Ofatumumab, an anti-CD20 MAb administered subcutaneously, appears to have only modest effects on serum immunoglobulins, according to an updated safety analysis from recent clinical trials (Hauser et al. Mult Scler 2022; epublished March 1, 2022). A preliminary analysis of the data was published at last year’s ECTRIMS (Wiendl et al. ECTRIMS 2021;P931) (see also ECTRIMS 2021 slide deck, NeuroSens, October 21, 2021).
The analysis included patients in ALITHIOS, the long-term safety study comprising subjects from the pivotal ASCLEPIOS I/II trials, the APLIOS bioequivalence study and the phase II APOLITOS study in Japanese and Russian MS patients (Saida et al. AAN 2021; abstract 2032). The safety population included patients treated with continuous ofatumumab and switch patients (total N=1969). Mean age was 38.7 years; mean time from diagnosis was 6.4 years; and median duration of drug exposure was 21 months (range 0.0-51.8 months).
Mean serum IgG levels were generally unchanged throughout the observation period. The mean change from baseline in the continuous ofatumumab group was +1.1% at week 168. IgG went below the lower limit of normal (LLN, <5.65 g/L) in 1.7% of patients receiving continuous ofatumumab.
There was a more substantial decline in serum IgM levels (-47% from baseline to week 168) with continuous ofatumumab. IgM remained >LLN in a majority of patients; the proportion with IgM <LLN (0.40 g/L) at any time was 25.1% with continuous ofatumumab.
The overall rate of serious infections was 2.9%. The rate of serious infections at the time of low IgG level was similar to that seen in patients with infections when IgG was >LLN (3.3% vs. 2.8%). A previous study reported that low IgG or IgM during anti-CD20 therapy was not associated with a risk of serious infections, although a low lymphocyte count was associated with a higher risk of Herpes zoster infection (Oksbjerg et al. Mult Scler Relat Disord 2021;52:102988). In the ALITHIOS study, only one zoster infection was reported (0.1%), which occurred in a patient with low IgM. There were no cases of opportunistic infections, hepatitis B reactivation or PML.
The effect of ofatumumab on immunoglobulins compares favourably to what has been reported with ocrelizumab (Derfuss et al. ECTRIMS 2019; abstract 65). In that analysis of patients in the OPERA I/II and ORATORIO trials, the mean decrease from baseline was 17% for IgG and 58.1% for IgM in RMS patients at 264 weeks. The proportion of patients with IgG or IgM below LLN at any time was 5.7% and 29.2%, respectively, at week 264.
Also noteworthy in the ALITHIOS study was the report of 139 cases of COVID-19 during ofatumumab; the incidence was 7.1%. Most patients (92.1%) recovered without sequelae although there was one death due to COVID pneumonia.