites) for referral of subjects to the main clinical research centres.
• Promotion of the DAVIAD study awareness within the healthcare and patient community though the following media:
▪ British Thyroid Foundation newsletter and website.
▪ NHS choices website.
▪ Clinical trials database - clinical trials.gov
▪ Royal College of General Practitioners newsletter.
▪ An advertising campaign for potential subjects in the media local to the centres.
▪ Clinical research network and GP meetings at the study centres.
▪ Investigator study newsletters
In WP6 (Clinical Analysis) assays were developed, validated and utilised for the endpoints: plasma anti-drug antibody (ADA) detection, PBMC T cell and cytokine characterisation and quantification of IL-10 mRNA and IL-10 pathway associated genes from whole blood. These assays were planned, executed, analysed and reported to Good Clinical Laboratory Practice procedures.
As part of WP7 activities, a press release reporting the positive outcome for the clinical trial under the DAVIAD programme was sent to online general and health specialist media and distributed to national and international press and published on the DAVIAD website as well as social media, i.e. LinkedIn; and regional trade associations such as FlandersBio.
Consortium members participated and attended many national and international conferences reporting progress on the DAVIAD programme and initiating partnering discussions with potential licensees.
The DAVIAD consortium continued to be actively involved with patient groups such as the British Thyroid Foundation and information was disseminated to patients about a potential new therapy. Also, details of the clinical trial, recruitment and recruitment centres was disseminated via patient groups, the NHS and the clinicaltrials.gov database.
A 3 minute video was prepared and posted in March 2018 on the EU science and innovation website and British Thyroid Foundation facebook and BTF website http://www.btf-thyroid.org/projects/graves-disease/365-project-daviad as well as the DAVIAD and Apitope websites.
Significant results achieved within this period include:
Work Package 5 – Clinical Trial
• Screening and enrolment was closed on 16 June 17 and 19 July 2017 respectively
• Data Safety Monitoring Committee meeting was held on 12 October 2017
• Last Subject Last Visit - 14 February 2018
• Database lock - 27 March 2018
• Tables, Listings and Figures finalised and approved - 15 May 2018
• Clinical Study Report finalised - 28 June 2018
Work Package 6 – Clinical Analysis Method Development
• ADA testing was used as part of the exclusion and withdrawal criteria for patients on the trial.
• Plasma anti ADA detection was presented in document “APT WP6-FP7-002-3 Final GCLP Report ADA”, report number 001-ADA.
• The ADA ELISA was employed during the clinical trial phase at the required blood sampling timepoints and the data uploaded to the database portal
• PBMC T cell and cytokine characterisation was carried out
• Quantification of IL-10 mRNA and IL-10 pathway associated genes from whole blood was also carried out.
Work Package 7 – Dissemination & Exploitation
• Significant third press release regarding the success of DAVIAD, i.e. the reporting of positive data from the first in human study was prepared and distributed worldwide.
• Potential new therapeutic for GD was presented at many international conferences
• The basis for the measurement of biomarkers and efficacy (WP6) was introduced at various specialist conferences
• A paper was published in a leading journal, Endocrinology Title: Immunotherapy with apitopes blocks the immune response to thyroid stimulating hormone receptor in HLA-DR transgenic mice
• News about the DAVIAD programme reached patients via publications and especially the active patient group, the British Thyroid Foundation via its newsletters and the NHS.
• Video produced and released highlighting patient need and the solution provided by this innovative therapy - http://www.btf-thyroid.org/projects/graves-disease/365-project-daviad
Potential Impact:
Project Impacts
Health Impacts:
GD is a chronic autoimmune disease especially in the more severe form GO including sight threatening GO and the difficult to treat paediatric patients (There are currently around 12,000 children diagnosed with GD in Europe and the US). Patients can experience a wide range of symptoms and suffer major impairment in most areas of health-related quality of life (HRQL). 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-of-principle 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 twofold. 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.
Main Dissemination Activities
Apitope, as the project co-ordinator and leader of WP7, has continuously promoted the project to the scientific community, key opinion leaders, patient community, and potential pharmaceutical partners. Very significant awareness and interest in the project has been created by these activities. This promotion is an ongoing activity. The following are some of the meetings that have been attended:
• Knowledge for Growth conference in Ghent where a poster titled “Antigen-specific peptide therapy prevents formation of TSHR antibodies in HLA-DR transgenic mice” was presented.
• FOCIS annual meeting, June 22-25th 2016, Boston, USA. Apitope presented titled “Switching off unwanted immune responses: the mechanism of antigen-specific immunotherapy with T cell epitopes”.
• The BioEurope conferences - Cologne, Germany, November 7th – 9th 2016; Barcelona 20th -22nd March 2017; Berlin 6-8th November 2017; Amsterdam 12th-14th March 2018; partnering meetings were held to update and engage with potential pharma licensees. Apitope also had a presence at the Belgian pavilion at the trade exhibition to attract potential interest.
• BIO US Conventions – San Francisco 6-9 June 2016; San Diego 19-22 June 2017 and Boston 4-7th June 2018 – again partnering meetings held in the partnering system as well as a presence at the Belgian pavilion to attract potential licensees
• The Society for Endocrinology BES 6-8 Nov 2017 in Harrogate.
• Welsh Endocrine and Metabolism Research Day 28th June 17
• Treg summit Boston 23rd-24th May 2018 – Induction of regulatory Tcells by antigen specific immunotherapy
Going forward Apitope will present data from the DAVIAD clinical trial at the following forthcoming conferences:
• The 41st Annual Meeting of the European Thyroid Association Sep 15 - 18, 2018 in Newcastle upon Tyne, England
• 5th European Congress of Immunology, September 2 – 5, 2018 in Amsterdam, The Netherlands. The accepted abstract is entitled: Immunotherapy with apitopes® blocks the immune response to thyroid stimulating hormone receptor in HLA-DR transgenic mice.’
• BioEurope Copenhagen 5-7th November 2018
• BIO Convention June 3rd-6th 2019 Philadelphia
News related to activities performed by the DAVIAD consortium was disseminated through press releases as well as postings on the DAVIAD website and LinkedIn social media platform to target general audiences to attract attention of potential licensees and investors. The following prominent press releases were disseminated:
• Recruitment of the first patient for the phase I clinical trial for ATX-GD-59 (16th October 2016)
• Positive results from the phase I first in man study (April 16th 2018)
• Publication in Endocrinology
Future press releases will include initiation of phase II trial, last patient last visit on trial and read out of the data from the trial. In addition to dissemination via our communication agency information will be disseminated via FlandersBio (networking organization in Flanders, Belgium). Examples of dissemination tools are shown in the attached appendices.
Exploitation of Results
The DAVIAD project has generated very good data on the DAVIAD therapeutic vaccine for the treatment of Graves’ disease. This vaccine will be further developed as a potential first in class treatment and the first innovative therapy for over 60 years.
The manufacturing activities have been very successful, demonstrating that the vaccine is both easy and cheap to make and is stable. The toxicology studies and clinical trials have demonstrated that the vaccine is safe both in animals and in humans. The clinical trials have also demonstrated that the vaccine is effective in Graves’ disease patients.
Exploitation of the results generated by the DAVIAD project is an extremely important endpoint for the project. In this context, exploitation means advancing the ATX-GD-59 candidate towards further clinical trials and marketing approval, so that the vaccine may be used in the treatment of Graves’ disease patients including paediatric Graves’ disease patients and sight threatening Graves’ disease patients who have very limited treatment options.
Apitope International N.V. as the sponsor of the first in human trial and the owner of the intellectual property covering the ATX-GD-59 vaccine, has been actively engaged in promoting the merits of the vaccine prior to and during the DAVIAD project. As explained above exploitation means advancing the programme towards further clinical development and ultimately marketing approval. Advancing the vaccine towards market approval requires either additional funding for clinical development by Apitope International N.V. itself, or identifying a large pharmaceutical partner willing to take the programme forward. Apitope International N.V. has been actively engaged in exploitation and has continuously sought additional funding to expand the project. As a consequence of these activities, Apitope has successfully raised 30 million EUR in funding from venture capitalists and is presently engaged in further financing to advance the project beyond that scope of the DAVIAD programme and towards Phase II clinical trials.
Apitope has undertaken primary and secondary research into the competitive environment, market access and pricing and further clinical development and also engaged with key opinion leaders, patient advocacy groups, pricing experts (DM pharma), epidemiologists (BioBusiness consultancy) and business consultants (Back Bay advisors). In consultation with its advisors, Apitope has prepared a target product profile, the current version of which is set out in Appendix A later in this document.
Apitope has being engaged in making development plans for advancing the project towards market approval, commercial positioning of the project, as well as now actively seeking a pharmaceutical partner for the project. Apitope has conducted a commercial assessment (see Appendix B) and has developed a target product profile (see Appendix A) which it has reviewed with key Opinion leaders) in the plan for further development.
An integrated development plan for ATX-GD-59 is shown in Figure 1. The plan includes taking the programme into a Phase II clinical trial by Q1/Q2 2019. Marketing approval is planned for 2023/4. Development costs for taking the project all the way to market approval is very significant, likely in the range of at least 170 million EUR. Raising this kind of money in itself would be a massive undertaking for a small biotech like Apitope. In addition, the Phase Ill clinical trial would require the enrolment of large patient numbers worldwide, which is something only a very big development organization would be able to conduct. It has therefore been decided that the primary focus of the exploitation plan will be to find a large pharmaceutical partner before the initiation of phase III. Apitope is currently looking to raise the funding needed to advance the project through the initial Phase II clinical trial.
The plan is to conduct a Phase II, multicentre, double-blind, placebo controlled, randomized, dose-range finding study in patients with Graves’ disease (see Appendix B). It is anticipated that approximately 250 subjects will be screened to give 180 subjects. Recruitment will be conducted over a period of approximately 9 months.
The study is designed to show the effect of different ATX-GD-59 doses: low (400μg), medium (800 μg) and high (1200 μg) on thyroid function (fT3 & fT4), between groups, after 34 weeks of study treatment. Additional efficacy, safety and exploratory endpoints will also be evaluated.
The aim of therapy with ATX-GD-59 is to treat the underlying cause of Graves’ disease and, as such, bring blood thyroid function tests (TFTs) back into normal range. Blood TFTs including fT3, fT4 and TSH, will be performed to evaluate the primary and secondary efficacy endpoints
Figure 1. Development plan for advancing ATX-GD-59 towards market approval by end 2024.
As partnering of the project with a larger pharmaceutical partner seems to most likely path forward for the project, Apitope has discussed the programme with a number of potential partners for the project. Several companies have expressed a significant interest in the project and are now actively engaged in due diligence of the data generated. As expected some companies have declined the opportunity, mostly due to the fact that the project is outside their current strategic focus or too early to fit within their partnering needs. An overview of the process and activities as of June 30th, 2018 is outlined in the slides 21 – 24 of Appendix B.
Given the very good data generated by the DAVIAD Project, the ability of Apitope International N.V. to attract continued funding for the project to date, and the very significant interest that has been gained from the scientific community and Key Opinion Leaders, patient organisations and advocacy groups and the larger pharmaceutical companies contacted as part of the exit process, Apitope International N.V. remains confident that it will succeed in advancing the project forward after the completion of the DAVIAD Project.
List of Websites:
Public Website www.daviad.eu
Contact Details Dr Hayley French, CBO & General Counsel
+44 1291 635 511
Hayley.french@apitope.com
Graves’ disease is an autoimmune disease characterised by antibodies targeting the Thyroid Stimulating Hormone Receptor (TSHR) resulting in hyperthyroidism and multiple organ damage. The ideal therapy for an autoimmune disease would switch off the abnormal response to the target and reinstate immune tolerance but, importantly, without altering any other component of the immune system. This is exactly the concept that the peptide vaccine in the DAVIAD programme aimed to deliver.
The development of a disease modifying vaccine for Grave’s Disease (GD) addresses a serious unmet need and presents a potential first innovative therapy for patients in over sixty years. The potential to offer a disease modifying therapy able to change the way in which this disease is treated offers a new hope for a better quality of life to patients and reduces the burden of care for families and health services alike.
The DAVIAD project successfully resulted in the manufacture GMP grade ATX-GD-59 and completion of pharmacodynamic and toxicology studies in order to progress the therapeutic vaccine into a Phase I/IIa clinical trial. In the clinical trial, he vaccine was proven to be safe and well tolerated. Furthermore, the improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for hyperthyroid GD. These data together with all of the other work completed to reach this outcome, reflect a successful consortium approach to this project and position the therapeutic vaccine, ATX-GD-59, for further clinical development and commercialisation.
The outcomes of the project were widely disseminated to audiences across the EU and beyond through publications in peer reviewed journals and conferences. A wide-ranging exploitation plan for ATX-GD-59 is now being implemented by the project co-ordinator.
Project Context and Objectives:
The aim of the DAVIAD project was 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 were 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 was targeted to 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:
Period One – M1 – M18
During this period the DAVIAD consortium developed plans to streamline the activities in the work packages, initiated research to further evaluate properties of the selected peptides; transferred technologies between consortium partners; finalised protocols and performed dosing and pilot experiments.
Several expert service providers were evaluated for their suitability to manufacture the GMP API (active pharmaceutical ingredient) and GMP IMP (investigational medicinal product) and to execute GLP compliant toxicity studies.
Additional preclinical data generated during this period supported the removal of one of the three peptides from the vaccine and the development of the optimised product ATX-GD-59. As this was a significant change in the product, a number of performed tasks had to be repeated including confirmation of activity in pre-clinical models (Work Package 1 (WP1)) manufacture of the technical and GMP batches of IMP and the toxicology programme. The need to repeat these tasks introduced an unavoidable delay to the submission of the CTA application.
In WP1 two animal models using HLA-transgenic mice were evaluated for TSHR-specific T and B cell responses and increased thyroid hormone levels to support optimal vaccine dose finding and co-medication. Investigations focused on a standard TSHR/CFA immunisation model and an adenoviral driven TSHR expression (AdV-TSHR) model in the HLA-DR transgenic strains. A revised design of the AdV-TSHR model was selected and the model validated using known current medications. The drug interactions between ATX-GD-459 and methimazole; and ATX-GD-459 and propranolol were then analysed in co-medication studies.
In WP1 the characterisation of the shortlisted peptides in short term human PBMC assays was also performed and peptides 4K-G, 5D-K and 9B-N were initially selected for inclusion in the IMP prior to obtaining the additional preclinical data indicated above.
All WP2 activities initiated in the period were successfully completed. These activities included vendor selection; manufacture of non-GMP API and IMP; manufacture of GMP grade API and IMP; analytical method development and validation and stability studies. All of the activities were completed as planned with all manufactured products meeting specification.
During this period, it was confirmed that a variety of potential toxicology strains in both mice and rats, possessed both MHC class II molecules and T cell receptors capable of recognising and eliciting responses to the peptides selected under WP1. Ultimately, the Sprague Dawley (SD) rat was chosen as the strain for toxicity studies and the planned toxicity studies were completed by the selected vendor; Aptuit. No findings of toxicological significance were reported.
Following discussions with the European Medicines Agency, the consortium concluded that it was unlikely that the planned application for EU Orphan Medicinal Product Designation would be successful. As the vaccine could potentially be used in the treatment of all GD patients and not just those with the highest unmet medical need (paediatric GD or sight threatening orbitopathy), the indication would not meet the prevalence criterion for orphan designation in the EU. The consortium agreed to focus on submitting an application for US Orphan Drug Designation based on ATX-GD-59, where it may be possible to get designation for subtypes of a disease. The consortium also held a successful Scientific Advice meeting with MHRA in November 2014. The MHRA agreed with the consortium position on all questions raised in particular plans for toxicity and clinical studies within WP4.
The consortium agreed the proposed clinical study design and the 12 clinical sites across 3 countries (UK, Germany and Belgium) were selected following the successful completion of a comprehensive feasibility study.
The DAVIAD website was launched in April 2014. A download section was included in the public part of the website to upload documents such as the DAVIAD poster and brochure, as well as other documents intended to inform the general public about the project. An event schedule was added to inform the general audience of upcoming conferences to which the consortium members will participate. News items relating to activities performed by the consortium, such as the initiation of preclinical development for ATX-GD-459, were disseminated through press releases. For example, the initiation of preclinical development for ATX-GD-459 was disseminated in a press release on 21st June 2014. News items were also posted on the DAVIAD project website (www.daviad.eu ) and consortium members’ websites, as well as the LinkedIn social platform. The British Thyroid Foundation’s involvement in DAVIAD was reported in the society newsletter issues 85 and 87.
Significant results achieved within this period include:
Work Package 1 - Candidates:
• Decision taken on the preferred animal model
• The efficacy of the drug, methyl-prednisolone, was demonstrated in the AdV-TSHR model. This validates the model as immunological driven and an appropriate model for ATX-GD-459 evaluation.
• One of the clinically used medications, methimazole (active component in carbamizole), used to reduce hyperthyroidism in patients, has been tested in the mouse disease model. The results show the drug is active in reducing the plasma T4 in the HLA-DR transgenic mice in a dose dependent manner but did not show any impact or alteration of the T cell or B cell immunological response.
• In co-medication experiments in the AdV-TSHR model, neither methimazole or propranolol (beta-adrenergic blocker) interfered with ATX-GD-459 T cell tolerance induction.
• Prophylactic treatment with ATX-GD-459 in the AdV-TSHR model – efficacy was demonstrated by suppression of the T cell dependent B cell produced anti-TSHR IgG antibodies by approximately 60-80% compared to controls. A further analysis of the quality of the TSHR-specific B cell response revealed the IgG subclass IgG2b was reduced compared with controls.
• The recognition of the peptides in ATX-GD-459 by T cells from GD patients was confirmed and supports the clinical development of the cocktail. The frequency of peptide specific T cell proliferation was summarised as follows:
o for 5D-K1 : 5 out of 20 patients tested (25%)
o for 4K-G: 6 out of 20 patients tested (30%)
o for 9B-N: 9 out of 24 patients tested (38%)
The requirement of 5% patients recognising each peptide was well met and supported the cocktail for clinical development.
• All generated data was compiled into reports.
Work Package 2 - CMC:
• Task 2.1 6 peptides each of 1g of non GMP technical batch were manufactured and released in 2 lots.
• A 1000 vial technical batch of ATX-GD-459 was manufactured and released
• The provisional specifications for the GMP grade batches of 5D-K1, 4K-G and 9B-N were established
• Task 2.2 HPLC methods were developed for API and IMP and validated
• Task 2.3 the forced degradation studies, were completed. (Results)
• Task 2.4 GMP peptide manufacture, was completed (Results – release of peptides). Certificates of Analysis were made available (D2.1)
• The IMP formulation was decided upon (Task 2.5)
• Provisional specifications for GMP ready API were established, indicative stability study initiated and provisional data shared with the MHRA
Work Package 3 - Toxicology:
• The scientific protocols for the toxicology studies were agreed and written.
• The validity of the key assay platform to be used for toxicology species selection was demonstrated.
• The SD rat was chosen as the strain to proceed with for toxicity studies.
• MHRA accepted both the choice of SD rat as a relevant species; and the design of the toxicology programme and in particular DAVIAD’s proposal to use a single species.
• Aptuit (Italy) was chosen as a vendor to complete Tasks 3.3 and 3.4 and the contracts signed.
• The toxicology studies were executed by Aptuit.
• An unexpected antibody response to 4K-G was observed in the high dose treated SD rats.
Work Package 4 - Regulatory:
• A decision was made to submit an orphan drug designation (ODD) application in the US once the results from WP1 were available. The ODD application will be based on ATX-GD-59 and not as originally envisaged ATX-GD-459
• An Informal meeting held with the EMA/COMP advised against submission of an EU application for Orphan medicinal product designation (OMPD).
• A scientific advice procedure was completed at MHRA (O4.1). Based on the advice received, no further engagement with regulatory agencies was envisaged prior to submission of the CTA.
Work Package 5 – Clinical Trial:
• The Feasibility study was completed and report finalised.
• Clinical study sites selected.
Work Package 6 – Clinical Analysis Method Development:
• Identification of Kahaly Laboratory to perform TSHR antibody analysis on clinical samples
Work Package 7 – Dissemination & Exploitation:
• The DAVIAD website was launched
• A first press release was prepared and distributed worldwide.
• A leaflet, poster and the press release were disseminated to the general public
• Apitope’s approach was published and presented at international conferences
• News about the DAVIAD programme reached patients via publications from the consortium and also via the British Thyroid Foundation newsletters.
Work Package 8 – Consortium Management and Reporting to the EC:
• Management Boards were set up and working initiated.
• Project Meetings were held as scheduled.
• Restricted Access Partner online area was created for document sharing and populated.
• A PCT patent application was filed for the initial GD patent application.
• A UK patent application was filed on the 24th of December 2014 to protect the cocktail and use of ATX-GD-459 peptides
• GSK terminated its participation in the consortium due to a change in strategic focus. The preparation of an amendment to the Grant Agreement was initiated to reflect this change and also the addition of various third parties.
Period Two – M19 – M36
During this period of the project the DAVIAD consortium made significant progress in the technical development of the vaccine such that the pre-clinical, analytical and regulatory activities were all completed to enable the clinical trial of the vaccine to be initiated.
In WP2 (CMC) the formulation and manufacturing process for small scale production of GMP drug product ATX-GD-59 for toxicity studies was completed. Stability studies were initiated with no concerns identified. In addition, the drug was 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 were also completed with no adverse effects reported.
Regulatory applications (WP4) for the Phase I clinical trial were 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) received approval to open six clinical sites in the UK. The protocols were written and accepted following some amendments requested by competent authorities. The trial was therefore started with screening and recruiting of subjects in the UK.
In WP6 (Clinical Analysis Method Development) the methodology for the antidrug antibody (ADA) was validated and implemented for screening and monitoring ADA during the ATX-GD-59-001 clinical trial. The design of flow cytometry antibody panels for use in testing the frequency and function of peptide-specific regulatory and effector T cell subsets was completed to test PBMC samples from patients enrolled in the trial in order to test for biomarkers of treatment efficacy. The assay was reported 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.
Significant results achieved within this period include:
Work Package 2 - CMC:
• Task 2.1 6 peptides each of 1g of non GMP technical batch were manufactured and released in 2 lots.
• A 1000 vial technical batch of ATX-GD-459 and ATX-GD-59 was manufactured and released.
• The provisional specifications for the GMP grade batches of API and IMP were established.
• Task 2.2 HPLC methods were developed for API and IMP and validated.
• Task 2.3 the forced degradation studies, were completed. (Results)
• Task 2.4 GMP peptide manufacture, was completed (Results – release of peptides). Certificates of Analysis were made available (D2.1)
• The IMP formulation was decided upon (Task 2.5)
• 2-year stability studies on the API peptides were completed and both peptides were within specification.
• 1-year indicative stability studies on the IMP formulation were completed. GMP stability studies reported as on-going and remained within specification. The 18- month timepoint was reported as June 2017.
• ATX-GD-59 was packaged and released to the clinic by a qualified person for use at approved clinical centres in the ATX-GD-59-001 clinical trial.
• A 2-year expiry date was applied to the packaged IMP.
Work Package 3 – Toxicology
• The scientific protocols for the toxicology studies were agreed and written.
• The validity of the key assay platform to be used for toxicology species selection was demonstrated.
• The SD rat was chosen as the relevant species for toxicity studies.
• MHRA accepted both the choice of SD rat as a relevant species; and the design of the toxicology programme and in particular DAVIAD’s proposal to use a single species.
• An unexpected antibody response to 4K-G was observed in the high dose treated SD rats and a new formulation (ATX-GD-59) omitting 4K-G was tested.
• The NOAEL (No observed adverse event level) for the revised formulation of ATX-GD-59 was considered to be above 1mg/kg.
Work Package 4 – Regulatory
• A decision was made to submit an ODD application in the US once the results from WP5 were available. The ODD application will be based on ATX-GD-59 and not as originally envisaged ATX-GD-459
• An Informal meeting held with the EMA/COMP advised against submission of an EU application for OMPD
• A scientific advice procedure was completed at MHRA (O4.1). Based on the advice received, no further engagement with regulatory agencies was considered necessary prior to submission of the CTA.
Work Package 5 – Clinical Trial
• Clinical Study Protocol, version 1.0 was signed 15 Jan 2016
• UK National Regulatory application to the MHRA submitted 19 Feb 2016
• German National Regulatory application to BfArM submitted 7 Mar 2016
• UK EC application to MREC submitted 8 Mar 2016
• Internal Team Kick-Off Meeting was held 9 Mar 2016
• Clinical Study Protocol, version 2.0 signed 5 Apr 2016
• UK MHRA approval received 20 Apr 2016
• Clinical Study Protocol, version 3.0 signed 17 May 2016
• Belgium National Regulatory application to famhp and EC Application to Saint Luc submitted 30 May 2016
• UK MREC approval received 6 Jun 2016
• UK HRA application submitted 10 Jun 2016
• Investigator Meeting held 13 Jun 2016
• Belgium famhp approval received 20 Jul 2016
• UK HRA approval received 26 Jul 2016
• First site initiated 5 August 2016
• First patient first screened 27 Sep 2016
• First patient first dose 18 October 2016
• No safety issues related to the study drug or procedures reported.
Work Package 6 – Clinical Analysis Method Development
• ADA assay was established, validated and routinely used for the ATX-GD-59-001 clinical trial.
• PBMC Assay panels were finalised – included proliferation, cell surface markers and cytokine measurement.
• PBMC T cell proliferation assay was validated.
Work Package 7 – Dissemination & Exploitation
• A significant second press release regarding initiation of patient enrolment was prepared and distributed worldwide.
• The clinical trial was published on the worldwide register clinicaltrials.gov
• The potential new therapeutic for GD was presented at many international conferences
• The basis for the measurement of biomarkers and efficacy (WP6) was also introduced at various specialist conferences
• News about the DAVIAD programme reached patients via publications and especially the active patient group, the British Thyroid Foundation via its newsletters and the NHS.
• The PCT patent application was filed for the peptide cocktail
Work Package 8 – Consortium Management & Reporting to the EC
• Changes to the project consortium as identified in the Period 1 report were implemented in the early part of Period 2 by means of a contract amendment.
Period Three – M37 – M55
Work in this period concentrated on the tasks remaining in the three outstanding technical work packages, WP2 – CMC, WP5, Clinical Trial, WP6 Clinical Analysis, together with the ongoing activities in WP7 – Dissemination & Exploitation and WP8 Consortium Management & Reporting to the EC.
In WP5 (Clinical Trial), the central set of activities in this period, the clinical trial was conducted at 8 sites. The Clinical Trial was implemented in accordance with all current global the DAVIAD consortium partners’ Standard Operating Procedures (SOP) to ensure that the delivery and quality of all aspects of studies adhere with ICH GCP guidelines and the guidelines of the UK where the clinical trial activities were performed. In terms of recruitment, 7 sites recruited at least 1 patient into the study prior to the completion of screening on 16 Jun 2018 and the last subject first visit recruitment was on 19th July 2017.
A number of recruitment initiatives were employed by the DAVIAD consortium team to maximise the number of subjects recruited into the clinical protocol. These included the following initiatives which commenced before 1st December 2016 and continued after that date as follows:
• Addition of patient identification centres (PIC sites) for referral of subjects to the main clinical research centres.
• Promotion of the DAVIAD study awareness within the healthcare and patient community though the following media:
▪ British Thyroid Foundation newsletter and website.
▪ NHS choices website.
▪ Clinical trials database - clinical trials.gov
▪ Royal College of General Practitioners newsletter.
▪ An advertising campaign for potential subjects in the media local to the centres.
▪ Clinical research network and GP meetings at the study centres.
▪ Investigator study newsletters
In WP6 (Clinical Analysis) assays were developed, validated and utilised for the endpoints: plasma anti-drug antibody (ADA) detection, PBMC T cell and cytokine characterisation and quantification of IL-10 mRNA and IL-10 pathway associated genes from whole blood. These assays were planned, executed, analysed and reported to Good Clinical Laboratory Practice procedures.
As part of WP7 activities, a press release reporting the positive outcome for the clinical trial under the DAVIAD programme was sent to online general and health specialist media and distributed to national and international press and published on the DAVIAD website as well as social media, i.e. LinkedIn; and regional trade associations such as FlandersBio.
Consortium members participated and attended many national and international conferences reporting progress on the DAVIAD programme and initiating partnering discussions with potential licensees.
The DAVIAD consortium continued to be actively involved with patient groups such as the British Thyroid Foundation and information was disseminated to patients about a potential new therapy. Also, details of the clinical trial, recruitment and recruitment centres was disseminated via patient groups, the NHS and the clinicaltrials.gov database.
A 3 minute video was prepared and posted in March 2018 on the EU science and innovation website and British Thyroid Foundation facebook and BTF website http://www.btf-thyroid.org/projects/graves-disease/365-project-daviad as well as the DAVIAD and Apitope websites.
Significant results achieved within this period include:
Work Package 5 – Clinical Trial
• Screening and enrolment was closed on 16 June 17 and 19 July 2017 respectively
• Data Safety Monitoring Committee meeting was held on 12 October 2017
• Last Subject Last Visit - 14 February 2018
• Database lock - 27 March 2018
• Tables, Listings and Figures finalised and approved - 15 May 2018
• Clinical Study Report finalised - 28 June 2018
Work Package 6 – Clinical Analysis Method Development
• ADA testing was used as part of the exclusion and withdrawal criteria for patients on the trial.
• Plasma anti ADA detection was presented in document “APT WP6-FP7-002-3 Final GCLP Report ADA”, report number 001-ADA.
• The ADA ELISA was employed during the clinical trial phase at the required blood sampling timepoints and the data uploaded to the database portal
• PBMC T cell and cytokine characterisation was carried out
• Quantification of IL-10 mRNA and IL-10 pathway associated genes from whole blood was also carried out.
Work Package 7 – Dissemination & Exploitation
• Significant third press release regarding the success of DAVIAD, i.e. the reporting of positive data from the first in human study was prepared and distributed worldwide.
• Potential new therapeutic for GD was presented at many international conferences
• The basis for the measurement of biomarkers and efficacy (WP6) was introduced at various specialist conferences
• A paper was published in a leading journal, Endocrinology Title: Immunotherapy with apitopes blocks the immune response to thyroid stimulating hormone receptor in HLA-DR transgenic mice
• News about the DAVIAD programme reached patients via publications and especially the active patient group, the British Thyroid Foundation via its newsletters and the NHS.
• Video produced and released highlighting patient need and the solution provided by this innovative therapy - http://www.btf-thyroid.org/projects/graves-disease/365-project-daviad
Potential Impact:
Project Impacts
Health Impacts:
GD is a chronic autoimmune disease especially in the more severe form GO including sight threatening GO and the difficult to treat paediatric patients (There are currently around 12,000 children diagnosed with GD in Europe and the US). Patients can experience a wide range of symptoms and suffer major impairment in most areas of health-related quality of life (HRQL). 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-of-principle 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 twofold. 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.
Main Dissemination Activities
Apitope, as the project co-ordinator and leader of WP7, has continuously promoted the project to the scientific community, key opinion leaders, patient community, and potential pharmaceutical partners. Very significant awareness and interest in the project has been created by these activities. This promotion is an ongoing activity. The following are some of the meetings that have been attended:
• Knowledge for Growth conference in Ghent where a poster titled “Antigen-specific peptide therapy prevents formation of TSHR antibodies in HLA-DR transgenic mice” was presented.
• FOCIS annual meeting, June 22-25th 2016, Boston, USA. Apitope presented titled “Switching off unwanted immune responses: the mechanism of antigen-specific immunotherapy with T cell epitopes”.
• The BioEurope conferences - Cologne, Germany, November 7th – 9th 2016; Barcelona 20th -22nd March 2017; Berlin 6-8th November 2017; Amsterdam 12th-14th March 2018; partnering meetings were held to update and engage with potential pharma licensees. Apitope also had a presence at the Belgian pavilion at the trade exhibition to attract potential interest.
• BIO US Conventions – San Francisco 6-9 June 2016; San Diego 19-22 June 2017 and Boston 4-7th June 2018 – again partnering meetings held in the partnering system as well as a presence at the Belgian pavilion to attract potential licensees
• The Society for Endocrinology BES 6-8 Nov 2017 in Harrogate.
• Welsh Endocrine and Metabolism Research Day 28th June 17
• Treg summit Boston 23rd-24th May 2018 – Induction of regulatory Tcells by antigen specific immunotherapy
Going forward Apitope will present data from the DAVIAD clinical trial at the following forthcoming conferences:
• The 41st Annual Meeting of the European Thyroid Association Sep 15 - 18, 2018 in Newcastle upon Tyne, England
• 5th European Congress of Immunology, September 2 – 5, 2018 in Amsterdam, The Netherlands. The accepted abstract is entitled: Immunotherapy with apitopes® blocks the immune response to thyroid stimulating hormone receptor in HLA-DR transgenic mice.’
• BioEurope Copenhagen 5-7th November 2018
• BIO Convention June 3rd-6th 2019 Philadelphia
News related to activities performed by the DAVIAD consortium was disseminated through press releases as well as postings on the DAVIAD website and LinkedIn social media platform to target general audiences to attract attention of potential licensees and investors. The following prominent press releases were disseminated:
• Recruitment of the first patient for the phase I clinical trial for ATX-GD-59 (16th October 2016)
• Positive results from the phase I first in man study (April 16th 2018)
• Publication in Endocrinology
Future press releases will include initiation of phase II trial, last patient last visit on trial and read out of the data from the trial. In addition to dissemination via our communication agency information will be disseminated via FlandersBio (networking organization in Flanders, Belgium). Examples of dissemination tools are shown in the attached appendices.
Exploitation of Results
The DAVIAD project has generated very good data on the DAVIAD therapeutic vaccine for the treatment of Graves’ disease. This vaccine will be further developed as a potential first in class treatment and the first innovative therapy for over 60 years.
The manufacturing activities have been very successful, demonstrating that the vaccine is both easy and cheap to make and is stable. The toxicology studies and clinical trials have demonstrated that the vaccine is safe both in animals and in humans. The clinical trials have also demonstrated that the vaccine is effective in Graves’ disease patients.
Exploitation of the results generated by the DAVIAD project is an extremely important endpoint for the project. In this context, exploitation means advancing the ATX-GD-59 candidate towards further clinical trials and marketing approval, so that the vaccine may be used in the treatment of Graves’ disease patients including paediatric Graves’ disease patients and sight threatening Graves’ disease patients who have very limited treatment options.
Apitope International N.V. as the sponsor of the first in human trial and the owner of the intellectual property covering the ATX-GD-59 vaccine, has been actively engaged in promoting the merits of the vaccine prior to and during the DAVIAD project. As explained above exploitation means advancing the programme towards further clinical development and ultimately marketing approval. Advancing the vaccine towards market approval requires either additional funding for clinical development by Apitope International N.V. itself, or identifying a large pharmaceutical partner willing to take the programme forward. Apitope International N.V. has been actively engaged in exploitation and has continuously sought additional funding to expand the project. As a consequence of these activities, Apitope has successfully raised 30 million EUR in funding from venture capitalists and is presently engaged in further financing to advance the project beyond that scope of the DAVIAD programme and towards Phase II clinical trials.
Apitope has undertaken primary and secondary research into the competitive environment, market access and pricing and further clinical development and also engaged with key opinion leaders, patient advocacy groups, pricing experts (DM pharma), epidemiologists (BioBusiness consultancy) and business consultants (Back Bay advisors). In consultation with its advisors, Apitope has prepared a target product profile, the current version of which is set out in Appendix A later in this document.
Apitope has being engaged in making development plans for advancing the project towards market approval, commercial positioning of the project, as well as now actively seeking a pharmaceutical partner for the project. Apitope has conducted a commercial assessment (see Appendix B) and has developed a target product profile (see Appendix A) which it has reviewed with key Opinion leaders) in the plan for further development.
An integrated development plan for ATX-GD-59 is shown in Figure 1. The plan includes taking the programme into a Phase II clinical trial by Q1/Q2 2019. Marketing approval is planned for 2023/4. Development costs for taking the project all the way to market approval is very significant, likely in the range of at least 170 million EUR. Raising this kind of money in itself would be a massive undertaking for a small biotech like Apitope. In addition, the Phase Ill clinical trial would require the enrolment of large patient numbers worldwide, which is something only a very big development organization would be able to conduct. It has therefore been decided that the primary focus of the exploitation plan will be to find a large pharmaceutical partner before the initiation of phase III. Apitope is currently looking to raise the funding needed to advance the project through the initial Phase II clinical trial.
The plan is to conduct a Phase II, multicentre, double-blind, placebo controlled, randomized, dose-range finding study in patients with Graves’ disease (see Appendix B). It is anticipated that approximately 250 subjects will be screened to give 180 subjects. Recruitment will be conducted over a period of approximately 9 months.
The study is designed to show the effect of different ATX-GD-59 doses: low (400μg), medium (800 μg) and high (1200 μg) on thyroid function (fT3 & fT4), between groups, after 34 weeks of study treatment. Additional efficacy, safety and exploratory endpoints will also be evaluated.
The aim of therapy with ATX-GD-59 is to treat the underlying cause of Graves’ disease and, as such, bring blood thyroid function tests (TFTs) back into normal range. Blood TFTs including fT3, fT4 and TSH, will be performed to evaluate the primary and secondary efficacy endpoints
Figure 1. Development plan for advancing ATX-GD-59 towards market approval by end 2024.
As partnering of the project with a larger pharmaceutical partner seems to most likely path forward for the project, Apitope has discussed the programme with a number of potential partners for the project. Several companies have expressed a significant interest in the project and are now actively engaged in due diligence of the data generated. As expected some companies have declined the opportunity, mostly due to the fact that the project is outside their current strategic focus or too early to fit within their partnering needs. An overview of the process and activities as of June 30th, 2018 is outlined in the slides 21 – 24 of Appendix B.
Given the very good data generated by the DAVIAD Project, the ability of Apitope International N.V. to attract continued funding for the project to date, and the very significant interest that has been gained from the scientific community and Key Opinion Leaders, patient organisations and advocacy groups and the larger pharmaceutical companies contacted as part of the exit process, Apitope International N.V. remains confident that it will succeed in advancing the project forward after the completion of the DAVIAD Project.
List of Websites:
Public Website www.daviad.eu
Contact Details Dr Hayley French, CBO & General Counsel
+44 1291 635 511
Hayley.french@apitope.com
