ProfK has volunteered me to do a debate on B cells and the value of the different B cell depleting therapies. So we need to understand how all B cell depleting antibodies work.
We have suggested that B cell depleting capacity is associated with an ability to inhibit relapsing MS. So what happens with ofatumumumab? This is injected monthly at a dose of 20mg and looking at this study if you deplete to cells below 8 cells per microlitre you get optimal effect.
The study below shows that on the whole, once dosing starts, it keeps B cells at a low level between 1-3 cells per microlitre. When you stop, B cell numbers recover. The lower limit of normal here is 40 cells per microlitre but most other people use 80 cells per microlitre. So you can see it takes about 6months to get back to the new normal when dosing was stopped after 2 years. For comparison it takes about 50-52 weeks for ocrelizumab to reach this number.
Did size matter? For B cell depletion not much but heavier people seemed to repopulate abit quicker…
However the thing they do not show is memory B cell repopulation. Is this back to normal at 24 weeks….I doubt it. How will we find out, the data is probably there but if may be difficult to get. It says the data can be obtained from clinicaltrialdatarequest.com…..Should we do it?
Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis. Yu H, Graham G, David OJ, Kahn JM, Savelieva M, Pigeolet E, Das Gupta A, Pingili R, Willi R, Ramanathan K, Kieseier BC, Häring DA, Bagger M, Soelberg Sørensen P. CNS Drugs. 2022. doi: 10.1007/s40263-021-00895-w.
Background: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses.
Objectives: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose.
Methods: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses.
Results: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels.
Conclusion: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.
Hauser SL, Cross AH, Winthrop K, Wiendl H, Nicholas J, Meuth SG, Giacomini PS, Saccà F, Mancione L, Zielman R, Bagger M, Das Gupta A, Häring DA, Jehl V, Kieseier BC, Pingili R, Stoneman D, Su W, Willi R, Kappos L.
Background: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile.
Objective: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years.
Methods: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide.
Results: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections.
Conclusion: In patients with up to 3.5 years’ exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.