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`Arq Neuropsiquiatr 2011;69(3):536-543
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`Classical immunomodulatory
`therapy in multiple sclerosis
`How it acts, how it works
`
`Amélia Mendes1, Maria José Sá1,2
`
`ABSTRACT
`Interferon beta (IFNβ) and glatiramer acetate (GA) were the first immunomodulators
`approved to the treatment of relapsing-remitting multiple sclerosis (MS) and clinically
`isolated syndromes. Despite the enlargement of the therapeutic armamentarium, IFNβ
`and GA remain the most widely drugs and the therapeutic mainstay of MS. Objective:
`To review the mechanisms of action of IFNβ and GA and main clinical results in MS.
`Results: IFNβ modulates T and B-cell activity and has effects on the blood-brain barrier.
`The well proved mechanism of GA is an immune deviation by inducing expression of
`anti-inflammatory cytokines. Some authors favor the neuroprotective role of both
`molecules. Clinical trials showed a 30% reduction on the annualized relapse rate and
`of T2 lesions on magnetic resonance. Conclusion: Although the precise mechanisms
`how IFNβ and GA achieve their therapeutics effects remain unclear, these drugs have
`recognized beneficial effects and possess good safety and tolerability profiles. The large
`clinical experience in treating MS patients with these drugs along almost two decades
`deserves to be emphasized, at a time where the appearance of drugs with more selective
`mechanisms of action, but potentially less safer, pave the way to a better selection of the
`most appropriate individualized treatment.
`Key words: multiple sclerosis, interferon beta, glatiramer acetate, immunomodulatory
`therapy.
`
`Terapêutica imunomoduladora clássica na esclerose múltipla: como atua, como
`funciona
`
`RESUMO
`O interferão beta (IFNβ) e o acetato de glatirâmero (GA) foram os primeiros
`imunomoduladores aprovados para o tratamento da esclerose múltipla (EM) surto-
`remissão e doentes com síndromes clinicamente isoladas. Apesar do alargamento
`do armamentário terapêutico, o IFNβ e o GA continuam a ser os medicamentos mais
`usados na EM. Objetivo: Rever os mecanismos de acção do IFNβ e do GA e os principais
`resultados na clínica. Resultados: O IFNβ modula a actividade das células T e B e tem
`efeitos sobre a barreira hemato-encefálica. O mecanismo melhor comprovado do GA é
`o desvio imune através da indução da expressão de citocinas. Alguns autores favorecem
`ainda um papel neuroprotetor para ambos. Os ensaios clínicos mostraram diminuição
`da taxa anualizada de surtos de 30% e das lesões em T2 na ressonância magnética.
`Conclusão: Embora os mecanismos pelos quais o IFNβ e o GA atingem os seus efeitos
`terapêuticos continuem a ser pouco claros, estes fármacos possuem efeitos benéficos
`reconhecidos e bons perfis de segurança e tolerabilidade. A grande experiência clínica
`no tratamento da EM com estes fármacos ao longo de quase duas décadas merece ser
`destacada, numa altura em que o aparecimento de novos fármacos com mecanismos de
`acção mais seletivos, mas potencialmente menos seguros, possibilitarão melhor seleção
`e individualização do tratamento.
`Palavras-chave: esclerose múltipla, interferão beta, acetato de glatirâmero, terapêutica
`imunomoduladora.
`
`1MD, Department of Neurology, Hospital de São João, Porto, Portugal; 2MD, PhD, Department of Neurology, Hospital de São
`João, Porto, Portugal; Health Sciences Faculty, University Fernando Pessoa, Porto, Portugal.
`
`Correspondence
`Amélia Mendes
`Department of Neurology
`Hospital de São João
`Alameda Prof. Hernâni Monteiro
`4200-319 Porto - Portugal
`E-mail: mendes.amelia@gmail.com
`
`Received 21 December 2010
`Received in final form 13 January 2011
`Accepted 20 January 2011
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`Multiple sclerosis (MS), the most frequent primary
`demyelinating pathology of the central nervous system
`(CNS), is a chronic and progressive autoimmune disease
`characterized by inflammation, demyelination and axonal
`injury1. The etiology of MS is ultimately unknown, al-
`though there is evidence that complex multifactorial fac-
`tors are implicated, in which environmental are hypothe-
`sized to interact with genetically susceptible individuals2.
`The clinical hallmarks of MS may be summarized
`as follows1: the disease typically begins in young adults
`and affects females more than males (1.77:1); most
`commonly, MS patients alternate relapses with remis-
`sion phases (relapsing-remitting MS or RRMS), some of
`them developing later on a secondary progressive course
`(SPMS), and in a fewer cases, the disease progresses ab
`initio without (progressive MS or PPMS) or with rare
`superimposed relapses (transitional or progressive re-
`lapsing MS-RPMS); the disease is heterogeneous as re-
`gards neurological manifestations, evolution and dis-
`ability; the diagnosis, based in international consensual
`criteria, depends strictly on clinical features and paraclin-
`ical exams, the most important of which is the magnetic
`resonance imaging (MRI); these criteria turned feasible
`the identification of patients with a clinically isolated de-
`myelinating event or syndrome (CIS) that are at risk of
`conversion to a clinically definite disease (CDMS); finally,
`the progressive course and consequent neurological def-
`icits inflict a significant disabling condition to the patient
`and a major burden to relatives, caregivers and society.
`Although on the grounds of non-curative approaches,
`since the early nineties several pharmacological treat-
`ments with immunomodulatory properties were devel-
`oped to treat MS and modify its natural history, com-
`monly designated “disease modifying drugs” (DMD),
`which recognizably represented a major step in the con-
`trol of the disease.
`In this practical review we will focus on the classical
`immunomodulators specifically approved in MS - inter-
`feron beta (IFNβ) and glatiramer acetate (GA) - high-
`lighting their mechanisms of action (how they act) and
`their main clinical and imaging effects (how they work),
`based on the results of pivotal and comparative clinical
`trials. Despite the fast enlargement of the therapeutic ar-
`mamentarium for MS in the last years, with the approval
`of drugs with better efficacy yet potential limiting ad-
`verse effects, as mitoxantrone and natalizumab (usually
`indicated in more severe non-IFNβ-responder cases),
`and the development of oral drugs, exemplified by the
`recently FDA approved fingolimod, IFNβ and GA remain
`up to now the worldwide therapeutic mainstay of MS.
`
`INTERFERON BETA
`Interferons (IFNs) are proteins secreted by cells and
`
`MS: immunomodulatory therapy
`Mendes and Sá
`
`are involved in self defense to viral infections, in the reg-
`ulation of cell growth and in the modulation of immune
`responses. Human IFNβ is a glycoprotein primarily pro-
`duced by fibroblasts with 166 amino acids and 22.5 kDa,
`which is encoded on chromosome 9 without introns3.
`IFNβ was the first therapy to have proved beneficial ef-
`fects on the natural course of MS and has two molecules:
`IFNβ-1a and -1b.
`IFNβ-1a is obtained by eukaryote cell lines derived
`from a Chinese hamster ovary and, similarly to native
`human beta interferon, is glycosilated and has the com-
`plete 166 amino acid sequence; yet, the glycosylation pat-
`tern is not necessarily equal to the human3. IFNβ-1b is
`a product of a bacterial (E. coli) cell line and is not gly-
`cosilated because bacteria do not glycosylate proteins;
`additionally the cystein residue has been substituted
`by a serine at position 17, which prevents incorrect di-
`sulphide bond formation and minimizes the risk of im-
`paired folding of the molecules and the consequent re-
`duced activity; also, the methionine at position 1 has
`been deleted, so the final protein has one less amino
`acid than the natural IFNβ3. Glycosylation decreases
`aggregates formation and immunogenicity, which may
`give a lower potency of IFNβ-1a4, but, on the other side,
`IFNβ-1b has a tight binding to human serum albumin,
`which may contribute to about 10% of IFNβ-1a potency3.
`
`How it acts
`IFNβ binds to a high-affinity type-1 IFN transmem-
`brane receptors and induces a cascade of signaling path-
`ways. After binding to the receptor, phosphorylation and
`activation of two cytoplasmic tyrosine kinases occur.
`This leads to activation of latent transcription factors in
`cell cytoplasm that translocate to the nucleus5. IFNβ has
`a role in the immune system by producing effects on T
`and B cells, and, additionally has influence in blood brain
`barrier (BBB) permeability6.
`
`EFFECTS ON T CELLS
`T cell activation – IFNβ is believed to reduce T cells
`activation, including myelin reactive T cells, because in-
`terferes with antigen processing and presentation by
`downregulating expression of major histocompatibility
`complex (MHC) class II, and reduces the levels of co-
`stimulatory molecules7 and other accessory molecules
`like intercellular cell adhesion molecule-1 (ICAM-1),
`vascular cell adhesion molecule-1 (VCAM-1), and very
`late activation antigen-4 (VLA-4)8.
`T cell differentiation and proliferation – IFNβ
`inhibits the expansion of T cell clones, acting as an
`anti-proliferative agent. The exact mechanism for this
`anti-proliferative effect is unclear. Recently, it was dem-
`onstrated that type I IFNs, in which IFNβ is included,
`
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`could activate the Mnk/eIF4E kinase pathway that plays
`important roles in mRNA translation for IFN-stimu-
`lated genes and generation of IFN-inducible anti-prolif-
`erative responses9. Previous studies have indicated that
`Th17 cells have a critical role in the development of the
`autoimmune response in MS10. IFNβ-1a could induce an
`up-regulation of the TLR (toll-like receptors)-7 signaling
`pathway and inhibit multiple cytokines involved in Th17
`cell differentiation. The authors propose that the exog-
`enously administered high-dose IFNβ-1a augments this
`naturally occurring regulatory mechanism and provides
`a therapeutic effect in patients with RRMS11. Further-
`more, IFNβ inhibits the expression of FLIP, an anti-apop-
`totic protein, leading to an increased incidence of T cells
`death12 and restores T-regulatory cell activity6.
`
`EFFECTS ON CYTOKINES AND CHEMOKINES
`It has been postulated that the modulation of the im-
`mune response by IFNβ may involve an immune devia-
`tion, consisting in a reduction of the expression of Th1
`induced cytokines while enhancing Th2 responses6. Ad-
`ditionally IFNβ has effects on chemokines: it could me-
`diate activity of the chemokine receptor CCR7 which is
`important to direct the entry of T lymphocytes to the
`peripheral lymph nodes rather than to the CNS6. An-
`other chemokine, Regulated on Activation, Normal T
`Expressed and Secreted (RANTES), appears to play a
`role in the pathogenesis of RRMS and was observed a de-
`crease of its sera and peripheral blood adherent mono-
`nuclear cell levels triggered by IFNβ-1b13. A recent study
`suggested that peripheral upregulation of the chemo-
`kines by IFNβ may reduce the chemoattraction of im-
`mune cells to the CNS14.
`
`ANTIGEN PRESENTATION
`Furthermore, IFNβ is postulated to inhibit antigen
`presentation to T cells in conjunction with MHC and
`co-stimulatory molecules as CD80 and CD86, which is a
`crucial event in the ensuing immune response8. Another
`mechanism by which IFNβ can affect antigen presenta-
`tion is by counteracting the effect of IFNγ, because the
`latter cytokine is a potent promoter of MHC class II ex-
`pression on many cell types8.
`
`EFFECTS ON B CELLS
`IFNβ upregulates a B-cell survival factor (BAAF) and
`for those patients in whom B cells play a major impor-
`tant role, this would be a quite undesirable consequence
`of IFNβ therapy. This might partially explain inter-indi-
`vidual differences in the therapeutic response. Other-
`wise, the systemic induction of BAFF by IFNβ therapy
`might facilitate the occurrence of various autoantibodies
`and IFN neutralizing antibodies (NAbs). The authors
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`conclude that individual MS patients with evidence for
`a significant role of B cells do not appear to be ideal can-
`didates for IFNβ therapy15. However, B cells may trigger
`neurotrophic cytokines that exert positive effects on MS
`autoimmunity, which could outweigh the negative effects
`of IFNβ-induced BAAF responses6.
`
`EFFECTS ON BBB
`IFNβ is able to inhibit the ability of T cells to get
`into the brain by interfering with the expression of sev-
`eral molecules. It was demonstrated that matrix metal-
`loproteinase type 9 (MMP-9) activity can be decreased
`by IFNβ-1b treatment in vitro16, which could difficult the
`migration of lymphocytes across the fibronectin of ce-
`rebral endothelium. Another study did not find any dif-
`ference in the MMP-9 levels during the treatment with
`IFNβ17. Besides the role of the metalloproteinases, IFNβ
`can modulate the expression and traffic of other mol-
`ecules like cytokines, chemokines, adhesion molecules
`and integrins16-18, improving endothelial barrier function
`and prevent the transmigration of leukocytes and other
`neurotoxic mediators across the BBB to sites of CNS
`inflammation10. One example is the possible induction
`of an increase in CD73 expression. Additionally, Uhm
`and colleagues found that the decrease in cell migration
`seems to wane with time as patients who have been re-
`ceiving IFNβ-1b treatment for more than 3.5 years had
`high levels of T-cell migration that were indistinguishable
`from those of MS patients who have never been treated
`with IFNβ19. IFNβ may interfere with T-cell/endothelial
`cell adhesion by inhibiting MHC class II expression on
`endothelial cells, which can also function as ligands for T
`cells20 and by decreasing the expression of VLA-48. IFNβ
`also increases serum concentrations of soluble VCAM1
`(sVCAM1), which might block leukocyte adhesion to ac-
`tivated cerebral endothelium by binding competitively
`with the VLA-4 receptor18. sVCAM1 had been correlated
`with a reduction in the number of MRI gadolinium-en-
`hancing lesions soon after the initiation of treatment21.
`
`ANTIVIRAL EFFECTS
`Both formulations of IFNβ have antiviral properties,
`although IFNβ-1a seems to be more potent in this field6.
`A group of investigators studied the relation of MS-as-
`sociated retrovirus (MSRV) in MS patients treated with
`IFNβ. They found that the viral load in the blood was
`directly related to MS duration and fell below detec-
`tion limits within 3 months of IFN therapy, suggesting
`that evaluation of plasmatic MSRV could be considered
`a prognostic marker for the individual patient to mon-
`itor disease progression and therapy outcome22. Another
`group aimed to analyze IFNβ antiviral efficiency through
`the measurement of human herpesvirus-6 (HHV-6)
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`prevalence in MS patients and they noted a decreased
`number of reactivations of the virus associated with less
`relapses (42.8% of patients with viral reactivations ex-
`perienced at least one relapse versus 22.5% of patients
`without viral reactivations)23.
`
`NEUROPROTECTIVE EFFECTS
`Some studies issued potential neuroprotective effects
`of IFNβ, inducing release of nerve growth factor from
`astrocytes or stimulate the protection of neurons them-
`selves6.
`Other investigators tried to measure the axonal in-
`jury in vivo using MRI spectroscopy to quantify the neu-
`ronal marker, N-acetylaspartate (NAA) and its relation
`with creatine (Cr) and found an increase in NAA/Cr in
`IFNβ-1b treated MS patients. Their data suggest that the
`axonal injury could be partially reversible with IFNβ-1b
`therapy24.
`
`How it works
`CLINICAL AND MRI OUTCOMES
`The first multicenter, randomized and placebo-con-
`trolled study in RRMS patients with IFNβ was pub-
`lished in 199325. This pivotal study demonstrated that
`IFNβ-1b 250 µg subcutaneous (SC) produced a 34% re-
`duction in the clinical relapse rate and in the confirmed
`1-point EDSS progression rate after 2 years, better than
`a lower dose (50 µg), yet the latter was not statistically
`significant compared with the placebo group25. Further-
`more, the number and frequency of T2 active lesions
`on brain MRI were decreased26. Three years later, the
`results of a phase III trial with a similar design using
`IFNβ-1a 30 µg/week intramuscular (IM) showed a 37%
`reduction in the confirmed 1-point EDSS progres-
`sion rate. The median number of MRI-gadolinium en-
`hancing lesions in MS was 33% inferior comparatively
`to the placebo arm. This pivotal trial also showed that
`IFNβ-1a slowed the accumulation of disability27. Since
`then, several trials confirmed these beneficial effects
`in RR form of MS28,29 and in secondary progressive
`with relapses30. The patients with CIS who are consid-
`ered with a high risk of CDMS have a proven benefit
`from early treatment with IFNβ to decrease clinical and
`MRI disease activity, as shown by specific studies con-
`ducted in CIS, either with IFNβ-1a31 or with IFNβ-1b32.
`As regards the route of administration, it does not
`seem to influence the biological effects of the IFNβ for-
`mulations33. Similarly, a dose-dependent effect remains a
`controversial issue. Although the pivotal trials suggested
`a dose-response curve, i.e., clinical and MRI outcomes
`seem to be better with higher doses, the evidence pro-
`vided by them was considered somewhat equivocal34.
`However, other studies pointed out a trend to the same
`
`MS: immunomodulatory therapy
`Mendes and Sá
`
`result, in which higher dose and more frequently admin-
`istered IFNβ was favored35,36, findings that were not cor-
`roborated by others37.
`
`NEUTRALIZING ANTIBODIES (NABS)
`During treatment with IFNβ, a proportion of MS pa-
`tients develop NAbs. The potential impact of NAbs on
`the efficacy of IFN-β treatment in MS is an area of de-
`bate and controversy, although their presence has been
`associated with a significant hampering of the treatment
`effect on the relapse rate and both active lesions and
`burden of disease in MRI. In Europe it is recommended
`that the patients treated with IFNβ are tested for the
`presence of NAbs at 12 and 24 months of therapy. In pa-
`tients with NAbs, the measurement should be repeated
`at intervals of 3-6 months and if the titers continue el-
`evated, IFNβ might be discontinued38. The American
`Academy of Neurology did not find enough evidence
`to make specific recommendations about when to test,
`which test to use, how many tests are necessary, and
`which cutoff titer to apply39.
`
`Side effects
`Therapy with IFNβ is usually well tolerated. The most
`frequent side effects are flu-like symptoms and injection-
`site reaction, which tend to reduce over time. Depres-
`sion, allergic reaction, haematologic and liver function
`abnormalities might also be observed40. IFNβ is a safe
`treatment, but usually is not recommended during preg-
`nancy because of the higher risk of fetal loss and low
`birth weight41.
`
`IFN formulations and indications
`The actual commercially available formulations of
`IFNβ include IFNβ-1a and IFNβ-1b. IFNβ-1a is dosed
`in 30 µg (Avonex®), 22 or 44 µg (Rebif®). The first is ap-
`plied once a week by IM and the second three times a
`week with a SC injection. IFNβ-1b formulations have 250
`µg (Betaferon® or Betaseron®, and Extavia®) and are ad-
`ministered by SC injection every other day. All formula-
`tions are indicated in RRMS, IFNβ-1a IM and IFNβ-1b
`are also approved in patients with CIS at risk of conver-
`sion to CDMS and IFNβ-1b is furthermore approved in
`Europe to treat patients with SPMS still with relapses.
`
`GLATIRAMER ACETATE
`Glatiramer acetate is a synthetic polypeptide com-
`posed of four amino acids (L-glutamic acid, L- lysine, L-
`alanine and L- tyrosine) with an average molecular mass
`of 4700-11.000 Da. It was discovered in the 1960’s, when
`studies to develop a polymer resembling myelin basic
`protein (MBP), a major component of myelin sheath, to
`the model of autoimmune encephalomyelitis (EAE), were
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`performed42. One of them, called copolymer 1, demon-
`strated to decrease or prevent EAE, and was later re-
`named as GA43.
`
`How it acts
`Several mechanisms of action have been proposed,
`yet the precise biological effects of GA are not fully un-
`derstood. We present the main effects on T and B lym-
`phocytes and on antigen presenting cells (APCs).
`
`EFFECTS ON T CELLS
`Inhibition of myelin reactive T cells and immune
`deviation – GA binds directly to MHC class II, but also
`seems to be able to interact with MHC class I44. GA in-
`terferes with the activation of myelin-specific T cells
`based on the observation that it acts as an antagonist to
`MBP/MHC at MBP-specific T cell receptor (TCR), op-
`erating as an altered peptide ligand to the 82-100 epitope
`of MBP in vitro42, displacing MBP from the binding site
`on MHC II molecules. Some authors argued that this
`“TCR antagonism” is controversial and, whether it oc-
`curs, is not probably relevant in vivo because GA is un-
`likely to reach sites where it could compete with MBP.
`However, GA-reactive Th2 cells are able to cross the
`BBB and might be activated not only by MBP, but also
`by other cross-reactive antigens44. Myelin reactive T cells
`exposed to increasing doses of GA manifest dose-de-
`pendent inhibition of proliferation and IFNγ production.
`That proliferative response of T cells to GA decreases
`with time. In addition, the observed decrease in GA-re-
`active T cells could be caused by the induction of T cell
`anergy and clonal elimination45. This mechanism of T cell
`anergy can occur in the periphery at the injections sites
`or in their draining lymph nodes where the MBP specific
`cells might be confronted with GA. The used regimen of
`daily SC administration may favor the induction of an-
`ergy rather than a full immunization that requires longer
`intervals between doses46. However, some clonal popula-
`tions of T cells could be expanded, since GA induced the
`conversion of peripheral CD4+CD25– to CD4+CD25+
`regulatory T cells through the activation of transcrip-
`tion factor Foxp3 and lead to proliferation of these cells.
`However, this fact must be interpreted with caution be-
`cause almost all activated human T cells express Foxp342.
`Therapy with GA may improve the immune regulatory
`function of CD8+ T cells42. These data suggest that the
`immunomodulatory effect of GA is attributed to the in-
`duction of a cytokine secretion pattern deviation from
`Th1 to Th2 cytokines, as happens with IFNβ43, which is
`the mechanism with the strongest experimental support.
`
`BYSTANDER SUPPRESSION
`Another potential mechanism of action is the so
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`called bystander suppression: a phenomenon of T cells
`specific to one antigen which suppress the immunolog-
`ical response induced by another antigen46. This implies
`that GA-reactive Th2 cells are capable of entering the
`CNS and recognizing cross-reactive antigen(s), probably
`myelin antigen(s)44. It is characterized by the secretion
`of anti-inflammatory cytokines by GA-activated T cells
`after they cross the BBB and accumulate in the CNS43.
`
`EFFECTS ON CELL-PRESENTING ANTIGENS
`Although the vast majority of evidence suggests that
`GA acts primarily at the level of T cells, additional ef-
`fects on other immune cells cannot be excluded. For ex-
`ample, GA was reported to inhibit a human monocytic
`cell line, THP-1. In THP-1 cells stimulated with lipopoly-
`saccharide or IFN-γ, GA reduced the percentage of cells
`expressing MHC-DR and DQ antigen and inhibited the
`production of TNF-α and cathepsin-B. In contrast, the
`production of interleukin(IL)-1β was increased47. This
`could also indicate antigen-unspecific modes of action. A
`further study also demonstrated that GA affects mono-
`cytes/macrophages by inducing the production of an
`anti-inflammatory cytokine, the IL-1 receptor antago-
`nist (IL-1Ra), but diminishing the production of IL-1β in
`monocytes, activated by direct contact with stimulated T
`cells in MS patients and in the EAE model48. IL-1Ra can
`be transported through the BBB and exert its immuno-
`modulatory effects in both systemic and CNS compart-
`ments. In addition to the modulation of the adaptive im-
`mune system, GA seems to affect significantly the innate
`immune system48.
`GA may also affect the immune response through
`modifying APCs into anti-inflammatory type II cells. The
`process begins with the presentation of GA to CD8+ and
`CD4+ T cells by APCs. The final step is an alteration of
`cytokine environment that subsequently affect T-cell dif-
`ferentiation as far as concerned to further cytokine se-
`cretion. The T cell CD8+ response becomes oligoclonal
`with expansion and maintenance of CD8+ clone popu-
`lation over long periods of time, in contrast to what hap-
`pens to T cells CD4+ which may increase in number42.
`
`NEUROPROTECTIVE EFFECTS
`Futhermore, GA specific T cells secrete neurotrophic
`factors as brain-derived neurotrophic factor and neuro-
`trophic growth factor, which might favor remyelination
`and axonal protection42,43,49. A study with MRI spectros-
`copy showed a significant increase in NAA/Cr in a group
`of treatment naïve patients with RRMS, who received
`GA compared with untreated patients, suggesting the
`potential role of GA in axonal metabolic recovery and
`protection from sublethal injury50. Another potential ef-
`fect of GA is the delivery of neuroprotective cytokines
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`to the site of inflammation in patients with MS. So, the
`role of GA seems to be the creation of an anti-inflamm-
`matory and neuroprotective environment instead of sup-
`pression the immune activity42.
`
`How it works
`CLINICAL AND MRI OUTCOMES
`The first studies on MS focusing treatment with co-
`polymer 1 were carried out in late 1970s and early 1980s.
`Ten years later, a phase III multicentre, double blind and
`placebo-controlled trial, performed in patients with
`RRMS, showed that 20 mg GA SC daily was effective in
`reducing the annualized relapse rate (ARR) by 29% over
`a 2-year period compared with the placebo51. It also re-
`duced the disability progression in 12%, although this
`change was not statistically significant51. After 10 years
`of open label extension of this pivotal trial, patients orig-
`inally randomized to GA were shown to maintain better
`outcomes than patients who were originally on placebo52,
`although the high dropout rate raised some concerns
`about the power of the study.
`As the initial phase III trial did not include MRI end-
`points, a European/Canadian study was undertaken to
`address this specific issue in MS patients treated with GA
`versus placebo during 9 months53. It was demonstrated a
`reduction in the frequency and volume of new enhancing
`lesions, such as a 35% and 8.3% decrease in the number
`of enhancing lesions and in the median change in T2
`burden of disease, respectively, for the treatment arm,
`an effect that was delayed until 6 months after initia-
`tion of treatment53. Later on, in various studies, ARR re-
`ductions with use of GA in RRMS patients were found
`to be much higher than those seen in its pivotal trial51.
`Recently, the effect of GA on delaying conversion of pa-
`tients presenting with CIS to CDMS was evaluated in
`the PreCISe study, which showed that GA has a benefi-
`cial effect for the treatment of patients with this condi-
`tion54. On the contrary, a large controlled trial with GA
`in PPMS failed to provide any evidence for benefit in this
`population55.
`
`Side effects
`The results of the studies indicate that GA is gener-
`ally safe. The most common adverse reaction is a local
`reaction in the site of injection with erythema and indu-
`ration. GA is less frequently associated with a transient
`post-injection systemic reaction of flushing, chest tight-
`ness, dyspnea, chest palpitations, and anxiety. This self-
`limited systemic reaction may be experienced in 15% of
`the patients and typically resolve within 15-30 minutes
`without sequelae. No significant laboratory abnormal-
`ities have been found. According to the manufacturer,
`rare cases of non-fatal anaphylaxis have also been re-
`
`MS: immunomodulatory therapy
`Mendes and Sá
`
`ported49. Opportunistic infections, malignancies, and the
`development of autoimmune diseases are not risks asso-
`ciated with GA52. Although its use is not recommended
`in pregnancy, there is no evidence to suggest increased
`risk of adverse fetal or pregnancy outcome49,56.
`
`GA formulation and indications
`Glatiramer acetate (Copaxone®) is approved in a SC
`formulation of 20 mg to be administered once a day, to
`treat patients with RRMS and with CIS at risk of con-
`version to CDMS.
`
`Comparative studies
`Recently, the results from three head-to-head trials
`(IFNβ and GA) were published and they did not find
`significant differences between the two molecules in
`the primary endpoints evaluating reduction in relapse
`rates40,57,58. The REGARD study, a randomized, compar-
`ative, parallel-group, open-label trial, compared 44 µg of
`IFNβ-1a SC 3 times a week with 20 mg of GA SC once
`a day for 96 weeks. There was no significant difference
`between groups in the time to first relapse and ARR. Re-
`garding MRI outcomes, no significant differences were
`found in the number and change in volume of T2 ac-
`tive lesions. Patients treated with IFNβ-1a SC had sig-
`nificantly fewer gadolinium enhancing lesions and pa-
`tients treated with GA experienced significantly less
`brain atrophy57. BEYOND study compared 3 groups for
`treatment-naïve early stages RRMS patients: 250 µg of
`IFNβ-1b, 500 µg IFNβ-1b, both SC dosed every other
`day and GA 20 mg SC daily over 2 years. No significant
`differences were found in time to first relapse, overall re-
`lapse rates and proportion of patients who remained re-
`lapse free during the study period. No differences were
`found in T1-hypointense lesion volume change among
`the groups when compared the baseline with the last
`MRI available or annual time points. Change in total
`MRI burden and T2 lesion volume was significantly
`lower in the patients in both IFNβ-1b compared with
`the patients who received GA. However, the differences
`in T2 lesion volume were noted during the first year but
`not in years 2 and 3. The overall median change in brain
`volume was similar in each group. MRI parameters did
`not differ between patients in either IFNβ-1b doses40.
`The BECOME study was conducted to determine the ef-
`ficacy of treatment with IFNβ-1b 250 µg SC every other
`day versus GA 20 mg SC daily in RRMS or CIS patients,
`evaluating MRI outcomes (total number of contrast-en-
`hancing lesions plus new non-enhancing lesions on long
`repetition time scans). The results were similar, as there
`were no significant differences in the effects of the med-
`ications on relapse rates58.
`Therefore, IFNβ and GA are both good options to
`
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`YEDA EXHIBIT NO. 2062
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`MS: immunomodulatory therapy
`Mendes and Sá
`
`modify the natural course of MS. The choice between
`them is usually a challenging issue in MS Clinics, which in
`our view must be centered on the patient informed deci-
`sion, after a thorough education about the disease and the
`real therapeutic expectations. However, the administra-
`tion routes are rather bothersome to the patients, which
`could contribute to a reduced therapeutic adherence59.
`Pivotal studies of IFNβ and GA in MS demonstrated
`that they are efficacious, lowering the ARR in approxi-
`mately 30%, the lesion burden and their activity, as well
`as the brain atrophy as measured by MRI.
`Even though the mechanisms of action of these clas-
`sical immunomodulatory drugs are not completely un-
`derstood, there is sound evidence that they act on impor-
`tant steps of the inflammatory processes underpinning
`MS. The appearance of drugs with more specific targets,
`as monoclonals and orals, increasing therapeutic efficacy,
`albeit raising new safety and tolerability problems, as well
`as a better understanding of the immunogenetic profiles
`of MS patients, are altogether expected to permit a more
`advanced therapeutic choice in the future. Actually, IFNβ
`and GA are the better known DMD in MS, with proofs
`of their safety and tolerability, so the large clinical expe-
`rience in treating MS patients with them along almost
`two decades, deserves to be emphasized.
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`REFERENC