Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis
Abstract Introduction Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing–remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab...
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Adis, Springer Healthcare
2024-09-01
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| Series: | Neurology and Therapy |
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| Online Access: | https://doi.org/10.1007/s40120-024-00659-w |
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| author | Fredrik N. Albach Christian Geier Christian Keicher Maximilian G. Posch Stephan J. Schreiber Gerald Grütz Levent Akyüz Xiaodong Luo Annaig Le-Halpere Philippe Truffinet Frank Wagner |
| author_facet | Fredrik N. Albach Christian Geier Christian Keicher Maximilian G. Posch Stephan J. Schreiber Gerald Grütz Levent Akyüz Xiaodong Luo Annaig Le-Halpere Philippe Truffinet Frank Wagner |
| author_sort | Fredrik N. Albach |
| collection | DOAJ |
| description | Abstract Introduction Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing–remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. Methods Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years. Results Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0–7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow’s disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. Conclusions These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. Trial registration NCT02282826, NCT02977533, NCT02313285. |
| format | Article |
| id | doaj-art-e79ea53e5efa49fd8676ff1f7d2685da |
| institution | DOAJ |
| issn | 2193-8253 2193-6536 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Adis, Springer Healthcare |
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| series | Neurology and Therapy |
| spelling | doaj-art-e79ea53e5efa49fd8676ff1f7d2685da2025-08-20T02:50:08ZengAdis, Springer HealthcareNeurology and Therapy2193-82532193-65362024-09-011361607162510.1007/s40120-024-00659-wPhase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple SclerosisFredrik N. Albach0Christian Geier1Christian Keicher2Maximilian G. Posch3Stephan J. Schreiber4Gerald Grütz5Levent Akyüz6Xiaodong Luo7Annaig Le-Halpere8Philippe Truffinet9Frank Wagner10Charité Research Organisation GmbHCharité Research Organisation GmbHCharité Research Organisation GmbHCharité Research Organisation GmbHDepartment of Neurology, Oberhavel ClinicBIH Centre for Regenerative Therapies (BCRT), Immunocheck-Biomarker Unit, Charité–Universitätsmedizin BerlinBIH Centre for Regenerative Therapies (BCRT), Immunocheck-Biomarker Unit, Charité–Universitätsmedizin BerlinSanofiSanofiSanofiCharité Research Organisation GmbHAbstract Introduction Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing–remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. Methods Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years. Results Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0–7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow’s disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. Conclusions These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. Trial registration NCT02282826, NCT02977533, NCT02313285.https://doi.org/10.1007/s40120-024-00659-wClinical trialDisease-modifying therapiesMultiple sclerosisProgressiveTreatment response |
| spellingShingle | Fredrik N. Albach Christian Geier Christian Keicher Maximilian G. Posch Stephan J. Schreiber Gerald Grütz Levent Akyüz Xiaodong Luo Annaig Le-Halpere Philippe Truffinet Frank Wagner Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis Neurology and Therapy Clinical trial Disease-modifying therapies Multiple sclerosis Progressive Treatment response |
| title | Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis |
| title_full | Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis |
| title_fullStr | Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis |
| title_full_unstemmed | Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis |
| title_short | Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis |
| title_sort | phase 1 trials of gatralimab a next generation humanized anti cd52 monoclonal antibody in participants with progressive multiple sclerosis |
| topic | Clinical trial Disease-modifying therapies Multiple sclerosis Progressive Treatment response |
| url | https://doi.org/10.1007/s40120-024-00659-w |
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