REVIEW ARTICLE
`
`Drug Safety 2001; 24 (13): 979-990
`0114-5916/01/0013-0979/$22.00/0
`
`© Adis International Limited. All rights reserved.
`
`Risk-Benefit Assessment of Glatiramer
`Acetate in Multiple Sclerosis
`Tjalf Ziemssen,1 Oliver Neuhaus2 and Reinhard Hohlfeld1,3
`1 Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
`2 Department of Neurology, Karl-Franzens University, Graz, Austria
`3 Institute for Clinical Neuroimmunology and Department of Neurology, Klinikum Grosshadern,
`Ludwig Maximilians University, Munich, Germany
`
`Contents
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979
`Abstract
`1. Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
`2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
`3. Risks Associated with Glatiramer Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
`3.1 Toxicological Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
`3.2 Local Site Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
`3.3 Immediate Postinjection Systemic Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
`3.4 Transient Chest Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
`3.5 Immunological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
`3.6 Pregnancy and Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
`3.7 Other Effects
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
`4. Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
`4.1 Preliminary Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
`4.2 Phase II Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
`4.3 Phase III Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986
`4.4 Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986
`4.5 Magnetic Resonance Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986
`5. Risk-Benefit Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
`6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
`
`Abstract
`
`Glatiramer acetate, formerly known as copolymer 1, is a mixture of synthetic
`polypeptides composed of four amino acids. Glatiramer acetate has been shown
`to be effective in preventing and suppressing experimental autoimmune enceph-
`alitis (EAE), the animal model of multiple sclerosis (MS). Therefore it was tested
`in several clinical studies, where it was found to slow the progression of disability
`and to reduce the relapse rate and the magnetic resonance imaging (MRI)–defined
`disease activity and burden in relapsing-remitting MS. As a daily standard dose,
`20mg of glatiramer acetate is injected subcutaneously. After injection, glatiramer
`acetate undergoes rapid degradation to amino acids and shorter peptides; so it is
`not possible to measure any systemic plasma concentrations or excretion rates.
`Two major mechanisms have been proposed to explain the effects of glatiramer
`acetate in EAE and MS: the induction of glatiramer acetate-reactive T helper 2
`(Th2)-like regulatory suppressive cells and the interference with T cell activation
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`as an altered peptide ligand. The most common adverse effects were mild injec-
`tion site reactions (erythema, inflammation and induration). The most remarkable
`adverse event is the acute and transient immediate postinjection reaction mani-
`fested by flushing, chest tightness, palpitations and dyspnoea. Other reported
`adverse effects are transient chest pain and lymphadenopathy. Antibodies to
`glatiramer acetate induced during treatment do not interfere with its clinical ef-
`fects. In several controlled clinical studies, glatiramer acetate has been shown to
`provide consistent, reproducible clinical benefits in the target population of pa-
`tients with relapsing-remitting MS. The safety profile and risk-benefit ratio are
`excellent. Overall, glatiramer acetate is very well tolerated and has an excellent
`risk-benefit profile in patients with relapsing-remitting MS.
`
`Glatiramer acetate, formerly known as copolymer
`1, is the acetate salt of a standardised mixture of
`synthetic polypeptides containing the four amino acids
`L-alanine, L-glutamic acid, L-lysine and L-tyrosine
`with a defined molar ratio of 0.14 : 0.34 : 0.43 : 0.09
`and an average molecular mass of 4.7 to 11.0kD,
`i.e. an average length of 45 to 100 amino acids.[1,2] In
`the 1960s Drs Sela, Arnon and their colleagues at
`the Weizmann Institute in Israel were involved in
`studies on the immunological properties of a series
`of polymers and copolymers which were developed
`to resemble myelin basic protein (MBP), a myelin
`protein. MBP in Freund’s complete adjuvant induces
`experimental allergic encephalitis (EAE), the best
`animal model of multiple sclerosis (MS). They were
`interested in evaluating the extent to which these
`polypeptides could simulate the ability of MBP and
`of fragments and regions of the MBP molecule to
`induce EAE.[3-6] None of these series was capable
`of inducing EAE, but several polypeptides were able
`to suppress EAE in guinea-pigs. Copolymer 1, later
`known as glatiramer acetate, was shown to be the
`most effective polymer in preventing or decreasing
`the severity of EAE.[6] The suppressive effect is a
`general phenomenon and not restricted to a partic-
`ular species, disease type or encephalitogen used for
`EAE induction.[7]
`Abramsky et al.[8] were the first to treat a group of
`patients with severe relapsing-remitting MS with
`intramuscular glatiramer acetate 2 to 3mg every 2
`to 3 days for 3 weeks, then weekly for 2 to 5 months.
`No conclusions could be drawn regarding drug ef-
`ficacy but there were no significant adverse effects.
`Three clinical trials performed in the 1980s showed
`
`some evidence of efficacy that was adequate to sup-
`port US Food and Drug Administration (FDA) ap-
`proval and a good safety profile.[9-11] However, the
`results of these studies must be interpreted with
`caution because before 1991 production of the drug
`was not standardised.[2,12] Different batches had
`variable suppressive effects on EAE, which could
`also imply variable effects in MS patients. In 1991
`a phase III multicentre trial with a daily 20mg dose
`of subcutaneously administered, highly stand-
`ardised glatiramer acetate preparation was started
`in the US. This double-blind, placebo-controlled
`study demonstrated that glatiramer acetate signifi-
`cantly reduced the relapse rate without significant
`adverse effects.[13] In 1996 glatiramer acetate was
`approved by the FDA as a treatment for ambulatory
`patients with active relapsing-remitting MS.[7] Since
`then, glatiramer acetate has been licensed for ap-
`proval in many other countries.
`This review considers the long-term risks of
`glatiramer acetate therapy of multiple sclerosis and
`also attempts to assess the benefit of glatiramer ac-
`etate. Because there are several recent studies on
`the immunobiological consequences of treatment
`with glatiramer acetate, this review places empha-
`sis on the possible mechanisms of action. Data was
`retrieved using a literature search of Medline up to
`August 2001 using the key words: glatiramer ace-
`tate, coploymer 1 and multiple sclerosis treatment.
`
`1. Mechanism of Action
`
`Until recently the effects of glatiramer acetate
`on the human immune system and its mechanisms
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`of action were largely unknown. Most data so far
`have been obtained in animal models. Several new
`papers, however, have shed light on the mechanisms
`of glatiramer acetate in MS and suggest several
`major effects on human T cells.[14]
`In contrast to its lack of effect on immune cells
`isolated from untreated animals, glatiramer acetate
`induces vigorous polyclonal proliferation of pe-
`ripheral blood lymphocytes from untreated (un-
`primed) human donors.[15-20] In glatiramer acetate–
`treated patients, the proliferative response to the
`agent decreases with time.[21] Recent results from
`our group indicate that this decrease is specific to
`glatiramer acetate, as it is not observed with recall
`antigens such as tetanus toxoid and tuberculin.[19]
`Theoretically, the observed decrease in glatiramer
`acetate–reactive T cells could be due to anergy in-
`duction or activation-induced cell death of glatira-
`mer acetate-specific T cells.
`Glatiramer acetate binds to major histocompat-
`ibility complex (MHC) class II and perhaps to MHC
`class I molecules, thereby competing with the MHC
`binding of other antigens.[22-24] This effect, which
`by its nature is antigen-nonspecific, is unlikely to
`play a role in vivo, since after subcutaneous admin-
`istration, glatiramer acetate is quickly degraded
`and thus it is not likely to reach the CNS, where it
`could compete with the relevant auto-antigens for
`MHC binding. Complexes of glatiramer acetate/
`MHC can compete with MBP/MHC for binding
`to the antigen-specific surface receptor of MBP-
`specific T cells (T cell receptor antagonism).[25]
`The experimental evidence supporting this effect
`is controversial.[26] If it occurs, it is unlikely to be
`relevant in vivo, since glatiramer acetate is unlikely
`to reach sites where it could compete with MBP.
`On the other hand, glatiramer acetate could act
`in the periphery as an ‘altered peptide ligand’ rel-
`ative to MBP.[27-31] As a consequence, some of the
`circulating myelin-specific, potentially pathogenic
`T cells might become ‘anergic’ or be otherwise chan-
`ged in their properties, e.g. in their migratory po-
`tential. This effect would be relatively antigen-spe-
`cific and presumably occur in the periphery at the
`injection sites or in the corresponding draining
`
`lymph nodes, where MBP-specific T cells might be
`confronted with glatiramer acetate. Although some
`in vitro findings support this mechanism, it is not
`yet known whether the functional properties of MBP-
`specific T cells are altered in glatiramer acetate–
`treated patients. It may be relevant in this connec-
`tion that we were unable to isolate MBP-specific T
`cell lines from glatiramer acetate–treated patients.[32]
`Glatiramer acetate treatment induces an in vivo
`change of the cytokine secretion pattern and the ef-
`fector function of glatiramer acetate–reactive T help-
`er (Th) cells, a so-called Th1 to Th2 shift.[18,19,32-36]
`Th cells can be divided into several types based on
`their characteristics.[37-39] Th1 cells produce pro-
`inflammatory cytokines such as interleukin (IL)-2,
`IL-12, interferon (IFN)-γ and tumour necrosis fac-
`tor (TNF)-α. In contrast, Th2 cells produce down-
`regulatory cytokines such as IL-4, IL-5, IL-6, IL-10
`and IL-13. Different lines of evidence suggest that
`glatiramer acetate treatment changes the properties
`of the glatiramer acetate–reactive T cells in such a
`way that they increasingly become Th2-like with
`time. Using intracellular double-immunofluores-
`cence flow cytometry, we demonstrated that long-
`term glatiramer acetate–reactive T cell lines from
`untreated MS patients and healthy controls pre-
`dominantly produce IFNγ and are to be classified
`as Th1 cells, whereas glatiramer acetate-reactive T
`cell lines from glatiramer acetate–treated MS pa-
`tients predominantly produce IL-4, i.e. behave like
`Th2 cells.[32]
`In addition, the study of Farina et al.[19] demon-
`strated that an automated ELISPOT assay, which
`is able to detect cytokine production of individual
`peripheral blood lymphocytes, allows the correct
`identification of glatiramer acetate–treated and un-
`treated donors in most cases. Glatiramer acetate–
`treated MS patients show: (i) a significant reduc-
`tion of glatiramer acetate-induced proliferation of
`peripheral blood mononuclear cells; (ii) a positive
`IL-4 ELISPOT response mediated predominantly
`by CD4+ T cells after in vitro stimulation with a
`wide range of glatiramer acetate concentrations;
`and (iii) an elevated IFNγ response partially medi-
`ated by CD8+ T cells after stimulation with high
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`glatiramer acetate concentrations. Glatiramer ace-
`tate–reactive T cells seem to not be physically de-
`leted, but rather they are modified in such a way
`that they respond to in vitro challenge with glatira-
`mer acetate by secretion of cytokines but not by
`proliferation. This ELISPOT assay may help to dis-
`tinguish between immunological responders and
`nonresponders to glatiramer acetate treatment.
`In summary, the following scenario has the
`strongest experimental support:[14] glatiramer
`acetate–reactive Th2-like T cells are able to cross
`the blood-brain barrier, since they are activated by
`daily immunisation.[40] Inside the CNS, glatiramer
`acetate–reactive T cells may cross-react with prod-
`ucts of the local myelin turnover presented by local
`antigen-presenting cells.[41] Thus, some of the
`glatiramer acetate–reactive Th2 cells may be stim-
`ulated to release anti-inflammatory cytokines and
`even neurotrophic factors.[42-44] Schori et al.[45] were
`able to demonstrate in an animal model different
`from EAE that immunisation with glatiramer ace-
`tate protected retinal ganglion cells against death
`from glutamate cytotoxicity and ocular hyperten-
`sion. Subsequently, the production of proinflam-
`matory cytokines by other inflammatory cells is re-
`duced via a suppressive bystander effect.[33,34,46,47]
`
`2. Pharmacokinetics
`
`Glatiramer acetate is administered daily as a
`subcutaneous injection of 20mg of a standardised
`mixture of the described polypeptides.[48,49] Injec-
`tion sites should be rotated between the upper arms,
`thighs and abdomen. After subcutaneous adminis-
`tration, glatiramer acetate is quickly absorbed with
`only 10% remaining at the injection site after 1
`hour. It undergoes rapid degradation to amino acids
`and shorter peptides. No systemic plasma concen-
`trations nor any urinary or faecal excretion can be
`detected.[50]
`There are only a few studies in vivo, using ra-
`dioactive labelling methods, on the pharmacoki-
`netics of glatiramer acetate in mice, rats and mon-
`keys.[51] The radioactivity in serum reaches a
`maximum after 1 to 2 hours in rats and after 2 to 4
`hours in monkeys. Long-term administration in
`
`rats did not affect the pharmacokinetic parameters
`of glatiramer acetate. The curves of plasma radio-
`activity are similar after oral administration and
`after intramuscular or subcutaneous injections. The
`distribution of iodinated material showed the high-
`est level in stomach and thyroid and the lowest in
`the brain, probably because the penetration through
`the blood-brain barrier is impeded by the high po-
`larity and the hydrophilic nature of glatiramer ac-
`etate. Urinary excretion is the major elimination
`pathway for the radioactive labels, and faeces con-
`tained only trace amounts. One should be aware of
`a general methodological problem of radioactive
`labelling: it is not known whether the widely dis-
`tributed radioactive label is still attached to intact
`glatiramer acetate or to fragments of glatiramer ac-
`etate.
`So far there is no evidence of relevant drug in-
`teractions in humans. Results from existing clinical
`trials do not suggest any significant interactions of
`glatiramer acetate with therapies commonly used in
`patients with MS, including the concurrent use of
`corticosteroids, antihistamines, antidepressants and
`muscle relaxants up to 28 days.[50,52] A clinical trial
`of combined treatment with IFNβ and glatiramer
`acetate is currently in progress. Animal experi-
`ments with a combination of IFNα and glatiramer
`acetate indicate that such a combination may not
`be beneficial.[53]
`
`3. Risks Associated with
`Glatiramer Acetate
`
`3.1 Toxicological Data
`
`Toxicological studies indicate that glatiramer ace-
`tate is well tolerated at the currently used dose (20
`mg/day) with an adequate safety margin. Repro-
`duction studies in rats and rabbits showed no im-
`pairment of fertility and no fetal loss or fetal abnor-
`malities. In vitro and in vivo studies demonstrated
`that glatiramer acetate is devoid of any mutagenic
`or carcinogenic potential. Serial analysis of urine
`and blood revealed no changes in liver, spleen, kid-
`ney, bone marrow, gastrointestinal, circulatory or
`pulmonary function.[13,50,52]
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`3.2 Local Site Effects
`
`As glatiramer acetate is given by daily subcuta-
`neous injection administered by the patient or car-
`er, this route of administration itself will inevitably
`result in local adverse effects. Across all trials, the
`most commonly reported local adverse events
`were, in isolation or combined, local reactions such
`as erythema, itching, burning, pain, inflammation,
`oedema and/or swelling.[52] The local adverse ef-
`fects seem not to be related to the dose per injec-
`tion. In controlled studies, local adverse effects
`were overall reported in 82% of the glatiramer
`acetate–treated group and in 48% of the placebo
`group.[12,13,49,54] Only 2% of patients receiving
`glatiramer acetate for injection in controlled clini-
`cal trials had local adverse effects that were graded
`severe (compared with 1.2% on placebo). In con-
`trolled studies, 2.1% of the glatiramer acetate–
`treated patients discontinued treatment because of
`local injection site reactions (compared with 1.1%
`of patients receiving placebo). There were isolated
`reports of injection site fibrosis, injection site atro-
`phy, abscess and injection site necrosis.[50] The fre-
`quency of injection site effects generally decreases
`with time except, most notably (as would be ex-
`pected), the rare events of atrophy and fibrosis, which
`tend to occur later.[52]
`Mancardi and co-workers described a localised
`lipoatrophy in 4 of 27 patients after prolonged treat-
`ment with glatiramer acetate.[55,56] After 3 years of
`treatment, well circumscribed areas of skin depres-
`sion were visible at the injection sites with a normal-
`appearing overlying skin. One erythematous indu-
`rated skin area showed perivascular infiltrates of
`lymphocytes and rare eosinophils in both superfi-
`cial and deep dermis on biopsy. In the other three
`cases, skin samples from atrophic areas showed
`fibrosis of the dermis and subcutis with a reduction
`in the size of fat lobules and only minimal inflam-
`mation. It is therefore possible that in some cases
`the drug itself induces a local inflammatory reac-
`tion with subsequent dermal fibrosis and fat atro-
`phy.
`Hofstadt et al.[57] reported 3 of 33 glatiramer
`acetate–treated patients who developed subcutane-
`
`ous masses with a diameter of 5cm or more. Skin
`biopsies showed lymphocytic and eosinophilic in-
`filtration. Epicutaneous tests were negative, and
`prick scratch and intracutaneous tests were posi-
`tive at a dilution of 1 : 2000 in a crescendo reaction
`until 72 hours. This reaction seems to be compati-
`ble with a delayed type hypersensitivity (type IV
`allergy). Glatiramer acetate should be discontin-
`ued in affected patients. The incidence of poten-
`tially serious reactions to glatiramer acetate (3 in
`33) in this report was much higher than that en-
`countered in clinical practice and controlled trials.
`
`3.3 Immediate Postinjection
`Systemic Reaction
`
`Apart from local injection site adverse events,
`the most common treatment-related adverse events
`were symptoms of immediate postinjection reactions
`that occurred in about 10% of the patients.[12,52,58]
`This infrequent adverse experience reported by pa-
`tients treated with glatiramer acetate includes, in
`isolation or combined, facial or more generalised
`flushing (vasodilation), chest discomfort (pain) and
`perceived shortness of breath (dyspnoea). These
`symptoms generally appear within minutes of an
`injection and resolve spontaneously in 5 to 15 min-
`utes, but in some situations they can last for more
`than 1 hour. The reaction typically occurs at home
`soon after injection and resolves spontaneously be-
`fore it can be observed by a health professional. No
`long-term or permanent sequelae of the immediate
`postinjection reaction have been reported.[50,58,59]
`Nearly half of all patients who developed one epi-
`sode of this type eventually experience it again.
`One patient had seven such reactions over approx-
`imately 30 months of using the drug.[52] However,
`on average, it occurred only once in approximately
`840 daily injections. Whether any of these symp-
`toms actually represent a specific syndrome is un-
`clear. The cause of this systemic reaction is unknown.
`Because it is self-limited and without relevant con-
`sequences there is no reason to stop treatment. Pa-
`tients should be informed that this reaction may
`occur, in order to reduce the emotional effect;
`moreover, re-injection after such a reaction should
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`preferably be done under medical observation to
`reassure the patient.[49]
`
`3.4 Transient Chest Pain
`
`Approximately 26% of glatiramer acetate–
`treated patients in the multicentre controlled trial
`(compared with 10% of the placebo-treated patients)
`experienced at least one episode of what was de-
`scribed as transient chest pain.[50] Although some
`of these episodes occurred in the context of the
`immediate postinjection reaction described above,
`many did not. The pain was transient, often unassoc-
`iated with other symptoms and appeared to have no
`important clinical sequelae. Electrocardiographic
`monitoring did not reveal any cardiac abnormal-
`ity.[13] The pathogenesis of this symptom is unknown.
`
`3.5 Immunological Effects
`
`Studies in both rat and monkey have suggested
`that immune complexes are deposited in renal glome-
`ruli.[50] In three different clinical studies, all patients
`(n = 130) developed glatiramer acetate–reactive
`antibodies.[13,21,60,61] Maximum levels were attain-
`ed after an average treatment duration of 3 to 4 months;
`thereafter antibodies declined, but remained posi-
`tive (about 50% greater than the baseline). No such
`antibodies were detected in placebo patients. Im-
`munoglobulin (Ig) G1 antibody levels were 2 to 3
`times higher than those of IgG2. The preferential
`production of IgG1 over IgG2 antibodies may in-
`dicate that Th2 responses are involved in mediating
`the clinical effect of glatiramer acetate.[14,21] The
`continued clinical benefit, observed in long-term
`studies, suggests that the modifying effect of
`glatiramer acetate in relapsing-remitting MS is not
`compromised by the appearance of neutralising anti-
`bodies.[59,62] Because levels of glatiramer acetate–
`specific antibodies have not been determined after
`the 24-month point, no direct information is cur-
`rently available.[59] The presence of anti-glatiramer
`acetate antibodies did not influence the clinical ef-
`ficacy of the drug, as these antibodies did not re-
`duce the effect of glatiramer acetate in mice with
`EAE or the proliferation of a glatiramer acetate–
`specific T cell line.[49,63] Furthermore, the humoral
`
`and cellular immunological responses to glatira-
`mer acetate do not correlate with the observed side
`effects of glatiramer acetate treatment. Antibodies
`and T cell responses to MBP were low and did not
`change significantly during treatment.[21]
`Anaphylaxis can be associated with the admin-
`istration of almost any foreign substance, and the
`protein nature of glatiramer acetate certainly en-
`tails the risk of anaphylaxis. Up to now, three nonfatal
`anaphylactic reactions have been reported.[50,64]
`Bayerl et al.[64] described a 30-year-old woman
`who developed an immediate postinjection reac-
`tion 2 months after starting glatiramer acetate treat-
`ment. She continued the daily glatiramer acetate
`injections without further notable adverse effects;
`6 weeks later she developed a second, this time
`systemic, allergic reaction with nausea, a sensation
`of heat, pressure and drowsiness in the head,
`generalised erythema and wheals on the trunk. She
`felt cold perspiration, collapsed and experienced
`gastric spasms and diarrhoea. After resting on the
`floor for half an hour she recovered, with wheals
`remaining for 4 hours. In this patient, there might
`have been an exaggerated specific activation of the
`humoral immune reaction against glatiramer ace-
`tate. In summary, anaphylactic reactions to glatira-
`mer acetate are rare but need to be taken seriously.
`There was one published report of the onset of
`myasthenia gravis during treatment with glatira-
`mer acetate in a patient with MS.[65] Heesen et
`al.[66] reported another autoimmune phenomenon
`during glatiramer acetate treatment. They describe
`the case of a 30-year-old woman with MS who de-
`veloped autoimmune hyperthyroidism after receiv-
`ing glatiramer acetate treatment for 3 years. Al-
`though it is not possible to derive a clear causal
`relationship from these case reports and one cannot
`exclude a coincidental occurrence of autoimmune
`phenomena, the treating physician should pay at-
`tention to complaints suggesting additional auto-
`immune diseases during glatiramer acetate treat-
`ment. Perhaps autoantibody production is somehow
`stimulated by the enhanced Th2 cell response that
`develops during glatiramer acetate treatment.
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`YEDA EXHIBIT NO. 2021
`MYLAN PHARM. v YEDA
`IPR2014-00644
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`Glatiramer Acetate in Multiple Sclerosis
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`985
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`Windhagen et al.[67] showed that glatiramer ac-
`etate induced a mild to moderate tender lymph-
`adenopathy in 9 of 27 glatiramer acetate–treated
`patients. Symptoms included touch sensitivity or
`mild pain. The size of the swollen lymph nodes
`ranged from 2 to 5cm. A lymph node biopsy in one
`patient with severe generalised lymphadenopathy
`revealed strong immune stimulation with lymph-
`ofollicular hyperplasia but no atypical cells. In 7
`of these 9 patients the lymphadenopathy remained
`localised to the draining lymph nodes.
`
`3.6 Pregnancy and Breastfeeding
`
`No adverse effects on embryofetal development
`occurred in reproduction studies in rats and rabbits
`receiving subcutaneous doses up to 37.5 mg/kg
`glatiramer acetate during the period of organogen-
`esis.[50] Because animal reproduction studies are
`not always predictive of human response, glatira-
`mer acetate should not be used during pregnancy.
`Thus far, however, there is no evidence that glatira-
`mer acetate is toxic for the fetus or embryo.[51] It
`is not known whether glatiramer acetate is excreted
`in human milk. Because many drugs may be ex-
`creted in human milk, caution should be exercised
`when glatiramer acetate is administered to a woman
`who is breastfeeding.
`
`3.7 Other Effects
`
`Compared with placebo, glatiramer acetate did
`not increase the incidence of flu-like syndrome, de-
`pression or suicidal ideation.[52]
`
`4. Clinical Studies
`
`4.1 Preliminary Trials
`
`Four early exploratory open studies were per-
`formed in the late 1970s and early 1980s to obtain
`indications of dosing and safety.[8-10,68] In total, 41
`patients with relapsing-remitting or secondary pro-
`gressive MS were enrolled in these studies. The
`treatment schedules, doses of glatiramer acetate and
`treatment duration were quite variable from study
`to study. The maximum dose of 20 mg/day was
`
`well tolerated and no severe adverse effects were
`detected in these studies.
`
`4.2 Phase II Studies
`
`Because there was evidence of some potential
`benefit, Bornstein et al.[60] started a double-blind,
`placebo-controlled pilot trial. 50 patients with MS
`received either 20mg glatiramer acetate dissolved
`in 1ml saline or just saline for 2 years. There were
`62 relapses in the placebo group (average 2.7 per
`patient) and 16 among patients in the glatiramer
`acetate treated group (average 0.6 per patient). In
`addition, the proportion of relapse-free patients
`was twice as great in the glatiramer acetate-treated
`group. Only five patients of the treatment group show-
`ed a confirmed progression of disability, compared
`with 11 patients in the placebo group (p = 0.005).
`The effects on relapse rate and on disability were
`more pronounced in patients who had the least dis-
`ability at entry. This study also reported the occur-
`rence of a postinjection systemic reaction in two
`patients.
`In the mid 1980s a subsequent double-blind, ran-
`domised study in 106 patients with primary and sec-
`ondary progressive MS was conducted.[11] No dis-
`tinction was made between primary and secondary
`MS courses or between progression due to incom-
`plete recovery from a relapse and progression unre-
`lated to relapses. The differences between the overall
`survival curves were not significant. The progres-
`sion rates at 12 and 24 months were nonsignificant-
`ly higher for the placebo group (p = 0.088) with
`2-year probabilities of progressing of 20.4% for gla-
`tiramer acetate and 29.5% for placebo. Only at one
`of the two centres was a significant difference at
`24 months detectable between placebo and glatira-
`mer acetate. In conclusion, there was no evidence of
`efficacy of glatiramer acetate in patients with pro-
`gressive MS, although a favourable trend was more
`marked in those whose disability was less at the
`time of beginning treatment. Currently the effect of
`glatiramer acetate on progressive MS is being ad-
`dressed in a large controlled study of efficacy in
`primary progressive MS.
`
`© Adis International Limited. All rights reserved.
`
`Drug Safety 2001; 24 (13)
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`YEDA EXHIBIT NO. 2021
`MYLAN PHARM. v YEDA
`IPR2014-00644
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`986
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`Ziemssen et al.
`
`4.3 Phase III Studies
`
`For a more comprehensive assessment of the ef-
`ficacy of glatiramer acetate in patients with relaps-
`ing-remitting MS, a definitive phase III trial was
`conducted at 11 US medical centres with a total of
`251 patients with relapsing-remitting MS who re-
`ceived glatiramer acetate 20mg or placebo by daily
`subcutaneous injection for 2 years.[13] As the pri-
`mary end-point, the mean annualised relapse rates
`were 0.59 for the glatiramer acetate-treated group
`and 0.84 for the placebo group; a 29% reduction
`was statistically significant (p = 0.007). Trends in
`the proportion of relapse-free patients and median
`time to first relapse favoured glatiramer acetate
`treatment. Patients in both groups with higher dis-
`ability at entry, measured by the Expanded Disabil-
`ity Status Scale (EDSS),[69] had a higher relapse
`rate, while the largest reduction in relapse rate be-
`tween groups occurred in patients with a baseline
`EDSS of 0 to 2 (33% versus a reduction of 22% in
`patients with an EDSS score at entry >2). When the
`proportion of patients who improved, were un-
`changed, or worsened by ≥1 EDSS step from base-
`line to end of study (2 years) was evaluated, signif-
`icantly more patients on glatiramer acetate improved
`and more on placebo worsened (p = 0.037). The
`effect of treatment was constant throughout the en-
`tire study duration. Patient withdrawals were 19
`(15.2%) from the glatiramer acetate group and 17
`(13.5%) from the placebo group at approximate