Abstract
B-cell depletion with anti-CD20 monoclonal antibody (mAb) represents a novel and highly effective treatment for patients with multiple sclerosis. Although all approved anti-CD-20 mAbs for multiple sclerosis (MS) treatment, ocrelizumab, ofatumumab, and ublituximab, target the same molecule on the B-cell surface, some differences in their molecular structure translate into important distinctions in their mechanisms of B-cell depletion. Differences between an antibody-dependent cell-mediated cytotoxicity (ADCC) versus a complement-dependent cytotoxicity (CDC) in anti-CD20 mAbs mechanism of action correspond to deeper B-cell depletion as well as better tolerability. Glycoengineering of the Fc portion of ublituximab with reduced fucosylation enhances affinity to Fc gamma receptor IIIa (FcγRIIIa) on natural killer (NK) cells. This molecular modification of ublituximab exhibits significantly higher ADCC activity in relation to CDC in B-cell depletion mechanisms. In addition, glycoengineering of ublituximab reduces the importance of the FcγRIIIa 158V/F polymorphism, which influences the effectiveness of B-cell depletion. In the ULTIMATE I and II studies, ublituximab showed a significant reduction in annual relapse rate versus teriflunomide in relapsing MS patients and strikingly reduced active and new/enlarging MRI lesions. Ublituximab also showed efficacy on the disease progression and increased disability improvement in the extended 5-year observation study. The advantage of ublituximab also correlates with good tolerability and reduced infusion-related reactions. Ublituximab infusion, 1 h, is significantly shorter in comparison to other intravenous (IV) preparations of anti-CD20 mAbs. Thus, ublituximab provides better convenience to MS patients as well as saves the time of healthcare providers.
Plain language summary
Multiple sclerosis is a severe neurological disorder which may result inpermanent neurological dysfunction and disability. In the recent years, significant progress in treatment of multiple sclerosis have been achieved. One of the most prominent strategies to treat patients with multiple sclerosis is depletion of B lymphocytes with monoclonal antibodies targeting a CD20 molecule on the surface of B cells. Several anti-CD20 monoclonal antibodies have been approved for treatment of patients with multiple sclerosis. Although targeting the same molecule for B lymphocyte depletion, there are important differences between anti-CD20 monoclonal antibodies. They bind to different fragments of CD20 molecule, and are composed of different proportions of human and mouse proteins, but most importantly have some changes in molecular structure which allow for more efficient B-cell depletion and more effective treatment of MS. Ublituximab is the most recently approved anti-CD20 monoclonal antibody with unique change in the molecular region responsible for induction of B-cell depletion. This modification depends on the removal of a sugar molecule, fucose, from the region binding to effector cells causing B-cell depletion. This modification resulted with higher depletion of B cells associated with additional benefits for MS patients, such as efficient prevention of clinical relapses, delayed disability progression and, most importantly, higher proportion of patients whose neurological status improved. In addition, the unique ublituximab structure allows better tolerance during its administration and shorter infusion time. Therefore, ublituximab with its unique molecular composition is a valuable improvement in management of multiple sclerosis.
Introduction
Multiple sclerosis (MS) therapy witnessed an unprecedented development within the last two decades. One of the biggest progresses occurred with the introduction of anti-CD20 monoclonal antibodies. 1 Initial results with rituximab, a chimeric anti-CD20, suggested that depleting B cells might represent a highly effective treatment of MS. 2 Following years allowed for the development of a number of anti-CD20 monoclonal antibodies with some different specificities and molecular changes with respect to B-cell interaction and molecular composition. In the OPERA I and II studies, ocrelizumab, a humanized anti-CD-20, showed a significant reduction in annualized relapse rate (ARR) versus interferon beta-1a and strikingly reduced gadolinium-enhancing lesions. 3 Ocrelizumab also showed efficacy on the disease progression in the primary progressive form of the disease. 4 Subsequently, ofatumumab, a fully humanized anti-CD20, offered a new subcutaneous way of administration with more flexibility, reduction of the use of infusion centers, and a benefit for patients preferring self-administration. 5 The recent development of ublituximab represents a next step in the development of anti-CD20 monoclonal antibodies in MS treatment. A unique property of ublituximab resulted from the glycoengineering of receptor binding Fc region, which allowed for the selection of more effective mechanisms of B-cell depletion, more consistent depletion and greater benefit to patients in regard to tolerability and convenience. 6
Differences in anti-CD20 monoclonal antibodies
Anti-CD-20 monoclonal antibodies have been developed to bind to the CD-20 molecule expressed on the surface of a large population of B cells and deplete them. The primary concept to use anti-CD20 in MS treatment was generated from earlier studies demonstrating a pivotal role of B cells in MS mechanisms 7 and, in particular, from the initial clinical studies with rituximab. 2 Depletion of B cells with anti-CD20 monoclonal antibodies was expected to eliminate B cells engaged in antigen presentation and T cell stimulation within the central nervous system, reduce proinflammatory cytokine and anti-myelin antibodies production, and reverse the proinflammatory environment, and implement immunoregulation. 8
Three out of four anti-CD20 mAbs, initially tested in MS, have been approved for MS treatment by the FDA and EMA: ocrelizumab, 3 ofatumumab, 5 and ublituximab. 6 The first anti-CD20 mAb, rituximab, although not approved, is widely used in many countries as a label therapeutic for MS. 9 All of these mAbs demonstrate some structural differences responsible for the mechanism of B cell binding as well as for efficacy and kinetics of B cell elimination (Table 1). This is particularly true for ublituximab, the most recent addition to the anti-CD20 mAbs family. Ublituximab is the only anti-CD20 mAb with a molecular structure manipulated and increased potency in the mechanism of B-cell depletion. 10
Anti-CD20 mAbs studied in MS patients.
ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; MOA, mechanism of action; MS, multiple sclerosis; NA, not applicaable; SC, subcutanous.
Ublituximab glycoengineered structure
Anti-CD20 mAbs activity requires specific binding to the CD20 molecule by the Fab region of the mAb and simultaneous binding of the Fc region to Fc receptors, in particular FcγRIIIa on effector immune cells, mainly NK cells or the C1q component of complement. 11 This type of interaction allows for induction of antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against B cells (Figure 1). All anti-CD20 mAbs utilized in MS treatment use these two mechanisms of B-cell depletion, but to a varying extent. Ublituximab has a unique glycoengineered structure of the Fc region with reduced fucosylation, which enhances affinity to FcγRIIIa. 12 Removal of fucose from the Fc region oligosaccharide reduces its blocking interaction with FcγRIIIa and allows for closer binding and higher effectiveness of ADCC (Figure 2(a)). Importantly, removal of fucose from the Fc region does not alter the effectiveness of CDC. As a consequence, ublituximab, a glycoengineered mAb with low fucose content exhibit significantly higher ADCC activity in relation to CDC.13,14 This structure of ublituximab leading to more effective activation of ADCC versus CDC is thought to exhibit higher potency to deplete B cells. Such a conclusion is supported by data from the comparison of obinutuzumab versus rituximab in chronic lymphocytic leukemia (CLL) and follicular lymphoma. Obinutuzumab is a glycoengineered mAb similar to ublituximab, and in a trial assessing its effectiveness versus rituximab in CLL showed more robust B-cell elimination and disease eradication. 15 Of interest, a similar glycoengineering of the Fc region with the removal of fucose was applied to inebilizumab, an anti-CD19 mAb approved for the treatment of aquaporin 4-positive NNMOSD. 16 Inebilizumab showed higher affinity to FcγRIIIa and higher depletion of B cells in comparison to rituximab. The unique glycoengineered structure of ublituximab with low fucose content in the Fc region resulted in significantly higher ADCC activity compared with all other anti-CD20 mAbs used for MS treatment. 17 Interestingly, ocrelizumab is glycoengineered with respect to amino acid composition and, as a consequence, has ADCC significantly higher than the parent mAb rituximab. 18 The two other mAbs used for MS treatment, rituximab and ofatumumab, have B-cell depletion mechanism mostly dependent on CDC.
Mechanism of anti-CD20 antibody-dependent cytotoxicity (ADCC) versus complement-dependent cytotoxicity (CDC) elimination of B cells.
Glycoengineering improves ublituximab interaction with Fcγ receptor IIIa on effector cells irrespective of its polymorphism. (a) Non-glycoengineered antibody has a “bulky” Fc portion (left panel), whereas a modified one has an improved fit for an Fc receptor (right panel). (b) FcyRIIIa polymorphism 158V/F additionally affects binding of an immunoglobulin: 158F variant binds IgG antibodies less tightly, resulting in less efficient effect of the regular monoclonal antibody, whereas a glycoengineered antibody action is likely to be unaffected.
Binding of anti-CD20 mAbs
Ublituximab binds an epitope on the large loop of CD20, with some overlap to the binding of ocrelizumab and rituximab. 19 In contrast ofatumumab binds to two epitopes, one on the large loop and one on the small loop. 20 The binding to the small loop causes a higher rate of CDC use in the mechanism of B-cell depletion by ofatumumab, resulting from oblique positioning of the antibody facilitating C1q recruitment. 21 This type of antibody binding might affect the efficacy of B-cell depletion and the occurrence of infusion-related reaction (IRR).
Ublituximab resistance to Fc gamma receptor IIIa polymorphism
Human genetic variants of FcγRIIIa depend on single-nucleotide polymorphism, which influences the strength of receptor binding to the Fc region of IgG and thus controls the effectiveness of B-cell depletion. 22 The FcγRIIIa 158F polymorphism has weaker IgG binding than the FcγRIIIa158V polymorphism 14 (Figure 2(b)). Patients with FcγRIIIa 158F polymorphism have NK cells with weaker ADCC potential compared to patients with FcγRIIIa 158V variant and thus weaker potency of B-cell depletion. This type of FcγRIIIa is present in 40% of the human population. The role of FcγRIIIa polymorphism was studied in several rituximab trials in a number of autoimmune disorders. 15 Most relevant to MS was a study Neuromyelitis optica spectrum disorder (NMOSD) in which patients with the 158F variant showed a greater risk of insufficient B-cell depletion and a higher risk for relapse during rituximab treatment. 23 Similarly, patients with rheumatoid arthritis and lupus erythematosus with the 158V variant showed significant higher rate of positive treatment response than patients with the 158F variant. 24 Importantly, glycoengineering of the Fc region of mAb may eliminate the differential effects of NK cell activation dependent on FcγRIIIa polymorphisms. The data from NMOSD studies with inebilizumab, which is similarly glycoengineered, such as ublituximab, did not show any difference in clinical outcomes and B-cell depletion between patients with the 158F and the 158V variants. 25 Interestingly, in the recent report on the clinical outcome in MS patients treated with ocrelizumab, it was found that there was no difference between patients with the 158F and the 158V polymorphism. 26 Ocrelizumab also has a glycoengineered Fc region of IgG, although in a different mechanism to ublituximab, amino acid substitution versus fucose removal. 18 Thus, glycoengineered Fc region with fucose removal might protect patients from the 158F polymorphism-mediated diminished B-cell depletion.
Results from the pivotal studies
Ublituximab efficacy was evaluated in two identical, phase III, double-blind, double-dummy trials (ULTIMATE I and II). 6 Patients with relapsing multiple sclerosis (pwRMS) were randomly assigned in a 1:1 ratio to receive intravenous ublituximab and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. Ublituximab was administered at a dose of 150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72. An antihistamine (oral diphenhydramine 50 mg or equivalent) and oral dexamethasone 10–20 mg or equivalent glucocorticoid were administered 30–60 min prior to each dose of ublituximab or intravenous placebo in all participants. The primary end point was the ARR defined as the number of confirmed relapses of multiple sclerosis per participant-year. Each suspected relapse was adjudicated by an independent panel to confirm a protocol-defined relapse. There were six hierarchically ordered secondary end points: total number of gadolinium-enhancing lesions per T1-weighted MRI scan by week 96; total number of new or enlarging hyperintense lesions per T2-weighted MRI scan by week 96; time to disability progression confirmed for at least 12 weeks (pooled across studies); proportion of participants with no evidence of disease activity (NEDA) from week 24 to week 96; proportion of participants reaching impaired Symbol Digit Modalities Test (SDMT) from baseline up to the week 96 visit; and percentage change in brain volume from baseline to week 96. Tertiary end points, which were not included in the hierarchical analysis, included time to disability progression, disability improvement, and change in Multiple Sclerosis Functional Composite score. Key eligibility criteria included an age of 18–55 years; a diagnosis of relapsing multiple sclerosis as per the 2010 revised McDonald criteria; at least two relapses in the previous 2 years, and/or one relapse in the 1 year prior, and/or at least one gadolinium-enhancing lesion in the year prior to screening; brain MRI with abnormalities consistent with multiple sclerosis; an Expanded Disability Status Scale (EDSS) score of 0–5.5 at screening and neurologic stability for at least 30 days prior to screening and baseline assessment. Adverse events were reported during all visits and graded according to the Common Terminology Criteria for Adverse Events. Clinical laboratory tests such as hematology, chemistry, pregnancy tests, electrocardiogram, and vital signs were also conducted. In both ULTIMATE studies, there were 1090 participants (104 sites from 10 countries), 549 in ULTIMATE I and 545 in ULTIMATE II. The median follow-up time was 95 weeks. The participants’ retention in both studies was very good, from 90.5% to 89.6% in the ublituximab and teriflunomide arms, respectively.
B-cell depletion
Participants receiving ublituximab had a rapid and significant decrease in the median number of CD19+ B cells 24 h after the first dose (96% reduction), while participants receiving teriflunomide had an increase (53% increase). Counts remained depleted (97% reduction) through the end of the double-blind period with ublituximab and modestly decreased with teriflunomide (18% reduction). 27
Annualized relapse rate
In the ULTIMATE I trial, the adjusted ARR over 96 weeks was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27–0.62; p < 0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33–0.78; p = 0.002) 6 (Table 2). Post hoc analysis revealed that Ublituximab was superior to teriflunomide in key efficacy measures across multiple demographic and disease characteristic participant subpopulations, including gender, age, EDSS, number of relapses, and Gad-enhancing lesions, previous MS treatment at baseline in ULTIMATE I and II. 28 In the treatment-naive subpopulation, significant improvements with ublituximab versus teriflunomide were observed at week 96, including an adjusted ARR of 0.081 versus 0.188, respectively (p < 0.0001), 56.7% difference, which was higher than in the previously treated subpopulation, 50.7% difference in ublituximab versus teriflunomide. 29
Efficacy measures of ublituximab in phase 3 trails
Difference between ublituximab and teriflunomide groups statistically significant, p < 0.002.
ARR, annualized relapse rate; HR, hazard ratio; NEDA, no evidence of disease activity; OR, odds ratio; RR, risk ratio; SDMT, Symbol Digit Modalities Test.
MRI
pwRMS in the ublituximab arms of both studies showed a significantly lower rate of gadolinium-enhancing lesions. 6 The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02–0.06; p < 0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02–0.06; p < 0.001), in the ULTIMATE II trial. The mean total number of new or enlarging hyperintense lesions per T2-weighted MRI scan for ublituximab versus teriflunomide in ULTIMATE I was 0.21 versus 2.79 (rate ratio, 0.08; 95% CI, 0.06–0.10) and in ULTIMATE II was 0.28 versus 2.83 (rate ratio, 0.10; 95% CI, 0.07–0.14) (Table 2). The percent change in brain volume was not significantly different between groups because of failure of the preceding clinical endpoint in the hierarchical analysis (disability progression at 12 weeks), and the confidence intervals for differences from placebo included zero. However, Ublituximab treatment significantly reduced thalamic volume loss relative to teriflunomide by 22%. Ublituximab treatment significantly reduced the number of new non-enhancing T1 lesions relative to teriflunomide by 40.1%, 98.1%, and 99.7% from 0 to 24, 24 to 48, and 48 to 96 weeks, respectively. Reduction in non-enhancing T1 lesion volume was more pronounced in Year 2 of Ublituximab treatment (85.5%) than in Year 1 (63%), compared to Teriflunomide over 2 years. 30 In a subgroup of participants with highly active disease, ublituximab significantly reduced key MRI measures of disease activity including: 83% reduction in Gd+T1 lesions (least squares mean per scan = 0.114 vs 0.683) with 88% of participants free from Gd+T1 lesions (both p < 0.0001) at this early timepoint, 58% reduction in new/enlarging T2 lesions (least squares mean per scan = 1.754 vs 4.127) (p < 0.0001). 31
Disability progression
In the prespecified pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50–1.41; p = 0.51) and 3.3% of participants treated with ublituximab had disability progression confirmed at 24 weeks, compared with 4.8% of participants treated with teriflunomide (hazard ratio, 0.66; 95% CI 0.36–1.21). The percentage of participants with SDMT impairment was similar across both treatment groups in each trial. However, in a pooled post hoc analysis, ublituximab was associated with a mean 4.1 increase in SDMT score at week 96 from baseline, established as a clinically meaningful improvement. 32 In the prespecified pooled tertiary analysis, 12% of participants treated with ublituximab had disability improvement confirmed at 12 weeks, compared with 6.0% of participants treated with teriflunomide (hazard ratio 2.16; 95% CI 1.41–3.31) and 9.6% of participants treated with ublituximab had disability improvement confirmed at 24 weeks, compared with 5.1% of participants treated with teriflunomide (hazard ratio 2.03; 95% CI 1.27–3.25). In the treatment-naïve subpopulation, estimated rates of 12 week-confirmed disability improvement (CDI) were 11.2% in ublituximab-treated patients versus 5.5% in the teriflunomide group, hazard ratio (95% CI), 2.031 (1.174–3.513; p = 0.0095). 29
No evidence of disease activity
In ULTIMATE I, 44.6% of participants treated with ublituximab and 15% of participants treated with teriflunomide achieved NEDA, and very similar results were observed in ULTIMATE II: ublituximab, 43.0%, and teriflunomide, 11.4%, respectively. Subsequent analysis evaluated the timing of NEDA onset and proportion of participants maintaining NEDA with ublituximab in pooled post hoc analyses of ULTIMATE I and II showed that 53.4% of ublituximab-treated participants achieved NEDA during weeks 0–24, 82.1% of ublituximab-treated participants had NEDA during weeks 24–96, 45.2% of participants achieved NEDA during weeks 0–24 and maintained NEDA during weeks 24–96, 36.9% of participants had evidence of disease activity (EDA) during weeks 0–24 but NEDA during weeks 24–96, 88.2% of ublituximab-treated participants had NEDA during weeks 48–96, 83.5% of participants achieved NEDA during weeks 24–48 and maintained NEDA during weeks 48–96. An additional 4.8% of participants had EDA during weeks 24–48 but achieved NEDA during weeks 48–96. 33
Safety
The data from the phase 2 ublituximab study showed a good safety profile with no adverse events related to discontinuations. 34 The pooled analysis of both ULTIMATE studies showed that adverse events occurred with equal frequency in patients with multiple sclerosis (pwMS) treated with ublituximab and teriflunomide, 89.2% and 91.4%, respectively. 6 The most common adverse events experienced by ublituximab-treated participants were infusion-related reactions (47.7%—see below), headache (34.3%), nasopharyngitis (18.3%), pyrexia (13.9%), and nausea (10.6%). In the teriflunomide group, additional adverse events were alopecia (15.3%) and diarrhea (10.6%). Serious adverse events occurred in 10,8% of participants treated with ublituximab and in 7.3% treated with teriflunomide. Three deaths occurred in the ublituximab treatment group as a result of pneumonia, post-measles encephalitis, and salpingitis after an ectopic pregnancy. Infections occurred in equal frequency in pwMS treated with ublituximab and teriflunomide, 55.5% versus 54.4%. Most infections were respiratory tract-related of mild severity (grade 1–2). Serious infections were observed in 5% of pwMS treated with ublituximab and in 2.9% treated with teriflunomide. No opportunistic infection was reported. No case of progressive multifocal encephalopathy (PML) occurred in both treatment arms.
Infusion-related reactions
IRR occurred in 47.7% of the ublituximab group. IRR symptoms included pyrexia, headache, chills, and influenza-like illness. On most occasions, IRR were mild to moderate in severity and occurred at the first infusion (43.3%), with a decrease in frequency with subsequent drug administration. Only two pwMS experienced a grade 4 IRR. One participant experienced an anaphylaxis during the second infusion with complete recovery and stopping of further treatment.
Relatively modest effect of IRR in ublituximab-treated pwMS might result from its mechanism of action. IRR are predominantly associated with cytokine release and complement activation, which generates anaphylatoxins, C3a and C5a components, which are strong cytokine releasers. 27 Thus, CDC has a predominant role in IRR induction. 35 Since in patients treated with ublituximab the balance of B cell depletion mechanisms is strongly shifted toward ADCC (see above) the risk for IRR is reduced.
Long term efficacy and safety
Following completion of the 2-year, multicenter, randomized, active-controlled, double-blind period of the ULTIMATE I and II phase 3 studies, participants enrolled in the ULTIMATE open-label extension (OLE) study. Patients treated with ublituximab continued with ublituximab and patients from teriflunomide arm switched to ublituximab. 36 The primary outcomes of the OLE study were ARR, 24 week-confirmed disability worsening, 24 week CDI. Above 85% of participants entered the OLE (422 continued ublituximab and 429 switched from teriflunomide), and >70% remained on ublituximab at year 5.
Participants who switched from teriflunomide experienced a 58.4% reduction in ARR at 1 year post switch (0.182 vs 0.076; p < .001). In subsequent years, 4 and 5, ARR continued to decrease to 0.048 and 0.045, respectively. Participants who continued on ublituximab had further reductions in ARR in years 3, 4, and 5 (0.053, 0.032, and 0.020). At year 5, 24-week-CDP was 8.0% in patients who continued ublituximab versus 14.3% in patients switched from teriflunomide (p = 0.013), and 24-week CDI was 17.0% in continued patients versus 12.2% in the switched participants (p = 0.025). Ninety-two percent of continued patients remained free from disability worsening. 37 Adverse events were consistent with the previous safety profile from phase III trials, and no new safety signals were reported. No increased rate of infection, including serious infections, was observed. Immunoglobulin levels, both IgM and IgG, remained on average above the lower limit of normal (LLN), and no higher rate of infections correlated with immunoglobulin levels. In the continuous cohort that received ublituximab for at least 5 years, the mean (SE) IgM levels were 0.69 (0.04) g/L, and the mean (SE) IgG levels were 8.06 (0.13) g/L. At year 5, IgG reduction versus randomization was limited, 12.9%, and IgM reduction was mild, 35%. 38
Real-world experience
Real-world experience with ublituximab treatment of MS patients was valuable to understand patient outcomes in regular clinical settings. A retrospective chart review of 163 patients who have been treated with ublituximab at one USA site showed that the majority, 77%, were switched from other therapies, including 38% switched from other B-cell agents. 39 Tolerability of ublituximab was very good with only 28.2% patients experiencing IRRs during the 1 dose compared to 43.3% in Phase 3 trials. All IRRs were mild to moderate. Patients were switched from their previous therapy due to efficacy wearing off, CD19 B-cell repletion, disability progression, and recurrence of MRI activity. Of the 12 patients that switched due to MRI activity, 83.3% had stable MRI’s post switch to ublituximab. Among 38 patients switched from prior ocrelizumab, 50% experiencing wearing-off effect on prior therapy, most commonly fatigue (52.3%) and cognitive impairment (19.7%), showed resolution of wearing-off symptoms on ublituximab in 84% within 1 year of treatment. B-cell repletion occurred in 21.05% of patients who experienced wearing off on ocrelizumab, and post-ublituximab, these patients’ B-cell values depleted to 0. On the whole, after switching to ublituximab, nearly all patients demonstrated significant control of disease activity with marked reduction in wearing-off symptomatology. Almost all patients experiencing repletion on prior B-cell therapy had complete resolution with ublituximab.
In another retrospective case series of seven individuals who switched to ublituximab from a different anti-CD20 mAb because of suboptimal B-cell depletion, inadequate MS disease control, and/or tolerability concerns, it has been proven that the disease was fully stabilized both at clinical and MRI measures. 40 These data indicate that within-class switching from a prior anti-CD20 mAb therapy to ublituximab is feasible and may improve outcomes in some people with MS. Overall, the real-world experiences reinforce the safety, tolerability, and efficacy of ublituximab in RMS patients. The ongoing ENHANCE study evaluates the efficacy, safety, and tolerability of transitioning from a previous disease-modifying therapies (DMT), including anti-CD20 mAbs, to ublituximab, exploring the elimination of the initial 150 mg dose in B-cell–depleted participants and shorter infusion durations for the full 450 mg doses. 41
Discussion
The family of anti-CD20 mAbs in multiple sclerosis has recently expanded by a new member, ublituximab. Ublituximab differs from other anti-CD20 mAbs in several features. The most important difference is its molecular composition. In contrast to the other anti-CD20 mAbs, ublituximab has a glycoengineered Fc region of its molecule. 12 The removal of fucose from Fc region oligosaccharides allowed for the generation of an antibody with higher efficacy binding to Fc gamma receptor on effector cells involved in the ADCC. This molecular modification increases the effectiveness of ADCC induced by ublituximab as well as its effectiveness in B-cell depletion.13,14 ADCC remains the most efficient mechanism of immunologically induced cytotoxicity. Ublituximab was shown to have higher FcγRIIIa binding and ADCC activity compared with other commercially available anti-CD20 mAbs. There are also some additional benefits from ublituximab’s molecular particularities. The polymorphism 158F versus 158V responsible for diminished efficacy of anti-CD20 mAbs in B-cell depletion seems to be, due to Fc region glycoengineering, of lesser importance in ublituximab-treated patients. 22 However, these data are still awaiting confirmation in a real-world setting. Thus, ublituximab represents a unique anti-CD20 mAb with several features that clearly distinguish it from other anti-CD20 mAbs.
Ublituximab was evaluated in two identical phase III double-blinded studies versus active comparator teriflunomide. Two-year observation under double-blind conditions demonstrated significant superiority of ublituximab versus teriflunomide in the primary outcome, ARR, as well as in a number of secondary and tertiary outcomes. 6 Although there is a lack of head-to-head comparisons between anti-CD20 mAbs, it should be emphasized that ARR = 0.08 in patients treated with ublituximab was among the lowest in MS clinical trials with this category of drugsand continued to reduce over time in the subsequent years of the extension program, reaching the value of 0.02 in year 5. 33 Treatment of naïve pwMS treated with ublituximab showed even better outcomes than the total ublituximab population compared with the teriflunomide group. This observation might have significant practical implications for treatment sequencing decisions with strong indication for early initiation of ublituximab treatment. Accordingly, ublituximab demonstrated significant reduction in new/enlarging and active MRI lesions similar to other anti-CD20 mAbs used in MS treatment. At year 5 of continued ublituximab exposure in a pooled data set significant decrease in disability progression was observed versus patients switched from teriflunomide at the end of the double-blinded period. 36 Importantly, the proportion of patients with improved disability after 5 years of ublituximab exposure was significantly increased versus the switched group. These encouraging data on ublituximab efficacy in MS should, however, be interpreted from the perspective of the lack of head-to-head studies with other anti-CD20 monoclonal antibodies.
Ublituximab treatment was well tolerated, and the rate of serious adverse events was low. No new safety signals were reported within 5 years of the extension program. Importantly, no increased rate of infections, including serious infections, was reported. IRRs represent an important event in patients treated with mAbs, which might affect treatment adherence and well-being. Since in patients treated with ublituximab, the mechanism of B-cell depletion is strongly shifted toward ADCC, the risk for IRR was reduced. Still, IRRs were the most common adverse events experienced by ublituximab-treated patients. In double-blinded phase III studies, IRRs occurred in 47.7% of patients, whereas the rate was lower in the 5-year extension study, 26.7%, indicating IRR reduction over time. The total number of infusions without interruption because of IRR was almost 99%, suggesting very good tolerance of ublituximab. Immunoglobulin levels, both IgM and IgG, remained on average above the LLN for 5 years with only a mild decrease in IgG and a moderate of IgM. 38 No correlation between immunoglobulin levels and infection rates was reported. Physicians treating pwMS with ublituximab should, however, be aware of the risk of hepatitis B reactivation, and complete liver serology is required prior to treatment initiation. Low rate of serious infections leading to treatment discontinuation was reported within a 5-year follow-up of clinical trials. Recently, a case of PML was reported in an MS patient treated with ublituximab in the post-marketing setting for 6 months. 42 This patient was treated earlier with ocrelizumab for nearly 3 years; thus, a carry-over mechanism might be suspected in this case. Additional diagnostic challenge refers to cerebrospinal fluid (CSF) negative PCR test and positive result of metagenomic JC virus sequencing. A brain biopsy was performed, which showed JC virus-positive glial cells, confirming the diagnosis of PML. This is the first case of PML reported in the ublituximab MS population of 16,000 patients with relapsing forms of MS who have been treated with ublituximab globally across clinical trials and in the post-marketing setting. Despite this very low risk of PML in patients treated with ublituximab, it should be remembered that PML cases did occur during treatment with other anti-CD20 monoclonals, for example, rituximab. Thus, careful monitoring for the risk of PML during ublituximab treatment is recommended. The incidence rate of all malignancies during ublituximab treatment was low, in the pooled 5-year data observation (SIR = 0.17), which was consistent with the double-blinded studies and within expected levels from the average population cancer death rate.
Not all MS patients respond optimally to anti-CD20 mAb therapy, and suboptimal B-cell depletion and breakthrough MS disease activity have been reported.43,44 The unique properties of ublituximab combined with its high potential for effective B-cell depletion prompted us to investigate the within-class switching from a prior anti-CD20 mAb. A substantial number, up to 26%, of people with MS treated with ocrelizumab had B-cell repletion at 6 months, and B-cell repletion at 6 months was associated with significantly higher MRI activity at 12 months. 45 In the pivotal ocrelizumab studies, body weight impacted ocrelizumab exposure and depletion of B cells, and >30% of participants in the lowest exposure quartile had incomplete B-cell depletion at week 96. 46 Efficacy of anti-CD20 therapies depends on depletion of CD20-positive B cells and possibly of CD20-positive T cells. Therefore, it was suggested that suboptimal response to one anti-CD20 mAb does not preclude improved response to a different anti-CD20 mAb, supporting the benefit of within-class treatment switching.
Within-class switching emerging as a novel clinical scenario in MS treatment with particular relevance to anti-CD20 monoclonal antibodies. Three approved anti-CD20 mAbs differ in their molecular structure, leading to some important functional differences. Importantly, nearly all patients experiencing repletion on prior B-cell therapy had near complete resolution with ublituximab.39,40 Overall, the real-world experience reinforces the safety, tolerability, and efficacy of ublituximab in RMS patients, also in patients previously treated with anti-CD20 mAbs. These observations might support attempts to switch to anti-CD20 therapy for patients with suboptimal response to a prior anti-CD20 mAb and not fully effective B-cell depletion.
Ublituximab is administered with IV infusions every 6 months at a dose of 450 mg, which is lower than other IV anti-CD20 mAbs used for MS treatment. An initial dose of 150 mg is given 2 weeks prior to the first 450 mg dose. Because of good tolerance, a low rate of IRR resulted from ublituximab molecular characteristics and higher efficacy of ADCC versus CDC in the B-cell depletion mechanism, the time of ublituximab infusion, 1 h, is significantly shorter in comparison to other IV preparations of anti-CD20 mAbs used for treatment of pwMS. Thus, ublituximab administration is more convenient to patients as well as saves the time of healthcare providers. The latter conclusion corresponds to the pharmaco-economic benefits during treatment of pwMS with ublituximab and improve cost-effectiveness of MS management. Further studies should detail the range of these savings. Altogether, balancing the efficacy and safety of ublituximab with the addition of its unique molecular composition represents a valuable improvement in the management of pwMS.
