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Autism Innovative Medicine Studies – 2 – Trials

Periodic Reporting for period 3 - AIMS-2-TRIALS (Autism Innovative Medicine Studies – 2 – Trials)

Reporting period: 2020-06-01 to 2021-05-31

Autism is a neurodevelopmental condition affecting ~1 in 58 people. There are no effective medical support options for autism core features and there is a critical need for more effective interventions for co-occurring conditions (epilepsy, anxiety). AIMS-2-TRIALS is an IMI JU2 funded public-private partnership that brings together experts in basic science, child development, psychiatry, neuroimaging, immune/metabolic functions and genetics to develop new ‘personalised medicine’ approaches. A key factor is the identification of stratification biomarkers - objective measures that enable us to identify clinically relevant biological subgroups within autism and predict each individual’s 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. World-wide unique set of linked multidisciplinary longitudinal research studies
We are expanding our world-wide unique, multidisciplinary longitudinal research platform of >1,500 individuals from infancy to adulthood - comprehensively characterised by their clinical, cognitive/ behavioural profiles, brain structure/function and genomics:
-Starting at the earliest timepoint, studying neonatal brain development and, now in P3, successfully following these individuals up during infancy
-Including the first European multi-center MRI study of preschoolers with autism, with >118 preschoolers now recruited
-Studying autism and related neurodevelopmental conditions in 4,500 South African children with increased environmental risk factors for social, emotional and cognitive difficulties, with >200 participants now recruited
-Comparing two rare monogenic forms of autism – Phelan McDermid Syndrome/NRXN1 deletion.
2. Progress in biomarker discovery/ validation
We have successfully completed a qualification advice procedure and received two letters of support from the EMA on an EEG face processing signal (N170 latency), with context of use as a baseline covariate to improve the efficiency of detecting intervention effects in autism trials. Significant differences between autistic and non-autistic individuals in N170 latency (particularly children) have been replicated by US ABC-CT, becoming the first autism candidate biomarker to be accepted by the US FDA to their biomarker qualification programme.
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. We have now achieved ~50% of our recruitment target for our trial of arbaclofen, targeting social functioning in autistic young people aged 5-17-years (NCT03682978). The arbaclofen trial incorporates EEG assessment and ‘wearable’ measures (e.g. smart watches) of physiology in everyday life, to ascertain whether intervention(s) may be more effective in particular autism subgroups and/ or whether physiological responses are a valid, objective measure of intervention effects.
4. Identifying and testing novel intervention targets
Building on results from P2, we we are currently performing proof-of-concept pharmacological experiments using MNK modulators to restore the synaptic phenotypes found in TSC2 mouse models, linking with TSC human studies. We have also identified a developmental sensory processing difference (in pre-pulse inhibition) across three genetic mouse models (Cntnap2, Nrxn1, and Shank3) and are working to identify the convergent mechanism and intervention possibilities (both target identification and developmental time window) underlying this generalizable phenotype, linking to human studies incorporating sensory processing measures in WP2 (Tasks 1, 2 and 3).
We continue to test the effectiveness of novel treatment targets (e.g. arbaclofen) across preclinical, proof of concept and trial settings to enhance translational work.
5. Creating a sustainable infrastructure for future clinical trials of autism
We have published meta-analyses to determine reasons for failure of previous clinical trials in autism (e.g. placebo effects, use of caregiver vs. clinician symptom ratings, heterogeneous samples) and delivered a white paper on innovative clinical trial designs to overcome these challenges. We have continued to consolidate our European clinical trials network to include 120 sites across 38 countries, with access to >28,000 newly diagnosed autistic individuals each year and trained to Good Clinical Practice standards. Demonstrating the capabilities and innovative potential of the AIMS-2-TRIALS Clinical Trials Network, this year we attracted additional investment (€1.7 million) from industry partner Roche to support project sustainability.
6. Establishing a scientific legacy
We have developed a secure, centralised database to include measures obtained from all AIMS-2-TRIALS studies to ensure efficient exploitation of data and establish a scientific legacy. We formulated a core set of data sharing principles that will support the release of project data to the wider community, with the highest regard for ethical standards. Utilising the rich AIMS-2-TRIALS dataset, well over 180 scientific papers have been accepted for publication, including in very high impact journals. We have also advanced our communication, outreach and education strategies - achieving >200,000 website views and 300,000 impressions on Twitter, as well as hosting several researchers- and industry-led conferences and the AIMS-2-TRIALS webinar series. We continue to develop sustainability models and strategies to facilitate cross-sector, international research collaborations and deliver high quality clinical trials training to the next generation of future leaders.
7. Impact for the autism community
We have enhanced research collaborations with autistic people and their families to ensure that AIMS-2-TRIALS outputs respond to priorities identified by the autism community and deliver real-world impact. Over the past year, there have been varied research engagement activities in the past year with a growing panel of 33 AIMS-2-TRIALS autism representatives (‘A-Reps’) across Europe. This work is informing EU policy and clinical/ regulatory practice to promote the best outcomes for autistic people, including promoting changes in neurodevelopmental diagnostic pathways in France, and consideration by the Social Affairs Committee of the Parliamentary Assembly of the Council of Europe (ACCESS-EU) and UK Department of Health and Social Care (COVID-19 policy).
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. We are the first neuropsychiatric consortium in Europe to receive biomarker qualification advice from the EMA/FDA and launch clinical trials in autism incorporating biomarkers (via our large-scale clinical trial network). The release of the AIMS-2-TRIALS database will enable researchers worldwide to conduct experiments with higher likelihood of gaining regulatory approval in future. We continue to enhance 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