Contributions
Abstract: EP1624
Type: ePoster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: The success of anti-CD20 monoclonal antibodies (mAbs) in clinical trials highlights a key role for B-cells in driving multiple sclerosis (MS) pathology and disease activity. Anti-CD20 mAbs differ in terms of epitope binding, potency and dosing regimen. Due to its unique biological properties, the fully human mAb ofatumumab (OFA) is given as subcutaneous (s.c.), low dose, monthly injections as maintenance therapy in ongoing Phase 3 studies.
Objective: To evaluate the B-cell recovery time after discontinuation of OFA compared with other anti-CD20 therapies.
Methods: We used the MIRROR Phase 2 dose-ranging study of s.c. OFA in relapsing−remitting MS (RRMS), which included a 24-week treatment phase and a 24-week follow-up, to describe B-cell repletion for OFA at different doses and administration frequencies in comparison with previously published results for intravenous (i.v.) ocrelizumab (OCR) and i.v. rituximab (RTX). In addition, we used a population kinetics-pharmacodynamic model developed using MIRROR data to predict time to B-cell repletion after OFA treatment stop. These predictions were done under conditions of the current OFA Phase 3 trials and compared with the published OCR data.
Results: The successful depletion of peripheral CD19+ B-cell counts by OFA, OCR and RTX has been reported previously. For OFA, median time to repletion (CD19+ B-cell count above the lower limit of normal or ≥baseline value) in weeks from last active dose was 36.7 (7.6, 97.1) for 30 mg every 12 weeks (Q12W), 36.1 (12.1, 111.0) for 60 mg Q12W, and 49.0 (14.4, 101.9) for 60 mg Q4W. For the humanised mAb OCR, median time to B-cell repletion was 71.0 weeks (95% CI: 59-76 weeks). Repletion of immature B-cells (CD19+CD27-IgD+CD38+bCD10+) to baseline occurred within 4 weeks with OFA. For RTX, a chimeric mAb, the naïve B-cell population (CD27-IgD+) slowly increased, reaching baseline only after 12-16 months. Our model-based predictions showed that by week 38 since last dose of OFA (loading of 20 mg three times weekly followed by 20 mg Q4W), 50% of patients repleted to either ≥110 B-cells/µl or baseline compared with 11% for OCR 600 mg.
Conclusions: OFA differs from other anti-CD20 therapies as it achieves faster post-treatment B-cell repletion. Faster repletion may be beneficial in the management of adverse events or in treatment sequencing. As the present analysis is based on a 24-week OFA treatment duration, B-cell recovery times may need to be confirmed after longer-term dosing.
Disclosure: Marina Savelieva, Joseph Kahn, Morten Bagger, Daniela Piani Meier, Davorka Tomic, David Leppert, and Erik Wallström are currently employees of Novartis. As of 1st July 2017, Erik Wallström will be employed by Sanofi.
Abstract: EP1624
Type: ePoster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: The success of anti-CD20 monoclonal antibodies (mAbs) in clinical trials highlights a key role for B-cells in driving multiple sclerosis (MS) pathology and disease activity. Anti-CD20 mAbs differ in terms of epitope binding, potency and dosing regimen. Due to its unique biological properties, the fully human mAb ofatumumab (OFA) is given as subcutaneous (s.c.), low dose, monthly injections as maintenance therapy in ongoing Phase 3 studies.
Objective: To evaluate the B-cell recovery time after discontinuation of OFA compared with other anti-CD20 therapies.
Methods: We used the MIRROR Phase 2 dose-ranging study of s.c. OFA in relapsing−remitting MS (RRMS), which included a 24-week treatment phase and a 24-week follow-up, to describe B-cell repletion for OFA at different doses and administration frequencies in comparison with previously published results for intravenous (i.v.) ocrelizumab (OCR) and i.v. rituximab (RTX). In addition, we used a population kinetics-pharmacodynamic model developed using MIRROR data to predict time to B-cell repletion after OFA treatment stop. These predictions were done under conditions of the current OFA Phase 3 trials and compared with the published OCR data.
Results: The successful depletion of peripheral CD19+ B-cell counts by OFA, OCR and RTX has been reported previously. For OFA, median time to repletion (CD19+ B-cell count above the lower limit of normal or ≥baseline value) in weeks from last active dose was 36.7 (7.6, 97.1) for 30 mg every 12 weeks (Q12W), 36.1 (12.1, 111.0) for 60 mg Q12W, and 49.0 (14.4, 101.9) for 60 mg Q4W. For the humanised mAb OCR, median time to B-cell repletion was 71.0 weeks (95% CI: 59-76 weeks). Repletion of immature B-cells (CD19+CD27-IgD+CD38+bCD10+) to baseline occurred within 4 weeks with OFA. For RTX, a chimeric mAb, the naïve B-cell population (CD27-IgD+) slowly increased, reaching baseline only after 12-16 months. Our model-based predictions showed that by week 38 since last dose of OFA (loading of 20 mg three times weekly followed by 20 mg Q4W), 50% of patients repleted to either ≥110 B-cells/µl or baseline compared with 11% for OCR 600 mg.
Conclusions: OFA differs from other anti-CD20 therapies as it achieves faster post-treatment B-cell repletion. Faster repletion may be beneficial in the management of adverse events or in treatment sequencing. As the present analysis is based on a 24-week OFA treatment duration, B-cell recovery times may need to be confirmed after longer-term dosing.
Disclosure: Marina Savelieva, Joseph Kahn, Morten Bagger, Daniela Piani Meier, Davorka Tomic, David Leppert, and Erik Wallström are currently employees of Novartis. As of 1st July 2017, Erik Wallström will be employed by Sanofi.