Monoclonal Antibodies for Multiple Sclerosis Treatment, Sclerosis for Multiple Antibodies Monoclonal F

- The accumulation 3 An important ligand of the integrin α4β1 integrin the of ligand important An 4 century, monoclonal antibodies have gained an increasing th The inflammatory process that produces demyelination of these molecules is the integrin α4β1, a glycoprotein that is expressed on the surface of lymphocytes, monocytes, mast cells, macrophages, basophils and eosinophils (but neutrophils). in not is which (VCAM-1), 1 molecule adhesion cell vascular the is of the profile of the drugs which will be presented and Table and presented be will which drugs the of profile the of 2 the most relevant data from focused). clinical Specificities of trials these drugs that require clinicians will to be supporting data efficacy and safety the mind in clearly have their practical use. In this paper we will mAbs investigation under still and approved currently about make a revision for MS treatment. Natalizumab and axonal loss in forms of MS patients is closely diagnosed linked to the with nervous infiltration system of (CNS) relapsing central by leukocytes. of lymphocytes and monocytes into complex the process that CNS affects molecular is factors promoting a very migration through the inside leukocytes of survival and the proliferation facilitating blood-brain-barrier activated of expression BBB, the across migration For (BBB) CNS. and adhesion molecules on leukocyte surface is required. One 640 century, th This method 2 Copyright © Ordem dos Médicos 2015 These experiments 1 century, Kitasato and Behring th R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m 1,2 Anticorpos Monoclonais; Ensaios Clínicos; Esclerose Múltipla.  Antibodies, Monoclonal; Clinical Trials; Multiple Sclerosis. Trials; Antibodies, Monoclonal; Clinical

Neurology is one of the medical disciplines currently At the end of the 19 monoclonais já em uso e também em desenvolvimento clínico para tratamento da esclerose múltipla. monoclonais já em uso e também em desenvolvimento Palavras-chave: Desde a sua introdução na terapêutica médica, no último quarto do século XX, os anticorpos monoclonais têm ganho cada vez mais importância no tratamento de várias doenças. A Neurologia tem terapêutico sido destes anticorpos monoclonais uma e algumas doenças das neurológicas podem já especialidades contar com fármacos médicas deste tipo nos a seus al beneficiar do esclerose potencial goritmos A múltipla terapêuticos. é uma dessas doenças e, para além dos já licenciados para utilização clínica, são vários os anticorpos monoclonais que se encontram em desenvolvimento para futura certamente por fármacos utilização deste tipo e, neste artigo, far-se-á nesta uma revisão dos dados mais área relevantes relacionados com os anticorpos específica. O futuro passará Since their introduction in medical therapy, in the last quarter of the 20 importance algorithms. in therapeutic their the in drugs treatment such contain of now may various conditions neurological diseases. certain and Neurology antibodies monoclonal has these of been potential one of the medical others several specialties use, clinical for licensed already benefitingantibodies monoclonal the to ofaddition in and, diseases these theof one is sclerosis therapeutic Multiple a article, this in and, drugs of kind this through pass certainly will future The area. specific this in utilization future for development in are sclerosis multiple for development clinical in also and use in already antibodies monoclonal to related data relevant most the of review treatment will be performed. Keywords: Autor correspondente: Filipe Palavra. [email protected] Anticorpos Monoclonais para Tratamento da Esclerose Múltipla da Esclerose para Tratamento Anticorpos Monoclonais Treatment Monoclonal Antibodies for Multiple Sclerosis Sclerosis for Multiple Antibodies Monoclonal ABSTRACT Recebido: 07 de Abril de 2015 - Aceite: 14 de Julho de 2015 | Abril de 2015 - Recebido: 07 de 1. Institute for Biomedical Imaging and Life Sciences, CNC. IBILI Research Unit. Faculdade de Medicina. Universidade de Coimbra. Coimbra. Portugal. 1. Institute for Biomedical Imaging and Life Sciences, CNC. IBILI Research Unit. Faculdade de Medicina. Universidade Applied to Health (ICNAS). Faculdade de Medicina. Universidade de Coimbra. Coimbra. Portugal. 2. Institute for Nuclear Sciences  in the market, there is a can fruitful run, medium and short the in that, mAbs research some includes pipeline, which summary a contains 1 (Table clinical usage availablefor be taking advantage from this already some knowledge neurological and conditions there that treated with mAbs. Multiple sclerosis can (MS) are is one of now those be conditions and, in addition to the drugs already available to start considering mAbs as valuable therapeutic agents in agents therapeutic valuable as mAbs considering start to diverse clinical settings. monoclonal antibodies (mAbs) that ensured generation of a specific and constant pure antibodies. opened a new chapter in modern Immunology and allowed changed the epidemiology of many (until then) diseases causing high common mortality rates. In 1975, Kohler and mouse of production the for procedure a developed Milstein diphtheria and tetanus preparations. established the basis for serum therapy and avenues opened of up research that, with throughout the the development 20 of multiple vaccines, dramatically performed a set of experiments that led to the demonstration the to led that experiments of set a performed that immunologically naïve animals could be protected by serum taken from animals treated with nonlethal doses of INTRODUCTION RESUMO Filipe PALAVRA Acta Med Port 2015 Sep-Oct;28(5):640-651

ARTIGO DE REVISÃO was maintained at two years and the proportions of patients year.one at 68% by rate relapse annualized reduction This ( significant a showed patients Natalizumab-treated 942). = (n years 50 - 18 aged patients RRMS in years two for placebo with compared was weeks) four every mg 300 (intravenous monotherapy natalizumab with Patients in Relapsing RemittingMultipleSclerosis) Beta-1a Interferon with Combination Natalizumab in of Efficacy and (Safety SENTINEL the and o hs rnoie t paeo t w yas n also ( and significant years a two at experienced placebo to randomized those to compared 42% by progression disability sustained of risk Sclerosis) Multiple Remitting Relapsing in double-blind, Efficacy and randomized, large, multicentre, published, phase III trials: the AFFIRM (Natalizumab fully Safety two from coming data by supported is RRMS with diagnosed relapsing-remitting MS(RRMS). the molecule adhesion of treatment the revolutionized completely ofselective which was inhibitors, newclass It a in α4β1. drug integrin first anti-human (mAb) monoclonal integrin murine antibody a the from against derived (CD49d), directed α4-subunit antibody humanized a is into inflamedareasoftheCNS. migrate to and wall vascular to adhere to lymphocytes and interaction with VCAM-1 are crucial for activated monocytes and activation α4β1 integrin cytokines, pro-inflammatory of increased in chronic MS plaques and that, under the control demonstrated that integrin α4β1 and VCAM-1 expression is expressed on the surface of vascular endothelial cells. It was and IgdomaincontainingNOGOreceptorinteractingprotein1;GM-CSF:Granulocyte-macrophagecolony-stimulatingfactor EMA: European Medicines Agency; FDA: United States Food and Drug Administration; MSRV-ENV: Multiple sclerosis-associated retrovirus-ENV protein; LINGO-1: Leucine-rich repeat Table 1 MEDI-551 MOR103 BIIB033 GNbAC1 Ofatumumab Ocrelizumab Daclizumab Alemtuzumab Natalizumab Name n h FIM td ( study AFFIRM the In The efficacy of the drug in the treatment of adult patients (Tysabri Natalizumab -SummaryoftheprincipaldatarelatedwithprofilemAbsalreadyinuseandunderinvestigationforMStreatment Palavra F. Monoclonalantibodiesformultiplesclerosistreatment, Humanized Fully human Fully human Humanized Fully human Humanized Humanized Humanized Humanized Type ® ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R Boe Ea Pharmaceuticals) Elan Biogen ; NCT00027300) p 001 rdcin n the in reduction 0.001) < p 5 6 < 0.001) reduction in the in reduction 0.001) <

8 trials. , the efficacy of efficacy the , CD19 GM-CSF LINGO-1 MSRV-ENV CD20 CD20 CD25 CD52 CD49d Target 7 641

ao polm soitd ih h amnsrto o this of administration the with the with associated in contact problem major time first the for neurologists placed study SENTINEL the but good, was natalizumab of profile years comparedwithinterferon beta-1aalone( the number of gadolinium-enhancing lesions by 89% over and 2 83% by lesions T2-hyperintense enlarging or new of number the reduced therapy combination outcomes, trial. MRI the of end the at maintained also ( year one at 54% by rate relapse annualized the reduced also and interferon to placebo of progression at two years by 24% compared with the addition beta-1a interferon significantly ( with natalizumab of combination 171). The 1 = (n years 55 - 18 aged patients RRMS in week) a once intramuscularly μg (30 therapy beta-1a interferon existing to placebo versus weeks) four every intravenously mg 300 of dose the in given (also natalizumab of addition 0.001). ( placebo with compared years, two at 83% by and year one at 74% by lesions T1-hypointense new of number the ( placebo with compared years, two and one both at 92% by lesions gadolinium-enhancing of number the reduced also It years. two at 83% by and year one at 80% by images weighted the number of new or enlarging hyperintense lesions on T2- with placebo. Natalizumab significantly ( superior,were mAb the with obtained results the compared view of point (MRI) imaging resonance magnetic the from natalizumab than with placebo at the ( end of significantly both years. were relapse of free oh ras eosrtd ht h gnrl tolerability general the that demonstrated trials Both ( study SENTINEL The Phase I/II Phase I Phase II Phase II Phase II Phase III Phase III Approved bytheEMA and FDA Phase IIIprogramcompleted Already usedinclinicalpractice(phaseIV) Phase ofdevelopment Acta MedPort2015Sep-Oct;28(5):640-651 7 p < 0.001) and, in addition, natalizumab reduced natalizumab addition, in and, 0.001) < p = 0.02) reduced the risk of sustained disability . NCT00030966) p p 001 hge with higher 0.001) < 001, hc was which 0.001), < p 8 < 0.001) reduced osdrn the Considering oprd the compared p <0.001). 7 Also p < 8

ARTIGO DE REVISÃO

Final data collection date for primary outcome measure. outcome primary for date collection data Final * neuritis. optic Acute AON: Scale; Status Disability Expanded EDSS: imaging; resonance Magnetic MRI: Interferon; IFN: progression;

mAb: Monoclonal antibody; MS: Multiple sclerosis; RRMS: Relapsing-remitting multiple sclerosis; PPMS: Primary progressive multiple sclerosis; SPMS: Secondary progressive multiple sclerosis; ARR: Annualized relapse rate; SDP: Sustained disability disability Sustained SDP: rate; relapse Annualized ARR: sclerosis; multiple progressive Secondary SPMS: sclerosis; multiple progressive Primary PPMS: sclerosis; multiple Relapsing-remitting RRMS: sclerosis; Multiple MS: antibody; Monoclonal mAb:

placebo) vs (MEDI-551 MS of available

Safety and tolerability of MEDI-551 of tolerability and Safety 2015 January 2012 April MEDI-551

NCT01585766 forms Relapsing Results not yet yet not Results

placebo)

serious adverse events adverse serious SPMS available

January 2014 January 2012 January vs mg/kg 2 or 1 0.5, (MOR103 MOR103

RRMS and and RRMS Results not yet yet not Results or treatment-emergent with patients of Percentages

NCT01517282 NCT01517282

1a 30 μg) 30 1a

and/or disability and/or

placebo + IFNβ- + placebo vs μg 30 IFNβ-1a MS of available (estimated)

improvement of neuro-physical and/or cognitive function function cognitive and/or neuro-physical of improvement 2013 August

(BIIB033 3, 10, 30 or 100 mg/kg + + mg/kg 100 or 30 10, 3, (BIIB033 forms Relapsing Results not yet yet not Results 2016 March

Number of participants experiencing confirmed confirmed experiencing participants of Number

SYNERGY

BIIB033

eye

placebo) vs mg/kg 100 (BIIB033 available

AON the affected eye from the baseline of unaffected fellow fellow unaffected of baseline the from eye affected the 2014 August 2012 December

RENEW Results not yet yet not Results

Change in optic nerve conduction velocity at week 24 for for 24 week at velocity conduction nerve optic in Change

placebo) vs mg 100 were observed were

SPMS of BIIB033 in subjects with MS with subjects in BIIB033 of

(BIIB033 0.3, 1, 3, 10, 30, 60 or or 60 30, 10, 3, 1, 0.3, (BIIB033 52 problems safety 2012 April 2010 October

RRMS and and RRMS Safety and tolerability profile of two intravenous infusions infusions intravenous two of profile tolerability and Safety

01244139 NCT No unexpected unexpected No

patients

placebo) vs mg/kg 6 or 2 (GNbAC1 available

MS GNbAC1 well as of repeated administrations of GNbAC1 in MS MS in GNbAC1 of administrations repeated of as well 2014 April 2012 July

NCT01639300 Results not yet yet not Results

Safety and tolerability of single ascending doses, as as doses, ascending single of tolerability and Safety

placebo) scans at weeks 4, 8 and 12 and 8 4, weeks at scans

available (estimated)

vs mg 60 and 30 3, (ofatumumab RRMS brain lesions at week 12 from screen based on MRI MRI on based screen from 12 week at lesions brain 2011 November

Results not yet yet not Results 2015 June

MIRROR Cumulative number of new T1 gadolinium enhancing enhancing gadolinium T1 new of number Cumulative

Ofatumumab

placebo) vs mg were observed were

laboratorial changes from baseline from changes laboratorial

(ofatumumab 100, 300 and 700 700 and 300 100, (ofatumumab RRMS 44 problems safety 2010 May 2008 May

Number of participants with adverse events and and events adverse with participants of Number

OMS115102 No unexpected unexpected No

least 12 weeks 12 least

placebo) vs mg 600 (ocrelizumab available (estimated)

PPMS as an increase in EDSS score that is sustained for at at for sustained is that score EDSS in increase an as 2011 March

Ocrelizumab

ORATORIO Results not yet yet not Results 2017 October

Time to onset of sustained disability progression, defined defined progression, disability sustained of onset to Time

g) μ 44

of MS of available (estimated)

-1a -1a β IFN vs mg 600 (ocrelizumab ARR 2011 September

Relapsing forms forms Relapsing Results not yet yet not Results 2020 January

OPERA II OPERA

g) μ 44

of MS of available (estimated)

-1a -1a β IFN vs mg 600 (ocrelizumab ARR 2011 August

Relapsing forms forms Relapsing Results not yet yet not Results 2019 November

OPERA I OPERA

(2 000 mg) 000 (2

primary endpoint endpoint primary

placebo) vs. μg 30 IFNβ-1a

96% reduction in in reduction 96% brain the of scans MRI on observed

September 2009 September 2008 January vs mg 2000 or 600 (ocrelizumab RRMS 42 Ocrelizumab Ocrelizumab

Total number of gadolinium-enhancing T1 lesions lesions T1 gadolinium-enhancing of number Total mg) (600

NCT00676715

primary endpoint endpoint primary

89% reduction in in reduction 89%

30 μg) 30

available

RRMS ARR 2014 March 2010 May IFNβ-1a vs mg 150 (daclizumab

Results not yet yet not Results

DECIDE continues in the next page Table

ARR (300 mg) (300 ARR

placebo)

50% reduction in in reduction 50%

RRMS ARR 2011 May 2008 February vs mg 300 or 150 (daclizumab 37

ARR (150 mg) (150 ARR Daclizumab

SELECT

54% reduction in in reduction 54%

treated patients treated

placebo + IFNβ) + placebo vs

of MS of between weeks 8 to 24 in daclizumab- daclizumab- in 24 to 8 weeks between primary endpoint primary placebo- vs.

October 2006 October 2005 April IFNβ + mg/kg 2 or 1 (daclizumab 36

Relapsing forms forms Relapsing enhancing lesions on monthly brain MRIs collected collected MRIs brain monthly on lesions enhancing 72% reduction in in reduction 72%

CHOICE

Number of new or enlarged gadolinium contrast contrast gadolinium enlarged or new of Number

* date

population

Acta Med Port 2015 Sep-Oct;28(5):xxx-xxx Sep-Oct;28(5):xxx-xxx Port 2015 Acta Med date

mAb Primary endpoint Primary completion trial Clinical Reference outcome Main

Target Target Study start start Study

Primary Primary mAbs under research research under mAbs

642

IFNβ-1a 44 μg) 44 IFNβ-1a

42% reduction in SDP in reduction 42%

September 2011 September 2007 October vs mg 24 and 12 (alemtuzumab 27

49.4% reduction in ARR in reduction 49.4%

CARE-MS II CARE-MS

Alemtuzumab RRMS

44 μg) 44

No statistically significant differences in SDP in differences significant statistically No

(alemtuzumab 12 mg mg 12 (alemtuzumab April 2011 April 2007 August IFNβ-1a vs 26

54.9% reduction in ARR in reduction 54.9%

I CARE-MS

placebo + IFN + placebo vs g μ g) μ 30 -1a β

24% reduction in SDP in reduction 24%

(natalizumab 300 mg + IFN + mg 300 (natalizumab April 2005 April 2002 January 30 -1a β 8

54% reduction in ARR in reduction 54%

SENTINEL

Natalizumab RRMS

R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m

(natalizumab 300 mg mg 300 (natalizumab placebo) vs 42% reduction in SDP in reduction 42%

November 2004 November 2001 November 7

AFFIRM 68% reduction in ARR in reduction 68%

Palavra F. Monoclonal antibodies for multiple sclerosis treatment, sclerosis for multiple antibodies Monoclonal F. Palavra

* date

date

mAb Clinical trial Clinical indication Main completion completion Main clinical outcomes clinical Main Reference

Study start start Study

Primary Primary

mAbs already approved for usage in clinical practice (only phase III studies are presented) are studies III phase (only practice clinical in usage for approved already mAbs

Table 2 Table Main data related to clinical trials that support the use or the study of several mAbs several of study the or use the support that trials clinical to related data Main -

ARTIGO DE REVISÃO Table 2 - Main data related to clinical trials that support the use or the study of several mAbs

mAbs already approved for usage in clinical practice (only phase III studies are presented)

Primary Study start mAb Main indication Clinical trial completion Main clinical outcomes Reference date date*

AFFIRM 68% reduction in ARR November 2001 November 2004 7 (natalizumab 300 mg vs placebo) 42% reduction in SDP

Natalizumab RRMS SENTINEL 54% reduction in ARR (natalizumab 300 mg + IFNβ-1a 30 January 2002 April 2005 8 24% reduction in SDP μg vs placebo + IFNβ-1a 30 μg)

CARE-MS I 54.9% reduction in ARR (alemtuzumab 12 mg vs IFNβ-1a August 2007 April 2011 26 No statistically significant differences in SDP 44 μg) Alemtuzumab RRMS CARE-MS II 49.4% reduction in ARR (alemtuzumab 12 and 24 mg vs October 2007 September 2011 27 42% reduction in SDP IFNβ-1a 44 μg)

mAbs under research

Primary Target Study start mAb Clinical trial completion Primary endpoint Main outcome Reference population date date*

Number of new or enlarged gadolinium contrast CHOICE Relapsing forms enhancing lesions on monthly brain MRIs collected 72% reduction in (daclizumab 1 or 2 mg/kg + IFNβ April 2005 October 2006 36 of MS between weeks 8 to 24 in daclizumab- vs. placebo- primary endpoint vs placebo + IFNβ) treated patients

54% reduction in SELECT Daclizumab ARR (150 mg) RRMS (daclizumab 150 or 300 mg vs February 2008 May 2011 ARR 37 50% reduction in placebo) ARR (300 mg)

DECIDE Results not yet RRMS (daclizumab 150 mg vs IFNβ-1a May 2010 March 2014 ARR available 30 μg)

89% reduction in primary endpoint NCT00676715 Total number of gadolinium-enhancing T1 lesions (600 mg) Ocrelizumab RRMS (ocrelizumab 600 or 2000 mg vs January 2008 September 2009 42 observed on MRI scans of the brain 96% reduction in IFNβ-1a 30 μg vs. placebo) primary endpoint (2 000 mg)

OPERA I Relapsing forms November 2019 Results not yet (ocrelizumab 600 mg vs IFNβ-1a August 2011 ARR of MS (estimated) available 44 μg)

OPERA II Relapsing forms January 2020 Results not yet (ocrelizumab 600 mg vs IFNβ-1a September 2011 ARR of MS (estimated) available 44 μg) Palavra F. Monoclonalantibodiesformultiplesclerosistreatment,

Time to onset of sustained disability progression, defined Ocrelizumab ORATORIO October 2017 Results not yet PPMS March 2011 as an increase in EDSS score that is sustained for at ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R (ocrelizumab 600 mg vs placebo) (estimated) available least 12 weeks

OMS115102 No unexpected Number of participants with adverse events and RRMS (ofatumumab 100, 300 and 700 May 2008 May 2010 safety problems 44 laboratorial changes from baseline mg vs placebo) were observed

Ofatumumab MIRROR Cumulative number of new T1 gadolinium enhancing June 2015 Results not yet RRMS (ofatumumab 3, 30 and 60 mg vs November 2011 brain lesions at week 12 from screen based on MRI (estimated) available placebo) scans at weeks 4, 8 and 12

643 Safety and tolerability of single ascending doses, as NCT01639300 Results not yet GNbAC1 MS July 2012 April 2014 well as of repeated administrations of GNbAC1 in MS (GNbAC1 2 or 6 mg/kg vs placebo) available patients

NCT01244139 No unexpected Acta MedPort2015Sep-Oct;28(5):xxx-xxx RRMS and Safety and tolerability profile of two intravenous infusions (BIIB033 0.3, 1, 3, 10, 30, 60 or October 2010 April 2012 safety problems 52 SPMS of BIIB033 in subjects with MS 100 mg vs placebo) were observed

Change in optic nerve conduction velocity at week 24 for RENEW Results not yet AON December 2012 August 2014 the affected eye from the baseline of unaffected fellow (BIIB033 100 mg/kg vs placebo) available eye BIIB033

SYNERGY Number of participants experiencing confirmed Relapsing forms (BIIB033 3, 10, 30 or 100 mg/kg + March 2016 Results not yet August 2013 improvement of neuro-physical and/or cognitive function of MS IFNβ-1a 30 μg vs placebo + IFNβ- (estimated) available and/or disability 1a 30 μg)

NCT01517282 RRMS and Percentages of patients with treatment-emergent or Results not yet MOR103 (MOR103 0.5, 1 or 2 mg/kg vs January 2012 January 2014 SPMS serious adverse events available placebo)

Relapsing forms NCT01585766 Results not yet MEDI-551 April 2012 January 2015 Safety and tolerability of MEDI-551 of MS (MEDI-551 vs placebo) available mAb: Monoclonal antibody; MS: Multiple sclerosis; RRMS: Relapsing-remitting multiple sclerosis; PPMS: Primary progressive multiple sclerosis; SPMS: Secondary progressive multiple sclerosis; ARR: Annualized relapse rate; SDP: Sustained disability progression; IFN: Interferon; MRI: Magnetic resonance imaging; EDSS: Expanded Disability Status Scale; AON: Acute optic neuritis. * Final data collection date for primary outcome measure.

ARTIGO DE REVISÃO

16-18 The results 20 , 44 μg three 24 ® 15 ; Genzyme, Sanofi) is a The high density of CD52 ® particularly in the early stages early the in particularly 19 22 , which was further planned. The investigators concluded that patients who Acta Med Port 2015 Sep-Oct;28(5):640-651 Port 2015 Acta Med 21-23 In this phase II rater-blinded trial 334 RRMS patients were patients RRMS 334 trial rater-blinded II phase this In Alemtuzumab (Lemtrada This antibody was firstly used patientsin with MS in Having these results, switching patients to fingolimod Nevertheless, on the basis of current evidence, NCT00050778) and these aspects were crucial inclusion to criteria the in the definition phase of II clinical the ( trial CAMMS223 randomized to receive cycles of intravenous alemtuzumab or subcutaneous interferon beta-1a (Rebif times per week). Alemtuzumab was given at two different daily doses (12 or 24 mg, administered for five consecutive the in days consecutive three for and month first the in days the market. Alemtuzumab humanized mAb directed which is a against membrane glycoprotein expressed on T the and B lymphocytes, CD52 natural killer antigen, (NK) cells, macrophages monocytes, dendritic cells and and the majority of granulocytes (excluding the neutrophils). expression on the cellular surface (mainly on lymphocytes) makes it a good target for antibody-mediated cytotoxicity and complement-mediated lysis, promoting a drug-induced cellular sustained depletion. However, that progenitors. haematological affect does not 1991 with the hope that exert longer the no T-cell would repertoire drug the regenerated by depletion lymphocyte after the aberrant responses characteristic of MS. of these initial studies were published in 1999 and then in 2006. benefited most from the therapeutic effect of alemtuzumab were those with an inflammatoryMS), phenotypeprogressive with those (more than of the disease. Having this, they proposed the concept of a ‘window of therapeutic opportunity’ using alemtuzumab randomized randomized to receive intravenous natalizumab patients the of 46% with recurrence, compared activity MRI showed taking placebo, 7% of 1a, those 53% receiving of those interferon under beta- glatiramer the methylprednisolone acetate arm. and Relapses occurred 40% in 4% in of the natalizumab-treated patients and in 15-29% of those receiving other treatments, being reported as early as 4-8 weeks after last natalizumab bolus administration. Overall, in this study, 30% of the patients restarted treatment with of disease activity. natalizumab because natalizumab a after agent first-line effective less a of instead washout period might be therapeutic considered option. as However, after patients of a proportion a a in reactivation disease reasonable reported number of publications a switch from natalizumab to fingolimod and thisstrategy explored in large clinical trials. needs yet to be further MS reducing for treatment effective proven a is natalizumab disease activity and severity. However, despite this strong evidence for the efficacy of the drug, the risk of PMLprobably limit the use will of this agent early in disease course, especially if (and when) safer options become available on

644 11

13 The virus infects virus The To be relapse- December 2014, December rd 15 9,10 was designed (it was but the timing of this return 14 R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m NCT01071083) Palavra F. Monoclonal antibodies for multiple sclerosis treatment, sclerosis for multiple antibodies Monoclonal F. Palavra The estimated incidence of PML in patients in PML of incidence estimated The 12 Thus, testing for JC virus antibodies prior to 11 According to the manufacturer’s data cited on a 9 This constant and dynamic process of risk assessment immunomodulatory drugs, such as intramuscular interferon beta-1a, subcutaneous glatiramer acetate or intravenous methylprednisolone, entering thereafter in a regular clinical and MRI assessment protocol. None (0%) of the patients MRI were the main inclusion eligible criteria for the for study. They patients were to randomized to be continue on natalizumab, to switch to placebo or to receive other remained on treatment with the free mAb). through the prior no year on gadolinium-enhancing natalizumab lesions and have on screening brain immune, pharmacokinetic and pharmacodynamic aspects in patients undergoing administration for up an to 24 weeks, comparing to those who interruption of natalizumab experience. In order to answer some of these questions, the RESTORE trial ( a randomized, partially placebo-controlled study aiming to explore the course of disease activity and the effects on is quite variable and optimal strategies for monitoring patients and discontinuing natalizumab treatment are currently established not and still rely on MS centres empirical in clinical practice: how to continue immunotherapy after drug cessation. After natalizumab disease activity withdrawal, may return, previous stratify the risk of the patient to develop PML. stratify the risk of the patient to develop exposes another very critical aspect of natalizumab usage antibody). starting natalizumab therapy and testing every 6 months thereafter is considered prudent practice, in order to better presenting all the risk factors is of about 1 11.2 cases 000 per patients, compared with of 0.1 an cases per estimated 1 000 incidence patients in (defined the by lowest those risk with group a negative result for anti-JC virus may also play a role in risk stratification and their inclusion in the algorithm may help to optimize the clinical approach problem. the to years), prior exposure to the effect of immunosuppressive drugs and positivity for anti-JC virus antibodies. In addition to this, titres of these antibodies (measured as an index) of nearly 3.9 cases per 1 000 patients receiving the drug. The risk factors associated with PML appear to be longer duration of natalizumab treatment (particularly beyond two matter. 3 of as website, research sclerosis multiple nearly among PML of cases confirmed 517 been have there 132 600 natalizumab-treated MS patients, producing a risk glial cells in the brain, leading to lysis of oligodendrocytes, which defines the underlying pathology and results in rapid predominantly the subcortical white demyelination affecting impaired immune surveillance following the leukocyte migration across the inhibition BBB by natalizumab and/or of cells. presenting antigen of depletion the of progressive multifocal PML is caused by leukoencephalopathy opportunistic infection of the CNS (PML). with the human polyomavirus JC virus, probably as a result of mAb, mAb, which turned out to be responsible for the approval of its clinical usage only in monotherapy: the incidence

ARTIGO DE REVISÃO three times per week) in patients who had a breakthrough a had who patients in week) per times three thesame μg 44 beta-1a, interferon (subcutaneous comparator active using ofalemtuzumab safety and efficacy the investigate to aiming rater-masked, largely trial, controlled NCT00548405 Rebif and trial wasdesigned:theCARE-MSII. new a question clinical this clarify to And option. relevant a be could alemtuzumab immunomodulators first-line with treatment despite disease breakthrough with patients for in patients with early and treatment-naïve RRMS. However, mAb this with treatment the of adequacy the about doubts some raising study, CAMMS223 the by generated those as strong so not were obtained data that is truth the trial, clinical III phase small – standards current to according – this of limitations methodological the all Despite 0.0001). ( 40% approximately by loss volume gadolinium-enhancing brain slowed and ( with beta-1a interferon to patients comparison in lesions of proportion the from MRI assessments, alemtuzumab significantlyreduced coming data mainly considering and endpoints secondary ( beta-1a interferon with treated those of alemtuzumab receive progression EDSS confirmed 6-month showed to randomized patients the of 8% to possible not was it demonstrate a significant reduction in because disability progression: met, was that endpoint ( rate relapse annualized the in 54.9% of reduction significant a represented this and so did ones alemtuzumab-treated the of 22% only years, two over relapse a experienced beta-1a interferon with treated patients the of 40% while trial, the of results the Considering manner. blinded a in performed not were physicians blinded to treatment, but EDSS and treating MRI assessments were and Patients year. during last relapse the one least at with years, in relapses two two previous least the at had all and 3.0) ≤ score (EDSS ambulatory fully were years, five than more no of duration RRMS. with patients (44 μg three times per week) in 581 included, therapy-naïve beta-1a interferon subcutaneous to comparison in mg/day) 12 of dosage the in (only alemtuzumab with treatment line study designed to investigate the efficacy and safety of first- NCT00530348 Rebif and studies III were thenconducted:CARE-MSIandII. phase two and program drug’s development forward clinical pushing in interest the reinforced results relapse-free. remained beta-1a interferon patients taking alemtuzumab and 52% of those treated with ( interferon than more ( 71% Scale) Status Disability (Expanded by EDSS measured the as disability, sustained of risk the reduced significantly alemtuzumab beta-1a, interferon to Compared total. in groups treatment three giving 24), and 12 months The CARE-MS II study (Comparison of Alemtuzumab of (Comparison study II CARE-MS The Alemtuzumab of (Comparison trial I CARE-MS The p p 001. oee, hs a te ny coprimary only the was this However, 0.001). < < 0.001) and decreased the relapse rate by 74% by rate relapse the decreased and 0.001) < ® ® Efficacy in Multiple Sclerosis, Study One, Study Sclerosis, Multiple in Efficacy Efficacy in Multiple Sclerosis, Study Two, Study Sclerosis, Multiple in Efficacy ws lo 2ya rnoie and randomised 2-year a also was ) ) was Palavra F. Monoclonalantibodiesformultiplesclerosistreatment, 26 2ya rnoie ad controlled and randomized 2-year a p l tee ains a a disease a had patients these All < 0.001). After 36 months, 80% of 80% months, 36 After 0.001). < ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R p 24 = 0.22). Among 0.22). = These positive These p versus 25 0.0001) < cr by score 11% p < 645 they also had a 42% ( 42% a had also they ( rate relapse annualized the in 49.4% of met. were both trial Patients treated with alemtuzumab experienced this a reduction in and endpoints coprimary as considered were progression disability sustained 6-month in patients to time and of rate relapse Again, groups. number remaining two the the increase to group 24-mg the suppressed amendment protocol further a but mg/day), 24 and (12 dosages different mAb two in initially on the administered was trial failed this had In who therapy. disease-modifying RRMS another early rather still active, with patients disabled moderately year.included last cohort this the Overall, during relapse one least at with years two previous the in relapses two EDSS least at with an and 5.0 years, ≤ score 10 than more no of duration with disease individuals a 840 included patients of population The natalizumab). and acetate interferon glatiramer preparations, (different beta immunotherapy another on disease it decreased the number o patients with new or enlarging or new with patients o number gadolinium-enhancing the decreased it with patients lesions in MRI comparing of to interferon beta-1a ( proportion the reduced significantly alemtuzumab endpoints, secondary sustained worsening of disability after two years. Regarding ih easn rmtig utpe ceoi (RS with (RRMS) sclerosis multiple remitting relapsing with patients ‘adult to restricted were indications therapeutic Its Lemtrada of marketing European authorization granted for alemtuzumab, under the the commercial name has and this, approved Having agency regulatory effects. side serious, potentially treatable, of interesting but frequency very high the a despite it drug, made accumulation disability and frequency relapse on effects significant and are administration II and I of convenience Alemtuzumab’s encouraging. CARE-MS nevertheless from results CAMMS223, from last alemtuzumabcourse. his after months 19 pancytopenia autoimmune presumed with diagnosed was patient another during and follow-up antibodies safety membrane basement elevated with anti-glomerular glomerulonephritis developed patient one treatment, requiring thrombocytopenia immune developed 1% disorders, thyroid autoimmune developed II CARE-MS of patients alemtuzumab-treated in CARE-MS I and 16% in and II raised the issue of autoimmune adverse events: 18% than in those receiving interferon beta-1a. Both CARE-MS I alemtuzumab taking patients in observed frequently were more infections herpes as and well as respiratory infections tract Nasopharyngitis, urinary drug. the receiving of patients infusions of and 90% in fever alemtuzumab, but their frequency decreased in subsequent recorded rash, were (headache, nausea) reactions infusion Acute were highlighted. be to also need issues and studies these all in raised tolerability and safety However, ofthis most treatment. benefiting patients of profile the clarifying in reduced brainvolumeloss( ( lesions T2-hyperintense Although not fulfilling all the high expectations derived expectations high the all fulfilling not Although help to seem trial II CARE-MS the by provided Data Acta MedPort2015Sep-Oct;28(5):640-651 ® , 12 mg concentrate for solution for infusion. for solution for concentrate mg 12 , p = 0.0084) relative risk reduction of reduction risk relative 0.0084) = 26,27 p p 000) n significantly and 0.0001) < =0.01). p < 0.0001) and 0.0001) < p < 0.0001), 27

ARTIGO DE REVISÃO

38 < < p p Safety and Safety NCT00870740).

< 0.0001) in the arm < 0.0001) in the group the in 0.0001) < 37 p p = 0.004). The study was not was study The 0.004). = p < 0.0001) in the arm receiving p In this trial, a slightly different formulation of 37 Acta Med Port 2015 Sep-Oct;28(5):640-651 Port 2015 Acta Med After this 1-year period, an extension study was The SELECT trial (Safety and Efficacy Study of = 0.0002). The number of new or enlarging T2 lesions p Completed Study 205MS201 Relapsing-Remitting [NCT00390221] Multiple to Sclerosis, Treat This was also a controlled 1-year, double-blind, study randomised with and 517 the patients SELECT trial. who The results participated were and, in recently published basically, SELECT patients daclizumab HYP under 150 or 300 treatment mg were with either randomised to a washout period of 24 weeks and then reinitiated on rate was defined as the primary endpoint and it was met as met was it and endpoint primary the defined as was rate patients with Compared endpoints. secondary the all nearly daclizumab of mg 150 with treated those placebo, receiving experienced a reduction of 0.0001) and those 54% receiving 300 mg had a in 50% reduction relapse rate ( ( at week 52 was reduced by 70% ( ( 79% by and daclizumab of dose lowest the with treated 0.0001) in the 300 mg group, comparing with placebo. The at lesions gadolinium-enhancing enlarged or new of number weeks 8 - 24 in the MRI sub-study (n = 309) was 4.8 in the placebo group, 1.5 (-69%; (-78%; 1.0 and mg 150 daclizumab treated with the highest dose of the mAb. Regarding safety were pharyngitis and infections tract respiratory upper data, more common in daclizumab-treated patients, as well as cutaneous events (nevertheless, injection site reactions, erythema and induration were equally distributed in each group, affecting approximately 2% of the cases). A more than fivefold increase of liverobserved in 4% of enzymesdaclizumab-treated patients and in less (AST/ALT) was than 1% of those receiving placebo. ( trial SELECTION the called was which planned, Process Yield High Daclizumab of Study Extension Efficacy [DAC HYP] in Subjects With Multiple Sclerosis Who Have for 24 weeks. The primary endpoint was the total number of new or enlarged gadolinium-enhancing lesions identified on brain MRI performed every four weeks between weeks 8 and 24. At the patients end receiving interferon beta of plus the highest the dose of study and daclizumab a significant difference only in the primary endpoint for those was found, comparing with those receiving interferon beta reduction; (72% placebo and clinical efficacy. powered to demonstrate Daclizumab High Yield Remitting Multiple Sclerosis, NCT00390221) was a 1-year, Process to double-blind, Treat phase IIb study Relapsing- investigating two subcutaneous doses daclizumab used of in monotherapy (150 and 300 mg) compared with placebo in 600 RRMS randomised patients. the has it used: was [HYP]) Process Yield (High daclizumab mAb, the of versions previous as sequence aminoacid same antibody- decreasing profile, glycosylation its in differs it but dependent At baseline, cytotoxicity. patients had an EDSS score ≤ 5.0 and at least one relapse in the previous year or enhancement gadolinium pathological showing scan MRI an Annualized relapse randomization. to prior weeks six within 646 The The and This 28 36 30,31 IL-2 is secreted 19 In this study it was possible 32 R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m Palavra F. Monoclonal antibodies for multiple sclerosis treatment, sclerosis for multiple antibodies Monoclonal F. Palavra and/or a method for reducing the risk 29 = 0.047). Three more small studies were thereafter were studies small more Three 0.047). = 33-35 p

32-38 After demonstrating that the drug could be effective In order to obtain more robust data, with a larger Daclizumab (Biogen and Abbott Biotherapeutics Corp.) There are future developments that could improve = 0.004) and a significant improvement in some clinical p patients. outcome measures, such as the relapse rate (a reduction of reduction (a rate relapse the as such measures, outcome 80.7%; published, either comparing daclizumab SPMS and RRMS in monotherapy in or beta interferon with in combination therapy experienced a 78% reduction enhancing lesions, in as compared new to the contrast- baseline moment ( of seven infusions) and interferon beta response to the after latter alone. suboptimal to demonstrate that patients undergoing this combination treated for six months with the combination of intravenous daclizumab (at 1 mg/kg/dose two weeks apart for the first two doses and once every four weeks thereafter for a total in animal models of the disease, 10 with RRMS patients and secondary diagnosed progressive MS (SPMS) were MS. six months and, despite of this therapy, presented active diseases. They were then randomized to receive add-on subcutaneous daclizumab in two different doses (2 mg/kg placebo or weeks) four every mg/kg 1 and weeks two every was a phase II, randomised, double-blind controlled study and that recruited placebo- 230 patients with relapsing forms of MS who were taking interferon beta for at least Subcutaneous Daclizumab was NCT00109161) Sclerosis, Multiple of Forms Relapsing in Patients designed and With the results were published Active, in 2010. population of patients, the CHOICE study (Study of combination regimen and accumulated showing that evidence this drug could also be effective was progressively in other diseases, such as non-infectious uveitis other proinflammatory cytokines while it is also involved in approved initially was Daclizumab proliferation. lymphocytic for the prevention of renal allograft rejection as part of a is a humanized mAb acting as a blocker of the α-subunit (CD25) of the high-affinity IL-2 receptor. by activated lymphocytes and stimulates production of Daclizumab of autoimmune adverse events (there using alemtuzumab is combined with palifermin, a a drug current that trial promotes thymic T cell regeneration – this possibility). exploring and testing NCT01712945 – individualize risks for patient counselling before treatment and to establish the administration) intensity of monitoring after drug patients’ patients’ access to the drug: first of all, a robust predictive biomarker of this autoimmunity mAb (IL-21 is being studied following as a possible marker to treatment with time to approve the use of the drug in clinical practice, but 2014. happened in November this actually active disease defined by clinical or imaging features’. imaging or clinical by defined disease active American Food and Drug Administration (FDA) took more

ARTIGO DE REVISÃO recruited into the small phase II HERMES trial ( trial HERMES II phase small the into recruited lymphoma, but showed to be effective in patients with RRMS non-Hodgkin’s of treatment the for 1997 in approval first its mAb (which binds specifically to the CD20 antigen) received Genentech) for MS treatment. This chimeric B-cell depleting (MabThera rituximab using intwo Such was knowledge used as rationale for a first attempt in and consist practice. in MS used currently tools the clinical of relevant extremely in system typical immune events humoral inflammatory the of components of cerebrospinal IgG participation the about evidence increased provide fluid/serum-index an and bands pathogenesis. oligoclonal MS in role important Ocrelizumab andOfatumumab is expectedtobecompletedbyDecember2016. BIIB019, of Efficacy and Safety the Evaluate to [NCT01064401] Have 205MS301 Study Who Completed Sclerosis Multiple With Participants in Study extension phase, the EXTEND study ( This trial objectives. secondary ended on March as 2014 and patients are currently entering defined an were life of quality and progression EDSS rate. relapse annualized the be will endpoint primary The comparator. active an as 1a beta- interferon intramuscular with weeks four every once mg 150 HYP daclizumab subcutaneous compares which Relapsing- With Patients Remitting Multiple Sclerosis, in Beta-1a Interferon Versus ( trial DECIDE the includes It report. to results yet not are there to includeaverystrictliverfunctionandskinmonitoring. adverse event). These aspects have led to phase III studies died from a psoas abscess (in recovering from a cutaneous hepatitis and in the previous SELECT study another patient patient receiving daclizumab 300 mg died from autoimmune trial. SELECT the in identified previously effect. The safety and tolerability issues were similar rebound MRI to any those identify to possible not was it weeks, 24 of period washout a After mAb. the of doses the both for year second the in evident more was lesions T2 enlarging or new of with reduction the and compared treatment under change year first the not did year second the on rate relapse the daclizumab, on continuing patients In 0.0001). ( placebo on weeks 52 after mAb the receiving patients in 86% by reduced was lesions gadolinium-enhancing of ( parameter this in 74% of reduction a justified trial SELECTION the in daclizumab to T2 enlarging or new lesions was of 8.0 after the first year on placebo number and switching The mAb. the of doses ( the relapse rate at the end of the study was reduced by 59% mg again in a 1:1 proportion during one year. In these patients, 300 or 150 HYP daclizumab received either placebo one for receiving previously Those dose proportion. 1:1 a same in more, year the on stayed or dose original their p < 0.001), with no discrimination between the two different hr i ln sadn eiec ta B el pa an play cells B that evidence standing long is There and ongoing currently is program III phase the fact, In Efficacy and Safety of Daclizumab High Daclizumab of Safety and Efficacy Process Yield Palavra F. Monoclonalantibodiesformultiplesclerosistreatment, ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R ® p

/Rituxan NCT01064401), a 3-year study 000) lo h number the Also 0.0001). < NCT01797965), which NCT01797965), ® ; Roche Pharma and Pharma Roche ; Long-Term Extension 39 h peec of presence The 38 oee, one However, A Study to Study A p < 647 mg or 2 000 mg, administered with half the dose on day one to receive intravenous placebo, intravenous ocrelizumab (600 randomized were Patients screening. before year the in relapses two and/or MRI on lesions T2 six least at and 6.0 and 1.0 between score EDSS an two year, previous the in least one at least at with have years three previous to the within relapses were: criteria inclusion main The (NCT00676715). trial II phase placebo-controlled blind, RRMS patients in a 96-week, are patients RRMS already published. in Genmab) and Roche (GlaxoSmithKline ofatumumab human (Hoffman-La totally the with ocrelizumab and Genentech) studies and humanized II phase the in with obtained results The therapeutics. MS newer in tested of being currently development are which the mAbs, anti-CD20 for basis the set Rituximab Sclerosis, Multiple Progressive Primary Evaluate the Safety and Efficacy of Rituximab in Adults With ( trial OLYMPUS II/III phase the in (PPMS) MS progressive primary with diagnosed patients effectin some Remitting Sclerosis, Relapsing Multiple With Adults in Rituximab Evaluate signs ofdisease activityevenafterB-cellrepletion. no with stable, clinically were patients the of majority the and administration dose last after detected were infections opportunistic No unknown. considered was reason the but infusion, ocrelizumab last after months 19 died patient One period. follow-up safety 144-week a completed included) previously were they group the on (depending patients of mild-to- 78% and 67 Between were reactions. infusion-related moderate patients by reported effects adverse main the Nevertheless, uncertain. remained event this with drug study the of relation the but pneumonia, and dysfunction died ocrelizumab of from disseminated intravascular coagulopathy, mg multiorganic 000 2 with treated woman One study.the of arms serious the all in reported issues, were events adverse safety Considering activity. disease low similarly reached beta-1a interferon or placebo with treated previously patients those ocrelizumab, to switching After by 73% ( 80% ( by reduced was rate relapse annualized estimated differ not did the endpoints, clinical drug secondary placebo. Among the from last this to response the surprisingly also reached better outcomes than interferon beta-1a, while ( ( 89% by reduced was it and endpoint primary the defined 24 and 20 16, 12, weeks the over lesions cycle of the trial). The total number of gadolinium-enhancing first the in mg 000 2 with treated patients for only mg 000 1 or mg (600 treatment continued mAb the receiving whereas those mg, 600 ocrelizumab to switched were interferon beta-1a or placebo receiving patients those weeks, 24 After 1:1:1:1. of proportion a in week), per μg (30 interferon beta-1a intramuscular or 15) day on half other the and p p p = 0.0005) in patients receiving 600 mg of the mAb and mAb the of mg 600 receiving patients in 0.0005) = doses ocrelizumab Both arm. mg 000 2 the in 0.0001) < 96% by and group mg 600 ocrelizumab the in 0.0001) < Ocrelizumab’s safety and efficacy were evaluated in 220 Acta MedPort2015Sep-Oct;28(5):640-651 p = 0.0014) in those treated with the highest dose.

NCT00097188 randomised, ) 40 n ee showed even and

NCT00087529). formally double- versus A Study to Study A placebo 42 41 43

ARTIGO DE REVISÃO Safety Study of NCT01639300) in

Further, a replication- 46 Each one of the participants 48 So far, it is not entirely clear if 47 Inhibition of LINGO-1 promotes 49 NCT01699555). First-in-Human Study With GNbAC1 in Healthy Since then, research has been made on this field and field this on made been has research then, Since Acta Med Port 2015 Sep-Oct;28(5):640-651 Port 2015 Acta Med 45 Nevertheless, a first-in-human, double-blind, rando- Leucine-rich repeat and Ig domain containing The trials with results already available demonstrate GNbAC1 (GeNeuro Innovation SAS) is a humanized to testing follow, the efficacy and safety of GNbAC1 in MS patients. BIIB033 (anti-LINGO-1) NOGO receptor interacting transmembrane protein receptor 1 that (LINGO-1) is and oligodendrocytes, expressed which acts as an important is negative on a neurons regulator of myelination. the HERV-W family of retroviruses was firstly described in 1997. frequent more is presence its that demonstrated been has it in MS patients than in found also was family HERV-W the controls. of member incompetent to be associated with MS. the higher frequency of these retrovirus in MS patients has any pathogenic role or if it may only represent an irrelevant epiphenomenon. mised, placebo-controlled, dose-ascending phase I was performed using trial GNbAC1 in 33 healthy male volunteers ( Volunteers, received a single intravenous infusion of the different mAb at doses six (from 0.0025 GNbAC1 was to well tolerated and 6 the maximum mg/kg) dose was and minor (only event adverse serious any without reached or placebo. nonspecific complaints were recorded). This study set the basis for a phase II, randomised, placebo-controlled and dose-ascending safety and tolerability trial ( GNbAC1 in Multiple Sclerosis Patients, 10 MS patients. The final data collection date for primary outcome measure was April 2014 and, to date, there are no results available. A large phase II program is planned safety, safety, tolerability, pharmacokinetics, pharmacodynamics, dose-response relationship and endpoints. several other clinical a very strong ofatumumab in RRMS therapeutic patients, mainly in the reduction effect of of MRI disease activity. They seem ocrelizumab to be well tolerated, and several but after mAbs anti-CD20 these of effects long-term the treatment cycles in MS patients over PML no date, the To trials. years early mentioned these all by were covered not cases have been reported after ocrelizumab administration and almost all the identifiedresolved associated infections with were appropriate therapy only one (as woman previously died said, with inflammatory syndrome). Also, pneumonia anti-CD20 therapy and has not a systemic been associated with an increased rate of cancer to date. Phase III trials will be crucial to establish the true potential of these drugs in MS therapeutics. GNbAC1 (anti-MSRV-ENV) (MSRV)- retrovirus MS-associated the against directed mAb ENV protein. A replication-competent MSRV, belonging to

648 ] in Patients ® were recently Infusion-related 44 NCT00640328) R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m placebo was estimated at 99.8%; Palavra F. Monoclonal antibodies for multiple sclerosis treatment, sclerosis for multiple antibodies Monoclonal F. Palavra Ofatumumab Subcutaneous Administration Subcutaneous Ofatumumab versus Thirty-eight individuals were enrolled, defining 44 The development of this mAb includes three phase III Considering now ofatumumab, the results of a 24- < 0.0001) and that peripheral B-cell depletion was 196 RRMS patients during 24 weeks. The primary outcome primary The weeks. 24 during patients RRMS 196 will be the number of new gadolinium-enhancing lesions in MRI scans at weeks 4, 8 objectives and include 12 and a the secondary number of further MRI measures, NCT01457924). It aims to efficacy of a subcutaneous ofatumumab formulation (using investigate the in placebo) against mg 60 to up mg 3 from safety doses increasing and controlled, parallel-group phase II trial currently ongoing: the the ongoing: currently trial II phase parallel-group controlled, ( study MIRROR in Subjects With Relapsing-Remitting Multiple Sclerosis, observed with all reactions the tested were doses. frequent, issues appeared. There is another but double-blind, placebo- no unexpected safety suppressed the development of new gadolinium-enhancing new of development the suppressed relative groups (the the all in scans MRI monthly lesions on risk reduction p treated patients (12 in total). Several primary and secondary and primary Several total). in (12 patients treated endpoints were defined, but the mostrelated relevant with the data are fact that ofatumumab nearly completely three sequential cohorts and receiving either intravenous ofatumumab 100 mg (n = 8), 300 mg (n = 11) or 700 mg (n = 7). Each one of the groups included four placebo- week, double-blind, randomised, placebo-controlled and dose-finding phase II trial ( published. for the ORATORIO study, November I 2019 for the OPERA study, for the ORATORIO II. and January 2020 for the OPERA EDSS progression over up to 5.5 years, change in timed 25-foot walk from baseline to week 120, again several MRI measures, as well as safety The and estimated tolerability. 2017 October are trials these all of dates completion primary study enrolled 734 patients and the primary endpoint will be 12-week sustained EDSS progression up to 5.5 years. Secondary outcomes will include 24-week confirmed 600 mg in adults diagnosed with PPMS: the ORATORIO study (A Study of Ocrelizumab in Patients Progressive With Primary Multiple Sclerosis, NCT01194570). This measures. There is also a parallel-group, third phase double-blind, III, placebo-controlled randomized, study ocrelizumab intravenous of safety and efficacy the evaluate to primary outcome measure will be annualized relapse rate outcomes secondary the others, among and, weeks 96 over will include confirmed disability progression, proportion of relapse-free patients over trial duration and several MRI With Relapsing 800 nearly included trials Multiple these of one Each NCT01412333). Sclerosis, NCT01247324 and participants that are currently under regular follow-up. The interferon beta-1a (44 μg administered I and II studies (Studies of Ocrelizumab week): the OPERA three times per in Comparison With Interferon Beta-1a [Rebif randomized, randomized, double-blind, double-dummy, parallel-group studies to evaluate the efficacy and safety of intravenous ocrelizumab 600 mg in comparison with subcutaneous studies that are currently ongoing. There are two 96-week,

ARTIGO DE REVISÃO really aclinicallyrelevantimpact. has mAb neuroprotecting and remyelinating promising this if realize community scientific the make to order in needed outcome measure was defined primary as March 2016. Time for will be date enrolled collection data being final the and currently study the to are patients Again, over weeks. disability of 72 and/or function improvement cognitive confirmed and/or a physical experiencing subjects of percentage the be will outcome primary The week). a once μg (30 beta-1a interferon intramuscular with concomitance in mg/kg) 100 and 30 10, (3, BIIB033 intravenous of doses different four with treatment receive to randomised be will relapses with SPMS which and RRMS in with diagnosed patients study placebo- dose-ranging double-blind, parallel-group, randomised, II, controlled, phase a also is Avonex With Sclerosis Concurrently Multiple Used of When BIIB033 Forms Relapsing of With Subjects Pharmacokinetics in and Tolerability, Safety, study this for ended inOctober2014andresultsarenotyetavailable. Recruitment eye. fellow unaffected the of baseline the from weeks 24 at potentials evoked visual on latency p100 of change the was outcome primary the and a ratio 1:1 a in placebo received or mg/kg 100 of dose BIIB033 single Patients accessibility). drug CNS increasing theBBB, of theopening for contribute may inflammation first episode of acute optic neuritis a (it is expected that acute with patients 80 included that study placebo-controlled Neuritis, II phase larger studies. in agent remyelination-promoting this of investigation further encouraged data collected the all but cerebrospinal fluid/serum ratio of BIIB033 was 0.06-0.09%), mean (the low was CNS the into penetration its mAb, a for recorded). were events adverse serious (no tolerated well be to revealed mAb the and trials these during implemented was protocol monitoring safety Sclerosis Multiple With RRMS 42 ( in patients mg/kg) SPMS and 100 to 0.3 ascending (from BIIB033 multiple of investigate doses to designed was study I the of phase bodyweight). Asecond mg/kg doses 100 to 0.1 (from mAb ascending single of infusions intravenous trial. randomised placebo-controlled I, phase tested and a firstly in volunteers and was adult healthy It 64 neuroprotection MS. in with promoting patients in for remyelination developed being protein extremelyattractiveforfuturedevelopments. this making aspect another is therapy cellular for relevance neurons to maturation cell stem neural of regulator important an as LINGO-1 described study recent in vivo myelination and differentiation oligodendroglial h SNRY td (td t Ass te Efficacy, the Assess to (Study study SYNERGY The ( study RENEW The mAb anti-LINGO-1 human fully a is (Biogen) BIIB033 , as well as remyelination in animal models of MS. C0716) s pae I rnoie and randomised II, phase a is NCT01721161) Palavra F. Monoclonalantibodiesformultiplesclerosistreatment, aey td o BI03 n Subjects in BIIB033 of Study Safety , NCT , 215ON201 BIIB033 In Acute Optic In Acute BIIB033 215ON201 ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R 01244139 52 hs sbet received subjects These 52 s eeal expected generally As ). A comprehensive A). ® NCT01864148) , in vitro in vitro 51 and this and and 50 A A 649 n SM ws eety opee ( completed recently was SPMS RRMS and with patients 30 in double-blind, MOR103 of pharmacokinetics randomised, and safety evaluate to a study Ib phase placebo-controlled and conditions different with diseaseactivityoverthisshortperiodoftime. related variables on effect measurable rapidly a and profile This drug demonstrated to have a good safety and tolerability Arthritis, Rheumatoid Active With Patients ( weeks four doses of MOR103 (0.3, 1.0 and 1.5 mg/kg bodyweight) multiple over of efficacy and safety evaluate to performed was study placebo-controlled randomised, I/II phase a disease, arthritis. in target therapeutic rheumatoid as such conditions, attractive immune-mediated various an be to been has demonstrated and microglia) and cells dendritic eosinophils, colony- and differentiation of macrophages, monocytes, neutrophils, granulocyte-macrophage proinflammatory cytokine (stimulating activation, maturation (GM-CSF). factor against stimulating directed MOR103 (anti-GM-CSF) and disadvantages regardingtheanti-CD20therapies. this understand drug’s potential to in all these conditions needed and also its advantages be will Time scleroderma. with malignancy trials and in a phase I study in patients diagnosed B-cell II and I phase of number a in tested being also is drug completion date was January 2015 for the primary phase I study. relapse-free The estimated The of II. phase proportion in days and 337 over I subjects phase in days 169 over in phase II. The primary outcome will be safety and tolerability interferon beta-1a (30 μg per week) as an active com-parator intramuscular or dosages MEDI-551 six of one and 28) = (n subcutaneous four of one I phase during placebo or dosages MEDI-551 intravenous or receive will who subjects 512 Sclerosis, Multiple of Forms Relapsing Treat to Agent, Depleting B-cell a 551, ( ongoing currently mAbs the than targeting CD20. activity expected B-cell-depleting broader is a MEDI-551 have to this, considering and, production is plasma cells, which are the main responsible for the antibody CD20) to precursors. their and (similarly which lymphocytes B on and cells dendritic follicular on expressed CD19, against directed MEDI-551 (anti-CD19) results wereannouncedinNovember2014). positive AG, MorphoSys by release press a in (however, date was January 2014, but the results are not yet published (0.5, 1.0 and 2.0 mg/kg) or placebo. The primary completion doses different three at MOR103 of infusions 6 intravenous receiving groups, three into randomised were Patients Sclerosis, Multiple in MOR103 Evaluate EI51 Mdmue L) s hmnzd mAb humanized a is LLC) (MedImmune MEDI-551 hs asd h itrs i tsig hs nioy in antibody this testing in interest the raised This mAb human fully a is AG) (MorphoSys MOR103 pae /I dpie ein ra i ptet wt M is MS with patients in trial design adaptive I/II phase A Acta MedPort2015Sep-Oct;28(5):640-651 54 In 96 patients diagnosed with this rheumatologic this with diagnosed patients 96 In Safety and Preliminary Efficacy of MOR103 in MOR103 of Efficacy Preliminary and Safety NCT01585766). It is expected to include to expected is It NCT01585766). aey n Tlrblt Suy f MEDI- of Study Tolerability and Safety 56 CD19 is also expressed on part of the of part on expressed also is CD19 53 This molecule can act as a as act can molecule This hs I Suy to Study Ib Phase NCT01023256). NCT01517282). 55

ARTIGO DE REVISÃO

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Annual Neurology of Academy American Acta MedPort2015Sep-Oct;28(5):640-651 Human endogenous retrovirus glycoprotein-mediated induction of induction glycoprotein-mediated retrovirus endogenous Human Molecular identification of a novel retrovirus novel a of identification Molecular aey tlrblt and tolerability Safety, LINGO-1

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Filipe PALAVRA Monoclonal Antibodies for Multiple Sclerosis Treatment Acta Med Port 2015:28:640-651

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