Table 3.
Association with infections, as reported in clinical trials
| Trial name, country | IgA | IgG | IgM |
|---|---|---|---|
| ASCLEPIOS I/II trials: ASCLEPIOS I/II trials [29] [abstract], Multinational | NR |
27.6% (37/134) reported infections during a drop in IgG < LLN (3 serious) vs. 50.6% (410/810) with IgG ⩾ LLN (21 serious) The most common infection was nasopharyngitis. Overall, 7/20 participants with concurrent IgG < LLN and lymphopenia and/or neutropenia reported infections; none were serious From presentation: 20/134 had concurrent IgG < LLN and lymphopenia and/or neutropenia. Of these 7 participants reported infection: upper respiratory tract infection = 2, nasopharyngitis = 2, UTI = 2, alveolar osteitis = 1 No association was observed with decreased Ig levels and increased risk of serious/nonserious infections or infections in conjunction with lymphopenia and/or neutropenia in participants treated with ofatumumab |
Proportion of participants on ofatumumab who experienced ⩾1 infection within 1 month prior and until 1 month after IgM < LLN was 31.1% (52/167; 2 serious) vs. 51.5% (400/777) with IgM ⩾ LLN (18 serious) Overall, 1/11 participants with concurrent IgM < LLN and lymphopenia and/or neutropenia No association was observed with decreased Ig levels and increased risk of serious/nonserious infections or infections in conjunction with lymphopenia and/or neutropenia in participants treated with ofatumumab |
| ASCLEPIOS I/II trials [31], multinational |
At week 120, no participants reached IgG levels < 50% LLN with ofatumumab (ASCLEPIOS I and II, median[g/L]: 10.57 and 9.57, respectively) or teriflunomide (10.01 and 9.65) The proportion of participants who experienced infections after the first drop of IgG levels below LLN was numerically higher for ofatumumab (45.5%) versus teriflunomide (36.4%). All infections were Grade 1/2, except 1 event in ofatumumab group (bilateral pneumonia, Grade 3) and 2 events in teriflunomide (pneumonia influenza and osteomyelitis, Grade 3) |
Proportion of participants with IgM levels < 50% LLN was 2.1% (n = 20/944) for ofatumumab (median [g/L]: 0.91 and 0.59) and 0.6% (n = 6/933) for teriflunomide (0.84 and 0.92) at week 120. Of these, 5 ofatumumab-treated participants experienced infections, mostly nonserious (Grade 1/2), except 1 recurrent urinary tract infection (Grade 3); all infections were resolved. One participant on teriflunomide who experienced nasopharyngitis had not recovered at the time of last follow-up | |
| ASCLEPIOS I/II trials [33], multinational | NR | During the RMS phase 3 clinical studies, decrease in mean value of immunoglobulin M (IgM) (30.9% decrease after 48 weeks and 38.8% decrease after 96 weeks) was observed and no association with risk of infections, including serious infections, was shown | |
| ASCLEPIOS I/II trials. [42], multinational | A decrease in the mean level of IgM was observed in ofatumumab-treated participants but was not associated with an increased risk of infections | ||
| OBOE [18], Multinational | NR | NR | NR |
| VELOCE [37], US and Canada | NR | NR | NR |
| OPERA I/II: OPERA I/II [35, 36], multinational |
Data were pooled for RMS and PPMS: Five serious infections occurred during a drop in IgA levels < LLN (5 AEs/215.8 PY; 2.3/100 PY) vs. IgA levels ⩾ LLN (200 AEs/9038.7 PY; 2.21/100 PY) Rates of serious infections per 100 PY during IgA < LLN = 166 episodes (127 participants), 256 PY, serious infections = 7 Rates of serious infections per 100 PY during IgA ≥ LLN = 2,131 episodes (1,965 participants) 9,726 PY, serious infections = 215 |
Data were pooled for RMS and PPMS: Overall, 14 serious infections occurred during a drop in IgG levels < LLN (14 AEs per 215.5 PY, equating to a rate of 6.50 AEs/100 PY), compared with IgG levels ⩾ LLN, (191 AEs/9,049.1 PY; 2.11/100 PY) Rates of serious infections per 100 PY during IgG < LLN = 288 episodes (152 participants), 255 PY, serious infections = 14. Rates of serious infections per 100 PY during IgG ≥ LLN = 2,269 episodes (1,940 participants) 9,737 PY, serious infections = 208 |
Data were pooled for RMS and PPMS: A total of 64 serious infections occurred during a drop in IgM < LLN (64 AEs/1,749.1 PY; 3.66/100 PY) vs. IgM levels ⩾ LLN (141 AEs/7,515.6 PY; 1.88/100 PY) Rates of serious infections per 100 PY during IgM < LLN = 929 episodes (729 participants), 2,003 PY, serious infections = 71 Rates of serious infections per 100 PY during IgM ≥ LLN = 2,368 episodes (1,383 participants) 7,989 PY, SI = 151 |
| OPERA I/II [37], multinational | NR | Serious infections rates per 100 participant-years (95% CI) were: Q1, 1.63 (0.95–2.61); Q2, 1.55 (0.90–2.48); Q3, 1.51 (0.86–2.45); Q4, 1.11 (0.57–1.94) by baseline IgG quartiles | NR |
| OPERA I/II [40], multinational |
Data were pooled for RMS and PPMS: For 61 participants with IgA < LLN (170.1 PY), there were 125 infections (73.48 per 100 PY, 95% CI = 61.16–87.55), and 8 serious infections (4.7 per 100 PY, 95% CI = 2.03–9.27) |
Data were pooled for RMS and PPMS: For 121 participants with IgG < LLN (410.2 PY), there were 285 infections (69.48 per 100 PY, 95% CI = 61.65–78.04), and 14 serious infections (3.41 per 100 PY, 95% CI = 1.87–5.73) |
Data were pooled for RMS and PPMS: For 426 participants with IgM < LLN (1,190.8 PY), there were 895 infections ( 75.16 per 100 PY, 95% CI = 70.31–80.25), and 36 serious infections (3.02 per 100 PY, 95% CI = 2,12–4.19) |
| OPERA I/II [43], multinational | NR | The pooled data of ocrelizumab clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG < LLN) and increased rates of serious infections. The type, severity, latency, duration, and outcome of serious infections observed during episodes of Igs below LLN were consistent with the overall serious infections observed in participants treated with ocrelizumab | NR |
| OMS115102 [21], multinational | NR | NR | NR |
| NCT00676715 [22], multinational | NR | NR | NR |
| ASCLEPIOS I/II, APLIOS, APOLITOS, ALITHIOS [17], multinational | NR |
No apparent association was observed between low IgG levels and risk of serious infections after 3.5 years of ofatumumab treatment; none of these participants with a serious infection suffered a recurrence. No COVID-19 infections were observed related to IgG < LLN during this period 1/30 (vs. 55/1,936 > LLN) participants had serious infections occurring up to 1 month prior and 1 month after any drop in IgG levels < LLN < LLN (N = 30): Participants with ≥ 1 serious infection = 1 (3.3); IR 7.02 Herpes zoster = 0 URTI = 0 UTI = 0 Pneumonia = 1 (3.3); IR 7.02 ≥ LLN (N = 1,936): Participants with ≥ 1 serious infection = 55 (2.8); IR 1.34 Herpes zoster = 1 (0.1); IR 0.02 URTI = 1 (0.1); IR 0.02 UTI = 6 (0.3); IR 0.14 Pneumonia = 8 (0.4); IR 0.19 |
No apparent association was observed between low IgM levels and risk of serious infections after 3.5 years of ofatumumab treatment; none of these participants with a serious infection suffered a recurrence. No COVID-19 infections were observed related to IgM < LLN during this period 3/454 (vs. 44/1512 > LLN) participants had serious infections occurring up to 1 month prior and 1 month after any drop in IgM levels < LLN < LLN (N = 454): Participants with ≥ 1 serious infection = 3 (0.7); IR 0.80 Herpes zoster = 1 (0.2); IR 0.27 URTI = 1 (0.2); IR 0.27 UTI = 1 (0.2); IR 0.27 Pneumonia = 0 ≥ LLN (N = 1,512): Participants with ≥ 1 serious infection = 44 (2.9); IR 1.38 Herpes zoster = 0 URTI = 0 UTI = 3 (0.2); IR 0.09 Pneumonia = 8 (0.5); IR 0.25 |
AE, adverse event; CI, confidence interval; COVID-19, coronavirus disease 2019; EMA, European Medicines Agency; FDA, Food and Drug Administration; Ig, immunoglobulin; IR, incidence rate; LLN, lower limit of normal; NR, not reported; PPMS, primary progressive multiple sclerosis; PY, person-years; RMS, relapsing multiple sclerosis; SI, serious infection; SPC, summary of product characteristics; URTI, upper respiratory tract infection; US, United States; UTI, urinary tract infection