Periodic Reporting for period 7 - AIMS-2-TRIALS (Autism Innovative Medicine Studies – 2 – Trials)
Reporting period: 2024-06-01 to 2025-05-31
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 people (meaning there is likely no “one-size-fits-all” support strategy); 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 ~4,000 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 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 N=346 preschoolers with autism (Wave 1/2 data collection completed)
-Studying autism and related neurodevelopmental conditions in South African children with increased environmental likelihood factors for social, emotional and cognitive difficulties, with almost 2,000 participants recruited
-Comparing two rare monogenic forms of autism – Phelan McDermid Syndrome/NRXN1 deletion
-Completed reassessing LEAP participants 6-30-years (N=365) at a third timepoint, approximately 7-years on from their first assessment
2. Progress in biomarker discovery/ validation
We have made further progress with analysis of our candidate EEG marker of brain response to faces that received letters of support from EMA (N170; https://bit.ly/3yLidvO(opens in new window); https://bit.ly/4dsv5Wz - also replicated by US ABC-CT to become the first autism candidate biomarker to be accepted by the US FDA to their biomarker qualification programme) to provide further clarity regarding context of use and application to a clinical trial context (https://osf.io/tbgz9(opens in new window); https://osf.io/9v7u3(opens in new window)) and are extending evidence regarding additional novel markers (i.e. sensory processing indices) to respond to priorities of the autism community.
3. Launching innovative clinical trials, enhanced by biomarkers
AIMS-2-TRIALS delivered the first academic, charity, industrial joint autism trial to incorporate biomarkers and wearables (https://doi.org/10.3389/fpsyt.2021.701729(opens in new window)) also at significantly lower cost than industry led trials (RCT1 cost ~€2.5million vs. €100-150million for an average EFPIA Phase 2b/Phase 3 study), recruiting N=123 young people in just 1-year, with very low drop out (N=9 in arbaclofen arm). A new trial protocol (RCT2) will commence in the next period.
4. Identifying and testing novel intervention targets
We have developed new objective measures of treatment impact on brain that address key concerns of autistic people (https://doi.org/10.1111/jcpp.13940(opens in new window)) and have attracted investment from industry to employ these in an independent study of COMP360 psilocybin in autistic adults. We now consistently demonstrate different responsivity of neurotransmitter systems consistently across drug targets and modalities in autism (e.g. https://doi.org/10.1126/scitranslmed.abg7859(opens in new window); https://doi.org/10.1038/s41398-023-02619-8(opens in new window)). This may explain increased side effects and/or reduced effectiveness of medications reported by autistic people and emphasises that drug development needs to consider neurodivergence. This links to our preclinical studies, where we identified developmental sensory processing differences in genetic mouse models of autism, and found that arbaclofen alleviated sensory sensitisation of some responses in the Nrxn1α knockout mouse model.
5. Creating a sustainable infrastructure for future clinical trials of autism
We 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 white papers on innovative clinical trial designs to overcome these challenges. We consolidated 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. From this, we attracted additional investment (€1.7 million) from Roche and have established a new European cohort/registry of re-contactable, whole-genome sequenced participants with a diagnosis of autism, or a rare genetic condition associated with autism in our European Autism GEnomics Registry project, which already includes >1,150 individuals (https://doi.org/10.1136/bmjopen-2023-080746(opens in new window)). This has led to us being selected (and provided with additional resources) by industry partners to deliver extra trials in autism.
6. Establishing a scientific legacy
We have developed a secure, centralised database to include measures obtained from all AIMS-2-TRIALS studies (OWEY) that will be pushed to ELIXIR Luxembourg in Summer 2025 to ensure efficient exploitation of data and establish a scientific legacy. We formulated a core set of data sharing principles with A-Reps that will support the release of project data to the wider community, with the highest regard for ethical standards. Our outputs have made us one of the most productive and highest impact IHI initiatives (https://www.ihi.europa.eu/sites/default/files/uploads/Documents/About/Reports/IHI%202024%20Bibliometrics%20report_Full_04.11.24%20.pdf(opens in new window)).
7. Impact for the autism community
We work 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 >52 varied research engagement activities in the past year with an advisory group of 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, with our work most recently presented to European Parliament 23rd April 2025 (https://www.youtube.com/watch?v=5k0UAzaYyQQ(opens in new window)).
We are expanding our world-wide unique, multidisciplinary longitudinal research platform of ~4,000 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 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 N=346 preschoolers with autism (Wave 1/2 data collection completed)
-Studying autism and related neurodevelopmental conditions in South African children with increased environmental likelihood factors for social, emotional and cognitive difficulties, with almost 2,000 participants recruited
-Comparing two rare monogenic forms of autism – Phelan McDermid Syndrome/NRXN1 deletion
-Completed reassessing LEAP participants 6-30-years (N=365) at a third timepoint, approximately 7-years on from their first assessment
2. Progress in biomarker discovery/ validation
We have made further progress with analysis of our candidate EEG marker of brain response to faces that received letters of support from EMA (N170; https://bit.ly/3yLidvO(opens in new window); https://bit.ly/4dsv5Wz - also replicated by US ABC-CT to become the first autism candidate biomarker to be accepted by the US FDA to their biomarker qualification programme) to provide further clarity regarding context of use and application to a clinical trial context (https://osf.io/tbgz9(opens in new window); https://osf.io/9v7u3(opens in new window)) and are extending evidence regarding additional novel markers (i.e. sensory processing indices) to respond to priorities of the autism community.
3. Launching innovative clinical trials, enhanced by biomarkers
AIMS-2-TRIALS delivered the first academic, charity, industrial joint autism trial to incorporate biomarkers and wearables (https://doi.org/10.3389/fpsyt.2021.701729(opens in new window)) also at significantly lower cost than industry led trials (RCT1 cost ~€2.5million vs. €100-150million for an average EFPIA Phase 2b/Phase 3 study), recruiting N=123 young people in just 1-year, with very low drop out (N=9 in arbaclofen arm). A new trial protocol (RCT2) will commence in the next period.
4. Identifying and testing novel intervention targets
We have developed new objective measures of treatment impact on brain that address key concerns of autistic people (https://doi.org/10.1111/jcpp.13940(opens in new window)) and have attracted investment from industry to employ these in an independent study of COMP360 psilocybin in autistic adults. We now consistently demonstrate different responsivity of neurotransmitter systems consistently across drug targets and modalities in autism (e.g. https://doi.org/10.1126/scitranslmed.abg7859(opens in new window); https://doi.org/10.1038/s41398-023-02619-8(opens in new window)). This may explain increased side effects and/or reduced effectiveness of medications reported by autistic people and emphasises that drug development needs to consider neurodivergence. This links to our preclinical studies, where we identified developmental sensory processing differences in genetic mouse models of autism, and found that arbaclofen alleviated sensory sensitisation of some responses in the Nrxn1α knockout mouse model.
5. Creating a sustainable infrastructure for future clinical trials of autism
We 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 white papers on innovative clinical trial designs to overcome these challenges. We consolidated 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. From this, we attracted additional investment (€1.7 million) from Roche and have established a new European cohort/registry of re-contactable, whole-genome sequenced participants with a diagnosis of autism, or a rare genetic condition associated with autism in our European Autism GEnomics Registry project, which already includes >1,150 individuals (https://doi.org/10.1136/bmjopen-2023-080746(opens in new window)). This has led to us being selected (and provided with additional resources) by industry partners to deliver extra trials in autism.
6. Establishing a scientific legacy
We have developed a secure, centralised database to include measures obtained from all AIMS-2-TRIALS studies (OWEY) that will be pushed to ELIXIR Luxembourg in Summer 2025 to ensure efficient exploitation of data and establish a scientific legacy. We formulated a core set of data sharing principles with A-Reps that will support the release of project data to the wider community, with the highest regard for ethical standards. Our outputs have made us one of the most productive and highest impact IHI initiatives (https://www.ihi.europa.eu/sites/default/files/uploads/Documents/About/Reports/IHI%202024%20Bibliometrics%20report_Full_04.11.24%20.pdf(opens in new window)).
7. Impact for the autism community
We work 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 >52 varied research engagement activities in the past year with an advisory group of 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, with our work most recently presented to European Parliament 23rd April 2025 (https://www.youtube.com/watch?v=5k0UAzaYyQQ(opens in new window)).
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 validation. We are the first neuropsychiatric consortium in Europe to receive biomarker qualification advice from the EMA/FDA and deliver clinical trials in autism incorporating biomarkers (via our large-scale clinical trial network). We continue to engage with autistic people and their families to ensure that AIMS-2-TRIALS outputs respond to community priorities (e.g. sensory processing, positive wellbeing) and delivers real world impact.