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

Figures & data

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.

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.

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.

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.

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.

Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK, CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359:1786–801.

 PubMed Web of Science ®Google Scholar

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, et al. CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819–28. doi:10.1016/S0140-6736(12)61769-3.

 PubMed Web of Science ®Google Scholar

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, et al. CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829–39. doi:10.1016/S0140-6736(12)61768-1.

 PubMed Web of Science ®Google Scholar

Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378:1779–87. doi:10.1016/S0140-6736(11)61649-8.

 PubMed Web of Science ®Google Scholar

Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, et al. Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376:221–34. doi:10.1056/NEJMoa1601277.

 PubMed Web of Science ®Google Scholar

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209–20. doi:10.1056/NEJMoa1606468.

 PubMed Web of Science ®Google Scholar

An extension protocol for multiple sclerosis patients who participated in genzyme-sponsored studies of alemtuzumab. [ accessed 1 Mar 2021]. https://clinicaltrials.gov/ct2/show/NCT00930553 .

 Google Scholar

Ziemssen T, Bass AD, Berkovich R, Comi G, Eichau S, Hobart J, Hunter SF, LaGanke C, Limmroth V, Pelletier D, et al. CARE-MS I, CARE-MS II, CAMMS03409, and TOPAZ investigators. Efficacy and safety of alemtuzumab through 9 years of follow-up in patients with highly active disease: post Hoc analysis of CARE-MS I and II patients in the TOPAZ extension study. CNS Drugs. 2020;34:973–88. doi:10.1007/s40263-020-00749-x.

 PubMed Web of Science ®Google Scholar

Steingo B, Al Malik Y, Bass AD, Berkovich R, Carraro M, Fernández Ó, Ionete C, Massacesi L, Meuth SG, Mitsikostas DD, et al. CAMMS223, CAMMS03409, and TOPAZ Investigators. Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223. J Neurol. 2020;267:3343–53. doi:10.1007/s00415-020-09983-1.

 PubMed Web of Science ®Google Scholar

Havrdova E, Arnold DL, Cohen JA, Hartung HP, Fox EJ, Giovannoni G, Schippling S, Selmaj KW, Traboulsee A, Compston DAS, et al. CARE-MS I and CAMMS03409 Investigators. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology. 2017;89:1107–16. doi:10.1212/WNL.0000000000004313.

 PubMed Web of Science ®Google Scholar

Coles AJ, Cohen JA, Fox EJ, Giovannoni G, Hartung HP, Havrdova E, Schippling S, Selmaj KW, Traboulsee A, Compston DAS, et al. CARE-MS II and CAMMS03409 Investigators. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology. 2017;89:1117–26. doi:10.1212/WNL.0000000000004354.

 PubMed Web of Science ®Google Scholar

Sacca F, Russo CV, Frau J, Annovazzi P, Signoriello E, Bonavita S, Grasso R, Clerico M, Cordioli C, Laroni A, et al. A real-world study of alemtuzumab in a cohort of Italian patients. ECTRIMS 2019 Online Library Sep 13, 2019; 278628, p. 1428S.

 Google Scholar

di Ioia M, Di SV, Farina D, Di TV, Travaglini D, Pietrolongo E, Sensi SL, Onofrj M, De LG. Alemtuzumab treatment of multiple sclerosis in real-world clinical practice: a report from a single Italian center. Mult Scler Relat Disord. 2020;38:101504. doi:10.1016/j.msard.2019.101504.

 PubMed Web of Science ®Google Scholar

Italian Alemtuzumab Study Group. Prosperini L, Annovazzi P, Boffa L, Buscarinu MC, Gallo A, Matta M, Moiola L, Musu L, Perini P, Avolio C, et al. No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study. J Neurol. 2018;265:2851–60. doi:10.1007/s00415-018-9070-x.

 PubMed Web of Science ®Google Scholar

Brecl Jakob G, Barun B, Gomezelj S, Gabelić T, Šega Jazbec S, Adamec I, Horvat Ledinek A, Rot U, Krbot Skorić M, Habek M. Effectiveness and safety of alemtuzumab in the treatment of active relapsing-remitting multiple sclerosis: a multicenter, observational study. Neurol Sci. 2021. doi:10.1007/s10072-021-05145-x.

 PubMed Web of Science ®Google Scholar

Moiola L, Zanetta C, Di Cristinzi M, Rinaldi F, Brambilla L, Frau J, Malucchi S, Annovazzi P, Puorro G, Bianco A. Italian prospective multicenter observational study conducted in daily clinical practice in patients affected by RRMS with highly active disease, naïve to therapies, who start a treatment with alemtuzumab (ALEM-NAIVE). ECTRIMS online library. Oct 11, 2018; 228739:896.

 Google Scholar

Ziemssen T, White R, Kern R, Engelmann U, Haase R, Guikema B, Akgün K, TREAT-MS Study Group. TREAT-MS study of real-world effectiveness of alemtuzumab in RRMS patients in Germany: subgroup analysis by number of prior disease-modifying therapies. ECTRIMS 2019 online library. Sep 12, 2019; 279348, p. 988.

 Google Scholar

Sempere AP, Berenguer-Ruiz L, Borrego-Soriano I, Burgos-San Jose A, Concepcion-Aramendia L, Volar L, Aragones M, Palazón-Bru A. Ocrelizumab in multiple sclerosis: a real-world study from Spain. Front Neurol. 2021;11:592304. doi:10.3389/fneur.2020.592304.

 PubMedGoogle Scholar

Fernandez-Diaz E, Perez-Vicente JA, Villaverde-Gonzalez R, Berenguer-Ruiz L, Candeliere Merlicco A, Martinez-Navarro ML, Gracia Gil J, Romero-Sanchez CM, Alfaro-Saez A, Diaz I, et al. Real-world experience of ocrelizumab in multiple sclerosis in a Spanish population. Ann Clin Transl Neurol. 2021;8:385–94. doi:10.1002/acn3.51282.

 PubMed Web of Science ®Google Scholar

Šega-Jazbec S, Barun B, Horvat Ledinek A, Fabekovac V, Krbot Skorić M, Habek M. Management of infusion related reactions associated with alemtuzumab in patients with multiple sclerosis. Mult Scler Relat Disord. 2017;17:151–53. doi:10.1016/j.msard.2017.07.019.

 PubMed Web of Science ®Google Scholar

Vukusic S, Brassat D, de Seze J, Izquierdo G, Lysandropoulos A, Moll W, Vanopdenbosch L, Arque MJ, Kertous M, Rufi P, et al. Single-arm study to assess comprehensive infusion guidance for the prevention and management of the infusion associated reactions (IARs) in relapsing-remitting multiple sclerosis (RRMS) patients treated with alemtuzumab (EMERALD). Mult Scler Relat Disord. 2019;29:7–14. doi:10.1016/j.msard.2019.01.019.

 PubMed Web of Science ®Google Scholar

European Medicines Agency. Lemtrada 12 mg concentrate for solution for infusion: EU summary of product characteristics. 2019. [accessed 25 Feb 2021]. https://www.ema.europa.eu/ .

 Google Scholar