Ignite Creation Date:
2024-06-16 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 3:32 PM
Study NCT ID:
NCT06455709
Status:
RECRUITING
Last Update Posted:
2024-06-12
First Post:
2024-06-03
Brief Title:
Markers of Favorable Response to Complement Inhibitors Therapy
Sponsor:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Organization:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Study Overview
Official Title:
Identification of Clinical Biological Cellular and Genetic Markers of Favorable Response Complement Inhibitors Therapy in Patients With Generalized Myasthenia Gravis
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
OPTIMISE
Brief Summary:
Myasthenia gravis is an autoimmune neurological disease caused by autoantibodies primarily directed against components of the postsynaptic membrane of the neuromuscular junction Approximately 85 of patients have antibodies directed against the acetylcholine receptor anti-AChR
Anti-AChR antibodies act through three distinct mechanisms
1 Activation of the classical complement pathway Formation of membrane-attack complexes MACs results in the destruction of the postsynaptic membrane
2 Mechanical blockade Anti-AChR antibodies block the acetylcholine binding site on its receptor
3 Internalization and lysosomal degradation Bivalent IgG causes cross-linking of adjacent receptors leading to internalization and degradation of AChRs antigenic modulation
Patient mortality has significantly reduced due to effective treatments preventing severe exacerbations of myasthenic symptoms
In the past five years the FDA and EMA have approved complement inhibitors for the treatment of generalized myasthenia gravis with anti-AChR antibody positivity Eculizumab a humanized monoclonal antibody binds to the complement fragment C5 inhibiting its cleavage into C5a and C5b and preventing the formation of the terminal complement complex C5b-9 MAC
Currently Eculizumab is approved in Italy for generalized myasthenia gravis associated with anti-acetylcholine receptor antibody positivity
This class of drugs is generally more effective than conventional immunosuppressive therapies though it comes with higher costs
There is heterogeneity among patients in their response to complement inhibitor therapies Currently there is no specific evidence indicating which patients may benefit most from this class of treatments Personalized therapy considering the predominant pathogenic mechanisms of anti-AChR in individual patients seems necessary Interindividual heterogeneity in the autoantibody repertoire could underlie different responses to complement inhibitor therapies For example inhibition of the complement cascade in patients whose autoantibodies also block receptors might result in an unsatisfactory treatment response Moreover C5 gene polymorphisms could explain a lack of response to these new drugs Investigating the immune genetic and cellular profile of myasthenic patients eligible for these new pharmacological therapies could be useful for identifying predictive markers of response and personalizing therapeutic choices
Anti-AChR antibodies act through three distinct mechanisms
1 Activation of the classical complement pathway Formation of membrane-attack complexes MACs results in the destruction of the postsynaptic membrane
2 Mechanical blockade Anti-AChR antibodies block the acetylcholine binding site on its receptor
3 Internalization and lysosomal degradation Bivalent IgG causes cross-linking of adjacent receptors leading to internalization and degradation of AChRs antigenic modulation
Patient mortality has significantly reduced due to effective treatments preventing severe exacerbations of myasthenic symptoms
In the past five years the FDA and EMA have approved complement inhibitors for the treatment of generalized myasthenia gravis with anti-AChR antibody positivity Eculizumab a humanized monoclonal antibody binds to the complement fragment C5 inhibiting its cleavage into C5a and C5b and preventing the formation of the terminal complement complex C5b-9 MAC
Currently Eculizumab is approved in Italy for generalized myasthenia gravis associated with anti-acetylcholine receptor antibody positivity
This class of drugs is generally more effective than conventional immunosuppressive therapies though it comes with higher costs
There is heterogeneity among patients in their response to complement inhibitor therapies Currently there is no specific evidence indicating which patients may benefit most from this class of treatments Personalized therapy considering the predominant pathogenic mechanisms of anti-AChR in individual patients seems necessary Interindividual heterogeneity in the autoantibody repertoire could underlie different responses to complement inhibitor therapies For example inhibition of the complement cascade in patients whose autoantibodies also block receptors might result in an unsatisfactory treatment response Moreover C5 gene polymorphisms could explain a lack of response to these new drugs Investigating the immune genetic and cellular profile of myasthenic patients eligible for these new pharmacological therapies could be useful for identifying predictive markers of response and personalizing therapeutic choices
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None