Periodic Reporting for period 2 - INNODIA HARVEST (Translational approaches to disease modifying therapy of type 1 diabetes - HARVESTing the fruits of INNODIA)
Reporting period: 2021-11-01 to 2023-04-30
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, which caused a delay in the first period of the project. We have therefore been granted a 1-year no-cost-extension, and are now fully back to speed! Several key deliverables and milestones have already 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 is running in 22 clinical sites, spread over 8 countries, of which 21 are open for recruitment. 79 patients shave been randomized till now and 29 have already completed the 12 month treatment period. A second study is the Iscalimab study, sponsored by Novartis. This is an investigator- and subject-blinded, randomized, placebo-controlled study where we wanted to evaluate the safety, tolerability and efficacy of CFZ533 (Iscalimab) in pediatric and young adults with ND T1D. The study was running in 5 INNODIA HARVEST clinical sites and 9 patients have been randomized. The trial was terminated early by Novartis in December, 2022 for strategic reasons, and not based on safety issues in the trial, in the CFZ533 development program, or new information on the pathway in T1D. 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, enrolment of the study was completed in February 2023 where a total of 213 patients were screened among which 110 participants were randomized. 62 of the patients were randomized in 12 INNODIA HARVEST clinical sites. Furthermore, new trial designs, evaluating combination therapies, have been developed, and a masterprotocol for speedy evaluation of combination therapies has received qualification advice from EMA. Moreover, the Vera-Plus program (testing different combinations of immune modulatory agents with verapamil, building on the Ver-A-T1D trial, is being designed. This will be a legacy of INNODIA HARVEST, as this will be running with additional external financial support.
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 has been 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 first results are presented in international conferences and are being published. 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. Biomarkers from INNODIA WP2 are being actively tested in clinical trial samples from the IMPACT clinical trials and similar efforts will be started with samples from MELD-ATG and Ver-A-T1D in the near future.
In WP3, the basic research arm in INNODIA HARVEST, several key methods were developed/validated during the first period of the project, and many collaborations have led to new discoveries towards a better understanding of mechanisms underlying the disease development. Some of the most relevant steps are the following: 1. We are evaluating novel beta-cell neoantigens; 2. Beta cell response could initiate autoimmunity via the release of mitochondrial DNA and activation of cytosolic sensors; 3. We are assessing the molecular mechanisms associated with transcriptomic traits of the functional recovery following stress conditions; 4. Long-range chromosomal interactions at regulatory elements are being identified in human beta cell line; 5. TYK2 inhibition (TYK2i) rescues the continued differentiation; 6. Validation of screening platform for beta-cell immune protection using our previously developed human beta cells and T cells transduced with autoimmune T-cell receptors recognizing beta-cell antigens; 6. The development of new analytical tools based on T cell infiltration will allow us to correlate islet infiltration with demographic and clinical variables; 7. Further progress on new tools for imaging of inflammatory process in T1D are ongoing.
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 specific communication efforts, to increase visibility of the project’s branding. In regard to intense sustainability efforts, we are happy to announce that a non-profit organization INNODIA iVZW was created on July 28, 2022, which is a crucial step towards the legacy of INNODIA and INNODIA HARVEST.
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 is running in 22 clinical sites, spread over 8 countries, of which 21 are open for recruitment. 79 patients shave been randomized till now and 29 have already completed the 12 month treatment period. A second study is the Iscalimab study, sponsored by Novartis. This is an investigator- and subject-blinded, randomized, placebo-controlled study where we wanted to evaluate the safety, tolerability and efficacy of CFZ533 (Iscalimab) in pediatric and young adults with ND T1D. The study was running in 5 INNODIA HARVEST clinical sites and 9 patients have been randomized. The trial was terminated early by Novartis in December, 2022 for strategic reasons, and not based on safety issues in the trial, in the CFZ533 development program, or new information on the pathway in T1D. 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, enrolment of the study was completed in February 2023 where a total of 213 patients were screened among which 110 participants were randomized. 62 of the patients were randomized in 12 INNODIA HARVEST clinical sites. Furthermore, new trial designs, evaluating combination therapies, have been developed, and a masterprotocol for speedy evaluation of combination therapies has received qualification advice from EMA. Moreover, the Vera-Plus program (testing different combinations of immune modulatory agents with verapamil, building on the Ver-A-T1D trial, is being designed. This will be a legacy of INNODIA HARVEST, as this will be running with additional external financial support.
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 has been 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 first results are presented in international conferences and are being published. 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. Biomarkers from INNODIA WP2 are being actively tested in clinical trial samples from the IMPACT clinical trials and similar efforts will be started with samples from MELD-ATG and Ver-A-T1D in the near future.
In WP3, the basic research arm in INNODIA HARVEST, several key methods were developed/validated during the first period of the project, and many collaborations have led to new discoveries towards a better understanding of mechanisms underlying the disease development. Some of the most relevant steps are the following: 1. We are evaluating novel beta-cell neoantigens; 2. Beta cell response could initiate autoimmunity via the release of mitochondrial DNA and activation of cytosolic sensors; 3. We are assessing the molecular mechanisms associated with transcriptomic traits of the functional recovery following stress conditions; 4. Long-range chromosomal interactions at regulatory elements are being identified in human beta cell line; 5. TYK2 inhibition (TYK2i) rescues the continued differentiation; 6. Validation of screening platform for beta-cell immune protection using our previously developed human beta cells and T cells transduced with autoimmune T-cell receptors recognizing beta-cell antigens; 6. The development of new analytical tools based on T cell infiltration will allow us to correlate islet infiltration with demographic and clinical variables; 7. Further progress on new tools for imaging of inflammatory process in T1D are ongoing.
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 specific communication efforts, to increase visibility of the project’s branding. In regard to intense sustainability efforts, we are happy to announce that a non-profit organization INNODIA iVZW was created on July 28, 2022, which is a crucial step towards the legacy of INNODIA and INNODIA HARVEST.
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 during the last year the project is fully back on speed. Clinical trials are running at full speed and analyses on the way. A major achievement was the creation of a non-profit organisation INNODIA iVZW, which opens the way to important next steps: more clinical trials, in more diverse participant profiles, more biomarker research and further expansion of INNODIA outside of the INNODIA and INNODIA HARVEST, towards till now unexploited areas in Europe. This will be done all in close harmony with our patient advisory committee (PAC), representing people living with T1D and their families.