Product review on MAbs (alemtuzumab and ocrelizumab) for the treatment of multiple sclerosis

ABSTRACT

Traditionally, the management of active relapsing remitting MS was based on the, so-called, maintenance therapy, which is characterized by continuous treatment with particular disease modifying therapy (DMT), and a return of disease activity when the drug is discontinued. Another approach is characterized by a short treatment course of a DMT, which is hypothesized to act as an immune reconstitution therapy (IRT), with the potential to protect against relapses for years after a short course of treatment. Introduction of monoclonal antibodies in the treatment of MS has revolutionized MS treatment in the last decade. However, given the increasingly complex landscape of DMTs approved for MS, people with MS and neurologists are constantly faced with the question which DMT is the most appropriate for the given patient, a question we still do not have an answer to. In this product review, we will discuss the first DMT that acts as IRT, an anti-CD52 monoclonal antibody alemtuzumab and an anti CD20 monoclonal antibody, ocrelizumab that has the potential to act as an IRT, but is administered continuously. Special emphasis will be given on safety in the context of COVID-19 pandemics and vaccination strategies.

KEYWORDS:

• Multiple sclerosis
• disease modifying therapy
• monoclonal antibodies
• alemtuzumab
• ocrelizumab

Introduction

Multiple sclerosis (MS) is a lifelong immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS) that according to 2020 data affects nearly 2.8 million people worldwide.^1,2

Although the exact cause of the disease remains unknown, the pathophysiological process engages environmental and genetic factors as well as altered immunological response. The pathological hallmark of these interactions in MS are inflammation, demyelination, axonal damage, gliosis, and remyelination.³

MS is categorized into three major clinical subtypes: relapsing-remitting MS (RRMS), affecting 85% of patients, that over time in part of the subjects proceeds to secondary progressive MS (SPMS), characterized by worsening disability. At the beginning of the disease 10–15% of MS patients are diagnosed with primary progressive MS (PPMS), a distinct clinical phenotype characterized by continuous clinical deterioration leading to impairment of ambulation.⁴

In recent years, following the rising knowledge about MS immunology, there has been an increase in available disease modifying therapies (DMT). Although these drugs have a marked impact on the reduction of inflammatory disease activity, the influence on disability progression is less pronounced.⁵ The treatment of progressive forms of MS continues to be a challenge with, at the moment, limited treatment options.

Treatment approaches in multiple sclerosis

Traditionally, the management of active RRMS is based on the, so-called, maintenance therapy, which is characterized by continuous treatment with particular DMT, and a return of disease activity when the drug is discontinued.⁶ In the event of occurrence of disease activity (in the form of relapses or new T2 or Gd+ lesions), a DMT with higher efficacy is usually initiated (Figure 1). This approach in sequencing of different DMTs depending on their efficacy/safety profile is called the escalation approach.

Figure 1. The management of active RRMS is based on the disease activity and prognostic factors. (A) Following the diagnosis of RRMS, treatment with disease modifying therapy (DMT) with moderate efficacy and good safety profile is initiated. In the event of occurrence of disease activity (in the form of relapses or new T2 or Gd+ lesions), a DMT with higher efficacy is usually initiated. This approach in sequencing of different DMTs depending on their efficacy/safety profile is called the escalation approach. (B) If the patient has highly active RRMS or poor prognostic factors, treatment with high-efficacy DMTs is started from the diagnosis of RRMS. Monoclonal antibodies which have the potential to act as an immune reconstitution therapy (alemtuzumab and ocrelizumab) are frequently used in this situation.

Another approach is characterized by a short treatment course of a DMT, which is hypothesized to act as an immune reconstitution therapy (IRT), with the potential to protect against relapses for years after a short course of treatment (Figure 1).⁶

In this product review we will discuss monoclonal antibodies which have the potential to act as an IRT: an anti-CD52 monoclonal antibody alemtuzumab indicated for the treatment of RRMS and an anti-CD20 monoclonal antibody ocrelizumab indicated for the treatment of RRMS and PPMS.

Alemtuzumab

Alemtuzumab (Lemtrada®) is a genetically engineered, humanized, IgG1 kappa monoclonal antibody with specific binding propensity toward CD52, a human cell surface antigen.⁷ Although the exact role of CD52 in immune response is not fully elucidated, there is evidence that it is an important contributor in T-cell costimulation and migration.⁸ CD52 antigen is highly expressed on T and B lymphocytes with low or no expression on cellular component of the innate immune system such as monocytes, macrophages, natural killer (NK) cells, neutrophils, bone marrow stem cells, or plasma cells.⁹ Thus, by depleting T and B lymphocytes, predominantly by mechanisms of antibody dependent cell-mediated cytolysis (ADCC), complement-dependent cytolysis (CDC), and induction of apoptosis,^10–12 it mostly leaves effectors of innate immune system intact.

Alemtuzumab was approved by the European Medicines Agency (EMA) under the name Lemtrada® for use in treatment of active relapsing-remitting multiple sclerosis (RRMS) in 2013¹³ based on results of 3 core clinical trials, one 3-year phase 2 (CAMMS223)¹⁴ and two 2-year phase 3 trials (CARE-MS I)¹⁵ and (CARE-MS II).¹⁶ However, the drug was previously in use under name Campath® and MabCampath® following its approval in 2001 by the US Food and Drug Administration (FDA) and the EMA for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).¹⁷ Currently, alemtuzumab is used in conditioning protocol prior to tissue transplantation, in prevention of transplant rejection and graft versus host reaction and in various hematological malignancies.¹⁸ Since November 2019, due to EMA restriction, alemtuzumab is used to treat patients with highly active RRMS, defined as highly active disease despite prior DMT use or rapidly evolving severe disease.¹⁹ Treatment regime includes 2 treatment courses with recommended dose of 12 mg/day administered by intravenous (IV) infusion. For the first course it is used for 5 consecutive days and 12 months thereafter the second course is administered for 3 consecutive days. In patients who after two treatment courses have breakthrough disease activity, it is possible to apply third and fourth course, each administered for 3 consecutive days and after at least 12 months from the previous one.

Mechanism of action

Mechanism of action of alemtuzumab in MS is not fully explained, but it is considered that the drug expresses its immunomodulatory effect through depletion and subsequent repopulation of T and B lymphocytes. Pharmacokinetics of alemtuzumab, considering data from phase 2 and 3 clinical trials for dose of 12 mg /day, indicate that serum concentrations increase with each consecutive dose and the mean maximum serum concentration (Cmax) is accomplished after the last infusion in a treatment course.⁷ The assumed metabolic pathway is protein catabolism,²⁰ and serum concentrations generally become below the Limit of Quantitation (BLQ) within approximately 30 days following each treatment course.⁷ Elimination of alemtuzumab is dependent on lymphocyte count with lower count decreasing clearance of alemtuzumab and is also dependent on presence of anti-drug antibodies (ADA).⁷ In CARE-MS I and CARE-MS II, 85.2% of the study population receiving 12 mg was positive for ADA at any time point during the 2-year treatment course and 92.2% developed inhibitory ADA. Presence of ADA was associated with slower clearance of alemtuzumab from circulation but had no significant impact on the pharmacodynamics.

It is considered that therapeutic effect of alemtuzumab is achieved by rebalancing of the immune system with repopulation of different lymphocytes subsets in various proportions, numbers, and time periods. Total lymphocyte counts return to baseline levels in the majority (80%) of patients after 12 months.⁹ After initial depletion, B lymphocytes repopulate to baseline levels by 6 months while T cell counts do not reach baseline levels by 12 months.²¹

B-cell reconstitution following alemtuzumab occurs in a manner of hyperpopulation. In a study including 78 patients with RRMS who participated in Phase II trials, after their return to baseline, B cells continued to rise, reaching 165% of baseline by 12 months.²² Also, the authors suggested that B-lymphocyte repopulation after alemtuzumab treatment resulted in a B-cell subtypes tending toward immature phenotypes, driven by increased serum levels of BAFF, and that prolonged memory B-cell depletion may contribute to the efficacy of alemtuzumab in MS.²² On the other hand, it was also suggested that hyperrepopulation of immature B cells in the absence of regulatory T cells may be one of the contributors in development of secondary B cell autoimmunity following alemtuzumab treatment.²¹

Based on the studies evaluating patterns of reconstitution of T cell subsets after alemtuzumab treatment, it is speculated that CD4 + T cell repopulation is responsible for remission or resumed disease activity.^23,24 Regulatory T-cells (Treg) are important mediators in the maintenance of peripheral immune tolerance by suppressing potentially auto-aggressive conventional CD4 + T-cells (Tcon) subtype. During immunological reconstitution CD4+ CD25+ CD127 low Treg cell expand,²⁵ and percentage of CD4+ CD25+ CD127lowTreg cell which produce TGF-b1–, IL-10–, and IL-4 is highest at month 3.²³ In another study significant increase in Treg cell percentage was observed at month 24 that was accompanied by an increase in Treg cell suppressive activity against myelin basic protein (MBP)-specific Th1 and Th17 cells which could explain the long-lasting therapeutic benefit of alemtuzumab in RRMS.²⁶ However, there is a recent study suggesting that Treg are not spared from alemtuzumab-mediate depletion and that enhanced inhibitory effect of Treg following alemtuzumab is due to altered composition and reactivity of postdepletional Tcon.²⁷

Although, CD52 antigen is far less expressed on cellular component of innate immune system such as dendritic cells (DC), monocytes, macrophages, natural killer (NK) cells, neutrophils, bone marrow stem cells, or plasma cells, it has been demonstrated that 6 months after alemtuzumab treatment, specific DC subsets were reduced, while CD56bright NK cells expanded in patients with MS.²⁸ Even though, increased number and function of the CD56bright NK-cell subset was associated with beneficial effects of daclizumab, a humanized monoclonal antibody directed against the IL-2 receptor chain,²⁹ increased numbers of CD56bright NK cells have also been noticed in several autoimmune disorders, one of them being Hashimoto thyroiditis,³⁰ very common side effect of alemtuzumab treatment. So, remodeling of the innate immune compartment may play a role in both efficacy of alemtuzumab but also in development of side effects, in particular secondary autoimmunity.

Efficacy of alemtuzumab

Evidence from core clinical trials

Core clinical trials in which efficacy of alemtuzumab in active RRMS was assessed included one 3-year phase 2 clinical trial (CAMMS223)¹⁴ and two confirmatory 2-year phase 3 trials (CAMMS323/CARE-MS I¹⁵ and CAMMS324/CARE-MS II¹⁶).

Treatment naïve patients were enrolled into CAMMS223 and CARE-MS I, whilst CARE-MS II enrolled patients who failed previous interferon (IFN) β-1a or glatiramer acetate therapy. Alemtuzumab significantly reduced the annual relapse rare (ARR) versus IFNβ-1a in all three clinical trials (Table 1). Subgroup analysis of patients from CARE-MS studies who fulfilled criteria for highly active RRMS showed similar findings (0.26 in the alemtuzumab group vs 0.51 in the IFNβ-1a; p < .001). In CARE-MS I studies alemtuzumab did not significantly reduced 6-month SAD versus interferon, while in CARE- MS II significantly less patient experienced SAD in alemtuzumab cohort (Table 1).

Table 1. Main outcomes of core clinical trials with alemtuzumab in RRMS and ocrelizumab in RRMS and PPMS

Clinical trial	Key inclusion criteria	Study drug vs. Comparator	Number of pwMS	ARR	MRI activity		SAD	SRD
					New or enlarging T2 lesion	Gd+ enhancing lesions
Alemtuzumab
CAMMS223 ^Citation14	RRMS based on 2001 McDonald criteria; Onset of symptoms <36 months before the screening; At least 2 clinical episodes during the previous 2 years; EDSS ≤3; ≥1 enhancing lesions	Alemtuzumab vs INFβ 1a s.c.	334	0.10 vs 0.36*,^#	NR	NR	9.0 vs 26.2*,^# (6 M)	NR
CAMMS323/CARE – MS I ^Citation15	RRMS based on 2005 McDonald criteria; Age 18–50 yrs; Disease duration ≤5 years; At least 2 clinical episodes during the previous 2 years and at least 1 in previous year; EDSS ≤3; MR lesions attributable to MS	Alemtuzumab vs INFβ 1a s.c.	581	0.18 vs 0.39*,^#	48% vs 58%”	7% vs 19%^#	8.0% vs 11.1%*,** (6 M)	NR
CAMMS324/CARE – MS II ^Citation16	RRMS based on 2005 McDonald criteria; Age 18–55 yrs; Disease duration ≤10 years; At least 2 clinical episodes during the previous 2 years and at least 1 in previous year; At least 1 relapse while on INFβ or GA after at least 6 months of treatment; EDSS ≤5; MR lesions fulfilling protocol defined criteria	Alemtuzumab vs INFβ 1a s.c.	667	0.26 vs 0.52*,^#	46% vs 86%^#	9% vs 23%^#	12.7% vs 21.1%*,” (6 M)	28.8% vs 12.9% (6 M)^#
Ocrelizumab in RRMS
Phase II study ^Citation103	RRMS based on 2001 McDonald criteria; Ages 18–55 yrs; 2 or more relapses in a period of 3 years before the screening, with the requirement of one relapse in the last 12 months. Baseline Expanded Disability Status Scale (EDSS) values ranged from 1.0 to 6.0	Ocrelizumab 600 or 2000 mg vs. placebo vs. interferon beta 1a i.m.	220	0.13 (OCR 600 mg) vs. 0.64*,^# (placebo) vs. 0.36” (INF beta 1a)	NR	23% (OCR 600 mg) vs. 65%^# (placebo) vs. 52% (INF beta 1a)	NR	NR
OPERA I ^Citation102	RRMS based on 2010 McDonald criteria; Age 18 to 55 yrs; EDSS 0–5.5; two documented relapses in the previous 2 years or 1 relapse in a year prior to the screening	Ocrelizumab vs INFβ 1a s.c.	821	0.156 vs. 0.292*^#	38.3% vs. 61.3%^#	8.3% vs. 30.2%^#	6.9% vs. 10.5%“ (6 M)	20.7% vs 15.6%”(3 M)
OPERA II ^Citation102	RRMS based on 2010 McDonald criteria; Age 18 to 55 yrs; EDSS 0–5.5; two documented relapses in the previous 2 years or 1 relapse in a year prior to the screening	Ocrelizumab vs INFβ 1a s.c.	835	0.155 vs. 0.290*^#	39.1% vs. 62.0%^#	9.8% vs. 36.1%^#
Ocrelizumab in PPMS
ORATORIO ^Citation108	PPMS based on 2005 McDonald criteria; age 18 to 55 yrs, EDSS 3– 6.5; duration of symptoms <15 years with EDSS of >5 or duration of <10 years with EDSS of ≤5; presence of elevated immunoglobulin G index or IgG oligoclonal bands CSF	Ocrelizumab vs placebo	732	NR	Adjusted mean number of new or enlarging T2 lesions: 0.31 vs. 3.88^#	NR	32.9% vs 39.3%*” (3 M)	NR

*primary endpoints; ^# statistically significant at p < 0.001; “ statistically significant at p < 0.05; ** not statistically significant.

INFβ: interferon beta; ARR: annualized relapse rate; SAD: sustained accumulation of disability; SRD: sustained recovery of disability; NR: Not reported; GA: glatiramer acetate; INFβ: interferon beta.

Regarding the MRI outcomes, no difference was observed between treatment groups in median change in volume of T2-hyperintense lesions in both CARE-MS I and II trials. However, in both trials, significantly less patients in alemtuzumab cohort had gadolinium-enhancing and new or enlarging T2-hyperintense lesions at 24 months. Median change in brain parenchymal fraction significantly differed between groups (–0.867% in the alemtuzumab group vs – 1.488% in the IFNβ-1a; p <.0001 in CARE-MS I and – 0.615% in the alemtuzumab group vs – 0.810% in the IFNβ-1a; p <.01 in CARE-MS II).

Finally, statistically significant improvements from baseline with alemtuzumab were observed health related quality of life (HR-QOL) at the earliest postbaseline assessment and sustained through Year 2.³¹

Evidence from extension studies

Long-term extension studies CAMMS03409 and TOPAZ evaluated long-term effectiveness and safety of alemtuzumab.^32,33 Participants who were previously on SC IFNβ-1a were switched to alemtuzumab. Participants previously treated with alemtuzumab could receive additional course of alemtuzumab 12 mg for 3 consecutive days if they had documented evidence of resumed disease activity.

For participants from CAMMS223 12-year follow-up,³⁴ and for participants from CAMMS323 and 324, 5-year follow-up data were reported.^35,36 Effectiveness data are summarized in Table 2. In CAMMS223, no evidence of disease activity (NEDA) from years 7 to 12 was accomplished in 34% participants.³⁴ NEDA in years 3, 4, and 5 was achieved in 61.7%, 60.2%, and 62.4% of participants from CAMMS323, respectively.³⁵ In years 3, 4, and 5, proportions of participants with NEDA were 52.9%, 54.2%, and 58.2% for participants from CAMMS324, respectively.³⁶

Table 2. Main outcomes of extension studies with alemtuzumab in RRMS

Core clinical trial	Extension studies	Longest duration reported	Proportion of patients completed the entire extension study	Received only two cycles of alemtuzumab	ARR	Free of SAD	Stable or improved EDSS
CAMMS223 ^Citation14	CAMMSS030409 ^Citation32 and TOPAZ ^Citation33	12 years ^Citation34	54/108	33.0%	0.09	69%	71%
CAMMS323/CARE – MS I ^Citation15	CAMMSS030409 ^Citation32 and TOPAZ ^Citation33	5 years ^Citation35	335/367	68.5%	0.15*	79.7%	82.2% (60% stable, 22.2% improved)
CAMMS324/CARE – MS II ^Citation16	CAMMSS030409 ^Citation32 and TOPAZ ^Citation33	5 years ^Citation36	357/435	59.8%	0.18*	75.1%	76.6% (51.7% stable, 24.9% improved)

* in year 5.

ARR: annualized relapse rate; SAD: sustained accumulation of disability.

A post-hoc analysis of CARE-MS study population investigated alemtuzumab outcomes by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years) in 8 year follow up to find that alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups.³⁷

Several other post-hoc analyses mainly investigated long-term effectiveness in participants with highly active disease,³³ and in participants who experience relapse in between 1^st and 2^nd cycles,³⁸ or after 2^nd cycle of alemtuzumab.³⁹ In all three analyses, alemtuzumab showed low ARR, high percentage of patients who were free of 6-month CDW and favorable MRI outcomes. Of 742 CARE-MS patients who entered the CARE-MS extension, 396 (53%) received no more than two courses over 8 years, 201 (27%) received three courses, 94 (13%) received four courses, and 51 (<7%) received five or more courses over 8 years.³⁹

Evidence from real-world studies

There are limited real world data on effectiveness of alemtuzumab (Table 3). A retrospective study using data from 8 Italian centers in which 322 patients were switching from other DMT (reason for switch was relapse-rate (41.3%), MRI activity (22.8%), JCV+ (18.2%), EDDS progression (4.9%), other (12.8%)) to alemtuzumab showed that ARR decreased independently of previous DMT (prealemtuzumab ARR was 0.99 and ARR during alemtuzumab was 0.13, p < .001). Additional finding of this study was that relapses between treatment courses were associated with higher disease activity during follow-up.⁴⁰ Four studies showed high variation in percentage of pwMS treated with alemtuzumab who achieve NEDA-3, ranging from 29.2 to 66.7%.^41–44 Nevertheless, the effectiveness of alemtuzumab seems to be higher if administered as first line therapy.^45,46

Table 3. Main outcomes from real-world studies with alemtuzumab in RRMS and ocrelizumab in RRMS and PPMS

Country	Number of participants	Months of follow-up	ARR in the year prior to therapy/ARR on therapy	SAD	NEDA-3
Alemtuzumab
Italy ^Citation40	322	NR	0.99/ 0.13	Progression free survival 95% after 1 year, 88.1% after 2 yrs	61.8% after 1 year; 53.6% after 2 years
Italy ^Citation41	35	36	Median number of relapses 1 (0–3)/90.5% of patients were relapse-free	14.3%	66.7%
Italy ^Citation42	40	36	Median number of relapses 2 (0–4)/75% were relapse-free	17.5%	45%
Croatia and Slovenia ^Citation43	71	36	1.69/0.18 (year 1); 0.19 (year 2); 0.30 (year 3)	16.1%	29.2%
Italy ^Citation44	89	15 (0,9–35,7) months	Mean number of relapses in the previous year 1.8 (1–4)/86.7% relapse-free in year 1 and 78.6% relapse-free in year 2	0%	62%
Germany ^Citation46	779	1.6 yrs	1.6/0.2	NR	NR
Ocrelizumab
Spain ^Citation110	49 RRMS 21 PPMS	13.6 months (median)	1.3/0.02 RRMS	0% RRMS 4.7% PPMS	94% RRMS
Spain ^Citation111	144 RRMS 25 SPMS 59 PPMS	12 months (median)	1.11/0.09 RRMS	37.5% PPMS, 3.3% RRMS 17.6% SPMS	91.2% RRMS

NR: Not reported; ARR: annualized relapse rate; SAD: sustained accumulation of disability; NEDA-3: No evidence of disease activity.

Of special interest are studies investigating comparative effectiveness of high-efficacy DMTs. A comparison between the effectiveness and safety of autologous hematopoietic stem cell transplant (aHSCT) (n = 25) and alemtuzumab (n = 32) in aggressive RRMS during 24 months of follow-up showed that NEDA-3 was more frequently achieved in aHSCT cohort than in alemtuzumab-treated patients (75% vs 56% p = .023).⁴⁷ In an international, observational study that compared effectiveness of alemtuzumab (n = 189), natalizumab (n = 1160), IFNβ-1a (n = 2155), and fingolimod (n = 828) over ≥ 5 years’ treatment, alemtuzumab, and natalizumab had similar effects on ARR but alemtuzumab seemed to be superior to fingolimod (0.15 vs 0.34, p < .0001) and interferon beta (0.19 vs 0.53, p < .0001). Natalizumab was superior to alemtuzumab in enabling recovery from disability.⁴⁸ On the other hand, another observational study that compared effectiveness of alemtuzumab and natalizumab showed that after 12 months of treatment, the EDSS score of RRMS patients treated with natalizumab was significantly lower compared with the patients treated with alemtuzumab (1.23 vs 2.56, p < .05).⁴⁹ A small observational study including 16 patients switching from natalizumab to alemtuzumab due to high risk of progressive multifocal leukoencephalopathy (PML) showed that clinical evaluation performed at 6 and 12 months showed stability, in particular neither relapses nor an increase in EDSS were observed.⁵⁰ Similar finding were obtained from a study on pediatric population in which after median of 3.9 years of follow-up NEDA-3 was sustained.⁵¹ In a larger, single-center Italian study with mean follow up of 27 months, involving 90 patients with RRMS who started alemtuzumab treatment either due to highly aggressive disease or high risk of PML, 43.7% of patients achieved NEDA-3. EDSS was reduced after the treatment with alemtuzumab (from a median of 2.5 (IQR 1.5–4) before to 2.0 (IQR 1.5–3.5) after, p = .025).⁵²

On the other hand, several studies have shown that therapy switch from fingolimod to alemtuzumab was highly effective in reducing clinical and MRI disease activity.^53–55 Unfortunately, there are no studies yet investigating comparative effectiveness of alemtuzumab with ocrelizumab or cladribine.

Finally, observational studies showed that alemtuzumab stabilized overall cognitive functioning in active RRMS and positively affected cognitive processing speed,⁵⁶ and also to improved patient-reported outcomes in the observational PRO-ACT,⁵⁷ and PROMiS studies.⁵⁸

Safety of alemtuzumab

The most common adverse events (AEs) in clinical trials were rash, headache, fever and respiratory tract infections.^13,15,16 The AEs of special interest in follow-up were infusion associated reactions (IARs), secondary autoimmunity and infections. The length of the time period from alemtuzumab administration and occurrence of AEs defines subgroups of AEs into: (i) immediate comprising of IARs, (ii) periinfusional AEs including infections and cardiovascular, cerebral, gastrointestinal, and pulmonary complication, and (iii) late, such as secondary autoimmune disorder (Table 4).

Table 4. Adverse events associated with alemtuzumab and ocrelizumab

		Mitigating strategies
Alemtuzumab
Immediate AEs
	IARs	Premedications ^Citation59,Citation60 Methylprednisolone 1 g i.v. for the first 3 days Antihistaminics Antypiretics
Periinfusional
	Infections Herpes infections Listeria infections Latent tuberculosis	Vaccinations prior starting alemtuzumab, annual papillomavirus screening ^Citation13 Anti-herpetic prophylaxis Listeria-free diet/chemoprophylaxis Tuberculosis prophylaxis
	Acalculous cholecystitis
	Vascular complications myocardial ischemia myocardial infarction arterial dissection hemorrhagic stroke pulmonary hemorrhage	Strict control of blood pressure
	Transient thrombocytopenia	CBC on days 1, 3, and 5
Late
	Secondary autoimmunity thyroid disorders ITP nephropathies autoimmune hepatitis other rare conditions	TSH level every 3 months CBC monthly Liver enzyme panel monthly Creatinine and urine examination monthly
Ocrelizumab
Immediate AEs
	IARs	Premedications Methylprednisolone 100 mg i.v. Antihistaminics Antypiretics
Late
	Infections	HBV screening before ocrelizumab introduction IgM and IgG monitoring
	Neoplasms	Cancer screening according to the national guidelines for early detection
	Late onset neutropenia	CBC monitoring
	Other rare conditions colitis pancreatitis

IAR: infusion associated reactions; ITP: immune thrombocytopenic purpura; AE: adverse event; CBC: complete blood count; HBV: hepatitis B virus; TSH: thyroid stimulating hormone.

Infusion associated reactions

Most common AEs (experienced by 90.1% of patient) in CARE-MS program were IARs considered to be consequence of cytokine release associated with alemtuzumab-induced lymphocyte lysis.^15,16 Most IARs were mild-to-moderate in severity while serious IARs such as fever, nausea, headache, urticaria, hypotension, tachycardia, atrial fibrillation, and chest discomfort were experienced in 3.1%. Treatment discontinuation due to IARs was low; one (0.03%) patient discontinued treatment in CARE-MS I study due to allergic dermatitis and five (1.1%) discontinued treatment in CARE-MS II due to noncardiac chest pain and dyspnea in one patient, and pharyngeal edema, rash, purpura, and urticaria each in one patient. Mitigation strategies for prevention of IARs are shown in Table 4.^59,60

Periinfusional AEs

The most common periinfusional AEs associated with alemtuzumab are infections, which are predominantly (>95%) mild to moderate and include upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Infections occur more frequently with alemtuzumab than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were not frequent (1.0%–1.9% per year) and most commonly included pneumonia, gastroenteritis, varicella zoster and appendicitis. Frequency of opportunistic infections was even lower and accounted 0.8% of participants who received alemtuzumab and included herpes infections (n = 3; varicella zoster meningitis, varicella zoster, multidermatomal varicella zoster), candidiasis (n = 4), cytomegalovirus infection (n = 1), and acute disseminated tuberculosis (n = 1). Lymphocyte counts after alemtuzumab therapy did not predict infection risk.⁶¹ Occasional cases from post-marketing setting have shown serious opportunistic infections in alemtuzumab treated patients such as Listeria monocytogenes, Cytomegalovirus, Pneumocystis jiroveci, and Nocardia spp.⁶² Recommended preventive measures are shown in Table 4.¹³

In postmarketing setting rare cases of acute acalculous cholecystitis developing during of shortly after alemtuzumab administration were described, and the underlying mechanism may be similar to infusion-associated reactions mediated by a systemic inflammatory response.⁶³

During postmarketing pharmacovigilance in April 2019, EMA issued an assessment report based on marketing authorization holder’s (MAH) safety database searched from September 2013 through 31 March 2019 with 55,431 patient-years (PY) of exposure. Two cases of myocardial ischemia, 27 cases of myocardial infarction, 22 cases of potential myocardial ischemia or myocardial infarction, 25 cases of cerebrovascular accidents, including 6 cases of arterial dissection, 7 cases of pulmonary hemorrhage, 20 cases of pulmonary embolism, and 68 cases of immediate nonimmune-mediated thrombocytopenia were identified as risks in close temporal (≤ 30 days) association with the infusion of alemtuzumab.¹⁹ The mechanism of these rare AEs is still unclear, but may be related to increased cytokine release following alemtuzumab infusion.

Secondary autoimmunity

Secondary autoimmunity in alemtuzumab-treated patients is not fully elucidated but one of the hypothesis is that CD52+ cells depletion followed by the rapid repopulation of B cells in the relative absence of T-cell regulatory mechanisms that promote immune tolerance may account for the secondary B-cell mediated autoimmunities.⁶⁴ Additionally, secondary autoimmunity may appear when homeostatic proliferation predominates thymopoiesis in repopulation of T cells.⁶⁵ Alemtuzumab is considered to increase risk of thyroid disorders, immune thrombocytopenic purpura (ITP), nephropathies, and autoimmune hepatitis.¹⁹ Furthermore, cases of severely exacerbated central nervous system (CNS) inflammation have been described,^66–68 as well as systemic erythematosus lupus (SLE),⁶⁹ cytopenias,⁷⁰ and acquired hemophilia A.⁷¹

The most common autoimmune AEs, experienced by 42% of patients are thyroid AEs such as hyperthyroidism (including Graves’ disease), hypothyroidism, thyroiditis, and goiter. The rate of thyroid AEs peaks in Year 3 and subsequently declines. Most thyroid disorders associated with alemtuzumab are mild or moderate and no deaths occurred as a result of thyroid events.⁷² A systematic review and meta-analysis including 1362 MS patients from seven studies treated with alemtuzumab found that prevalence of newly diagnosed thyroid adverse events was 33%. Graves’ disease was the most represented (63% of cases), followed by Hashimoto thyroiditis (15%). Spontaneous remission was observed in 12% of patients with Graves’ disease, 56% were treated with antithyroid drugs only but 22% (95% CI 13–32%) needed additional radioiodine. Definitive surgery was performed in 11% of patients with Graves’ disease.⁷³

In the clinical development program over a median of 6.1 years of follow-up 33 (2.2%) patients treated with alemtuzumab developed ITP.⁷⁴ Corticosteroids, platelets, and/or intravenous immunoglobulins are used as first line treatment for ITP. ITP incidence in postmarketing setting is considered to be 0.72%.⁷⁴

Autoimmune nephropathies associated with alemtuzumab include antiglomerular basement membrane (anti-GBM) disease, membranous glomerulonephropathy and serum anti-GBM antibody without typical anti-GBM disease. The incidence of autoimmune nephropathies within clinical trials was 0.34% (5/1485 patients) and 0.05% in the postmarketing setting. The five cases from clinical trials were identified early, responded to conventional therapy (where needed), and had favorable outcomes. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria.⁷⁵

Autoimmune hepatitis (AIH) was found in a total of 40 unique case reports in the MAH’s database but only 9 cases had enough information and no known concomitant conditions/events/medications. The nine cases of AIH in alemtuzumab-treated patients translate into a reporting rate of 16 cases per 100,000 person-years.¹⁹ Additionally, 9 out of 11 cases with biopsy proven AIH had preexisting or had developed autoimmune thyroid conditions prior to the development of AIH suggesting that autoimmune propensity and the potential for poly-autoimmunity are important factors to take into account for minimizing the risk of autoimmune conditions associated with alemtuzumab. In addition, a new signal was identified and analyzed in this procedure and that were cases of acquired hemophilia A (antifactor VIII antibodies) that have been reported in both clinical trial and postmarketing setting. In addition, 13 cases of autoimmune-mediated CNS disease and 10 cases of Guillain-Barre Syndrome (GBS). Hemophagocytic lymphohistiocytosis in 11 cases, 2 with fatal outcome. Overall mortality rate in the postmarketing setting is 0.42% for EU patients. Finally, Epstein-Barr virus (EBV) hepatitis, another opportunistic infection, was described.¹⁹

Therapeutic indication, dosage, administration, and monitoring

Alemtuzumab is indicated in treatment of adults with highly active RRMS either in patients with highly active disease despite a full and adequate course of treatment with at least one DMT or in patients with rapidly evolving severe RRMS defined by two or more disabling relapses in one year, and with one or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI. Treatment should only be initiated and supervised by a neurologist experienced in the treatment of patients with MS in a hospital with ready access to intensive care. Contraindication for alemtuzumab are: hypersensitivity to the active substance or to any of the excipients, HIV infection, severe active infection until complete resolution, uncontrolled hypertension, history of arterial dissection of the cervicocephalic arteries, history of stroke, history of angina pectoris or myocardial infarction, known coagulopathy, on antiplatelet or anticoagulant therapy and other concomitant autoimmune diseases (besides MS). The recommended dose of alemtuzumab is 12 mg/day administered by intravenous infusion (duration of each infusion should be approximately 4 hours) for two initial treatment courses, with up to two additional treatment courses if needed. For the first course alemtuzumab is administered for 5 consecutive days and 12 months thereafter the second course is administered for 3 consecutive days. Each additional course should be 12 months after the previous one and the drug is administered for 3 consecutive days. Immediately prior to each alemtuzumab infusion patients should be pre-treated with corticosteroids each of the first 3 days of any treatment course. Pretreatment with antihistamines and/or antipyretics prior to alemtuzumab administration may also be considered. Oral prophylaxis for herpes infection should be administered to all patients starting on the first day of each treatment course and continuing for a minimum of 1 month following treatment. In addition, prior to each infusion a baseline ECG and heart rate and blood pressure measurement should be obtained. At least every hour during infusion monitoring of heart rate, blood pressure and overall clinical status of the patients should be performed. Observation for infusion reactions is recommended for a minimum of 2 hours after infusion. Platelet count should be obtained immediately after infusion on days 3 and 5 of the first infusion course, as well as immediately after infusion on day 3 of any subsequent course. Complete blood count with differential, serum transaminases, serum creatinine levels and urine analysis should be performed at monthly intervals at least 48 months following the last treatment and thyroid stimulating hormone level should be obtained every 3 months for the same time period. Before initiation of therapy, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection, according to local guidelines. To reduce the risk of listeriosis/listeria meningitis, patients should avoid ingestion of uncooked or undercooked meats, soft cheeses and unpasteurized dairy products 2 weeks prior to, during, and for at least 1 month after alemtuzumab infusion. If compliance with Listeria-free diet cannot be achieved than cotrimoxazole 960 mg three times a week for 1 month after each cycle of alemtuzumab should be administered. It is recommended that HPV screening be completed annually for female patients.⁷⁶

Alemtuzumab and pregnancy

Data from the use of alemtuzumab in pregnant women are limited. It is not known whether alemtuzumab can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity. Serum concentrations generally fall below the limit of quantitation (BLQ) within approximately 30 days following each treatment course,⁷ and women of childbearing potential have to use effective contraception when receiving a course of treatment with alemtuzumab and up to 4 months after each treatment course.⁷⁶ A report of pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years found 264 pregnancies in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion and the risk was not increased neither in women with pregnancy onset within 4 months of alemtuzumab exposure nor in women having autoimmune thyroid AEs.⁷⁷ Breast-feeding should be discontinued during each treatment course and for 4 months following the last infusion of each treatment course.⁷⁶

Alemtuzumab and COVID-19

COVID-19 is the pandemic disease caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection.⁷⁸ Considering significant infectious risks with alemtuzumab especially in the first two years of treatment initially it was speculated that the risk of COVID19 may be higher in patients treated with alemtuzumab.⁷⁹ However, there are cases reported even with a short time period between last alemtuzumab infusion and SARS-CoV-2 infection with favorable clinical outcome,⁸⁰ and also there is a report of a patient who acquired COVID-19 only 3 months after the last cycle of alemtuzumab and was able to produce SARS-CoV-2 antibodies.⁸¹ A study involving 565 MS patients with suspected SARS-CoV-2 infection and 279 MS patients with confirmed SARS-CoV-2 infection from 85 Italian MS centers found that progressive MS course, higher EDSS, higher body mass index (BMI), comorbidities, and recent methylprednisolone use as well as therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = .015) with increased risk of severe COVID‐19. No warning signal for alemtuzumab has been reported in this cohort.⁸² A recent systematic review that included 2493 MS patients and 37 neuromyelitis optica spectrum disorder (NMOSD) patients with COVID-19 from 84 studies found 37 reported patients on alemtuzumab and COVID-19. Most of them had a benign course and recovered completely, and none of them died. Of all MS patients included in this review 46 (1.8%) had fatal outcomes.⁸³

Vaccination and alemtuzumab treatment

Although vaccinations are safe and effective for the vast majority of pwMS, some specific considerations should be kept in mind when planning vaccination strategies before, during and after receiving alemtuzumab.⁸⁴ Live attenuated vaccines are contraindicated during treatment with alemtuzumab. However, pwMS who have been treated with an immune reconstitution therapy like alemtuzumab in the past and have reconstituted their peripheral immune systems should be able to respond to any vaccine (including live attenuated vaccines). If an individual had an incomplete immune reconstitution, they may still consider having a COVID-19 vaccine with the potential for a blunted immune response, as studies have shown that vaccination within 6 months of treatment with alemtuzumab results in a smaller proportion of vaccine responders.⁸⁵ Although some of the vaccines used for COVID-19 are live attenuated vaccines, the adenovirus genes required for viral replication are disabled. Thus, the adenovirus vector used in these vaccines is not able to cause adenoviral infection, making it highly likely to be safe for people with MS using any DMT, including alemtuzumab.⁸⁶

Ocrelizumab

Ocrelizumab (Ocrevus®) is a recombinant humanized monoclonal antibody that targets CD20-expressing B cells. Although MS was previously considered to be a predominantly T cell-mediated autoimmune disease, in the last decade, especially with the introduction of B-cell depleting therapies for other immunological diseases, it became obvious that B cells have a major contribution to MS pathogenesis.⁸⁷

The era of B-cell depletion therapy started in 1997, when rituximab, a chimeric monoclonal antibody was approved by the European Medical Agency (EMA) and the US Food and Drug Administration (FDA) for the oncologic treatment of B-cell non-Hodgkin’s lymphoma.⁸⁸ Rituximab was later used in the treatment of various autoimmune diseases, most commonly in the treatment of rheumatoid arthritis and systemic lupus erythematosus.⁸⁹ Following the pathological basis of therapeutic effects in autoimmune diseases, rituximab was also introduced in MS treatment. In 2008, the results of phase II of randomized double-blinded clinical trial HERMES conducted on pwRRMS were published, showing that rituximab reduces inflammatory lesions on MRI, as well as the proportion of relapses.⁹⁰ Positive results of rituximab treatment in MS encouraged investigators to evaluate other anti-CD20 antibodies in the treatment of MS and today we have 4 available anti CD20 treatment. The aim of this review was to evaluate the role of ocrelizumab, the second developed monoclonal antibody, in the treatment of relapsing-remitting and primary progressive forms of MS.

Mechanism of action

B cells originate from hematopoietic stem cell precursors in the bone marrow and their development consists of the maturation, selection, and differentiation process that takes place within the bone marrow, as well as in the secondary lymphoid organs.⁹¹ During the development process, B cells are expressing different CD markers and for ocrelizumab treatment consideration the most important marker is CD20. This marker is not expressed on stem cell precursors, antibody-secreting plasmablasts, and plasma cells, but it is present on immature, naive, and memory B-cells.⁹²

Initial evidence of B-cell involvement in MS came with the identification of specific IgG fraction in the cerebrospinal fluid analysis (CSF).⁹³ These fractions are known as oligoclonal bands and exhibit the activity of clonally expanded B cells within the intrathecal space. Oligoclonal bands are present in almost 90% of all patients with MS and they can substitute dissemination in time according to the 2017 diagnostic criteria for MS.^94,95

Within the CSF of pwMS polyclonal B cell response to measles, rubella, and varicella-zoster virus (MRZ reaction) is found, and it is considered to be a highly specific laboratory marker of MS.⁹⁶

Another important contribution to the proof of B-cell presence in the CNS was discovered in 2004 when ectopic lymphoid follicle-like structures containing CD20 + B cells as well as CD138+ plasma cells and follicular dendritic cells were found in the leptomeninges of SPMS patients.⁹⁷ Immunohistochemical analysis of brain specimens obtain from RRMS and PPMS patient revealed signs of pathologic meningeal aggregates of CD20 + B cells and CD3 + T cells that correlated with cortical demyelination.^98,99 In PPMS patients meningeal infiltration was associated with a more severe clinical course and younger age of death.⁹⁹

Selective depletion of CD20 B cells in ocrelizumab-treated patients is achieved through 4 mechanisms: ADCP, ADCC, CDC, and apoptosis. Innate immunity and the T-cell are not affected in ocrelizumab treated patients. Due to the fact that stem cells, pro-B cells, and plasma cells do not express CD20, the capacity of B-cell reconstitution and antibody production is retained.^100,101

In phase III studies on people with RRMS, ocrelizumab demonstrated to completely decrease the CD19 + B-cell count (equivalent in an assay measuring CD20+ cells) in blood after 2 weeks of treatment.¹⁰²

The median time to B-cell repletion after the last infusion of ocrelizumab in the phase II study was 72 weeks.¹⁰³ Ocrelizumab displays dose-dependent depletion of B cells. Patients with mild renal and hepatic impairment were also included in clinical trials and no change in the pharmacokinetics was observed. Ocrelizumab is cleared primarily via catabolism and degrades into smaller peptides and amino acids and its half-life is 26 days.¹⁰¹

Pooled analysis from RRMS and PPMS studies demonstrated the correlation between the B-cell depletion in blood with higher ocrelizumab exposure and body weight.¹⁰⁴ Another study supporting these findings showed that patients with fast repopulation rate of B cells had higher BMI.¹⁰⁵

Efficacy of ocrelizumab

Evidence from core clinical trials – RRMS

The safety and efficacy of ocrelizumab in people with RRMS was tested in one phase II,¹⁰³ and two identical phase III studies OPERA I and II (Table 1).¹⁰² Results of the phase II study

demonstrated in both dosing regimen of ocrelizumab (600 and 2000 mg) significant reduction in the number of gadolinium-enhancing T1 lesions at weeks 12, 16, 20, and 24 in comparison to placebo and INF beta 1a i.m.¹⁰³ Similar efficacy on MRI parameters was demonstrated in phase III studies.¹⁰² Additionally, 46 and 47% relative reduction in ARR in OPERA I and II, respectively, and 40% lower risk of 12-week (p < .001) and 24-week confirmed disability progression (p = .003) in pooled analysis of both studies was seen.

Evidence from extension studies – RRMS

Long term data from open label ocrelizumab extension in RRMS patients demonstrated that earlier and continuous ocrelizumab treatment up to 5 years provides sustained benefit on clinical and MRI measures of inflammatory disease activity. The beneficial effect was also observed in a smaller percentage of patients with disease progression as well as in a slower rate of brain volume loss.¹⁰⁶

Evidence from core clinical trials – PPMS

In 2009 the results of the OLYMPUS trial were published in which rituximab was evaluated in people with PPMS (pwPPMS). Although this trial failed to demonstrate the efficacy of rituximab in pwPPMS, a subgroup analysis demonstrated delayed disability progression in participants who were <51 years of age and had signs of the inflammatory activity of the disease.¹⁰⁷

The results provided in a subset of patients from OLYMPUS trial were the rationale for the design of ORATORIO, a phase III randomized, double-blind, placebo-controlled trial, in which ocrelizumab was investigated in pwPPMS (Table 1).¹⁰⁸ The percentage of patients with 12-week disability progression was significantly lower in ocrelizumab treated pwPPMS compared to participants receiving placebo. Statistically significant results in favor of ocrelizumab were demonstrated in following secondary outcomes: decrease in disability progression at 6 months, 25-foot walk (T25FW) change at 120 weeks, the percentage change in total T2-weighted lesions, the number of new or enlarging T2 lesions and the percentage of brain volume loss.

Evidence from extension studies – PPMS

After completion of the double-blind period in the ORATORIO study, participants were offered to enter an open-label extension phase in which they continued ocrelizumab or were switched from placebo to ocrelizumab.¹⁰⁹ All included patients were followed during the period of the at least 6.5 study years out of which 3.5 study years were in the open-label extension.

Out of 732 subjects included in the ORATORIO study, 451 participants were included in the open-label extension. At the last available analysis, disability measures (24-week confirmed disability progression, 9HPT, composite progression, and confirmed time to requiring a wheelchair) and MRI parameters (percentage change from baseline for T2 lesion volume and T1 hypointense lesion volume) were in favor of patients who were treated from the beginning in the ocrelizumab arm.

Evidence from real-world studies

Only a couple of studies investigated the effectiveness of ocrelizumab in a real-world setting (Table 3).^110,111 In pwRRMS NEDA-3 was achieved in >90% of participants in both studies. Furthermore, in pwPPMS disease progression ranged from 4.7 to 37.5%. However, these data are limited by short follow-up and real-world studies of longer duration are needed. No new safety signals were identified.

Safety of ocrelizumab

More than 80% participants in OPERA 1 and more than 85% of OPERA 2 in both treatment arm reported AE,¹⁰² while serious AE were present in 1.3% of ocrelizumab and in 2.9% of the IFN-beta-1a sc. group. In the ORATORIO trial, 95.1% of patients in the ocrelizumab group and 90% in the placebo group reported at least one AE while 20.4% in ocrelizumab and 22.2% in the placebo-treated arm had serious AE.¹⁰⁹ The most common AEs in the ocrelizumab treated group in both studies were IRR and infections while side effects of special interest were malignant diseases (Table 4).

Infusion associated reactions

In core clinical trials for both RRMS and PPMS, IARs occurred in 34.3 and 39.9% of participants, respectively.^102,108 Most of them were mild to moderate with exception of one life-threatening episode of bronchospasm in pwRRMS and two treatment discontinuation in pwPPMS. The most frequent ocrelizumab IRR presentations were pruritus, rash, throat irritation, and flushing. (102, 108) Short infusion period of 2 hours in comparison with 3.5 hours did not increase the risk of IRRs.¹¹²

Infections

In OPERA trials the most common infections (≥10% in both trials and treatment groups) were upper respiratory tract infection, nasopharyngitis, and urinary tract infection. There were no reports of opportunistic infections during the trials. Herpesvirus-associated infections were reported in 5.9% of the ocrelizumab and 3.4% of the INF group and were classified as mild or moderate with the exception of one ocrelizumab treated patient with severe genital herpes simplex infection.

In ORATORIO trial the percentage of any reported infection was 71.4% in the ocrelizumab and 69.9% in the placebo-treated group. The most common infections were nasopharyngitis, urinary tract infection, influenza, and upper respiratory tract infection. Upper respiratory tract infections were more common in ocrelizumab than in the placebo arm (10.9% vs. 5.9%). The percentage of serious infections (SI) according to system organ class was without significant difference, 6.2% with ocrelizumab and 5.9% with placebo. Herpesvirus-related infections were detected in 4.7% of ocrelizumab and 3.3% of placebo-treated patients, among which oral herpes was more common with mild to moderate clinical features.

In a recent systematic review of ocrelizumab associated AEs, that included reports of 7000 ocrelizumab treated patients, authors found that 61% of ocrelizumab-treated subjects had at least one AE, with the most common being infection (39%) and IRR (26%).¹¹³ The most commonly reported infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections as well as skin reactions. PPMS patients in comparison with RRMS patients had higher prevalence of AE,^102,108 but it is important to note that PPMS patients in clinical trials were 8 years older on average in comparison with RRMS.

According to published data, there were in total 10 cases of PML in ocrelizumab treated patients. Out of 10 PML cases, 9 were considered to be carryover due to previous exposure to either natalizumab or fingolimod, and 1 case was observed in 78-year-old patient with lymphopenia grade 2 and no prior DMD exposure.^114,115

In the ocrelizumab all-exposure treated population the most common serious infections (SI) were urinary tract infection, pneumonia and cellulitis. More than 95% of SI resolved without treatment discontinuation. There were no reports of new SI or new patterns of SI than those reported previously. As in clinical trials, SI were more prevalent in PPMS patients in comparison with RRMS phenotype.¹¹⁶ Moreover, it was demonstrated that a decreased level of serum immunoglobulins, particularly IgG levels are related to increased risk of SI.¹¹⁷

After 7 years of follow-up a reduction in serum IgG levels at an approximate mean rate of 3–4% per year was observed, but the profile of SIs verified during the hypogammaglobulinemia did not differ from patients with normal levels of IgG.¹¹⁶ Due to the fact that ocrelizumab administration can cause reactivation of latent hepatitis B virus (HBV) infection,¹¹⁸ HBV screening is mandatory before ocrelizumab introduction. Active HBV infection is a contraindication for ocrelizumab treatment while in cases of HB core antibody or surface antigen positivity consultation of a hepatologist is warranted.

Neoplasms

In OPERA trials, four neoplasms (0.5% of patients) occurred in the ocrelizumab group (two cases of invasive ductal breast carcinoma, one case of renal cell carcinoma, and one case of malignant melanoma), and two occurred (0.2%) in the INF group (mantle-cell lymphoma and squamous-cell carcinoma in the chest). In the open-label extension study, during which all participants were treated with ocrelizumab, five additional cases of neoplasm (two cases of breast cancer, two cases of basal-cell skin carcinoma, and one case of malignant melanoma) were reported.¹⁰²

In core clinical trials there were three deaths, one death in the ocrelizumab group (suicide in the OPERA II trial) and two in the INF group (one suicide in the OPERA I trial, and one death due to mechanical ileus in the OPERA II trial).¹⁰²

Neoplasms were reported in ORATORIO trial in 11 out of 486 patients (2.3%) in the ocrelizumab group (breast cancer in 4 patients, basal-cell carcinoma in 3, endometrial adenocarcinoma, anaplastic large-cell lymphoma, malignant fibrous histiocytoma, and pancreatic carcinoma) and in 2 of 239 patients (0.8%) in the placebo group (cervical adenocarcinoma in situ and basal-cell carcinoma).

In total five deaths were reported: four (0.8%) in the ocrelizumab arm due to pulmonary embolism, pneumonia, pancreatic carcinoma, and aspiration pneumonia and one (0.4%) in the placebo arm owing to a road-traffic accident.¹⁰⁸

In long term follow up that included all exposureocrelizumab treated patients yearly crude incidence of all malignancies (breast cancer and non-melanoma skin cancer included) remained stable over time. There was a higher number of breast cancers in ocrelizumab-treated patients in clinical trials but in long-term follow-up the age-standardized incidence of female breast cancer remained within epidemiological references.¹¹⁹

In data that included clinical trials and open-label extensions of ocrelizumab-treated patients, there was no increase in fatalities and no pattern of fatalities was observed in the ocrelizumab-treated patients.¹²⁰

Less common side effects

In 2020 the first case of ocrelizumab-induced colitis was described,¹²¹ followed by case of severe colitis,¹²² and ocrelizumab-induced colitis and esophagitis.¹²³ Pathophysiologically, this could be explained with regulatory B-cell depletion that was found to be associated with colitis in animal models and found also in specimens of intestinal tissue in patients with ulcerative colitis.¹²⁴

Due to the fact that colitis was described with rituximab treatment,¹²⁴ medical professionals prescribing ocrelizumab need to be vigilant in treated patients presenting with new onset gastrointestinal symptoms.

Our group published the case of acute pancreatitis in a patient without risk factors that occurred four months after second ocrelizumab cycle. Patient had mild clinical presentation and recovered completely.¹²⁵ In clinical trials five cases of pancreatitis were described and third patients had hepatobiliary risk factors.¹²⁶

A case of fulminant hepatitis induced by Echovirus 25 during ocrelizumab monotherapy was published as well and resulted in liver failure that was treated with liver transplantation. Several Echovirus cases causing fulminant hepatitis were confirmed in rituximab-treated patients as well.¹²⁷

Late onset neutropenia is defined as decrease of neutrophils <1.5 × 10⁹ more than 4 weeks after ocrelizumab exposure in a person with previously normal neutrophil count.¹²⁸

Similar cases were described in rituximab,¹²⁹ and only a few so far in ocrelizumab-treated patients.¹³⁰ Neutropenia can occur weeks to months after ocrelizumab treatment and it could be caused by alterations in growth factors that affect B-cell production at the level of bone marrow.¹³⁰

Therapeutic indication, dosage, administration, and monitoring

Ocrelizumab is indicated in the treatment of adult patients with relapsing or primary progressive forms of MS.¹³¹ European indication limits the use of Ocrelizumab in patients with relapsing forms of MS with active disease defined by clinical or imaging features and early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity.¹⁰¹

The starting ocrelizumab dose is 300 mg in 250 mL 0.9% NaCl, followed by a second infusion after 2 weeks, and thereafter every 6 months of 600 mg in 500 mL 0.9% NaCl, IV administered. Duration of the two 300 mg infusions should be approximately 2.5 hours. In order to avoid IRR, patients are at least 30–60 min prior to administration of ocrelizumab premedicated with 100 mg methylprednisolone (or an equivalent) and an antihistamine. Some centers in addition use paracetamol as well in premedication protocols. In subsequent cycles, two-hour infusion protocol can be applied in case patients did not experience any previous serious IRR. Patients are monitored at the infusion center for at least 60 min following ocrelizumab infusion.¹⁰¹

In our center, before every ocrelizumab cycle, we perform analysis of complete blood count and biochemistry including liver enzymes, lgM, IgG, and IgA levels, and absolute number of CD4 lymphocytes. Ocrelizumab is not administered in the following cases: number of absolute lymphocytes < 800, number of CD4 lymphocytes < 250, liver enzymes > 5× of upper normal level and when the level of any evaluated immunoglobulin is < 50% of the lower normal level.

Ocrelizumab and pregnancy

Rituximab and ocrelizumab are class of IgG1 antibodies and the placental transfer of these immunoglobulins occurs in a linear fashion with minimal transport in the first trimester, and maximal transport during the third trimester. Therefore, minimal fetal exposure is expected during the early stages of pregnancy while an increasing rate can occur during the third trimester.^132,133 There are limited data regarding the usage of B cell treatment during pregnancy; however, several publications evaluated the safety and effectiveness of rituximab administration in patients with NMOSD and MS as well as other immunological, rheumatological, and hemato-oncological diagnosis before and during pregnancy. Results of these studies demonstrated no major safety signals.^134,135

A small number of studies evaluated ocrelizumab exposure and pregnancy outcomes. A cohort study from Germany evaluated pregnancy outcomes and disease activity in women with NMOSD and MS that were treated with ocrelizumab or rituximab.¹³⁶ The study cohort included 68 known outcomes of 88 pregnancies from 81 women. Significantly more preterm births occurred in women with exposure during pregnancy and 2 major congenital abnormalities were observed in the same group of treated patients. Other evaluated pregnancy outcomes were similar between groups. Out of the whole cohort, three women had SI during pregnancy, and SI leading to hospitalization occurred in 3 newborns. There were no relapses during pregnancy in women with MS, one relapse occurred in the NMOSD group. Postpartum relapse occurred in 17.2% of RRMS and 8.3% of NMOSD women.¹³⁶ Most neonates had normal B-cell counts and for those with decreased B cell count recovery was complete at the age of 5 months with no observed increase of SI.

A study presented at ECTRIMS 2019 reported 118 pregnancies in women with MS exposed to ocrelizumab in utero with 54 known pregnancy outcomes and demonstrated the results that are not suggestive of an increased risk of adverse pregnancy or fetal outcomes.¹³⁷

The concentration of rituximab in breast milk was also shown to be minimal with no signs of developmental delay or SI in the follow-up period.¹³⁸

Because of the potential fetal B-cell depletion, decrease immunoglobulin levels and the possibility of SI the current label proposes discontinuation of anti-CD20 treatment at least 6 (FDA)¹³¹ to 12 months (EMA)¹⁰¹ before planned pregnancy.

Ocrelizumab and COVID-19

Recently published data that included SARS-CoV-2 positive patients treated with ocrelizumab during clinical trials, postmarketing safety database data and real-world data indicate similar rates of hospitalization, invasive ventilation and death in the ocrelizumab-treated and nonocrelizumab-treated patients.¹³⁹

More severe clinical features of SARS-CoV-2 infection, in ocrelizumab-treated patients as well as in general population, was associated with advanced age, male sex and the presence of comorbidities.¹⁴⁰

According to data presented in Hughes et al. dataset, COVID-19 in ocrelizumab-treated subjects was predominantly mild to moderate in severity what is in accordance with the reported general population and MS datasets.¹³⁹

On the other hand, data presented from the Italian group demonstrated that besides progressive MS course and comorbidities, recent methylprednisolone use as well as therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [95% CI] = 1.18–4.74, p = .015) with increased risk of severe COVID-19.⁸²

North American Registry of Patients with MS evaluated the clinical outcome in 1626 patients with SARS-CoV-2 infection. Increased disability and older age were each independently correlated with increased odds of all evaluated clinical severity levels. Among specific MS treatment rituximab and recent treatment with corticosteroids were associated with worse COVID-19 clinical severity.¹⁴¹

Due to COVID-19 pandemic and lockdown measures that were in place in many countries a delay in ocrelizumab infusions may have occurred. However, real-world data demonstrated that delaying ocrelizumab infusions up to three months had no impact on disease activity as measured by relapses with the number of previous ocrelizumab cycles being a significant predictor of peripheral B cells (CD19+) count.¹⁴²

Vaccination and ocrelizumab treatment

Preventing infections by vaccination is one of the most important parts of a comprehensive medical approach to patients with MS, even more so during COVID-19 pandemic.

In general, patients with MS should receive vaccinations in accordance with the local or national vaccination schedule. Special consideration exists regarding the administration of live and live-attenuated vaccines that are not recommended for MS patients taking a DMT.¹⁴³

Another specific consideration is related to the type of DMT and its mechanism of action.

Although treatment with ocrelizumab leads to a continuous depletion of CD20+ cells the capacity of B-cell reconstitution, as well as preexisting humoral immunity, should remain intact. In order to assess the influence of ocrelizumab administration on the humoral response on most commonly administered vaccines, VELOCE (Phase IIIb) study was conducted in pwRRMS.¹⁴⁴ Results of the study demonstrated attenuation of humoral responses at all time points in ocrelizumab treated patients but with antibody titers that are still expected to be protective. Based on these results, it would be advisable to administer all vaccines at least 6 weeks before ocrelizumab introduction.^101,144 Taking into account data from the VELOCE study, a similar response with diminished immunogenicity to COVID-19 vaccine may be anticipated in ocrelizumab treated patients. In a recently published case report authors presented vaccine failure in an ocrelizumab treated patient who developed symptomatic COVID-19 infection 19 days after the last dose of COVID-19 mRNA vaccine.¹⁴⁵ First dose of the vaccine was given within 3 weeks from last ocrelizumab infusion and this may have affected antibody development. It is worth mentioning that the patient was treated with casirivimab and imdevimab, monoclonal antibodies that are FDA approved in mild to moderate COVID-19 patients who are at high risk for progressing to severe COVID-19.¹⁴⁶

Taken all this into account, it has been suggested that dose interruption will be needed to allow effective vaccination against SARS-CoV-2, without the effect on inflammatory disease control.¹⁴⁷

Conclusions

Introduction of monoclonal antibodies in the treatment of MS have revolutionized the MS treatment landscape in the last decade. With the introduction of alemtuzumab into clinical practice, we have witnessed the first immune reconstitution therapeutic approach in MS, with a potential of long lasting remission after only two cycles of therapy. Similarly, with the introduction of ocrelizumab we have witnessed a first DMT having a positive effect on delaying progression in pwPPMS. With the increasingly complex landscape of DMTs approved for MS, people with MS and neurologists are constantly faced with the question which DMT is the most appropriate for the given patient. There are two important fact that one has to bear in mind in this decision process: (i) DMTs should be commenced within a year from the disease onset to reduce the risk of disability accumulation over the long term¹⁴⁸ and (ii) initial treatment with higher efficacy DMTs is associated with a lower risk of conversion to SP MS vs initial treatment with lower efficacy DMTs.¹⁴⁹ Further clinical and real-world studies are needed to obtain long-term efficacy and safety evidence and comparative effectiveness for these therapies. Furthermore, personalized approach to MS treatment and management is warranted and studies investigating potential biomarkers of treatment response are of utmost importance.

Disclosure of potential conflicts of interests

TG: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.

BB: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals.

IA: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.

MKS: received consultation and/or speaker fees from: Sanofi Genzyme, Roche.

MH: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.

Authors’ contributions

Study concept and design: Habek. Acquisition of data: Gabelić, Barun, Adamec, Krbot Skorić, Habek. Analysis and interpretation of data: Gabelić, Barun, Adamec, Krbot Skorić, Habek. Drafting of the manuscript: Gabelić, Barun. Critical revision of the manuscript for important intellectual content: Gabelić, Barun, Adamec, Krbot Skorić, Habek. Administrative, technical, and material support: Gabelić, Barun, Adamec, Krbot Skorić, Habek.