No Association Between Decreases in Serum Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN) and Serious Infections (SI) with Long-term Ublituximab (UBL) Treatment in Patients with Relapsing Multiple Sclerosis (RMS)
Lawrence Steinman1, Edward Fox2, Hans-Peter Hartung3, Enrique Alvarez4, Peiqing Qian5, Sibyl Wray6, Derrick Robertson7, Krzysztof Selmaj8, Daniel Wynn9, Koby Mok2, Yanzhi Hsu2, Yihuan Xu2, Chris Rowland2, Karthik Bodhinathan2, Peter Sportelli2, Jackie Parker2, Hari Miskin2, Bruce Cree10
1Stanford Medicine, 2TG Therapeutics, 3Heinrich Heine University Medical Faculty, 4University of Colorado, 5Swedish Medical Center, 6Hope Neurology, 7University of South Florida, 8University of Warmia and Mazury, 9Consultants in Neurology, Ltd., 10UCSF, Multiple Sclerosis Center
Objective:

To evaluate the immunological safety profile of prolonged UBL treatment.

Background:

UBL provides sustained clinical benefit over five years of treatment. Immunoglobulin and infection profile with prolonged UBL treatment are presented. 

Design/Methods:

After 2 years in double-blind period, RMS patients either continued UBL treatment, or switched from teriflunomide to UBL during open-label extension. At 5 years, mean serum Ig levels were calculated. LLN thresholds were (g/L): 5.65 (IgG), 0.4 (IgM), 0.7 (IgA). Severity of hypogammaglobulinemia (g/L) were classified as mild: <5.65 to ≥ 4.0, moderate: <4.0 to ≥ 2.0, severe: <2.0 for IgG, and mild: <0.4 to ≥ 0.36, moderate: <0.36 g/L to ≥ 0.2, and severe: <0.2 for IgM.

Results:

Mean serum IgG and IgM levels remained stable and above LLN after continuous UBL treatment for 5 years [mean (SD), 8.1 (2.23) g/L and 0.7 (0.66) g/L, respectively]. At year 5, IgG drops were limited and mild (12.6%) to moderate (0.3%), none were severe, and IgM were mild (4.9%), moderate (18.9%) or severe (11.2%). Rates of SI per 100 patient-years and 95% CI for UBL-treated patients <LLN or ≥LLN were 3.26 (2.10, 5.05) and 2.44 (1.94, 3.07]) for IgM, 2.92 (0.94, 9.06) and 2.57 (2.09, 3.16) for IgG, and 3.66 (1.37, 9.76) and 2.55 (2.07, 3.13) for IgA respectively, indicating no significant difference in the incidence of SI regardless of Ig levels above or below LLN. The rate of SIs occurring within 1 month of <LLN or ≥LLN Ig evaluation did not differ, further supporting lack of relationship between decreases in Ig below LLN and SI.

Conclusions:
Mean Ig levels remained stable and above LLN at year 5, and no association between decreased immunoglobulins and risk of SI was observed. Thus, UBL confers a benefit risk balance suitable for long-term clinical management of RMS.
10.1212/WNL.0000000000211852
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