Periodic Reporting for period 3 - ICOD (Improving COgnition in Down syndrome)
Período documentado: 2023-08-01 hasta 2025-01-31
The general ambition of the ICOD project is to develop the first pharmacological therapy of cognitive impairments in Down syndrome (DS) and make it available to patients worldwide.
The ICOD project funded by the European Union (EU) (Grant Agreement ID 899986) will fill that gap by providing a demonstration of feasibility of a new therapy for improving cognitive impairments in subjects with DS. We performed first-in-humans safety and tolerability studies in healthy subjects and in subjects with DS and we plan to initiate an efficacy multicentre clinical trial in subjects with DS with a new molecular entity (AEF0217) in end of Q3/beginning of Q4 2025. AEF0217 has been shown to reverse cognitive impairments particularly related with working memory and cognitive flexibility in surrogate murine models of DS.
AEF0217 is the first pharmacological treatment specifically designed to address the core cognitive impairments of individuals with DS: working memory and cognitive flexibility, which should significantly increase their autonomy and quality of life.
The specific objectives of the ICOD project are:
1) Complete first in human clinical trials (Phase I) with AEF0217 in healthy volunteers and Down syndrome subjects to attest its safety and tolerability
2) Get AEF0217 ready to enter Phase II.
3) Complete an international multicentre Phase II clinical trial to obtain the first proof of efficacy of AEF0217 on cognitive deficits in Down syndrome. (not applicable for the current reporting period)
4) Raise awareness on pharmacological treatments for cognitive disorders.
The ICOD project funded by the European Union (EU) (Grant Agreement ID 899986) will fill that gap by providing a demonstration of feasibility of a new therapy for improving cognitive impairments in subjects with DS. We performed first-in-humans safety and tolerability studies in healthy subjects and in subjects with DS and we plan to initiate an efficacy multicentre clinical trial in subjects with DS with a new molecular entity (AEF0217) in end of Q3/beginning of Q4 2025. AEF0217 has been shown to reverse cognitive impairments particularly related with working memory and cognitive flexibility in surrogate murine models of DS.
AEF0217 is the first pharmacological treatment specifically designed to address the core cognitive impairments of individuals with DS: working memory and cognitive flexibility, which should significantly increase their autonomy and quality of life.
The specific objectives of the ICOD project are:
1) Complete first in human clinical trials (Phase I) with AEF0217 in healthy volunteers and Down syndrome subjects to attest its safety and tolerability
2) Get AEF0217 ready to enter Phase II.
3) Complete an international multicentre Phase II clinical trial to obtain the first proof of efficacy of AEF0217 on cognitive deficits in Down syndrome. (not applicable for the current reporting period)
4) Raise awareness on pharmacological treatments for cognitive disorders.
The main scientific and technical project achievements from the beginning of the project to the end of the third project period consist in:
- Completion of the complementary ADMET characterization of AEF0217 in order to ready the drug candidate for a Phase 2 study. This package includes:
• Complementary metabolism studies including CYP isoenzymes & Drug Transporters phenotyping interactions
• Completion of the full genotoxicity package showing that AEF0217 is not genotoxic nor mutagenic by completion of an in vivo genotoxicity study
• Completion of the toxicological package including the maximum period required by the ICH guidelines (6 months in rat and 9 months in dog)
- Improvement of the AEF0217 oral formulation to reach the specifications of a Phase 2 formulation as requested by the ICH guidelines
- Demonstration of the favourable safety, tolerability and pharmacokinetics profiles of AEF0217 in adult healthy volunteers by completing a Phase 1 program including:
- A Single Ascending Doses study (SAD) and a Multiple Ascending Doses (MAD) study
- A Single Dose crossover food effect study assessing the potential effect of food on the PK of AEF0217 administered in fed or fasted conditions to provide adequate recommendations for the AEF0217 administration
- Completion of a Phase 1/2 in Down syndrome people to analyse the safety and the pharmacokinetics of AEF0217 in people with Down syndrome. Potential therapeutic effects of AEF0217 were measured by two assessment tools, the Vineland Adaptive Behavior Scale (VABS) and the NIH-Toolbox Cognitive Battery for intellectual disabilities. Initially intended to be monocentric (IMIM, Barcelona), the study has been transformed into a multicentric study by adding two additional centres in Spain.
- Completion of a feasibility study (NIUS study) with the tools that will be used for cognitive assessments in Phase 2 studies and the initiation of the translation of these tools in different European languages.
- Development of tools regarding ethical aspects of clinical studies: video to inform people with Down syndrome why and how to participate in clinical trials and PICTEA project to develop a tool to assess the adverse effects of drugs in people with Down syndrome.
A multicentric Phase 2 study is planned to begin in Q3/Q4 2025.
- Completion of the complementary ADMET characterization of AEF0217 in order to ready the drug candidate for a Phase 2 study. This package includes:
• Complementary metabolism studies including CYP isoenzymes & Drug Transporters phenotyping interactions
• Completion of the full genotoxicity package showing that AEF0217 is not genotoxic nor mutagenic by completion of an in vivo genotoxicity study
• Completion of the toxicological package including the maximum period required by the ICH guidelines (6 months in rat and 9 months in dog)
- Improvement of the AEF0217 oral formulation to reach the specifications of a Phase 2 formulation as requested by the ICH guidelines
- Demonstration of the favourable safety, tolerability and pharmacokinetics profiles of AEF0217 in adult healthy volunteers by completing a Phase 1 program including:
- A Single Ascending Doses study (SAD) and a Multiple Ascending Doses (MAD) study
- A Single Dose crossover food effect study assessing the potential effect of food on the PK of AEF0217 administered in fed or fasted conditions to provide adequate recommendations for the AEF0217 administration
- Completion of a Phase 1/2 in Down syndrome people to analyse the safety and the pharmacokinetics of AEF0217 in people with Down syndrome. Potential therapeutic effects of AEF0217 were measured by two assessment tools, the Vineland Adaptive Behavior Scale (VABS) and the NIH-Toolbox Cognitive Battery for intellectual disabilities. Initially intended to be monocentric (IMIM, Barcelona), the study has been transformed into a multicentric study by adding two additional centres in Spain.
- Completion of a feasibility study (NIUS study) with the tools that will be used for cognitive assessments in Phase 2 studies and the initiation of the translation of these tools in different European languages.
- Development of tools regarding ethical aspects of clinical studies: video to inform people with Down syndrome why and how to participate in clinical trials and PICTEA project to develop a tool to assess the adverse effects of drugs in people with Down syndrome.
A multicentric Phase 2 study is planned to begin in Q3/Q4 2025.
The ICOD project aims to develop a pharmacological therapy of cognitive deficits in Down syndrome which is lacking today. A pharmacotherapy in this area will change clinical practice providing practitioner with a long-awaited therapeutic tool that will improve considerably the healthcare paradigm for treating cognitive deficits in individuals with Down syndrome.
The intellectual disability in Down syndrome and its social dependence, with the associated high health care costs, derive from a profound impairment in working memory and cognitive flexibility. This deficit has major consequences in the performance of simple cognitive tasks. Based on the preclinical proof of concept of AEF0217, it will be reasonable to expect that a patient, after several weeks or months of treatment with AEF0217 will improve enough cognitive flexibility and adaptive behaviours to significantly improve his/her daily skills, capacity of communication and social relationships and consequently his/her autonomy with a significant improvement in quality of life and reduction in healthcare costs.
Another significant advantage of AEF0217 is the excellent safety and tolerability which has been confirmed following the Phase 1 clinical program in healthy volunteers and in subjects with DS. This will allow a ready acceptance by families of individuals with DS facilitating development and adherence to the treatment. Thus, families are extremely protective of children with DS and consequently highly concerned by the adverse effects of new potential treatments, which can become an unsurmountable barrier to the adoption of a new treatment.
In conclusion, AEF0217 meets the needs of subjects with Down syndrome, their families and society.
The intellectual disability in Down syndrome and its social dependence, with the associated high health care costs, derive from a profound impairment in working memory and cognitive flexibility. This deficit has major consequences in the performance of simple cognitive tasks. Based on the preclinical proof of concept of AEF0217, it will be reasonable to expect that a patient, after several weeks or months of treatment with AEF0217 will improve enough cognitive flexibility and adaptive behaviours to significantly improve his/her daily skills, capacity of communication and social relationships and consequently his/her autonomy with a significant improvement in quality of life and reduction in healthcare costs.
Another significant advantage of AEF0217 is the excellent safety and tolerability which has been confirmed following the Phase 1 clinical program in healthy volunteers and in subjects with DS. This will allow a ready acceptance by families of individuals with DS facilitating development and adherence to the treatment. Thus, families are extremely protective of children with DS and consequently highly concerned by the adverse effects of new potential treatments, which can become an unsurmountable barrier to the adoption of a new treatment.
In conclusion, AEF0217 meets the needs of subjects with Down syndrome, their families and society.