Periodic Reporting for period 2 - MAP-AD (A Methylation Profiling Diagnostic for Early Diagnosis of Alzheimer’s disease)
Berichtszeitraum: 2022-01-01 bis 2024-03-31
Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia in the elderly expected to triple by 2050 to reach 150M of affected people. A strong scientific consensus exists that the recruitment of patients for trials at late stages of AD is the primary reason for the high rate of failure rendering any therapeutic intervention impossible. This has led to a paradigm shift in the design of AD clinical trials, with many new trials now focusing on enrollment of patients in predementia stages of AD, specifically in the Prodromal AD (P-AD) stage i.e. patients who manifest minor change in cognition and short-term memory loss. Identifying which individuals with mild cognitive impairment (MCI) are more likely to develop AD dementia (ADD) is an unmet prognosis need for optimizing patients' recruitment for clinical trials, which would boost their success rate and lead to preventive treatment in the clinical practice. The main aim of the present project is to develop and validate the MAP-AD Test®, an in vitro diagnostic medical device for the prognosis of progression from MCI to ADD, combining the analysis of novel epigenetic AD biomarkers in blood samples with clinical data collected as part of routine clinical practice.
ADmit Therapeutics (ADmit) implemented a new generation sequencing infrastructure in-house for the epigenetic analysis of samples encouraging the optimization and the introduction of several improvements in their protocols for time-effective management of the the MAP-AD platform. The standardization of the protocols was consolidated by the establishment of a Quality Management System (QMS) certified with the ISO13485 and based on the requirements of the European regulation for in vitro diagnostic devices (IVDR).
The company designed and developed the MAP-AD Test®, a medical device comprised by a kit with reagents for the analysis of distinctive methylation patterns in blood samples, and a dedicated medical software that computes the probability of progression to ADD using the methylation patterns and patient clinical information. This is the first epigenetic prognostic model, amyloid-beta (Aβ) independent, intended to provide the prognosis of progression from MCI to ADD. The product validation and verification, including the analytical validation, were performed to demonstrate the robustness of the medical device developed.
During the project, a multicentric observational study was performed to evaluate the clinical performance of the MAP-AD Test®. The recruitment of patients for the study was hampered by the COVID-19 pandemic worldwide situation. Nonetheless, 600 prospective and retrospective samples from three groups [cognitively normal subjects (CN), MCI patients non-progressed to ADD, and MCI patients that progress to ADD] were collected from Spanish hospitals and private collections, and American and Australian biobanks. The performance of the MAP-AD Test® for the classification of those MCI patients that will progress to ADD yielded a sensitivity and specificity of 95% and 71%, respectively. Moreover, the model showed a positive predictive value of 77% and a negative predictive model of 93%, and an area under the curve (AUC) of 90.3%. No adverse effects or device deficiencies were reported during the clinical performance study. This data was part of the performance evaluation of the test for the CE-mark submission.
The present project allowed to conclude that the MAP-AD Test® is a safe medical device that provides results that correlate with ADD progression in MCI patients. The probability of progression from MCI to ADD can be used by neurologists in patients and the appropriate action may be taken according to standard clinical practice. This cutting-edge technology and previous prototypes have been presented at several international congresses and fairs such as the Clinical Trials on Alzheimer’s Disease (CTAD) Congress, Alzheimer’s & Parkinson’s Disease Conference (AD/PD), and the Bio International Convention (BIO).
Finally, the company closed a €5,4 million Equity Round with Clave Capital, EIC Fund, and Alzheimer’s Drug Discovery Foundation (ADDF), among other investors, allowing the consolidation of the company and start preparing for the market launch of the MAP-AD Test®.
The company designed and developed the MAP-AD Test®, a medical device comprised by a kit with reagents for the analysis of distinctive methylation patterns in blood samples, and a dedicated medical software that computes the probability of progression to ADD using the methylation patterns and patient clinical information. This is the first epigenetic prognostic model, amyloid-beta (Aβ) independent, intended to provide the prognosis of progression from MCI to ADD. The product validation and verification, including the analytical validation, were performed to demonstrate the robustness of the medical device developed.
During the project, a multicentric observational study was performed to evaluate the clinical performance of the MAP-AD Test®. The recruitment of patients for the study was hampered by the COVID-19 pandemic worldwide situation. Nonetheless, 600 prospective and retrospective samples from three groups [cognitively normal subjects (CN), MCI patients non-progressed to ADD, and MCI patients that progress to ADD] were collected from Spanish hospitals and private collections, and American and Australian biobanks. The performance of the MAP-AD Test® for the classification of those MCI patients that will progress to ADD yielded a sensitivity and specificity of 95% and 71%, respectively. Moreover, the model showed a positive predictive value of 77% and a negative predictive model of 93%, and an area under the curve (AUC) of 90.3%. No adverse effects or device deficiencies were reported during the clinical performance study. This data was part of the performance evaluation of the test for the CE-mark submission.
The present project allowed to conclude that the MAP-AD Test® is a safe medical device that provides results that correlate with ADD progression in MCI patients. The probability of progression from MCI to ADD can be used by neurologists in patients and the appropriate action may be taken according to standard clinical practice. This cutting-edge technology and previous prototypes have been presented at several international congresses and fairs such as the Clinical Trials on Alzheimer’s Disease (CTAD) Congress, Alzheimer’s & Parkinson’s Disease Conference (AD/PD), and the Bio International Convention (BIO).
Finally, the company closed a €5,4 million Equity Round with Clave Capital, EIC Fund, and Alzheimer’s Drug Discovery Foundation (ADDF), among other investors, allowing the consolidation of the company and start preparing for the market launch of the MAP-AD Test®.
The main results of the project are:
1. The development of the first epigenetic prognostic model, amyloid-beta (Aβ) independent, that efficiently identifies the MCI patients that will likely progress to ADD.
2. The optimization of protocols and development of Standard Operative Procedures (SOPs) for high-quality data. The implementation and certification of the Quality Management System according to the ISO 13485 (Medical Devices Quality Management Systems Requirements for Regulatory Purposes).
3. The completion of a multicenter clinical validation with prospective and retrospective samples to validate the classifie model.
4. The application to the European Medicines Agency to obtain regulatory approval and move into the commercialization phase.
The impact of our project is huge in both societal and economic terms. The MAP-AD Test® will allow the identification of the patients with a high probability of progression to ADD which will be helpful to physicians counseling patients who have MCI that may be AD, improving their management and standard of care. These MCI patients who will progress to ADD are those who really will benefit from a deeper clinical exploration (such as the detection of diagnostic biomarkers: lumbar punction/CSF, amyloid PET, etc). Moreover, this innovative technology will provide an easy-to-implement, blood-based approach that can be readily incorporated into the clinical laboratory workflow. This will reduce the barriers to equity in AD care, as the device is cheaper than the current prognostic tools and will be more accessible to everyone. This is important to patients because most medical centers do not have the technology for the currently available imaging modalities or patients present with contraindications for lumbar puncture. Additionally, this test is minimally invasive. In addition, the MAP-AD Test® will significantly reduce costs of patient recruitment in clinical trials for AD therapies, positively impacting the drug development process and leading to novel treatments in the clinic. Bringing these treatments to the market will lead to drastic reductions in these socioeconomic costs as well.
1. The development of the first epigenetic prognostic model, amyloid-beta (Aβ) independent, that efficiently identifies the MCI patients that will likely progress to ADD.
2. The optimization of protocols and development of Standard Operative Procedures (SOPs) for high-quality data. The implementation and certification of the Quality Management System according to the ISO 13485 (Medical Devices Quality Management Systems Requirements for Regulatory Purposes).
3. The completion of a multicenter clinical validation with prospective and retrospective samples to validate the classifie model.
4. The application to the European Medicines Agency to obtain regulatory approval and move into the commercialization phase.
The impact of our project is huge in both societal and economic terms. The MAP-AD Test® will allow the identification of the patients with a high probability of progression to ADD which will be helpful to physicians counseling patients who have MCI that may be AD, improving their management and standard of care. These MCI patients who will progress to ADD are those who really will benefit from a deeper clinical exploration (such as the detection of diagnostic biomarkers: lumbar punction/CSF, amyloid PET, etc). Moreover, this innovative technology will provide an easy-to-implement, blood-based approach that can be readily incorporated into the clinical laboratory workflow. This will reduce the barriers to equity in AD care, as the device is cheaper than the current prognostic tools and will be more accessible to everyone. This is important to patients because most medical centers do not have the technology for the currently available imaging modalities or patients present with contraindications for lumbar puncture. Additionally, this test is minimally invasive. In addition, the MAP-AD Test® will significantly reduce costs of patient recruitment in clinical trials for AD therapies, positively impacting the drug development process and leading to novel treatments in the clinic. Bringing these treatments to the market will lead to drastic reductions in these socioeconomic costs as well.