Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis

Abstract

Rituximab, ocrelizumab, ofatumumab and ublituximab are disease modifying therapies (DMT) currently used in the treatment of multiple sclerosis (MS) or are in advanced stages of clinical trials. These monoclonal antibodies deplete B cells by targeting the cell surface protein CD20. This review highlights the similarities and major differences between the four agents. We summarize data from various clinical trials of each of these therapeutics and discuss their efficacy and safety. Additional considerations regarding the route of administration and cost are presented. Among the four therapeutics, only ocrelizumab is approved for primary progressive (PP) MS. Infusion/injection related reactions (IRRs) are the most common adverse events associated with all four therapeutics. In phase III trials of ocrelizumab and ofatumumab, the incidence of IRRs was lower with ofatumumab. Ofatumumab is unique among the four therapeutics due to its availability as a subcutaneous injection (SQ). Although SQ administration may be appealing for some patients it may raise concerns regarding medication compliance among physicians. Phase II trials studying ublituximab for the treatment of RMS yielded promising results. Phase III trials are currently comparing the efficacy of ublituximab to teriflunomide.

1. Introduction

Multiple sclerosis (MS) is an incurable, lifelong neurodegenerative disease that is thought to be driven by an autoimmune response to myelin antigens (Goldenberg, 2012, Filippi et al., 2018). Inflammation within the central nervous system (CNS) leads to accumulation of immune cells, demyelination and subsequent neuronal loss (Goldenberg, 2012, Filippi et al., 2018). MS is generally classified based on its clinical course into relapsing remitting MS (RRMS) or secondary progressive MS (SPMS), which can be further divided into active versus inactive (referring to visible inflammatory activity, whether detected by MRI or superimposed clinical relapses) and primary progressive MS (PPMS) (Goldenberg, 2012, Filippi et al., 2018).

There is no cure for MS, but disease modifying therapies (DMT) that target the immune response have been shown to reduce relapse rates, the formation of new or active MRI brain lesions and slowing the disease progression in some patients (reviewed in (Vargas and Tyor, 2017)). More recently, treatment goals included no evidence of disease activity (NEDA), which refers to the absence of new relapses, new or active MRI lesions and disease progression. This is often referred to as NEDA-3. NEDA-4 further adds the absence of accelerated brain volume loss, and NEDA-5 refers to the absence of biomarkers suggestive of neuronal or axonal loss (Cree et al., 2019).

Of the various FDA approved DMTs available to treat MS (reviewed in (Baecher-Allan et al., 2018)), B cell depletion with anti-CD20 has emerged as both efficacious and relatively safe (Gelfand et al., 2017, Greenfield and Hauser, 2018). CD20 is a glycoprotein expressed on the cell surface of B cells starting early in their development in the bone marrow through the mature B cell stages (Ernst et al., 2005, Pavlasova and Mraz, 2020). B cells recognize antigen via the antigen binding domains of their B cell receptor (BCR) leading to their activation (Adler et al., 2017). After recognition, antigen is internalized and the proteins are processed and presented on the cell surface as peptide/major histocompatibility complexes (MHC) (Adler et al., 2017). MS is classically considered a CD4 T cell-mediated disease, which recognize peptide antigens complexed to MHC class II molecules (Legroux and Arbour, 2015). The presentation of antigen to CD4 T cells by B cells, results in crosstalk between the two cell types and signaling leading to B cell differentiation into antibody secreting cells (Hua and Hou, 2020). B cells first undergo differentiation into plasmablasts, which begin to secrete antibodies (Nera et al., 2015). Antibodies are a secreted version of the BCR and are also known as immunoglobulins (Ig). Plasmablasts can further differentiate into long-lived plasma cells that migrate back to the bone marrow and secrete antibodies into the blood for decades (Nutt et al., 2015). After activation, B cells can also undergo a fate decision to become long-lived memory B cells (Palm and Henry, 2019). The function of memory B cells is to provide fast and efficient antibody responses upon re-exposure to the same antigen (Palm and Henry, 2019, Kurosaki et al., 2015).

Upon differentiation into plasmablasts, B cells begin to downregulate the expression of CD20, which is not expressed by plasma cells (Uchida et al., 2004). Thus, some plasmablasts and virtually all plasma cells are refractory to anti-CD20 B cell depletion. In contrast, memory B cells retain CD20 and are depleted with anti-CD20. Although, oligoclonal Ig bands are found in the cerebrospinal fluid (CSF) of most MS patients, there is no concrete evidence that antibodies are pathogenic in MS (Holmoy, 2009). Thus, the efficacy of B cell depletion in MS has placed a focus on a potential role for effector/memory B cells with the capacity to present antigen to autoreactive T cells (Baker et al., 2017, Li et al., 2018).

Currently, there are two FDA approved anti-CD20 antibodies for the treatment of MS: ocrelizumab and ofatumumab (Gelfand et al., 2017). While rituximab is commonly used in MS treatment, it never obtained FDA approval for MS. Several other FDA indications for rituximab included non-Hodgkin’s lymphoma and rheumatoid arthritis (RA) (Salles et al., 2017, Tavakolpour et al., 2019). Rituximab has been shown in multiple studies to be effective and relatively safe for the treatment of MS. It has been shown to reduce relapse rates and MRI activity and the number of B and T cells in the cerebrospinal fluid (Naismith et al., 2010, Piccio et al., 2010, Bar-Or et al., 2008, Cross et al., 2006). Ocrelizumab is biologically similar to rituximab and was FDA approved in 2017 for both RRMS and PPMS (Montalban et al., 2017). The newest antibody on the market is ofatumumab, which was FDA approved for relapsing forms of MS in 2020. Ofatumumab differs in its CD20 binding site and mode of administration from the other two antibodies (Gelfand et al., 2017). Ublituximab, a chimeric antibody glycoengineered to exhibit potent B cell depletion, is currently being studied in phase III trials. The aim of this review was to comprehensively compare and contrast the four anti-CD20 therapeutics in regard to biological properties, efficacy and safety profiles for the treatment of MS.

2. Literature Search Strategy

We performed a systematic search in PubMed for original research articles and ClinicalTrials.gov, for clinical trials through August 2020. We used the search terms “Rituximab, Multiple Sclerosis”, “Ocrelizumab, Multiple Sclerosis”, “Ofatumumab, Multiple Sclerosis”, “B cell depletion, Multiple Sclerosis” and “Ublituximab, Multiple Sclerosis”. We further searched the references of each of the eligible publications for any relevant studies. Also, we searched the manufacturer websites for rituximab, ocrelizumab and ofatumumab. For each of the drugs, we searched for the associated terms “PML”, “progressive multifocal leu-koencephalopathy”, “cancer” and “breast cancer”.

We screened abstracts and titles and included publications in the English language that addressed the safety and efficacy of rituximab, ocrelizumab, ofatumumab and ublituximab in MS, and studies that addressed the mechanism of action of rituximab, ocrelizumab, ofatumumab and ublituximab in MS.

3. Mode of Antibody Administration

The route of administration is similar between rituximab, ocrelizumab and ublituximab (intravenous (IV)) but different from ofatumumab (subcutaneous (SQ)). A major difference between the two dosing approaches is pharmacokinetics in regard to how fast the drug reaches systemic circulation. IV administered drugs directly enter the systemic circulation thereby offering fast 100% bioavailability (Sanchez-Felix et al., 2020). Due to the presence of loose capillaries in the spleen and the presence of B cells to which anti-CD20 binds, IV administered antibodies induce profound depletion of splenic B cells (Cataldi et al., 2017). However, some drawbacks are the expense of hospital administration, infusion/injection related reactions (IRRs), pain and reduced patient tolerability (Viola et al., 2018). SQ administration delivers drugs into the hypodermis and are dependent upon drug absorption rate pharmacokinetics (Sanchez-Felix et al., 2020, Viola et al., 2018, Richter and Jacobsen, 2014). Drug absorption rates of SQ administered drugs are dependent upon a variety of physiological factors and need to be transported through the interstitium to the lymphatics prior to reaching the systemic blood circulation (Sanchez-Felix et al., 2020, Viola et al., 2018, Richter and Jacobsen, 2014). Due to their size, antibodies likely cannot undergo direct absorption into the blood (Sanchez-Felix et al., 2020). SQ administration has some advantages over IV including at home administration that may appeal to some patients and slower absorption rates that may abrogate side effects (Viola et al., 2018, Richter and Jacobsen, 2014). However, the slower absorption is also a drawback if rapid drug action is required (Richter and Jacobsen, 2014).

4. B Cell and Immunoglobulin Depletion

4.1. Dosing, B cell depletion kinetics and time to repletion

Following rituximab administration in RA patients of either four weekly infusions of 375 mg/m² or two 1,000 mg infusions two weeks apart, naïve B cells returned to baseline levels after 12-16 months (Roll et al., 2006). In contrast, CD27⁺ memory B cells were present at 25% of their baseline level at 25 months. IgD⁺CD27⁺ B cells were present at 33.3% of baseline levels at 25 months. Given its off label use in MS, the administration of rituximab is variable. Common approaches include the IV administration of two 1000 mg at day 0 and 14, also referred to as induction. This can be followed by single or repeat double doses of 1000 mg each at 6 months intervals. Alternative approaches include the administration of 375 mg/m² at intervals following B cell repopulation measured by CD19 or CD20 of 1% or more. Interestingly, recent studies have shown that less frequent dosing may result in similar therapeutic efficacy to traditional dosing and with possibility of improved safety. One study showed maintenance of therapeutic effect at 500 mg instead of 1000 mg, and another extended the interval of dosing by tailoring administration based on memory B cell reappearance (Disanto et al., 2020, Novi et al., 2020)

IV ocrelizumab is administered in two doses of 300 mg at day 0 and day 14. This is followed by 600 mg at 6 months intervals. Following ocrelizumab infusion, B cells returned to baseline or lower limits of normal in 90% of patients within 2.5 years of the last infusion. The median time for B cells to return to baseline was 72 weeks (range: 27-175 weeks) after the final infusion (Genentech, 2017).

Ofatumumab is available as a SQ injection that can be self-administered at home by patients. In the clinical trials, the first injection of 20 mg was given by health care providers at the trial site. The subsequent two loading doses of 20 mg each, were administered by the patient under the supervision of a health care provider at the trial site to ensure proper use. Proper use had to be documented before patients were authorized to administer the medication at home of 20 mg monthly. A pre-filled syringe was used in the parallel ASCLEPIOS trials with 20 mg administered at week 0, 1 and 2 followed by 20 mg monthly starting at week 4. Time to repletion following ofatumumab is faster than with other anti-CD20 antibodies. Following ofatumumab, B cells surpassed the lower limit of normal in over 50% of patients 24 to 36 weeks after the final injection. Median time to recovery is predicted to be 40 weeks following the final injection (Novartis Pharmaceuticals Corporation 8/2020). B cell repletion is an important factor to consider given the risk of infection when B cell populations are low. The more rapid repletion of B cells seen with ofatumumab has the potential to present a more appealing safety profile than seen with rituximab or ocrelizumab.

Ublituximab is currently being studied against teriflunomide in two parallel phase III trials (ULTIMATE I and II) in patients with RMS. In these studies, 450 mg of ublituximab is being infused over a one-hour period (Fox et al., 2020). Limited data is available regarding B cell repletion following administration of the glycoengineered antibody ublituximab. In phase II trials, reductions in the level of B cells was sustained prior to the final dose at week 24 and at study completion (week 48) (Fox et al., 2020).

4.2. Serum immunoglobulin decline

Although CD20 is not preset on plasma cells, a decline in immunoglobulins occurs with anti-CD20 therapies. IgM is declined more than other isotypes of immunoglobulins following both ocrelizumab and ofatumumab. At week 96 of the parallel OPERA I and II trials, IgG, IgA and IgM were below the lower limit of normal in 1.5%, 2.4% and 16.5% of RMS patients who received ocrelizumab (Genentech, 2017). Across the parallel ASCLEPIOS I and II trials, serum IgM levels were below 0.34 g/dL in 14.3% of RMS patients who received ofatumumab. Mean IgG declined by 4.3% at 48 weeks and increased by 2.2% after 96 weeks (Novartis Pharmaceuticals Corporation 8/2020). However, it is unclear how long-term B cells depletion (years-decades) will impact serum immunoglobulin levels and rates of infections.

5. Mechanism of B Cell Depletion

Monoclonal antibodies primarily deplete cells via antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) (Fig. 1) (Weiner, 2010). ADCC is a phenomenon where the effector cells of the immune system with an Fc receptor (FcR) recognize and kill cells that have been coated with IgG via its Fc region (Vidarsson et al., 2014, Ochoa et al., 2017). These effector cells include granulocytes and NK cells that release granules upon FcR engagement that induce apoptosis in the target cell. In contrast, CDC is a phenomenon where IgM and IgG antibodies coat a cell leading to activation of the complement system, which then kills the target cells (Vidarsson et al., 2014). The complement system culminates with terminal complement proteins (C5b-9) forming a membrane attack complex (MAC) on the surface of the target cell. This complex forms pores in the cell membrane which causes osmotic lyses of the cell.

Fig. 1. Mechanisms of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

A) For the initiation of ADCC an antibody recognizes and binds to a cell surface antigen on the target cell. An effector immune cell binds to the Fc portion of the antibody via a FcR. The resulting opsonization leads to degranulation and death by apoptosis of the antibody bound cell. B) CDC occurs after complement proteins bind to an antibody bound to the target cell surface initiating the complement cascade leading to the formation of the membrane attack complex (MAC) resulting in death of the target cell.

Rituximab, ocrelizumab, ofatumumab and ublituximab are IgG₁ monoclonal antibodies, which is the most efficient IgG isotype in complement activation (Fox et al., 2020, Bindon et al., 1988). The four drugs differ in the amount of the immunoglobulin that is human. Chimeric antibodies (rituximab and ublituximab) and humanized antibodies (ocrelizumab) have a human constant region and a variable region that is murine and human. Chimeric antibodies are two-thirds human while humanized antibodies are close to 90% human. Ofatumumab is fully human. Rituximab, ocrelizumab, ofatumumab and ublituximab are classified as type 1 antibodies. Type 1 anti-CD20 antibodies are characterized by their ability to induce the translocation of CD20 into lipid rafts within the plasma membrane, allowing for greater recruitment and activation of complement proteins (Klein et al., 2013). These antibodies exert more potent CDC than their type 2 counterparts (tositumomab and obinutuzumab) (Beers et al., 2008, Bologna et al., 2011). Although rituximab, ocrelizumab, ofatumumab and ublituximab are all type 1 antibodies, the relative level of CDC activity differs between them.

Rituximab and ofatumumab exert higher levels of CDC activity than ADCC activity (Gelfand et al., 2017, Klein et al., 2013, Hauser et al., 2020). In contrast, ocrelizumab and ublituximab exert more ADCC activity than CDC activity (Gelfand et al., 2017, Fox et al., 2020, Klein et al., 2013). The predominance of ADCC in ublituximab is due to a low fucose content in the Fc region which increases affinity for FcγRIIIa (Fox et al., 2020). The weaker CDC activity seen with ocrelizumab and ublituximab is of clinical significance as CDC is believed to play a role in triggering infusion related systemic reactions (Gelfand et al., 2017). Thus, ocrelizumab and ublituximab, in theory, should be associated with a lower incidence of infusion related reactions. However, the exact pathophysiology of infusion related reactions remains unknown and no studies, to date, have been conducted to compare the incidence of systemic administration related reactions between the four therapies.

Although CDC predominates in both ofatumumab and rituximab, studies comparing the two therapeutics in B cell lines have found that ofatumumab exerts more potent CDC than rituximab (Klein et al., 2013, Teeling et al., 2006). Ofatumumab binds to CD20 more tightly and has a slower dissociation rate from CD20 than rituximab (Klein et al., 2013, Teeling et al., 2006). Ofatumumab exhibited more effective C3b deposition and signs of cell lysis induced by the MAC complex in CDC including blebbing (bulging of the plasma membrane) and streamer formation (long structures that extend from the plasma membrane) in various B cell lines than rituximab (Klein et al., 2013, Beum et al., 2008). This may be due in part to greater deposition of complement proteins on the surface of target cells as well as more efficient induction of blebbing and streamer formation via MAC (Kumar et al., 2020). Additionally, rituximab required a 10-fold higher concentration of CD20 on the surface of target cells to induce CDC than was needed by ofatumumab (Teeling et al., 2006). This indicates that ofatumumab is less dependent on the density of CD20 on the surface of target cells than rituximab.

The four monoclonal antibodies differ in the epitope of CD20 that they bind. Rituximab, ocrelizumab and ublituximab bind to the large extracellular loop of CD20, while ofatumumab binds to the large and the small extracellular loops (Fig. 2). The epitope recognized by ocrelizumab overlaps that which is recognized by rituximab. The two drugs also share the same core epitope, the ANPS motif (residues 170-173 on the large extracellular loop of CD20) (Klein et al., 2013). Ofatumumab has a unique core epitope, the FLKMESLNFIRAHT region of the large extracellular loop of CD20 (Klein et al., 2013). Ublituximab binds a unique portion of the large extracellular loop as well as a region overlapping with the epitopes of rituximab and ocrelizumab (Fox et al., 2020). A schematic of the binding epitopes is shown in Fig. 2.

Fig. 2. CD20 binding domains of rituximab, ocrelizumab, ofatumumab and ublituximab.

The binding domains for therapeutic anti-CD20 monoclonal antibodies are shown for A) rituximab (yellow), B) ocrelizumab (red), C) ofatumumab (green) and D) ublituximab (brown).

6. Efficacy

Rituximab led to 88% and 91% reductions in T1 gadolinium enhancing (GdE) lesions in RRMS clinical trials (Naismith et al., 2010, Hauser et al., 2008). Relapse rates were lower in patients treated with rituximab than those who received placebo (14.5% vs. 34.3% at week 24 and 20.3% vs. 40% at week 48) (Hauser et al., 2008). Despite the efficacy of rituximab in RRMS, studies were stopped following phase II trials and the focus shifted to ocrelizumab and ofatumumab.

Ocrelizumab and ofatumumab showed high efficacy in RRMS studies. Ocrelizumab led to 94% and 95% reductions in the number of total T1 GdE lesions in the parallel OPERA I and II trials compared to interferon beta-1a (Hauser et al., 2017). The use of ocrelizumab in the OPERA I and II trials led to 46% and 47% reductions in annualized relapse rate (ARR) compared to an active comparator (Interferon beta (Rebif)) (Hauser et al., 2017). Ofatumumab led to 97% and 94% reductions in Gd T1 lesions and 50.5% and 58.5% reductions in ARR in the ASCLEPIOS I and II trials compared to an active comparator (teriflunomide (Aubagio)), respectively (Hauser et al., 2020). Ofatumumab did not yield a significant reduction in brain volume loss when compared to teriflunomide (annual rate of brain volume loss: −0.28% and −0.29% with ofatumumab and −0.35% and −0.35% with teriflunomide in ASCELPIOS I and II, respectively).Results from other clinical trials using rituximab, ocrelizumab or ofatumumab are presented in Table 1.

Table 1.

summary of clinical trial data

Study	Study Design	Efficacy	Adverse Effects
Clinical trials studying rituximab
Naismith et al. (Naismith et al., 2010)	MS subtype: RMS Trial design: 52-week, MRI blind, RTX add on, phase II trial for patients relapsing while on injectables Subject groups: 30 subjects received 375 mg/m2 RTX IV weekly at weeks 1, 2, 3 and 4. Baseline characteristics of patients: Age, median:: 43.5 years (range: 20-53) Disease duration, median: 7.5 years (range: 2-32) EDSS, mean: 4.7 Number of Gd lesions, mean: 2.81 T2 lesion volume, mean: 25.87 cm3	MRI Measurements: • 74% of post treatment MRI scans did not show GdE activity vs 26% of GdE activity free MRI scans at baseline. • An 88% reduction was seen in the mean number of enhancing lesions per month with RTX. • A 78% decrease in mean volume enhancing lesions per month was seen following RTX treatment. Clinical Measurements: • EDSS remained stable in 27 subjects. Improvements were seen in 7 subjects and a decline was seen in 2 subjects.	IRRs: • 11/30 subjects had minor IRRs. • 2/30 subjects had infusion related reactions that led them to discontinue the trial.
Hauser et al. (HERMES) (Hauser et al., 2008) ClinicalTrials.gov number: NCT00097188	MS subtype: RRMS Trial design: Phase II, randomized, double blind, 48-week trial Subject groups: 69 subjects received 1000 mg IV RTX and 35 subjects received placebo on days 1 and 15 Baseline characteristics of patients: Age, mean: 39.6-41.5 years Time since diagnosis, mean: 6.2-6.9 years EDSS, median: 2.5 Number of GdE lesions, mean: 0.3-2.1	MRI Measurements: • A significant reduction was seen in counts of total and total new GdE lesions at weeks 12, 16, 20 and 24 compared to placebo. • A 91% relative reduction in GdE lesions was seen in the RTX group. • A greater reduction in the volume of T2 lesions was seen in the RTX group than the placebo group from baseline to weeks 24 and 36. Clinical Measurements: • Significantly less subjects in the RTX group had relapses at weeks 24 and 48 compared to placebo. • The proportion of patients with relapses was lower in the RTX group at week 24 and week 48 compared to placebo.	IRRs: • More subjects in the RTX group (78.3%) had AE in the 24 hours following the first infusion than seen in placebo group (40%). Infections: • Infections were reported in 71.4% of the RTX group and 69.6% of placebo. • 2.9% of RTX group had infection associated serious adverse events compared of 5.7% of placebo. Neoplasms: • 1 case of malignant thyroid neoplasm was reported in the RTX group.
Hawker et al. (OLYMPUS) (Hawker et al., 2009) ClinicalTrials.gov number: NCT00087529	MS subtype: PPMS Trial design: Phase II/III, randomized, double-blind, placebo-controlled trial. Subject groups: • 292 subjects received 1,000 mg IV RTX and 147 subjects received placebo on weeks 0, 2, 24, 26, 48, 50, 72 and 74. Baseline characteristics of patients: Age, mean: 49.9 years Time since diagnosis, mean: 4.0 years EDSS, mean: 4.8 0 Total GdE lesions: 75.5% of patients T2 lesion volume, mean: 9,173.25 mm3	MRI Measurements: • Subjects in the RTX group had significantly less increase in T2 lesions volume from baseline to week 96 compared to placebo. • Brain volume change was not significantly different between groups (p=0.62). Clinical Measurements: • No significant difference to CDP was found between groups (p=0.1442). However, subgroup analyses of subjects under 51 years of age or those with gadolinium lesions at baseline showed a delay in time to CDP compared to placebo (p=0.010, p=0.007, respectively)	IRRs: • 67.1% of subjects in the RTX group experienced IRRs on first infusion, compared to 23.1% of placebo. Infections: • Total infection associated events & serious events were reported in 68.2% of the RTX group and 65.3% of the placebo group. • Serious infections associated events were reported in 4.5% of RTX group and less than 1% of placebo.
Bar-Or et al. (Bar-Or et al., 2008)	MS subtype: RRMS Trial design: open label, 72-week, phase I trial. Subject groups: 26 subjects received 1000 mg IV RTX on weeks 0, 2, 24 and 26. Baseline characteristics of patients: Age, mean: 40.4 years Time since diagnosis, mean: 5.4 years EDSS, mean: 2.3 Total Gd lesion count, mean: 1.3 T2 lesion volume, mean: 8566.4 mm3	MRI Measurements: • The mean number of GdE lesions decreased from 1.31 at trial entry to 0.73 at week 4, 0.04 at week 48 and 0 at week 72. • The mean number of new T2 lesions declined from 0.92 at week 4 to 0 at week 72. Clinical Measurements: • 80.8% of patients were relapse free during the 72-week period • The mean relapse rate from baseline to week 24 was 0.25 and 0.22 from baseline to week 72.	IRRs: • 65.4% of subjects experienced IRRs during the study. • 42% of subjects had an IRR following the first infusion. Infections: • 61.5% of subjects experienced infection, all of which were mild to moderate.
Clinical trials studying ocrelizumab
(Kappos et al., 2011) ClinicalTrials.gov number: NCT00676715	MS subtype: RRMS Trial design: phase II, randomized, double-blind, 48-week, placebo-controlled trial. Subject subgroups: subjects received 600 mg IV OCR (n=55), 2000 mg OCR (n=55), or placebo (n=54) in 2 doses on days 1 and 15. 54 subjects received IFN β-1a once a week. At week 24 the placebo, 600 mg and IFN β-1a groups received 600 mg OCR. The 2000 mg group received 1000 mg. Baseline characteristics of patients: Age, mean: 35.6- 38.1 years Time since diagnosis, mean: 2.7- 4.4 years EDSS, mean: 3.1-3.5 Absence of T1 GdE lesions: 49-66% of patients T2 lesion volume, mean: 8951- 13973 mm3	MRI Measurements: • At week 24 the number of GdE T1 lesions was 89% lower in the 600 mg group and 96% lower in the 2000 mg group. • The number of new & persisting GdE lesions were significantly lower in both OCR groups than placebo. • The change in total volume of T2 lesions was not significantly different between groups at week 24. Clinical Measurements: • Over 24 weeks the ARR was 80% lower in the 600 mg group and 73% lower in 2000 mg group.	IRRs: • 35, 44, and 9 percent of subjects had IRRs following the first infusion in the 600 mg, 2000 mg and placebo groups respectively. • IRRs were reported in 51.85% of placebo, 45.45% of 600 mg, 52.73% of 1000 mg, & 37.04% of IFN β-1a Infections: • Incidence of serious infection were similar between both OCR groups and placebo. From weeks 0 to 24 serious infections occurred in 2% of the placebo group. From weeks 24 to 48, serious infections occurred in 2% of patients in the following groups: placebo, 600 mg OCR, and IFN β-1a. No serious infections occurred in the 2,000 mg OCR group. Neoplasms: • 1 case of breast cancer and 1 case of squamous cell carcinoma were reported in the higher dose OCR group.
Hauser et al. (OPERA I & II) (Hauser et al., 2017) ClinicalTrials.gov numbers: NCT01247324 and NCT01412333, respectively	MS subtype: RMS Trial design: Two identical, parallel phase III, 96-week trials Subject subgroups: Across both trials, 827 subjects received 600 mg IV OCR every 24 weeks and 829 received 44 μu SQ IFN β-1a 3 times per week for 96 weeks. All patients received 100 mg IV methylprednisolone before each infusion. Prophylaxis with analgesic or antipyretics and an antihistamine was recommended. Baseline characteristics of patients: Age, mean: 36.9-37.4 years Time since diagnosis, mean: 3.71-4.15 years EDSS, mean: 2.75-2.86 Absence of T1 GdE lesions: 57.5-61.9% of patients T2 lesion volume, mean: 9.74-10.85 cm3 Normalized brain volume, mean: 1499.18-1503.90 cm3	MRI Measurements: • The total mean number of T1 GdE lesions was 94% (OPERA I) and 95% (OPERA II) lower in the OCR groups. • The total mean number of new or newly enlarged hyperintense T2 lesions was 77% (OPERA I) and 83% (OPERA II) lower in the OCR groups. Clinical Measurements: • The ARR was 46% (OPERA I) and 47% (OPERA II) lower with OCR. • Across both trials, 9.1% of subjects in the OCR group had confirmed disease progression at 12 weeks (a 40% lower risk), vs 13.6% in IFN β-1a.	IRRs: • Across both trials, 34.3% of subjects in the OCR group experienced IRRs compared to 9.7% in IFN β-1a. Infections: • 56.9% (OPERA I) & 60.2% (OPERA II) of OCR patients had infections vs IFN β-1a 54.3% (OPERA I) & 60.2% (OPERA II). Most common infections: URI, nasopharyngitis & UTI. • Serious infections occurred in 1.2% (OPERA I) and 1.4% (OPERA II) of the OCR group and 2.9% (OPERA I) and 2.9% (OPERA II) of the IFN β-1a group. Neoplasms: • Across both trials, neoplasms were reported in 0.5% of the OCR group and 0.2% in the IFN β-1a group. 2 of the cases in the OCR group were invasive ductal breast carcinoma. • 5 additional neoplasms were reported in the open label extension period. 2 of these cases were breast cancer.
Montalban et al. (ORATORIO) (Montalban et al., 2017) ClinicalTrials.gov number: NCT01194570	MS subtype: PPMS Trial design: phase III, 120-week, double blind trial. Subject subgroups: 488 received 600 mg IV OCR (as 2 × 300 mg infusions) 14 days apart every 24 weeks. 244 subjects received placebo at the same time points. All subjects were given 100 mg IV methylprednisolone prior to each infusion. Optional prophylactic analgesics or antipyretics and antihistamine was recommended. Baseline characteristics of patients: Age, mean: 44.4-44.7 years Time since diagnosis, mean: 2.8-2.9 years EDSS, mean: 4.7 Absence of T1 GdE lesions: 72.5-75.3% of patients T2 lesion volume, mean: 10.9-12.7 cm3 Normalized brain volume, mean: 1462.9-1469.9 cm3	MRI Measurements: • The volume of hyperintense T2 lesions decreased by 3.4% in the OCR group and increased by 7.4% in placebo from baseline to week 120. • A smaller percentage of brain volume loss from week 24 to week 120 was seen in the OCR group (0.90%) than in the placebo group (1.09%). Clinical Measurements: • 32.9% of OCR patients had 12 week confirmed disability progression compared to 39.3% of placebo. • OCR group showed a 38.9% mean change from baseline to week 120 in the timed 25-foot walk compared to a 55.1% change in placebo.	IRRs: • More subjects in the OCR group (39.9%) reported at least 1 IRR than those in placebo group (25.5%). Infections: • 71.4% of OCR patients had infections vs 69.9% of placebo. Most common nasopharyngitis, UTI, influenza & URI. • Serious infections occurred in 6.2% of OCR group and 5.9% of placebo group. Neoplasms: • Neoplasms were found in 2.3% of subjects in the OCR group and 0.8% of placebo. In OCR, 4 of the 11 cases were of breast cancer. • 2 additional cases of neoplasm were detected during the open label extension phase.
Clinical trials studying ofatumumab
Sorensen et al. (Sorensen et al., 2014) ClinicalTrials.gov number: NCT00640328	MS subtype: RRMS Trial design: phase II, randomized, double-blind, 48-week, placebo-controlled study. Subject subgroups: subjects received 2 IV OFA infusions (100 mg, n=8; 300 mg, n=11; or 700 mg, n=7) or placebo (n=12) 2 weeks apart. At week 24 subjects underwent alternate treatment. All subjects received Acetaminophen, an antihistamine & a corticosteroid prior to each infusion. Baseline characteristics of patients: Age, mean: 36.0-36.3 years Time since diagnosis, mean: 1.7-3.8 years EDSS, mean: 1.0-1.3 Number of new T1 GdE lesions: 0.2- 2.2 Number of new and/or enlarging T2 lesions: 0.3-1.5	MRI Measurements: • Significant reductions in the number of new T1 GdE lesions, total T1 GdE lesions and new and/or enlarging T2 lesions were seen in the OFA groups compared to placebo from weeks 8 to 24. • From weeks 8 to 24, the total number of T1 GdE lesions decreased by 99% from week 8 to 24 in the OFA group. Clinical Measurements: • 19% of patients in the OFA group relapsed from weeks 0 to 24 compared to 25% of placebo.	IRRs: • IRRs were more common in the OFA group than in placebo. The most common IRR was rash. Infections: • Infections were reported in 38.5% of OFA subjects and 50% of placebo subjects from weeks 0 to 24. • One serious infection (Influenza) occurred in the placebo group during the first period of trial.
Bar-Or et al. (MIRROR) (Bar-Or et al., 2018) ClinicalTrials.gov number: NCT01457924	MS subtype: RRMS Trial design: phase IIb double-blind, 48-week study. Subject subgroups: 34 subjects received 3 mg OFA every 12 weeks, 32 subjects received 30 mg every 12 weeks, 34 subjects received 60 mg every 12 weeks, 64 subjects received 60 mg every 4 weeks, 62 subjects received placebo. At week 12 the placebo group received 3 mg OFA. Acetaminophen and an antihistamine were given prior to each injection. Baseline characteristics of patients: Age, mean: 37.2 years Disease duration, mean: 4.38 years MRI with active lesions (last 12 months): 43% of patients	MRI Measurements: • A 65% reduction in the cumulative number of new GdE lesions in all OFA groups vs placebo from weeks 0 to 12. • From weeks 4 to 12 the reduction in rate of new GdE lesions ranged from 71% to 92% across OFA groups vs placebo. Clinical Measurements: • Over the 24-week treatment period, 9% to 22% of subjects across OFA groups relapsed vs 25% of placebo.	IRRs: • IRRs were reported in 52% of OFA subjects and 15% of placebo. Infections: • The incidence of infection was similar across treatment groups. Neoplasms: • 1 case of malignant melanoma in the 60 mg OFA group was reported in the follow up phase.
ASCLEPIOS I and II (Hauser et al., 2020) ClinicalTrials.gov number: NCT02792218 and NCT02792231, respectively	MS subtype: RMS Trial design: Two parallel, randomized double-blind, double-dummy, phase III trials. Subject subgroups: Across both trials 946 subjects received 20 mg SQ OFA every 4 weeks after receiving 20 mg loading doses at days 1, 7 and 14. 936 subjects received 14 mg oral teriflunomide daily. Subjects in the OFA group received oral placebo and subjects in the teriflunomide group received SQ placebo. The first injection was given by a health care provider on the trial site. The following 2 injections were self-administered on the trial site under the supervision of a health care provider who trained patients on use. Ability to administer the injection had to be documented before patients were authorized to do so at home. Premedication with acetaminophen and/or antihistamines was recommended. Premedication with steroids was only recommended for the first injection. Baseline characteristics of patients: Age, mean: 37.8-38.9 years Time since diagnosis, mean: 5.48-5.77 years EDSS, mean: 2.86-2.97 0 total T1 GdE lesions: 56.1-63.4% of patients T2 lesion volume, mean: 12.0-14.3 cm3 Normalized brain volume, mean:1439-1446 cm3	MRI Measurements: • The mean number of GdE lesions on T1- weighted MRI was 0.01 with OFA and 0.45 with teriflunomide in ASCLEPIOS I (97% relative reduction with OFA). The corresponding values in ASCLEPIOS II were 0.03 and 0.51 (94% relative reduction). • Serum neurofilament light chain was 7% lower at 3 months, 27% lower at 12 months and 23% lower at 24 months than teriflunomide in ASCLEPIOS I. Corresponding values in ASCLEPIOS II were 11%, 26% and 24%. • The annualized rate of brain volume loss did not differ significantly between subjects treated with OFA or teriflunomide (ASCLEPIOS I: −0.28% with OFA, −0.35% with teriflunomide. ASCLEPIOS II: −0.29% with OFA, −0.35% with teriflunomide). Clinical Measurements: • The adjusted ARR was 0.11 (50.5% relative reduction) in subjects given OFA and 0.22 in subjects given teriflunomide in ASCLEPIOS I (difference: −0.11). The corresponding values in ASCLEPIOS II were 0.10 (58.5% relative reduction) and 0.25 (difference: −0.15).	IRRs: • IRRs were reported in 20.2% of OFA subjects vs 15.0% of teriflunomide subjects (placebo injection). Infections: • Serious infections occurred in 2.5% of OFA subjects and 1.8% of teriflunomide subjects. • Appendicitis occurred in 8 (0.8%) patients who received OFA and 2 (0.2%) patients who received teriflunomide Neoplasms: • Neoplasms were detected in 0.5% of OFA subjects. One case each of malignant melanoma in situ, recurrent non-Hodgkin’s lymphoma, invasive breast carcinoma and two cases of basal cell carcinoma. Neoplasms were detected in 0.4% of teriflunomide subjects. Once case each of cervical carcinoma and fibrosarcoma and two cases of basal cell carcinoma.
Clinical Trials with Ublituximab
Fox et al. (Fox et al., 2020) ClinicalTrials.gov number: NCT02738775	MS subtype: RMS Trial design: Phase II, 48-week, placebo-controlled trial. Subject subgroups: Subjects received 3 UTX infusions (150 mg over 1-4 hours on day 1 and 450-600 mg over 1-3 hours on day 15 and week 24) in 6 dosing cohorts. • 36 subjects received UTX. 13 subjects received placebo. Subjects in the placebo group received UTX after the placebo phase. • An oral antihistamine and an oral corticosteroid were administered 30 minutes prior to UTX. Baseline characteristics of patients: Age, mean: 40 years Disease duration, mean: 7.7 years EDSS, mean: 2.44 Number of GdE lesions, mean: 3.63 T2 lesion volume, mean: 14.87 cm3	MRI Measurements: • At weeks 24 and 48 no new or persisting T1 GdE lesions were seen in any patients. • A 10.6% decline in volume of T2- weighted lesions was seen by week 48. Clinical Measurements: • 93% of subjects were relapse free during the study. • 17% of subjects met criteria for 24-week confirmed disability improvement.	IRRs: • 50% of patients experienced IRRs. All IRRS were grade 1 or 2 in severity. •77% of the 141 UTX infusions did not result in an IRR. Infections: • The most common infection was upper respiratory tract infection, occurring in 15% of subjects.

Abbreviations: MRI= magnetic resonance imaging, IV= intravenous, SQ= subcutaneous, IRRs= Infusion/Injection related reactions, ARR= annualized relapse rate, GdE= Gadolinium enhancing, RTX= rituximab, OCR= ocrelizumab, OFA=ofatumumab, UTX= ublituximab, EDSS= expanded disability status scale, clinical disease progression= CDP.

Fewer data are available on the efficacy of ublituximab in MS. A phase II, 48-week trial on the use of ublituximab in RMS yielded promising results. No new or persisting T1 GdE lesions were detected at weeks 24 or 48. Further, 93% of patients remained relapse free during the 48-week trial period (Fox et al., 2020). Additional data from this trial is summarized in Table 1. The phase III parallel ULTIMATE I and II trials are currently assessing the efficacy of ublituximab in comparison to teriflunomide in RRMS patients.

When comparing drug efficacy based on the results of various clinical trials it is important to note differences in the baseline characteristics of patients as well as the type of drug used in comparator trials. Patient baseline characteristics as well as comparator drugs are reported in Table 1. Phase III trials of ocrelizumab included IFN beta-1a as a comparator while phase III trials of ofatumumab included teriflunomide. The two drugs (teriflunomide and Interferon beta-1a) were found to be comparable in efficacy in a phase III head to head study (Vermersch et al., 2014).

Ocrelizumab is the only monoclonal antibody currently FDA approved for the treatment of PPMS. In clinical trials with rituximab, a significant difference was not seen in clinical disease progression between PPMS patients in rituximab and placebo groups. The average brain volume change from baseline to week 96 was similar in PPMS patients who received rituximab and those who received placebo (mean change from baseline to week 96: −10.8 cm³ with rituximab vs −9.9 cm³ with placebo) (Hawker et al., 2009). Of note, subgroup analyses revealed that time to clinical disease progression was delayed with rituximab compared to placebo in patients under 51 years old or with T1 GdE lesions at baseline. The lack of efficacy of rituximab in PMS was attributed to poor CNS penetration. An induction dose of IV and intrathecal rituximab was administered in the RIVITALISE trial to improve B cell depletion in the CNS. Although CSF B cells were significantly depleted, CNS tissue B cells were not depleted to a level sufficient for trial continuation (Komori et al., 2016). The ORATORIO trial found that ocrelizumab led to a 3.4% reduction in the volume of T2 hyperintense lesions compared to a 7.4% increase seen in those who received placebo (p<0.001). Further, confirmed disability progression at 12 weeks was seen in 32.9% of patients who received ocrelizumab vs 39.3% of patients who received placebo (p=0.03). At 24 weeks, confirmed disability progression was seen in 29.6% of patients who received ocrelizumab and 35.7% of those who received placebo (p=0.04). The percentage of brain volume loss was 0.90% in patients who received ocrelizumab and 1.09% in those who received placebo (p=0.02) (Montalban et al., 2017).

7. Adverse Effects

7.1. Infusion/Injection Related Reactions

Infusion or injection related reactions (IRRs) are the most common adverse effects to occur in patients treated with rituximab, ocrelizumab, ofatumumab and ublituximab. The highest incidence of IRRs occurs within 24 hours of the first dose and decreases with subsequent use, the majority of which were of mild to moderate severity (Naismith et al., 2010, Bar-Or et al., 2008, Montalban et al., 2017, Fox et al., 2020, Hauser et al., 2020, Hauser et al., 2008, Hauser et al., 2017, Hawker et al., 2009, Kappos et al., 2011, Sorensen et al., 2014, Bar-Or et al., 2018). Patients may be given methylprednisolone, antihistamine, and/or antipyretics before treatment with rituximab or ocrelizumab to reduce the risk of IRRs. These prophylactics were used in some, but not all trials referenced in this article. See Table 1 for details. The US prescribing label of OCREVUS (ocrelizumab) recommends premedication with 100 mg of methylprednisolone (or an equivalent corticosteroid) 30 minutes prior to infusion as well as an antihistamine 30 to 60 minutes prior to reduce the incidence and severity of IRRs. The use of an antipyretic, such as acetaminophen, is also suggested. Of note, the incidence of IRRs was not significantly different in patients who received pre-medications prior to ofatumumab than in those who did not in the ASCLEPIOS trials. 12.3% and 13% (ASCLEPIOS I and II, respectively) of patients who received premedication experienced injection systemic reactions following the first injection of ofatumumab. In comparison, 10% and 25.8% (ASCLEPIOS I and II, respectively) of patients who did not receive premedication experienced injection systemic reactions following the first injection of ofatumumab. The use of pre-medications is not outlined as a recommended step in the prescribing information for ofatumumab (KESIMPTA). The document noted the limited prophylactic benefit of these medications and instead recommended symptomatic treatment of IRRs if needed. Additionally, the use of a conditioning dose (3 mg one week prior to the first treatment dose) of ofatumumab did not reduce the incidence of IRRs in the MIRROR study (Bar-Or et al., 2018).

CDC is believed to trigger infusion/injection related reactions. It has been proposed that there may be a lower incidence of IRRs with ocrelizumab than rituximab and ofatumumab due to its relatively less potent CDC activity. If this theory holds true, the incidence of IRRs should be lower with ublituximab as well. No studies have been conducted to compare the rates of IRRs in rituximab, ocrelizumab and ofatumumab. The percentage of subjects who experienced IRRs in clinical trials studying ocrelizumab ranged from 34.3% to 52.73% (Hauser et al., 2017, Kappos et al., 2011). In comparison, the percentage of subjects who experienced IRRs in clinical trials studying ofatumumab ranged from 20.2% to 52% (Hauser et al., 2020, Bar-Or et al., 2018). The incidence of IRRs in various trials are reported in Table 1.

IgG monoclonal antibodies typically have a have a half-life of 21 days. The terminal elimination half-lives of rituximab, ocrelizumab and ofatumumab are 22 days, 26 days and 16 days respectively. More rapid excretion of ofatumumab will be beneficial to patients who need to discontinue treatment for safety concerns. The shorter half-life requires more frequent administration in order to maintain therapeutic effects. The inconvenience of more frequent administration with ofatumumab is ameliorated by its availability as a self-administered injection. Increased frequency of use may raise concerns for increased probability of experiencing adverse events such as IRRs. However, the highest incidence of IRRs with rituximab, ocrelizumab and ofatumumab occur following the first dose and decline with subsequent use.

7.2. Immunogenicity

Immunogenicity leads to the production of anti-drug antibodies (ADAs) which can cause two major problems. ADAs may interfere with the efficacy of a drug and/or cause adverse effects. Immunogenicity varies among the therapeutics due to the differing percentage of antibody that is human. Fully human monoclonal antibodies, such as ofatumumab, are the least immunogenic category of monoclonal antibodies. Ofatumumab should have a lower incidence of production of ADAs than the chimeric antibody rituximab or the humanized antibody ocrelizumab. In the OLYMPUS study, 20 out of 286 (7%) patients with PPMS who received rituximab tested positive for human anti-chimeric antibodies (HACA) during the treatment or safety follow up. No relationship was found between HACA positivity and adverse effects or efficacy. (Hawker et al., 2009). Across three studies, 12 out of 1,311 (~1%) patients with RMS who received ocrelizumab tested positive for ADAs. Two of these patients tested positive for neutralizing antibodies (Genentech, 2017). Thus, the number of patients who developed ADAs was insufficient to determine any association with safety or efficacy. Across the two parallel ASCLEPIOS trials, 2 out of 914 (0.2%) patients with RMS who received ofatumumab tested positive for ADAs. No neutralizing antibodies were detected and the number of patients was insufficient to study the impact of ADAs in ofatumumab treated patients (36.

7.3. Infections

The incidence of infections occurring in each trial is outlined in Table 1. Overall, the occurrence of infection is comparable between the three therapeutics. However, the incidence of infections may differ, in real world experience, when used in patients of advanced age or other co-morbidities. Cases of progressive multifocal leukoencephalopathy (PML), have not been reported in patients treated with rituximab strictly for MS (Berger, 2017). PML has occurred in patients treated with rituximab for other conditions such as chronic lymphocytic leukemia (CLL) and RA (Gelfand et al., 2017, Genentech, 1997). However, CLL is itself a risk factor for PML (Berger et al., 2018). Nine cases of PML have been reported in MS patients treated with ocrelizumab as of January 2020 (Remaly, 30 April 2020). Eight of the cases were considered carry over cases and attributed to prior treatment with natalizumab or fingolimod, both of which are associated with an increased risk of PML (Remaly, 30 April 2020, Hughes, 25 May 2017). A single case of PML has been reported in a PPMS patient with no prior history of treatment with immunotherapy (Remaly, 30 April 2020). The patient was a 78-year-old male who received ocrelizumab monotherapy for two years. Prior to starting ocrelizumab, lab results showed the presence of antibodies to the John Cunningham virus (JCV), the cause of PML, and an absolute lymphocyte count that was normal or indicated mild lymphopenia. No cases of PML were reported in MS patients treated with ofatumumab in the clinical trials. While cases of PML have been reported in patients treated with IV ofatumumab for CLL, the dosage used for CLL is much higher (300 mg on day 1 and 1000 mg on day 8 followed by subsequent 28-day cycles of 1000 mg for a minimum of three or a maximum of twelve cycles depending on responsefor a ) (Novartis Pharmaceuticals Corporation 8/2020, Novartis Pharmaceuticals Corporation 2009). No cases of PML were reported I phase II trials of ublituximab in RRMS (Fox et al., 2020).

Prolonged B cell depletion following anti-CD20 therapy may increase the risk of infection. Of the three therapeutics discussed, B cell repletion occurs most rapidly with ofatumumab. The availability of ofatumumab as a SQ injection may also have safety benefits. Antibodies administered subcutaneously do not cause the extensive B cell depletion in the spleen seen with IV therapies. The preservation of B cells in the spleen and the more rapid repletion of B cells seen with ofatumumab may lead to a lower incidence of infections. However, more information is needed to address this theoretical possibility.

Although not a classic infection, an imbalance in the occurrence of appendicitis was noted in the ASCLEPIOS trials. Appendicitis was reported in eight patients (0.8%) who received ofatumumab and two (0.2%) patients who received teriflunomide (Hauser et al., 2020). No such imbalance was seen in phase II trials with ofatumumab or other CD20 therapies used for MS.

A study examining risk of infections with MS therapies found rituximab to have the highest incidence of serious infections compared to natalizumab, fingolimod, interferon beta, or glatiramer acetate. However, rituximab had a lower incidence of herpetic infections than fingolimod or natalizumab. The incidence of all infections was higher with each DMT than in the general population (Luna et al., 2020). Due to their recent marketing approval, information regarding long term infection rate is unavailable for ocrelizumab and ofatumumab, but are expected in the upcoming years with continued pharmacovigilance efforts.

Immune suppression increases the risk of Hepatitis B (HBV) reactivation, which is a well described complication of anti-CD20 therapies. Of note, anti-CD20 therapies are often used in combination with other immunosuppressants for non-MS conditions such as methotrexate for RA and polychemotherapy for malignancies (Gelfand et al., 2017). HBV reactivation has occurred with rituximab during treatment of non-MS disorders such as RA (Ciardi et al., 2019). HBV reactivation did not occur in clinical trials of rituximab, ocrelizumab, ofatumumab or ublituximab for MS (Naismith et al., 2010, Teeling et al., 2006, Hawker et al., 2009, Bar-Or et al., 2008, Komori et al., 2016, Hauser et al., 2017, Montalban et al., 2017, Kappos et al., 2011, Sorensen et al., 2014, Hauser et al., 2020, Fox et al., 2020). A case of HBV reactivation was reported in a 60-year-old male treated with ocrelizumab for PPMS. Prior to ocrelizumab initiation, the patient was HBV surface antigen (HBsAg) negative and HBV core antibody (HBcAb) positive with undetectable HBV DNA. HBV DNA became detectable 6 weeks following ocrelizumab initiation and increased at weeks 10 and 13. Entecavir was started for HBV reactivation. HBV DNA then became undetectable at 24 weeks after ocrelizumab initiation. The patient received a scheduled dose of ocrelizumab at this time (Ciardi et al., 2019). HBV reactivation was also reported in a patient co-treated with ocrelizumab and methotrexate for RA (Ciardi et al., 2019). HBV reactivation has occurred in patients treated with ofatumumab for CLL, although at a higher dose but shorter duration than used for MS (Novartis Pharmaceuticals Corporation 8/2020, Novartis Pharmaceuticals Corporation 2009).

The safety and efficacy of vaccination against infectious diseases are important considerations for immunocompromised patients. This issue is timely given FDA approval of vaccines for the prevention of the novel corona virus associated disease. Inactivated vaccines are safe for patients before recovery from B cell depletion. Following vaccination, vaccine response should be assessed to determine efficacy (Genentech, 2017, Novartis Pharmaceuticals Corporation 8/2020). Vaccination may be more efficacious for patients on ofatumumab than those on ocrelizumab due to more rapid B cell repopulation and less extensive peripheral depletion. Vaccination with live or live attenuated vaccines is not recommended until B cell repletion. Live or live attenuated vaccines may be given four weeks prior to starting ocrelizumab or ofatumumab and two weeks prior for non-live vaccines. Response to vaccination was evaluated in patients with RMS 12 weeks following initiation of ocrelizumab to examine efficacy while peripherally B-depleted (Bar-Or et al., 2020). Patients were able to mount an immune response, although less robust than seen in the control cohort. See Table 2 for the response rates reported in the VELOCE study (Bar-Or et al., 2020).

Table 2.

Immune response to vaccination in the VELOCE study.

Response rates were measured 8 weeks following vaccination with tetanus toxoid and 4 weeks following vaccination with pneumovax, or influenza.

Immune response to vaccination in the VELOCE study
Vaccine	Immune response in Ocrelizumab treated	Immune response in control
tetanus toxoid	positive response rate: 23.9%	positive response rate: 54.5%
Pneumovax (23-PPV)	positive response rate to ≥5 serotypes: 71.6%	positive response rate to ≥5 serotypes: 100%
2015/2016 or 2016/2017 Northern Hemisphere seasonal influenza	Seroprotection rates to all 5 strains: 55.6%-80.0%	Seroprotection rates to all 5 strains: 75.0%-97.0%

7.4. Neoplasms

A higher incidence of neoplasms was seen with ocrelizumab in RRMS and PPMS trials when compared to comparator and placebo groups (Montalban et al., 2017, Hauser et al., 2017). Moreover, there was an imbalance in the incidence of neoplasms occurring in the breast compared to other tissues. During the treatment period of the PPMS study 2.3% of patients (11 of 486) who received ocrelizumab reported neoplasms versus 0.8% of patients who received placebo (2 of 239) (Montalban et al., 2017). Four of the eleven patients found to have neoplasms had breast cancer. During the open label extension phase, two additional neoplasms were reported (one case of basal cell skin carcinoma and one case of squamous cell carcinoma) (Montalban et al., 2017). Collectively, four neoplasms (0.5% of patients) were reported in patients receiving ocrelizumab as part of the OPERA I and OPERA II RMS trials (Hauser et al., 2017). Two of the four neoplasms were invasive ductal breast carcinomas. Two neoplasms (0.2%) occurred in patients receiving IFN beta-1a (one case of mantle-cell lymphoma and one case of squamous-cell carcinoma of the chest). During the open label extension phase, five additional cases of neoplasm were reported. Two of these five neoplasms were of the breast. The incidence of both neoplasms and breast neoplasms specifically were comparable to that seen in the general population. The imbalance in the occurrence of breast cancer should be further studied. Patients undergoing treatment with anti-CD20 antibodies are advised to follow standard breast cancer screening guidelines according to their age.

Neoplasms occurred in 0.5% of patients who received ofatumumab (2 cases of basal cell carcinoma, and 1 case each of malignant melanoma in situ, recurrent Non-Hodgkin’s lymphoma and invasive breast carcinoma) and 0.4% of those who received teriflunomide (2 cases of basal cell carcinoma and 1 case each of cervical carcinoma and fibrosarcoma) across the parallel ASCLEPIOS trials (Hauser et al., 2020) Rituximab was found to have a similar incidence of neoplasms compared to the general population in a study evaluating cancer risk with DMTs. The most common invasive cancers in rituximab treated patients were breast, melanoma, colon and nonmelanoma skin cancer. No imbalance in subtypes of invasive cancers was found (Alping et al., 2020).

8. Cost Efficacy

Medications for MS are some of the most expensive drugs on the market. The financial burden can put excess stress on patients and their families, which can exacerbate disease state and induce flares (Mohr et al., 2004). Rituximab is the most cost effective of the three available therapeutics with an annual listed price of roughly $10,000. However, rituximab is not FDA approved for MS. The annual listed price of OCREVUS (ocrelizumab) is $65,000. The annual out of pocket cost for patients covered by Medicare ranges from $0 to $13,000 and for patients with Medicaid ranges from $0 to $30. Additional costs associated with the administration of rituximab and ocrelizumab should be taken into account when calculating the final cost of treatment. The most expensive annual listed price is attached to KESIMPTA (ofatumumab) with an annual listed price of $83,000. However, no additional costs need to be considered as this drug is self-administered at home.

9. Conclusions

In this article we have highlighted the major similarities and differences between rituximab, ocrelizumab, ofatumumab and ublituximab. None of these drugs is a superior choice for all patients. When choosing which therapeutic is the best choice for each patient there are a few key differences to consider. Chief among these are efficacy, adverse events, time to B cell repletion, pharmacokinetics, route of administration and price. Rituximab, ocrelizumab and ofatumumab are all viable options, with comparable efficacy, for the treatment of RRMS. However, only ocrelizumab is approved for PPMS. The results of the phase III ULTIMATE trials (currently underway) will help determine whether or not ublituximab is a suitable option for the treatment of RMS.