Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study
Objective To assess the safety and biological activity of rozibafusp alfa, a first‐in‐class bispecific antibody–peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). Methods This phase 1b, double‐blind, plac...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | ACR Open Rheumatology |
| Online Access: | https://doi.org/10.1002/acr2.11487 |
| _version_ | 1797995781073928192 |
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| author | Lubna Abuqayyas Laurence E. Cheng Marcia Teixeira dos Santos Barbara A. Sullivan Norma Ruiz‐Santiago Hui Wang Yanchen Zhou Vishala Chindalore Stanley Cohen Alan J. Kivitz Maximilian G. Posch Jane R. Parnes |
| author_facet | Lubna Abuqayyas Laurence E. Cheng Marcia Teixeira dos Santos Barbara A. Sullivan Norma Ruiz‐Santiago Hui Wang Yanchen Zhou Vishala Chindalore Stanley Cohen Alan J. Kivitz Maximilian G. Posch Jane R. Parnes |
| author_sort | Lubna Abuqayyas |
| collection | DOAJ |
| description | Objective To assess the safety and biological activity of rozibafusp alfa, a first‐in‐class bispecific antibody–peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). Methods This phase 1b, double‐blind, placebo‐controlled, multiple ascending dose study included 34 patients (18–75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints–C‐reactive protein [DAS28‐CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow‐up. The primary end point was the incidence of treatment‐emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28‐CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). Results TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2 = 4.6–9.5 days) and dose‐related, reversible PD (>90% ICOSL receptor occupancy in 210‐ and 420‐mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti–rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210‐ and 420‐mg cohorts. Conclusion Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease. |
| first_indexed | 2024-04-11T10:07:12Z |
| format | Article |
| id | doaj.art-5676c94a2dbb4dc3a8d16a7cdd33da21 |
| institution | Directory Open Access Journal |
| issn | 2578-5745 |
| language | English |
| last_indexed | 2024-04-11T10:07:12Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | ACR Open Rheumatology |
| spelling | doaj.art-5676c94a2dbb4dc3a8d16a7cdd33da212022-12-22T04:30:12ZengWileyACR Open Rheumatology2578-57452022-10-0141090391110.1002/acr2.11487Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose StudyLubna Abuqayyas0Laurence E. Cheng1Marcia Teixeira dos Santos2Barbara A. Sullivan3Norma Ruiz‐Santiago4Hui Wang5Yanchen Zhou6Vishala Chindalore7Stanley Cohen8Alan J. Kivitz9Maximilian G. Posch10Jane R. Parnes11Amgen Inc. Thousand Oaks CaliforniaAmgen Inc. South San Francisco CaliforniaAmgen Inc. Thousand Oaks CaliforniaAmgen Inc. South San Francisco CaliforniaAmgen Inc. Thousand Oaks CaliforniaAmgen Inc. Thousand Oaks CaliforniaAmgen Inc. South San Francisco CaliforniaPinnacle Research Group Anniston AlabamaMetroplex Clinical Research Center Dallas TexasAltoona Center for Clinical Research Duncansville PennsylvaniaCharité Research Organisation GmbH Berlin GermanyAmgen Inc. Thousand Oaks CaliforniaObjective To assess the safety and biological activity of rozibafusp alfa, a first‐in‐class bispecific antibody–peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). Methods This phase 1b, double‐blind, placebo‐controlled, multiple ascending dose study included 34 patients (18–75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints–C‐reactive protein [DAS28‐CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow‐up. The primary end point was the incidence of treatment‐emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28‐CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). Results TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2 = 4.6–9.5 days) and dose‐related, reversible PD (>90% ICOSL receptor occupancy in 210‐ and 420‐mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti–rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210‐ and 420‐mg cohorts. Conclusion Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.https://doi.org/10.1002/acr2.11487 |
| spellingShingle | Lubna Abuqayyas Laurence E. Cheng Marcia Teixeira dos Santos Barbara A. Sullivan Norma Ruiz‐Santiago Hui Wang Yanchen Zhou Vishala Chindalore Stanley Cohen Alan J. Kivitz Maximilian G. Posch Jane R. Parnes Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study ACR Open Rheumatology |
| title | Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study |
| title_full | Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study |
| title_fullStr | Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study |
| title_full_unstemmed | Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study |
| title_short | Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind, Placebo‐Controlled, Multiple Ascending Dose Study |
| title_sort | safety and biological activity of rozibafusp alfa a bispecific inhibitor of inducible costimulator ligand and b cell activating factor in patients with rheumatoid arthritis results of a phase 1b randomized double blind placebo controlled multiple ascending dose study |
| url | https://doi.org/10.1002/acr2.11487 |
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