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Autism Innovative Medicine Studies – 2 – Trials

Periodic Reporting for period 2 - AIMS-2-TRIALS (Autism Innovative Medicine Studies – 2 – Trials)

Reporting period: 2019-06-01 to 2020-05-31

Autism is a neurodevelopmental condition affecting ~1 in 58 individuals in Europe. Currently, there are no effective medical treatments for autism core features (social-communication difficulties and restricted/repetitive behaviours) and there is a critical need for more effective treatments for frequently comorbid medical (e.g. epilepsy)/mental health (e.g. anxiety, depression) conditions.
AIMS-2-TRIALS consortium brings together experts in basic science, child development, psychiatry, neuroimaging, immune/metabolic functions and genetics to develop new ‘personalised medicine’ approaches. A key factor in these approaches is the identification of stratification biomarkers - objective measures that enable us to identify clinically relevant biological subgroups within autism and predict each individual’s likely therapeutic needs. The consortium also aims to: develop objective outcome measures to assess the effectiveness of treatments that are acceptable to autistic people; and create a sustainable European clinical trials network to test new therapies.
1.Creating a world-wide unique set of multidisciplinary longitudinal research studies
The AIMS-2-TRIALS consortium has established a world-wide unique, multidisciplinary longitudinal research platform, comprising over 1500 individuals from infancy to adulthood. This dataset significantly extends upon existing cohort studies set up in EU-AIMS (STAARS study of early development/ Longitudinal European Autism Project; LEAP), as we now:
-Start at the earliest timepoint, studying fetal/ neonatal brain development in those with elevated familial likelihood of autism
-Include the first European multicentre MRI study of preschoolers with autism
-Study neurodevelopmental conditions cross-culturally in 4500 South African children with increased environmental risk factors for social, emotional and cognitive difficulties
-Compare two rare monogenic forms of autism – Phelan McDermid Syndrome and NRXN1 deletion
2.Biomarker discovery and validation
Group has made significant progress in the identification and validation of stratification biomarkers for autism. We showed that infants at elevated familial likelihood for autism exhibit differences in early brain development and response to motion/ face stimuli. Further, >36 LEAP analysis projects have been launched or completed (including in cognition, neuroimaging and eye-tracking), from which we have already discovered 11 candidate stratification or prognostic biomarkers.
Most notably, we have achieved significant progress in obtaining regulatory approval for a stratification biomarker based on EEG measurement of brain response to faces. The EEG signal to faces marker has been independently replicated in a US cohort, becoming the first biomarker in autism to be accepted to the Food and Drug Administration biomarker development programme. We also engaged with the European Medicines Agency (EMA) to obtain qualification advice on this biomarker and received supportive feedback. We have now secured independent Horizon 2020 funding to ascertain whether stratification markers identified in AIMS-2-TRIALS are autism-specific or shared with other neurodevelopmental conditions.
3.Launching innovative clinical trials, enhanced by biomarkers
AIMS-2-TRIALS is the first neuropsychiatric consortium in Europe to incorporate candidate biomarkers in clinical trials of autism. This year, we launched a randomised-controlled trial of arbaclofen, targeting social functioning and incorporating EEG assessment and wearable measures (e.g. smart watches) of physiology in everyday life. This will help us to ascertain whether treatment may be more effective in particular autism subgroups/ whether physiological responses are a valid measure of treatment effects. We will extend this work in the next clinical trial in Part 2, taking forward one of eight candidate compounds identified by our new Trial Advisory Board.
We also demonstrated the value of our Clinical Trials Network, which attracted industry partners to select our clinical network sites for their multicentre clinical trials (phase 3 trial of balovaptan for adults, phase 1 trial of balovaptan/ phase 3 trial of bumetanide for autistic young people).
4.Identifying/ testing novel treatment targets
We have overseen the translation of preclinical work in cellular/rodent models to advances in human studies. We discovered signalling dysfunction in the ventral tegmental area (associated with social/ reward processing) of Nlgn3 mutant mice, providing a mechanism-based rationale for testing the effectiveness of arbaclofen for modifying brain responses in mouse models. This work links to our arbaclofen trial and findings from arbaclofen/ tianeptine proof of concept studies, showing: 1) differences in visual sensory processing in autistic adults can be ‘shifted’ with arbaclofen; 2) differences in brain response during executive function can be shifted with tianeptine.
5.Creating a sustainable infrastructure for future clinical trials of autism
We conducted meta-analyses to determine reasons for failure of previous clinical trials in autism (e.g. placebo effects, heterogeneous samples) and delivered a white paper on innovative trial designs to overcome these challenges. We also expanded our European trial network to 120 sites across 38 countries, with access to >28,000 newly diagnosed autistic individuals each year and trained to Good Clinical Practice standards.
6.Establishing a scientific legacy
We developed a centralised database of AIMS-2-TRIALS study measures to ensure efficient data exploitation by the wider scientific community following database release in early 2021; and led the development of one of the richest phenotypic and genomic autism databases worldwide (‘Autism Sharing Initiative’) – chosen as a 2019 Global Alliance for Genomics and Health driver project.
Our network has published well over 100 scientific papers, including in very high impact journals. Additionally, the testing of novel compounds that inhibit a group of proteins (‘MAP kinase-interacting kinases’) resulted in the filing of a patent (US 2015/0038506 A1).
We also launched a new initiative linking to North America that will underpin a platform trial approach for designing proof-of-concept clinical studies of autism (via the Autism Spectrum Proof Of Concept Initiative) that can be conducted through a public–private partnership, with the aim of finding effective treatments in the most expeditious manner.
Unparalleled scale and depth of phenotyping in AIMS-2-TRIALS linked clinical cohorts and findings from our preclinical/ proof of concept studies have led to significant advances in biomarker discovery and validation. We are the first neuropsychiatric consortium in Europe to receive biomarker qualification advice from the EMA and launch clinical trials in autism incorporating biomarkers (via our large-scale clinical trial network) – supporting industry partners to reduce the time/ cost of trials by minimising placebo effects and facilitating regulatory alignment between the EU/ US. The release of the AIMS-2-TRIALS database in early 2021 will enable researchers worldwide to conduct experiments with higher likelihood of gaining regulatory approval in future. Furthermore, we have enhanced collaborations with a dedicated panel of autism representatives to ensure AIMS-2-TRIALS responds to the priorities of the autism community and delivers real-world impact
Logo of the project AIMS-2-TRIALS