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Autism Innovative Medicine Studies – 2 – Trials

Periodic Reporting for period 4 - AIMS-2-TRIALS (Autism Innovative Medicine Studies – 2 – Trials)

Reporting period: 2021-06-01 to 2022-05-31

Autism is a neurodevelopmental condition affecting ~1 in 58 people. The lack of effective interventions and supports currently available to autistic people who would like them results from a combination of factors, including substantial variability (in lived experiences and biology) between autistic individuals (meaning there is likely no “one-size-fits-all” intervention approach); and a poor understanding of underpinning mechanisms for both core (social-communication difficulties, restricted and repetitive behaviours, sensory processing difficulties) and commonly co-occurring (e.g. anxiety, epilepsy) features. Autism Innovative Medicines Studies-2-Trials (AIMS-2-TRIALS) is a public–private partnership that brings together academia with industry, charities, regulators, and the autism community, to improve outcomes for autistic people by matching mechanism-based therapies to individual needs and biological profiles.
1. World-wide unique set of linked multidisciplinary longitudinal research studies
We are expanding our world-wide unique, multidisciplinary longitudinal research platform of >2,000 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, successfully following these individuals up during infancy to understand the developmental mechanisms that shape how children learn about the world to better identify those who might need additional support to reach their full potential
-Including the first European multi-center MRI study of preschoolers with autism, with >211 preschoolers now recruited
-Studying autism and related neurodevelopmental conditions in 4,500 South African children with increased environmental likelihood factors for social, emotional and cognitive difficulties, with >449 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 and to be supported by the FDA with limited context of use as a stratification marker (in agreement with EMA advice).
3. Launching innovative clinical trials, enhanced by biomarkers
AIMS-2-TRIALS is the first neuropsychiatric consortium in Europe to incorporate candidate biomarkers and 'wearable' measures in clinical trials of autism. We have now achieved 85% of our recruitment target for our trial of arbaclofen, targeting social functioning in autistic young people aged 5-17-years (NCT03682978). We have also made an unprecedented investment to finalise contractual agreements and build a protocol for a second clinical trial that would make us one of the first academic medical trials worldwide to test a novel proprietary compound provided by industry and chosen by the AIMS-2-TRIALS Trial Advisory Board (Janssen JNJ-42165279)
4. Identifying and testing novel intervention targets
We continue to build translational links between our clinical and cellular/ animal research studies. For instance, we have identified a developmental sensory processing difference (in startle responses to single auditory cues) in genetic mouse models – including two implicated in rare monogenic forms of autism under investigation in AIMS-2-TRIALS (Nrxn1, and Shank3). Notably, in Nrxn1 knockout mice, we have demonstrated elevated brain excitation during sensory visual gating, as compared to wildtype littermates, which we now plan to target with arbaclofen. This directly aligns with results from human studies, where we have provided the first evidence that differences in visual sensory processing in autistic, as compared to non-autistic, adults can be ‘shifted’ using arbaclofen.
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, 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, over 220 scientific papers have been accepted for publication, including in very high impact journals. 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. There have been varied research engagement activities in the past year with an advisory group of 30 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). We continue to work to enhance research collaborations with autistic people and their families to ensure that AIMS-2-TRIALS outputs respond to community priorities and delivers real world impact.
Logo of the project AIMS-2-TRIALS