Final Report Summary - BEST MS (Best EScalation Treatment in Multiple Sclerosis (MS))
Executive Summary:
Objective
The best-MS project (a better escalation therapy in Multiple sclerosis) objective was to determine the best composite criteria of response to Natalizumab (NTZ) during the first year of treatment that best predict disease activity during the second and third years of treatment with NTZ and serious adverse event.
Material and methods
We collected 1500 NTZ treated patients stratified as responders and non-responders in a prospective cohort that gathered clinical radiological and biological multi-samples. Thirty patients developed a progressive multifocal leukoencephalopathy (PML) including more than 50 PML samples a unique sample collection worldwide. We applied innovative technology such as metabolomics, genomics, diverse cellular assays, and metagenomics (that explore the microbiome).
Results
At the time of the final report we were able to patent a prediction test for PML using CD62L. This test is more effective than biological markers used so far for PML prediction since we need to stop NTZ in 10% of the patients in order to prevent 85% of PML. As a comparison with the index value 30% of patients need to stop NTZ in order to avoid 80% of the PML.
Further biological markers are now in the patent process such as MMP9, and NFK beta pathway
Regarding NTZ response prediction we found that genes in the GABA receptors family are associated with non-response to NTZ.
Conclusion and perspective
Our project is an important step for precision medicine since we allow monitoring at the individual level the risk of developing PML. Beyond this result, our project is a paradigm for precision medicine in neurodegenerative disease, oncology internal medicine and HIV since all of them use biology therapy or develop PML
Project Context and Objectives:
Objective
The best-MS project (a better escalation therapy in Multiple sclerosis) objective was to determine the best composite criteria of response to Natalizumab (NTZ) during the first year of treatment that best predict disease activity during the second and third years of treatment with NTZ and serious adverse event.
Material and methods
We collected 2000 NTZ and fingolimod treated patients stratified as responders and non-responders in a prospective cohort that gathered clinical radiological and biological multi-samples. Thirty patients developed a progressive multifocal leukoencephalopathy (PML) including more than 50 PML samples a unique sample collection worldwide. We applied innovative technology such as metabolomics, genomics, diverse cellular assays, and metagenomics (that explore the microbiome).
CHUT cohort 1 1212
CHUT cohort 2 540
Biodonostia (Spain) 43
VHIR 44
Basel (Switzerland) 50
UKMuenster 95
Results
At the time of the final report we were able to patent a prediction test for PML using CD62L. This test is more effective than biological markers used so far for PML prediction since we need to stop NTZ in 10% of the patients in order to prevent 85% of PML. As a comparison with the index value 30% of patients need to stop NTZ in order to avoid 80% of the PML.
Further biological markers are now in the patent process such as MMP9, and NFK beta pathway
Regarding NTZ response prediction we found that genes in the GABA receptors family are associated with non-response to NTZ.
Conclusion and perspective
Our project is an important step for precision medicine since we allow monitoring at the individual level the risk of developing PML. Beyond this result, our project is a paradigm for precision medicine in neurodegenerative disease, oncology internal medicine and HIV since all of them use biology therapy or develop PML
Project Results:
See the attached pdf
Potential Impact:
Background : Multiple sclerosis, Neurodegenerative diseases, biologic drugs HIV and precision medicine
The best-MS project (a better escalation therapy in Multiple sclerosis) objective was to determine the best composite criteria of response to Natalizumab (NTZ) during the first year of treatment that best predict disease activity during the second and third years of treatment with NTZ and serious adverse event.
NTZ is a biologic drug and multiple sclerosis (MS) a neurodegenerative disease of the young adult, mainly driven by autoimmune mechanisms. The main strength of the project was to use a biological database of 1200 patients prospectively collected and available at the beginning of the project.
Therefore this project was a paradigm for how precision medicine could be use in the near future especially in the field of neurodegenerative diseases (Alzheimer’s, Parkinson’s, diseases, Amyotrophic lateral sclerosis, Multiple sclerosis, or biologic drugs (oncology, internal medicine). Further serious adverse events with biologic drugs are opportunistic infection especially the progressive multifocal leukoencephalopathy (PML). PML is a common problem in the HIV field that will be impacted by this project
Precision medicine, (formerly called personalized medicine), importance has been pointed out recently by president Obama, when launching the precision medicine initiative in 2015. The FP7 program was pioneering and our project was clearly related to this field.
The concept of precision medicine — prevention and treatment strategies that take individual variability into account — is not new: blood typing, for instance, has been used to guide blood transfusions for more than a century. But the prospect of applying this concept broadly has been dramatically improved by the recent development of large-scale biologic databases (such as the human genome sequence), powerful methods for characterizing patients (such as proteomics, metabolomics, genomics, diverse cellular assays, and even mobile health technology), and computational tools for analyzing large sets of data. What is needed now is a broad research program to encourage creative approaches to precision medicine, test them rigorously, and ultimately use them to build the evidence base needed to guide clinical practice. (See A New Initiative on Precision Medicine Francis S. Collins, M.D. Ph.D. and Harold Varmus, M.D. N Engl J Med 2015; 372:793-795.
Impact 1 : METHODS OF RISK ASSESSMENT OF PML AND RELATED APPARATUS patent WO2013057092 (A1) ― 2013-04-25
The invention provides a method of assessing the risk of occurrence of progressive multifocal leukoencephalopathy (PML) in a subject as well as a method of stratifying a subject undergoing VLA-4 blocking agent treatment for suspension of VLA-4 blocking agent treatment. These methods comprise detecting the level of L-selectin (CD62L) and optionally LFA-1 expressing T cells in a sample from the subject
In this patent we are able to predict the occurrence of PML in NTZ treated patients but also in HIV patients
Impact 2 : Pattent project with other biological marker for predicting PML
Preliminary data are promising for the development of biomarker beyond CD62L. Afetr an exome sequencing of PML patients versus controls we are confident that genes of the NFKappa B pathway are of interest for the prediction
Based on a RNA sequencing we believe that information from the MMP-9 pathway may help us in PML prediction and diagnosis
Based on a metagenomic approach we found that clostridium bacteria family are involved in PML prediction
A combination of the 4 makers developed during the project (CD62L, MMP9, NFKb) and those already used (index value and JC virus serology) is also ongoing
Conclusion impact 1 and 2
With our project we are confident that PML a severe adverse drug reaction due to an opportunistic infection and may cause death will be decrease. Therefore we increased the safety of a usefull drug. Our findings also impact the HIV field and PML related to other biologic drugs.
Impact 3 prediction of NTZ response
During the best-MS project with a GWAS of responders versus non responders we found that genes of the GABA receptors family are associated with non response to natalizumab. This is an important findings since we are designing a response prediction test that will allow to better choose between the 15 biologic drugs available in MS.
Further this response test with be an important complementary test to adverse event prediction test.
A global prediction test for NTZ
Even if this goal was not done at the end of the project a mathematical model is now possible and we will answer to the H2020 call: SC1-PM-17-2017: Personalised Computing Models and In-silico Systems for well-being. Our Project with now a 10 year follow up is a rare database for precision medicine
A paradigm for neurodegenerative diseases
We have now a 10 year follow up since our first patient has been included in the database. It is a unique database compelling clinical radiological and biological data. Since 5% of our relapsing remitting patients develop under NTZ a progressive form of the disease we gathered a rare cohort that will allow us to explore the immunology to neurodegeneration interplay.
Sophie Mourgues, european project manager : mourgues.s@chu-toulouse.fr ; +33561778286
Vincent Jouanolou, european project ingeneer : jouanolou.v@chu-toulouse.fr ; +33561778436
Direction de la Recherche Médicale et Innovation
CHU de Toulouse Hôtel-Dieu Saint Jacques
2, rue Viguerie 31059 Toulouse Cedex 09
Tel : +33 5 61 77 82 86
Fax : +33 5 61 77 84 11
Email : mourgues.s@chu-toulouse.fr
Objective
The best-MS project (a better escalation therapy in Multiple sclerosis) objective was to determine the best composite criteria of response to Natalizumab (NTZ) during the first year of treatment that best predict disease activity during the second and third years of treatment with NTZ and serious adverse event.
Material and methods
We collected 1500 NTZ treated patients stratified as responders and non-responders in a prospective cohort that gathered clinical radiological and biological multi-samples. Thirty patients developed a progressive multifocal leukoencephalopathy (PML) including more than 50 PML samples a unique sample collection worldwide. We applied innovative technology such as metabolomics, genomics, diverse cellular assays, and metagenomics (that explore the microbiome).
Results
At the time of the final report we were able to patent a prediction test for PML using CD62L. This test is more effective than biological markers used so far for PML prediction since we need to stop NTZ in 10% of the patients in order to prevent 85% of PML. As a comparison with the index value 30% of patients need to stop NTZ in order to avoid 80% of the PML.
Further biological markers are now in the patent process such as MMP9, and NFK beta pathway
Regarding NTZ response prediction we found that genes in the GABA receptors family are associated with non-response to NTZ.
Conclusion and perspective
Our project is an important step for precision medicine since we allow monitoring at the individual level the risk of developing PML. Beyond this result, our project is a paradigm for precision medicine in neurodegenerative disease, oncology internal medicine and HIV since all of them use biology therapy or develop PML
Project Context and Objectives:
Objective
The best-MS project (a better escalation therapy in Multiple sclerosis) objective was to determine the best composite criteria of response to Natalizumab (NTZ) during the first year of treatment that best predict disease activity during the second and third years of treatment with NTZ and serious adverse event.
Material and methods
We collected 2000 NTZ and fingolimod treated patients stratified as responders and non-responders in a prospective cohort that gathered clinical radiological and biological multi-samples. Thirty patients developed a progressive multifocal leukoencephalopathy (PML) including more than 50 PML samples a unique sample collection worldwide. We applied innovative technology such as metabolomics, genomics, diverse cellular assays, and metagenomics (that explore the microbiome).
CHUT cohort 1 1212
CHUT cohort 2 540
Biodonostia (Spain) 43
VHIR 44
Basel (Switzerland) 50
UKMuenster 95
Results
At the time of the final report we were able to patent a prediction test for PML using CD62L. This test is more effective than biological markers used so far for PML prediction since we need to stop NTZ in 10% of the patients in order to prevent 85% of PML. As a comparison with the index value 30% of patients need to stop NTZ in order to avoid 80% of the PML.
Further biological markers are now in the patent process such as MMP9, and NFK beta pathway
Regarding NTZ response prediction we found that genes in the GABA receptors family are associated with non-response to NTZ.
Conclusion and perspective
Our project is an important step for precision medicine since we allow monitoring at the individual level the risk of developing PML. Beyond this result, our project is a paradigm for precision medicine in neurodegenerative disease, oncology internal medicine and HIV since all of them use biology therapy or develop PML
Project Results:
See the attached pdf
Potential Impact:
Background : Multiple sclerosis, Neurodegenerative diseases, biologic drugs HIV and precision medicine
The best-MS project (a better escalation therapy in Multiple sclerosis) objective was to determine the best composite criteria of response to Natalizumab (NTZ) during the first year of treatment that best predict disease activity during the second and third years of treatment with NTZ and serious adverse event.
NTZ is a biologic drug and multiple sclerosis (MS) a neurodegenerative disease of the young adult, mainly driven by autoimmune mechanisms. The main strength of the project was to use a biological database of 1200 patients prospectively collected and available at the beginning of the project.
Therefore this project was a paradigm for how precision medicine could be use in the near future especially in the field of neurodegenerative diseases (Alzheimer’s, Parkinson’s, diseases, Amyotrophic lateral sclerosis, Multiple sclerosis, or biologic drugs (oncology, internal medicine). Further serious adverse events with biologic drugs are opportunistic infection especially the progressive multifocal leukoencephalopathy (PML). PML is a common problem in the HIV field that will be impacted by this project
Precision medicine, (formerly called personalized medicine), importance has been pointed out recently by president Obama, when launching the precision medicine initiative in 2015. The FP7 program was pioneering and our project was clearly related to this field.
The concept of precision medicine — prevention and treatment strategies that take individual variability into account — is not new: blood typing, for instance, has been used to guide blood transfusions for more than a century. But the prospect of applying this concept broadly has been dramatically improved by the recent development of large-scale biologic databases (such as the human genome sequence), powerful methods for characterizing patients (such as proteomics, metabolomics, genomics, diverse cellular assays, and even mobile health technology), and computational tools for analyzing large sets of data. What is needed now is a broad research program to encourage creative approaches to precision medicine, test them rigorously, and ultimately use them to build the evidence base needed to guide clinical practice. (See A New Initiative on Precision Medicine Francis S. Collins, M.D. Ph.D. and Harold Varmus, M.D. N Engl J Med 2015; 372:793-795.
Impact 1 : METHODS OF RISK ASSESSMENT OF PML AND RELATED APPARATUS patent WO2013057092 (A1) ― 2013-04-25
The invention provides a method of assessing the risk of occurrence of progressive multifocal leukoencephalopathy (PML) in a subject as well as a method of stratifying a subject undergoing VLA-4 blocking agent treatment for suspension of VLA-4 blocking agent treatment. These methods comprise detecting the level of L-selectin (CD62L) and optionally LFA-1 expressing T cells in a sample from the subject
In this patent we are able to predict the occurrence of PML in NTZ treated patients but also in HIV patients
Impact 2 : Pattent project with other biological marker for predicting PML
Preliminary data are promising for the development of biomarker beyond CD62L. Afetr an exome sequencing of PML patients versus controls we are confident that genes of the NFKappa B pathway are of interest for the prediction
Based on a RNA sequencing we believe that information from the MMP-9 pathway may help us in PML prediction and diagnosis
Based on a metagenomic approach we found that clostridium bacteria family are involved in PML prediction
A combination of the 4 makers developed during the project (CD62L, MMP9, NFKb) and those already used (index value and JC virus serology) is also ongoing
Conclusion impact 1 and 2
With our project we are confident that PML a severe adverse drug reaction due to an opportunistic infection and may cause death will be decrease. Therefore we increased the safety of a usefull drug. Our findings also impact the HIV field and PML related to other biologic drugs.
Impact 3 prediction of NTZ response
During the best-MS project with a GWAS of responders versus non responders we found that genes of the GABA receptors family are associated with non response to natalizumab. This is an important findings since we are designing a response prediction test that will allow to better choose between the 15 biologic drugs available in MS.
Further this response test with be an important complementary test to adverse event prediction test.
A global prediction test for NTZ
Even if this goal was not done at the end of the project a mathematical model is now possible and we will answer to the H2020 call: SC1-PM-17-2017: Personalised Computing Models and In-silico Systems for well-being. Our Project with now a 10 year follow up is a rare database for precision medicine
A paradigm for neurodegenerative diseases
We have now a 10 year follow up since our first patient has been included in the database. It is a unique database compelling clinical radiological and biological data. Since 5% of our relapsing remitting patients develop under NTZ a progressive form of the disease we gathered a rare cohort that will allow us to explore the immunology to neurodegeneration interplay.
Sophie Mourgues, european project manager : mourgues.s@chu-toulouse.fr ; +33561778286
Vincent Jouanolou, european project ingeneer : jouanolou.v@chu-toulouse.fr ; +33561778436
Direction de la Recherche Médicale et Innovation
CHU de Toulouse Hôtel-Dieu Saint Jacques
2, rue Viguerie 31059 Toulouse Cedex 09
Tel : +33 5 61 77 82 86
Fax : +33 5 61 77 84 11
Email : mourgues.s@chu-toulouse.fr
