Markers of Favorable Response to FcRn Inhibitors(INFORM)

NCT ID: NCT06685055

Last Updated: 2024-11-12

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 50 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-07-09
• Study Completion Date: 2026-07-09

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 and FcRn inhibitors for treating generalized myasthenia gravis with anti-AChR antibodies. Many other therapies are currently in phase 3 clinical trials or under regulatory review. However, there is no specific evidence to support which patients benefit most from one treatment class over another.

Given their relative efficacy compared to conventional therapies and high costs, their future role in the therapeutic arsenal is unclear. A personalized approach considering the different pathogenic mechanisms of anti-AChR and single gene polymorphisms involved in treatment response is essential for effective therapeutic choice. In July 2023, AIFA approved the reimbursement of Efgartigimod in Italy for treating adult patients with generalized myasthenia gravis with anti-AChR antibodies, in addition to standard therapy.

FcRn inhibitors (including Efgartigimod) prevent the interaction of IgG with the neonatal Fc receptor for immunoglobulin fragments, reducing IgG recycling and promoting the degradation of IgG and pathogenic antibodies without affecting albumin levels.

There is heterogeneity among patients in their response to FcRn inhibitors therapies. Currently, there is no specific evidence indicating which patients may benefit most from this class of treatments. Interindividual heterogeneity in the autoantibody repertoire, predominance of different pathogenic mechanisms, and single gene polymorphisms affecting treatment response. Investigating the immune profile and specific gene polymorphisms in myasthenic patients needing these innovative therapies could identify predictive biomarkers and personalize therapeutic choices.

Conditions

Myasthenia Gravis Generalized

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Eligibility Criteria

Inclusion Criteria

• Age ≥18 years.

• Diagnosis of generalized anti-AChR positive Myasthenia Gravis.
• Need for therapy with neonatal Fc receptor inhibitors for immunoglobulins (FcRn) as per AIFA-approved therapeutic indications (14).
• Ability to follow up at the reference center.
• Signed informed consent for the study.

Exclusion Criteria

• Age <18 years.

• Poor compliance with drug therapy.
• Concurrent autoimmune diseases.
• Insufficient availability of clinical information.
• Ongoing neoplasm or infection at the time of biological sample collection.
• Refusal to sign the informed consent for the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Raffaele Iorio

Role: PRINCIPAL_INVESTIGATOR

Fondazione Policlinico Universitario A. Gemelli, IRCCS

Locations

Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Raffaele Iorio, MD, PhD

Role: CONTACT

raffaele.iorio@policlinicogemelli.it

+390630154807

Silvia Falso, MD

Role: CONTACT

falsosilvia@gmail.com

+390630154807

Facility Contacts

Raffaele Iorio, MD, PhD

Role: primary

raffaele.iorio@policlinicogemelli.it

+390630154807

Silvia Falso, MD

Role: backup

falsosilvia@gmail.com

+390630154807

Other Identifiers

6717

Identifier Type: -

Identifier Source: org_study_id