Periodic Reporting for period 2 - ICOD (Improving COgnition in Down syndrome)
Periodo di rendicontazione: 2022-02-01 al 2023-07-31
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 European Union (EU) funded the ICOD project to fill that gap by providing a demonstration of feasibility of a new therapy for cognitive impairment in DS. We will perform first-in-humans safety and tolerability studies in healthy subjects and an efficacy multicentre clinical trial in subjects with DS with a new molecular entity (AEF0217), which reverses cognitive impairments 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, 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 European Union (EU) funded the ICOD project to fill that gap by providing a demonstration of feasibility of a new therapy for cognitive impairment in DS. We will perform first-in-humans safety and tolerability studies in healthy subjects and an efficacy multicentre clinical trial in subjects with DS with a new molecular entity (AEF0217), which reverses cognitive impairments 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, 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 first and second project periods focused on finishing first in human clinical trials (Phase I) with AEF0217 in healthy volunteers and initiating the first clinical trial with AEF0217 in Down syndrome subjects to confirm its safety and tolerability.
In summary, at the end of the second period, the main scientific and technical achievements have resulted 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)
- Start of the improvement of the AEF0217 oral formulation to reach the specifications of a Phase 2 formulation as requested by the ICH guidelines
- Demonstration of the favorable 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
- Initiation of a Phase 1/2 in Down syndrome people to analyze the safety and the pharmacokinetics of AEF0217 in people with Down syndrome. Initially intended to be monocentric (IMIM, Barcelona), the study has been transformed into a multicentric study by adding two additional centers in Spain to obtain more robust results which will pave the way for a multicentric Phase 2 study planned to begin in 2024.
- 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.
In summary, at the end of the second period, the main scientific and technical achievements have resulted 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)
- Start of the improvement of the AEF0217 oral formulation to reach the specifications of a Phase 2 formulation as requested by the ICH guidelines
- Demonstration of the favorable 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
- Initiation of a Phase 1/2 in Down syndrome people to analyze the safety and the pharmacokinetics of AEF0217 in people with Down syndrome. Initially intended to be monocentric (IMIM, Barcelona), the study has been transformed into a multicentric study by adding two additional centers in Spain to obtain more robust results which will pave the way for a multicentric Phase 2 study planned to begin in 2024.
- 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.
The ICOD project aims to develop a pharmacological therapy of cognitive deficit 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 learning disability in Down syndrome and its social dependence, with the associated high health care costs, derive from a profound impairment in working memory. This deficit has the major consequence to make learning even of simple tasks quite laborious. 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 working memory to significantly gain in learning skills and consequently in autonomy with a significant improvement in quality of life and reduction in healthcare costs.
Another significant advantage of AEF0217 is the absence of behavioural side effects and toxicity which has been confirmed following the Phase 1 clinical program in healthy volunteers. This will allow a ready acceptance by families of individuals with Down syndrome facilitating development and adherence to the treatment. Thus, families are extremely protective of children with Down syndrome and consequently highly concerned by the side effects of new potential treatments, which can become an unsurmountable barrier to the adoption of a new treatment.
In conclusion, AEF0217 respond to needs of subjects with Down syndrome, their families and society.
The learning disability in Down syndrome and its social dependence, with the associated high health care costs, derive from a profound impairment in working memory. This deficit has the major consequence to make learning even of simple tasks quite laborious. 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 working memory to significantly gain in learning skills and consequently in autonomy with a significant improvement in quality of life and reduction in healthcare costs.
Another significant advantage of AEF0217 is the absence of behavioural side effects and toxicity which has been confirmed following the Phase 1 clinical program in healthy volunteers. This will allow a ready acceptance by families of individuals with Down syndrome facilitating development and adherence to the treatment. Thus, families are extremely protective of children with Down syndrome and consequently highly concerned by the side effects of new potential treatments, which can become an unsurmountable barrier to the adoption of a new treatment.
In conclusion, AEF0217 respond to needs of subjects with Down syndrome, their families and society.