Periodic Reporting for period 1 - INNODIA HARVEST (Translational approaches to disease modifying therapy of type 1 diabetes - HARVESTing the fruits of INNODIA)
Reporting period: 2020-05-01 to 2021-10-31
The overall objective of INNODIA HARVEST is to consolidate a sustainable type 1 diabetes (T1D) network in Europe that matches discovery science to clinical advances for patient benefit at an unprecedented scale in Europe. To reach this objective INNODIA HARVEST is building on the achievements already obtained within the original project INNODIA.
INNODIA HARVEST started in May 2020, in the middle of the first COVID-19 lockdown and all partners have been working for this first 18 months during this continuous difficult COVID situation. Despite this, several key milestones have been reached, as described below per workpackage.
The clinical network, which was established in INNODIA (grant 115797) has been transformed into a clinical trial network in INNODIA HARVEST (WP1), which focuses on intervention studies for Type 1 Diabetes, starting with 3 trials in people with newly diagnosed (ND) T1D and gearing up towards interventions in individuals at high risk for T1D. The network consists of 22 clinical centers spread over 13 countries in Europe. Three clinical trials have been initiated. Ver-A-T1D is an academic sponsored, randomized double-blind placebo-controlled parallel group multi-center trial in adults (18-45 years) with ND T1D investigating the effect of verapamil sustained release on preservation of beta-cell function. The study will run in 22 clinical sites, spread over 8 countries. 14 patient shave been randomized till now. A second study is the Iscalimab study, sponsored by Novartis. This is an investigator- and subject-blinded, randomized, placebo-controlled study where we want to evaluate the safety, tolerability and efficacy of CFZ533 (Iscalimab) in pediatric and young adults with NDT1D. The study is running in 3 INNODIA HARVEST clinical sites and till now 2 patients have been randomized. A third study which was initiated in INNODIA HARVEST, is the IMPACT trial, sponsored by Imcyse. This is a multi-centre, dose comparison, randomized, double-blind, placebo-controlled study in patients with T1D within maximum 9 weeks of diagnosis (defined as the day of first insulin injection) at screening and within a maximum of 12 weeks from diagnosis to randomization. Here, 40 patients have already been randomized in 17 INNODIA HARVEST clinical sites. Furthermore, new trial designs, evaluating combination therapies, have been developed, and a masterprotocol for speedy evaluation of combination therapies has been submitted to EMA.
In WP2 new biomarkers are being evaluated, with major focus on the role of the gut microbiome, and wearable continuous glucose monitoring devices. As such, the intestinal microbiota is evaluated in samples from participants in the natural history study, including autoantibody positive individuals and those with ND T1D (these samples were stored during the first years of the INNODIA project) and results are expected early in 2022. Collection of stool samples from individuals participating in INNODIA and INNODIA Harvest clinical trials is ongoing and will be analysed in batches, once samples from all timepoints for a group of individuals are available. Wearable technology to facilitate continuous glucose monitoring has been implemented in both the INNODIA autoantibody positive natural history study (dysglycemic and thus high risk individuals) and individuals participating in INNODIA and INNODIA HARVEST clinical trials. Data has been uploaded to Dexcom Clarity and integration in the INNODIA HARVEST eCRF and analysis is underway.
In WP3, the basic research arm in INNODIA HARVEST, several key methods were developed/validated during the first 18 months of research, and relevant discoveries were made. Some of the most relevant steps are described here: 1. The selection of the most adequate reference gene(s) for gene expression normalization is an important pre-requisite to obtain reliable results from qPCR.; 2. HLA peptidomics studies on the human insulin-producing ECN90 cells exposed or not to IFN- identified peptides derived from β-cell-enriched proteins - data mining for identification of neoantigens in T1D is ongoing; 3. A global mapping of translation initiation in stressed human -cells points toward a widespread and novel translatome composed of ribosomal errors and lncRNA products that may impact -cell immunogenicity; 4. To study the role of the diabetes candidate gene TYK2 in human pancreatic -cell development and IFN responsiveness, TYK2 knockout (KO) iPSC lines were generated using the CRISPR-CAS9 approach.; 5. There is an ongoing search for novel compounds that may increase the -cell expression of PDL1, an inhibitory molecule that may induce protection against CD8+ T cells in T1D, with initial promising results.
WP4 groups all the work of managing and running INNODIA HARVEST. This is done in close collaboration with INNODIA. Next to overall project management, specific attention has been dedicated in 2021 to communication on the aspects related to the COVID-19 pandemic and increasing visibility of the project’s branding. Moreover, expansion (in budget, partners and projects), long term sustainability and dealing with Brexit were prioritized. We stepped up communication to partners and increased the use of external communication channels to promote our work.
The clinical network, which was established in INNODIA (grant 115797) has been transformed into a clinical trial network in INNODIA HARVEST (WP1), which focuses on intervention studies for Type 1 Diabetes, starting with 3 trials in people with newly diagnosed (ND) T1D and gearing up towards interventions in individuals at high risk for T1D. The network consists of 22 clinical centers spread over 13 countries in Europe. Three clinical trials have been initiated. Ver-A-T1D is an academic sponsored, randomized double-blind placebo-controlled parallel group multi-center trial in adults (18-45 years) with ND T1D investigating the effect of verapamil sustained release on preservation of beta-cell function. The study will run in 22 clinical sites, spread over 8 countries. 14 patient shave been randomized till now. A second study is the Iscalimab study, sponsored by Novartis. This is an investigator- and subject-blinded, randomized, placebo-controlled study where we want to evaluate the safety, tolerability and efficacy of CFZ533 (Iscalimab) in pediatric and young adults with NDT1D. The study is running in 3 INNODIA HARVEST clinical sites and till now 2 patients have been randomized. A third study which was initiated in INNODIA HARVEST, is the IMPACT trial, sponsored by Imcyse. This is a multi-centre, dose comparison, randomized, double-blind, placebo-controlled study in patients with T1D within maximum 9 weeks of diagnosis (defined as the day of first insulin injection) at screening and within a maximum of 12 weeks from diagnosis to randomization. Here, 40 patients have already been randomized in 17 INNODIA HARVEST clinical sites. Furthermore, new trial designs, evaluating combination therapies, have been developed, and a masterprotocol for speedy evaluation of combination therapies has been submitted to EMA.
In WP2 new biomarkers are being evaluated, with major focus on the role of the gut microbiome, and wearable continuous glucose monitoring devices. As such, the intestinal microbiota is evaluated in samples from participants in the natural history study, including autoantibody positive individuals and those with ND T1D (these samples were stored during the first years of the INNODIA project) and results are expected early in 2022. Collection of stool samples from individuals participating in INNODIA and INNODIA Harvest clinical trials is ongoing and will be analysed in batches, once samples from all timepoints for a group of individuals are available. Wearable technology to facilitate continuous glucose monitoring has been implemented in both the INNODIA autoantibody positive natural history study (dysglycemic and thus high risk individuals) and individuals participating in INNODIA and INNODIA HARVEST clinical trials. Data has been uploaded to Dexcom Clarity and integration in the INNODIA HARVEST eCRF and analysis is underway.
In WP3, the basic research arm in INNODIA HARVEST, several key methods were developed/validated during the first 18 months of research, and relevant discoveries were made. Some of the most relevant steps are described here: 1. The selection of the most adequate reference gene(s) for gene expression normalization is an important pre-requisite to obtain reliable results from qPCR.; 2. HLA peptidomics studies on the human insulin-producing ECN90 cells exposed or not to IFN- identified peptides derived from β-cell-enriched proteins - data mining for identification of neoantigens in T1D is ongoing; 3. A global mapping of translation initiation in stressed human -cells points toward a widespread and novel translatome composed of ribosomal errors and lncRNA products that may impact -cell immunogenicity; 4. To study the role of the diabetes candidate gene TYK2 in human pancreatic -cell development and IFN responsiveness, TYK2 knockout (KO) iPSC lines were generated using the CRISPR-CAS9 approach.; 5. There is an ongoing search for novel compounds that may increase the -cell expression of PDL1, an inhibitory molecule that may induce protection against CD8+ T cells in T1D, with initial promising results.
WP4 groups all the work of managing and running INNODIA HARVEST. This is done in close collaboration with INNODIA. Next to overall project management, specific attention has been dedicated in 2021 to communication on the aspects related to the COVID-19 pandemic and increasing visibility of the project’s branding. Moreover, expansion (in budget, partners and projects), long term sustainability and dealing with Brexit were prioritized. We stepped up communication to partners and increased the use of external communication channels to promote our work.
All activities have progressed well, although some deliverables and milestones encountered delays for which new delivery dates had to be proposed. This was mainly due to COVID which affected our work, but overall the network is growing and delivering. We are now ready for important next steps: more clinical trials, in more diverse participant profiles, more biomarker research and further branding of the project, in close collaboration with INNOIDA. This will include exploring of new collaboration opportunities outside of the consortium, seeking for strategic partnership for future expansion of the network with new partners, all in close harmony with our patient advisory committee (PAC), representing people living with T1D and their families.