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`I Cl) CURRENT CONCEPTS
`
`Current and Investigational Therapies Used
`to Alter the Course of Disease in Multiple
`Sclerosis
`
`AARON MILLER, MD, Brooklyn, NY
`
`ABSTRACT: Extensive research is under way to develop pharmacotherapeutic agents that will
`prevent the exacerbations and the progression of neurologic disability associated with
`multiple sclerosis (MS). The most intensive research strategy has involved agents intended to
`limit demyelination by reducing inflammation and modifying the immune response. In this
`category are interferon beta-lb, the first compound approved for use outside of clinical trials;
`interferon beta-la; and copolymer 1. Experimental agents include other interferons,
`methotrexate, linomide, monoclonal antibodies, T-cell receptor peptides, and 2-
`chlorodeoxyadenosine. Although they have been used effectively to treat exacerbations of MS,
`corticosteroids and corticotropin are now under evaluation as disease-modifying agents. A
`second strategy, enhancing remyelination by limiting demyelination and oligodendrocyte
`injury, is represented by protein growth factors. A third therapeutic approach, improving
`conduction in demyelinated fibers, is represented by the potassium channel blockers 4-
`aminopyridine and 3,4-diaminopyridine.
`
`MULTIPLE SCLEROSIS (MS) is a demyelinating
`disease of the central nervous system that is
`marked by focal or multifocal destruction of
`myelin sheaths accompanied by inflammation.
`Limited axonal destruction may also occur.
`Clinically, MS is characterized by recurrent
`attacks of neurologic dysfunction.
`From a pathophysiologic standpoint, MS
`can be identified by the presence of diffuse,
`discrete demyelinated areas, called plaques. As
`the disease progresses, plaques increasingly
`arise in the paraventricular areas of the cere(cid:173)
`brum, in the subpial area, and within the
`brain stem and spinal cord. A local breakdown
`of the blood-brain barrier occurs in areas of
`active lesions.'
`Although the etiology of MS remains
`unknown, epidemiologic studies suggest that
`both environmental and genetic factors play a
`role. 2 MS is now widely viewed as an autoim(cid:173)
`mune disease that develops early in life in the
`
`From the Division of Neurology, Maimonides Medical Center,
`Brooklyn, NY; and the Department of Neurology, State University
`of New York Health Science Center at Brooklyn.
`Supported by an unrestricted educational grant from Berlex
`L'lboratories, Richmond, Calif.
`Reprint requests to Aaron Miller, MD, Division of Neurology,
`Maimonides Medical Center, 4802 Tenth Ave, Brooklyn, NY
`11219.
`
`genetically susceptible person, perhaps after a
`viral infection initiates a T-cell-mediated
`immune response. 3
`Multiple sclerosis is usually classified accord(cid:173)
`ing to one of four recently standardized clini(cid:173)
`cal courses: relapsing-remitting, primary-pro(cid:173)
`gressive, secondary-progressive, or progressive(cid:173)
`relapsing.'1 In the relapsing-remitting form,
`which accounts for two thirds of cases at the
`onset of the disease, attacks occur randomly
`over many years. 5 The extent of recovery
`among patients and from attack to attack is
`variable, but permanent deficits can accrue
`with each exacerbation, especially later,in the
`course of the disease.;;.7 This neurologic deteri(cid:173)
`oration, which may still be punctuated by
`intermittent acute attacks, is classified as sec(cid:173)
`ondary-progressive, as opposed to primary(cid:173)
`progressive, and progressive-relapsing. These
`forms are progressive from the onset.'1
`
`EVALUATION OF DISEASE BURDEN
`Depending on the location of the lesions,
`signs and symptoms of MS may include vision
`disturbances, nystagmus, dysarthria, dimin(cid:173)
`ished perception of vibration and position
`sense, ataxia and intention tremor, weakness
`or paralysis of one or more limbs, spasticity,
`
`MIiier • MULTIPLE SCLEROSIS: ALTERING THE COURSE 367
`
`MERCK 2037
`HOPEWELL v MERCK
`IPR2023-00481
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`and bladder disorders. Neurologic abnormali(cid:173)
`ties that are highly suggestive of MS are optic
`neuritis, internuclear ophthalmoplegia, and
`Lhermitte's sign, which is often described as
`an electrical sensation that passes down the
`back and into the legs when the neck is
`flexed. 8
`Disability attributable to MS is usually mea(cid:173)
`sured by the Expanded Disability Status Scale
`(EDSS) developed by Kurtzke. 9 This system
`uses findings from a standard neurologic
`examination to establish a functional status
`score. Functional systems scores and gait then
`guide the evaluator in assessing clinical
`impairment with the EDSS, which defines dis(cid:173)
`ability in half-point increments ranging from 0
`(normal neurologic findings) to 10 (death
`due to MS).
`Magnetic resonance imaging (MRI) pro(cid:173)
`vides the most accurate assessment of disease
`burden, identifying multifocal cerebral white
`matter lesions in more than 90% of people
`with MS. 2 Even when there are no clinical
`signs, serial MRI studies of patients with
`relapsing-remitting MS can identify develop(cid:173)
`ing lesions. 2 In fact, it is now well established
`that new lesions as identified by MRI occur 5
`to 10 times more often than clinical changes. 10
`Recent refinements in MRI, such as gadolin(cid:173)
`ium enhancement, magnetization transfer,
`and magnetic resonance spectroscopy, have
`improved the sensitivity of detecting MS-asso(cid:173)
`ciated lesions. 11
`
`TREATMENT OF MULTIPLE SCLEROSIS
`Current therapy for MS includes relief of
`symptoms, amelioration of exacerbations, and
`reduction in the number of exacerbations and
`subsequent progression of neurologic disabil(cid:173)
`ity. Symptomatic treatment addresses both the
`physical and psychologic needs of the patient.
`It includes pharmacotherapy, diet, energy con(cid:173)
`servation, physical therapy, patient and family
`counseling, support groups, mechanical
`devices, and surgery. 12
`13 Exacerbations are usu(cid:173)
`•
`ally treated with corticosteroids or corti(cid:173)
`cotropin (ACTH), and administration of high
`doses of intravenous methylprednisolone
`(IVMP) has become particularly widely used. 13
`The third area of MS therapy, preventing
`exacerbations and progression of neurologic
`disability associated with the disease, has stim(cid:173)
`ulated various approaches. These can be
`grouped into three major categories: limiting
`demyelination by reducing inflammation and
`regulating the immune response, enhancing
`
`remyelination by limiting demyelination and
`oligodendrocyte injury, and improving con(cid:173)
`duction in demyelinated fibers.:1 The remain(cid:173)
`der of this review discusses each of these thera(cid:173)
`peutic strategies and the specific treatments
`that have been developed, or are in develop(cid:173)
`ment, in response to each approach.
`
`EFFORTS TO LIMIT DEMYELINATION
`Most pharmacologic treatments aimed at
`reducing or preventing exacerbations of MS
`and associated neurologic disability fall into
`the category of limiting demyelination by
`reducing inflammation and suppressing the
`immune response.3
`
`Interferon beta
`The first agent shown to alter the natural
`course of MS by reducing the frequency of
`clinical exacerbations is interferon beta-I b
`(IFNl3-lb [Betaseron]), a recombinant inter(cid:173)
`feron-beta produced in Escherichia coli. IFNl3-
`l b differs from natural interferon-13 in that it
`is not glycosylated and has serine substituted
`for the cysteine residue at• amino acid position
`17. It is indicated for use in ambulatory
`patients with relapsing-remitting MS to reduce
`the frequency of clinical exacerbations. 1
`1
`•
`Although the overall mechanisms by which
`IFNl3-lb exerts its actions are unknown, it is
`believed to bind to the same cell surface
`receptor as interferon-alpha and natural inter(cid:173)
`feron:-!3. 15 It induces the expression of a num(cid:173)
`ber of proteins, via transcription factors, that
`mediate its immunologic, antiproliferative,
`and antiviral effects. 16 The immunomodula(cid:173)
`tory effects ofIFNl3-lb are believed to play the
`major role in reducing the number and fre(cid:173)
`quency of exacerbations in patients with
`Ms.rn,11
`A double-blind, randomized, placebo-con(cid:173)
`trolled, multicenter phase III trial was con(cid:173)
`ducted in which 372 patients with relapsing(cid:173)
`remitting MS received placebo (n = 123) or
`either 1.6 million IU (n = 125) or 8 million IU
`(n = 124) of IFNl3-lb subcutaneously, every
`other day, for 2 years. 18
`19 Eligibility criteria
`•
`included clinically evident MS of at least 1
`year's duration and at least two exacerbations
`in the 2 years preceding the trial without an
`exacerbation in the preceding month. Other
`inclusion criteria were an EDSS score of 5.5 or
`less (ambulatory without aids) and clinically sta(cid:173)
`ble disease at study entry. Patients who had
`received previous immunosuppressant therapy
`were excluded, and those needing more than
`
`368 April 1997
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`three brief courses of corticosteroids during a
`12-month period were withdrawn from the
`study. At the end of 2 years, 80% of patients
`remaining in the study elected to continue
`treatment under double-blind conditions.
`Some patients were treated for as long as 5 ½
`years.
`After 2 years of treatment, the annual exac(cid:173)
`erbation rates in patients who received
`placebo or 1.6 million or 8 million IU IFN[3-lb
`were 1.27, 1.17, and 0.84 per year, respectively.
`The lower rate in the group given 8 million IU
`represents a 34% decrease from the placebo
`exacerbation rate and is highly significant
`(P = .0001). After 3 years, the exacerbation
`rate in the high-dose group (0.84) compared
`with that in the placebo group (1.21) was still
`significantly reduced (P= .0004). 18
`There was also a significant difference in
`the proportion of exacerbation-free patients
`among the treatment groups. After 2 years,
`the percentage of patients without exacerba(cid:173)
`tions in the 8 million IU IFN[3-1 b group
`(31 %) was almost twice that in the placebo
`group (16%) (P = .007). At 3 years, 22% of
`patients in the high-dose group were exacer(cid:173)
`bation free, compared with 14% in the
`placebo group, but the difference was no
`longer statistically significant (P= .097) .1
`K
`Serial annual MRis showed no significant
`progression in lesion burden in the 8 million
`IU IFNl3-l b group in each successive year,
`whereas there was a highly significant increase
`in lesion area in the placebo group
`(P= .0001) .19
`Of the 124 patients who received IFNl3-lb
`therapy at the recommended dose of 8 million
`IU every other day during clinical trials, 76%
`reported a flu-like symptom complex. H Over 3
`years, the incidence of these events declined,
`with only 4% of patients experiencing the
`complex during the last 6 months. Other com(cid:173)
`mon adverse clinical and laboratory events
`associated with IFN[3-lb therapy include injec(cid:173)
`tion site reactions and menstrual disorders.
`The former are generally mild, but in approxi(cid:173)
`mately 5% of patients, skin necrosis may
`occur. This has occasionally required surgical
`treatment. Absolute neutrophil count less
`than 1,500/mm3, white blood cell count less
`than 3,000/mm3, and AST and ALT levels
`greater than 5 times baseline value may occur
`on occasion. H Neutralizing antibodies to IFN[3-
`1 b developed in 27% of patients in the 8 mil(cid:173)
`lion IU group in year 1, 6% of patients in year
`
`2, and 2% in year 3; antibody positivity, which
`was sporadic in some patients and sustained in
`others, was associated with an increased exac(cid:173)
`e r ba ti on rate comparable to · that in the
`placebo group. rn
`The approval of IFN[3-lb has had a notice(cid:173)
`able effect on patients with MS and their fami(cid:173)
`lies, neurologists, and clinical investigators
`and has brought about a new sense of thera(cid:173)
`peutic optimism?>
`A second recombinant interferon-13, IFNl3-
`la (Avonex), a natural sequence, glycosylated
`IFN-13 produced in Chinese hamster ovary
`cells, is now marketed for the treatment of
`relapsing MS. IFN[3-la also has been tested in
`a phase III randomized, placebo-controlled,
`double-blind multicenter trial, in which 301
`patients received placebo (n = 143) or 6 mil(cid:173)
`lion IU IFN[3-la (n = 158) intramuscularly,
`once a week for 2 years. 21 In contrast to the
`IFNl3-lb phase III trial, the primary outcome
`measure in the IFNl3-la trial was progression
`of disability rather than exacerbation rate.
`Progression of disability was measured by the
`time taken for an increase to occur in the
`EDSS score of 1.0 unit above baseline persist(cid:173)
`ing for at least 6 months. Secondary outcome
`measures included time to first exacerbation,
`exacerbation rate, proportion of patients
`remaining exacerbation free, and change in
`disease burden as measured by MRl.21
`Time to sustained progression of disability
`was significantly greater in the IFNl3-la group
`than in the placebo group (P= .02) .21 The pro(cid:173)
`portion of patients with progression of disabil(cid:173)
`ity at 2 years was 21.9% in th~ IFN[3-la group
`compared with 34.9% in the placebo group. 21
`In addition, patients receiving IFNl3-la had
`one third fewer exacerbations and a signifi(cid:173)
`cant reduction in the number of lesions as
`detected by gadolinium (Gd)-enhanced MRI,
`as compared with placebo. 21
`As in the IFNl3-l b clinical trial, the most fre(cid:173)
`quent adverse effects in patients receiving
`IFNl3-la were flu-like symptoms, injection site
`reactions, and menstrual disorders. However,
`in contrast to IFNl3-lb, local skin irritation and
`necrosis do not occur. Serum neutralizing
`anti-IFN activity was observed in 14% of
`patients receiving IFNl3-la at week 52, in 21 %
`of patients at week 78, and in 22% of patients
`at week 104; the majority of patients remained
`positive for neutralizing activity on repeat test(cid:173)
`ing.21 It is not yet clear whether this will affect
`clinical efficacy.
`
`23
`•
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`Other Interferons
`Early clinical trials of both natural and
`recombinant IFN-a in patients with MS were
`not too promising. 17 This is surprising, since
`both IFN-13 and IFN-cx bind to the same cell
`surface receptor and have similar immunoreg(cid:173)
`ulatory functions. 16 It is possible that the rela(cid:173)
`tively small doses and the frequency and route
`of administration used in the early trials were
`suboptimal. A recent 6-month randomized,
`double-blind, placebo-controlled pilot trial
`involving 20 patients with relapsing-remitting
`MS had more promising results. 24 Patients
`receiving 9 million IU of IFNcx-2a (Roferon-A)
`intramuscularly every other day for 6 months
`had a significant reduction in exacerbation
`rate (P < .03), and a higher proportion
`remained exacerbation free (P < .02) com(cid:173)
`pared with the placebo group. In addition, the
`median time to first exacerbation was approxi(cid:173)
`mately twice as long in the IFNcx-2a group as
`in the placebo group ( 111 days versus 58
`days). 24 MRI studies done before and after
`treatment revealed only one active lesion in
`the IFNcx-2a group compared with 27 lesions
`in the placebo group-a significant difference
`(P< .01). Thus, the MRI data verified the clini(cid:173)
`cal information regarding the benefits of
`IFNcx-2a treatment.24
`As with all interferon compounds, IFNcx-2a
`caused moderate side effects, mainly a flu-like
`complex and some mild laboratory abnormali(cid:173)
`ties similar to those observed with IFNl3-la
`and IFNl3-l b. 19
`24 IFN--y has also been tested in
`21
`•
`•
`clinical trials of MS, but it causes significant
`increases in disease activity. 17
`
`Corticosteroids and Corticotropin
`These compounds are thought to exert
`their beneficial effect in MS by reducing
`abnormalities in the blood-brain barrier,
`decreasing edema, improving axonal conduc(cid:173)
`tion, reducing intrathecal immunoglobulin G
`synthesis, and inducing immunosuppression
`by the steroid-mediated blockade of cytokine
`gene expression. 20 Despite their established
`role in managing exacerbations of MS, the use
`of corticosteroids and corticotropin (ACTH)
`to prevent acute attacks and favorably alter dis(cid:173)
`ease progression· has not been thoroughly
`investigated.20 Early trials showed that neither
`low doses of oral prednisolone 25 nor intramus(cid:173)
`cular ACTH26 had any benefits after 18 months
`of treatment when compared with placebo.
`In one study, Compston and colleagues27
`concluded that a short course of high-dose
`
`IVMP, frequently used to treat the exacerba(cid:173)
`tions of MS, did not have a prolonged effect
`on the immunologic abnormalities associated
`with the disease and thus had no long-term
`therapeutic value in patients with relapsing(cid:173)
`remitting or chronic-progressive MS.
`However, a recent study by the Optic
`Neuritis Study Group to evaluate the effect of
`corticosteroid therapy on the development of
`definite MS in patients treated for optic neuri(cid:173)
`tis, often the first manifestation of MS, had a
`positive outcome.28 Within 2 years, definite MS
`developed in 7.5% of patients treated with
`1,000 mg of IVMP for 3 days and in 16.7% of
`those in the placebo group, a statistically sig(cid:173)
`nificant difference (P = .006) .28 Interestingly,
`the beneficial effect of IVMP occurred most in
`patients at greatest risk for developing clini(cid:173)
`cally definite MS, as judged by the multifocal
`lesions seen on their MRI scans. 28 This study
`may encourage clinicians to administer IVMP
`for the first episode of optic neuritis, or any
`other neurologic abnormality that might sig(cid:173)
`nal the onset of MS, in an attempt to favorably
`alter the course of the disease. 29 In patients
`whose MS has progressed further, cortico(cid:173)
`steroids may be most valuable when they are
`used in conjunction with other immunologic
`agents. 27 In patients with progressive MS,
`IVMP did not seem to affect the natural pro(cid:173)
`gression of the disease. 30
`In addition to this study, a 2-year clinical
`trial· comparing the relative benefits of
`bimonthly pulses of 10 mg versus 500 mg of
`IVMP is now in progress, and a separate study
`comparing the benefits of IVMP and IFNl3-lb
`is being planned.20 There is evidence from one
`study3° that 1,000 mg of IVMP daily for 10 con(cid:173)
`secutive days significantly reduced the relapse
`rate over an average of 2.6 years in patients
`with relapsing-remitting or progressive-relaps(cid:173)
`ing MS ( compared with rates 1 year before
`study entry [P< .0001]).
`
`Azathioprine
`Azathioprine, a purine analogue that sup(cid:173)
`presses cell-mediated hypersensitivity reactions
`and alters antibody production,20 has been used
`in clinical trials of patients with MS. Results of
`22 such trials have been published.20 Seven of
`these, two single-blind and five double-blind
`studies, were reviewed in a meta-analysis by
`Yudkin et al. 31 This analysis evaluated data from
`793 patients with relapsing-remitting, progres(cid:173)
`sive, or progressive-relapsing MS, 459 of whom
`had been treated for at least 3 years. 31 Mean
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`changes in Kurtzke disability scores, reported in
`six of the trials, indicated increased neurologic
`impairment after 1, 2, and 3 years; although the
`degree of neurologic impairment was less than
`that observed in the control groups, it was not
`statistically significant. 31 Azathioprine signifi(cid:173)
`cantly reduced the risk of relapse, and the
`probability of remaining disease free was 1.51,
`2.04, and 1.97 times greater after 1, 2, and 3
`years, respectively. However, adverse effects
`were common in treated patients and included
`leukopenia, anorexia, diarrhea, vomiting,
`abdominal pain and other gastrointestinal dis(cid:173)
`turbances, abnormal liver function, and skin
`rash. 31 Despite lingering concerns that cancer
`may develop after long-term administration,
`this association has not been substantiated.32
`Although azathioprine remains an investiga(cid:173)
`tional agent for the treatment of MS and its
`clinical benefit appears to be modest, it is the
`most commonly used form of immunosup(cid:173)
`pressant therapy for this disease.20 It is proba(cid:173)
`ble that azathioprine will continue to have a
`limited role in the management of patients
`with MS because of its relatively acceptable
`toxicity, favorable cost, and comparative ease
`of administration.20
`
`Cyclophosphamide
`Administration of cyclophosphamide, an
`alkylating agent with cytotoxic as well as
`immunosuppressive effects, reduces the num(cid:173)
`bers of helper T cells and suppressor T cells.
`This reduction is more pronounced in the for(cid:173)
`mer. 2°
`Many trials have confirmed that the clinical
`benefits of cyclophosphamide therapy for MS
`are restricted to the short term and are mar(cid:173)
`ginal at best, with toxicity being a major prob(cid:173)
`lem.20 Acute toxicity includes nausea and vom(cid:173)
`iting, alopecia, hemorrhagic cystitis, and
`myelosuppression, whereas long-term toxicity
`may involve induction of leukemia or bladder
`cancer. Accordingly, cyclophosphamide is an
`unlikely candidate for long-term therapy for
`patients with MS. 33
`34 However, a recent study in
`•
`which patients with MS were given pulse IV
`cyclophosphamide therapy in combination
`with monthly IVMP suggested a clinical bene(cid:173)
`fit due to a shift from a Thl-type to a Th2-type
`cytokine profile (IFN--y, lymphotoxin versus
`IL-4, IL-5).35
`
`Cyclosporine
`• Cyclosporine ( cyclosporin A), which is
`widely used to prevent graft rejection after
`
`organ transplantation, is an immunosuppres(cid:173)
`sive agent with a relatively specific, but
`reversible, inhibitory effect on helper T
`cells. 7
`36 Since preliminary reports have shown
`•
`that cyclosporine can modify the course of
`experimental allergic encephalomyelitis in
`animals and may have value in the treatment
`of other autoimmune diseases in humans, its
`possibl_e therapeutic role in MS has been inves(cid:173)
`tigated.36
`The Multiple Sclerosis Study Group con(cid:173)
`ducted a placebo-controlled, double-blind
`trial of 554 patients wi_th progressive MS in
`which 273 patients received a daily dose of
`oral cyclosporine for 2 years.36 Patients in the
`treatment group had a statistically significant
`delay in disease progression, but the clinical
`effects of treatment were slight. Furthermore,
`the nephrotoxicity and hypertensive effects of
`the drug outweighed its benefits. Adverse
`effects were also a cause for concern in a mul(cid:173)
`ticen ter, double-blind, randomized trial of
`cyclosporine versus azathioprine involving 194
`patients, the majority of whom had relapsing(cid:173)
`remitting MS. 37 No significant differences in
`exacerbation rates or disability progression
`were shown ove~_gyears, and more than twice
`as many side effects were reported in the
`cyclosporine group as in the azathioprine
`group.
`
`Methotrexate
`Because of its anti-inflammatory and im(cid:173)
`munomodulatory actions, in addition to its
`beneficial effect in rheumatoid arthritis,
`another autoimmune disease, methotrexate is
`now under investigation for the treatment of
`progressive MS. 38 In a double-blind, placebo-•
`controlled phase II study, 60 patients with an
`EDSS score of 3.0 to 6.5 received weekly
`placebo or 7.5 mg of oral methotrexate. A com(cid:173)
`posite of outcome measures reflecting both
`upper and lower extremity function was used to
`measure efficacy of treatment. At the end of
`the 2-year study period, progression of neuro(cid:173)
`logic impairment was significantly less in the
`group given methotrexate (P = .011), and
`adverse effects were minimal. 38
`
`Roquinimex
`The synthetic immunomodulator roquin(cid:173)
`imex (Linomide) has shown promise in
`patients with relapsing-progressive MS.
`Roquinimex increases natural killer cell activ(cid:173)
`ity and stimulates other lymphocyte subpopu(cid:173)
`lations.39 It also interferes with antigen presen-
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`tation, inhibiting T-cell activation early
`enough so that induction of generalized
`immunosuppression does not occur. 39 Because
`roquinimex was extremely effective in limiting
`the clinical and pathologic signs of experi(cid:173)
`mental allergic encephalomyelitis in mice, a
`recent double-blind, placebo-controlled study
`involving 30 patients with relapsing-progres(cid:173)
`sive MS (EDSS scores of 3.0 to 7.0) was done.
`Patients received either 2.5 mg of roquinimex
`per day or placebo orally and had follow-up
`for 6 to 12 months, with monthly Tl Gd(cid:173)
`enhanced and T2 MRI. Initial reports showed
`that after 6 months of treatment, patients
`receiving roquinimex had a significant favor-
`---able change in their EDSS score (P < .036)
`and significantly fewer new enhancing lesions
`(P< .021) than patients who received placebo.
`Side effects were mild and included myalgia,
`arthralgia, and edema. 39 A large, multicenter
`phase III trial in patients with progressive MS
`was begun in 1996.
`
`Copolymer 1
`Copolymer 1 (COP l, Copaxone) is a syn(cid:173)
`thetic polypeptide composed of L-alanine,
`L-glutamic acid, L-lysine, and L-tyrosine, amino
`acids commonly found in myelin basic protein
`(MBP) .4° COP 1 is a mixture of polymers, the
`sequence and length of which vary randomly.
`It was originally developed as an MBP ana(cid:173)
`logue, and like MBP itself, COP 1 inhibits
`experimental allergic encephalomyelitis in sev(cid:173)
`eral mammalian species.
`In a double-blind, placebo-controlled pilot
`trial, 50 patients with relapsing-remitting MS
`self-injected 20 mg of COP 1 or placebo sub-
`. cutaneously daily for 2 years. Over the 2 years,
`an average of 2.7 exacerbations occurred per
`patient in the placebo group and an average
`of 0.6 in the COP 1 group.41
`COP 1 has recently been under evaluation in
`an 11-center, phase III double-blind clinical
`trial in the United States, involving 251 patients
`with relapsing-remitting MS. Results indicate a
`significant reduction of 29% in the exacerba(cid:173)
`tion rate over the 2 years of study in the COP
`I-treated patients compared with that in the
`placebo-treated patients (P = .007). 42 The
`median time to first relapse was longer in COP
`I-treated patients (287 days) than in placebo(cid:173)
`treated patients (198 days), and the percentage
`of COP I-treated patients· remaining exacerba(cid:173)
`tion free was higher than that of placebo(cid:173)
`treated patients (33.6% vs 27.0%); these last
`results approached statistical significance.42 Like
`
`the earlier pilot trial, the therapeutic effect of
`COP 1 appeared to be more pronounced in
`patients with minimal disability (EDSS score of
`0 to 2). Also, in both trials irritation at the injec(cid:173)
`tion site and rare transient reactions character(cid:173)
`ized by chest tightness or flushing combined, at
`times, with dyspnea, palpitations, or anxiety
`were the only side effects noted.41 •'12
`
`Monoclonal Antibodies
`The use of lymphocytotoxic monoclonal
`antibodies against specific T-cell subpopula(cid:173)
`tions in patients with MS is another promising
`avenue of therapy. Two types of monoclonal
`antibody are under investigation: humanized
`and chimeric. In humanized monoclonal anti(cid:173)
`bodies, only the complementary determining
`regions (also known as hypervariable regions) .
`are nonhuman; in chimeric monoclonal anti(cid:173)
`bodies, the complete Fab portion is nonhu(cid:173)
`man and has been fused onto a human Fe por(cid:173)
`tion. 43 It is believed that these antibodies will
`be less immunogenic than complete mouse
`monoclonal antibodies and thus can be used
`repeatedly in patients to reduce the activity of
`specific lymphocyte populations. In prelimi(cid:173)
`nary studies using the humanized antibody
`CAMPATH-lH, which is directed against the
`lymphocyte surface antigen CDw52, 44 seven
`ambulatory patients with chronic-progressive
`MS had rapid and profound lymphopenia. 43
`Gadolinium-enhanced MRI showed a substan(cid:173)
`tial reduction in new lesion formation,
`although some active lesions found at the start
`of treatment continued to develop for approx(cid:173)
`imately 3 months. Several patients had tran(cid:173)
`sient but marked neurologic changes, includ(cid:173)
`ing deterioration in vision, inability to walk,
`and bilateral internuclear ophthalmoplegia.
`These temporary effects were attributable to
`substantially increased levels of circulating
`tumor necrosis factor-a, interferon--y, and
`interleukin-6; values returned to normal
`within 18 hours.
`The potentially hazardous effects of CAM(cid:173)
`PATH-lH on the immune system indicate that
`this particular form of monoclonal antibody
`therapy should be regarded only as a clinical
`experiment. 43 However, it is likely that investi(cid:173)
`gation of monoclonal antibody therapy for MS
`will continue.43
`
`T-Cell Receptor Peptides
`Studies in rodents have shown that vaccina(cid:173)
`tion with attenuated encephalitogenic T cells
`specific for MBP induces cell-mediated protec-
`
`372 April 1997
`
`• SOUTHERN MEDICAL JOURNAL • Vol. 90, No. 4
`
`

`

`ReprintsDesk | 3/16/2023 8:13:03 PM
`
`tion against experimental allergic enceph(cid:173)
`alomyelitis. Moreover, experimental allergic
`encephalomyelitis can be treated and pre(cid:173)
`vented by vaccination of the animals with cer(cid:173)
`tain peptides from the antigen-recognizing
`portion of T-cell receptors (TCRs) expressed
`by MBP-specific T cells. 45
`These results have led to a recently reported
`double-blind, placebo-controlled pilot study to
`evaluate the clinical and immunologic effects
`ofTCR peptide vaccination in 23 patients with
`progressive MS. A native peptide (n = 8) with
`the Vf35.2 sequence expressed in MS plaques
`and on MBP-specific T cells and a substituted
`peptide (n = 9) were tested. Treatment con(cid:173)
`sisted of 100 µg of peptide or placebo adminis(cid:173)
`tered weekly for 4 weeks, then monthly for an
`additional 10 months, by intradermal injec(cid:173)
`tion. Response to vaccination, defined as
`increased frequency of TCR peptide-reactive T
`cells, was accompanied by decreased fre(cid:173)
`quency of MBP-specific T cells (P< .001); 6 of
`the 17 peptide recipients responded to vacci(cid:173)
`nation, 1 in response to the native peptide and
`5 in response to the substituted peptide. All 6
`vaccine responders remained clinically stable
`or showed improvement over the course of
`the trial, without any reported side effects; in
`contrast, 10 of the 17 nonresponders receiving
`either peptide or placebo progressed clinically
`(P = .019). Further study of the TCR peptide
`vaccination approach and development of
`more sensitive techniques may enable more
`widespread application to MS as well as other
`tissue-specifi~ autoimmune diseases involving
`T cells. 45
`
`Cladribine
`The highly specific antilymphocyte/anti(cid:173)
`monocyte immunosuppressive nucleoside,
`cladribine (2-chlorodeoxyadenosine [2-CdA]),
`has been shown in preliminary investigations
`to have potential value in altering the clinical
`course of chronic-progressive MS. 46 In a dou(cid:173)
`ble-blind, placebo-controlled study, 49 patients
`received 7-day infusions of 2-CdA (0.1 mg/kg)
`or saline infusions monthly for 4 months.
`After 1 year, there was a significant difference
`in the mean change in EDSS scores between
`the two groups (P= .003). As measured by
`MRI, total lesion burden after 1 year was also
`significantly less in the 2-CdA group than in
`the placebo group (P = .003) .46 After 2 years,
`the number of active lesions was markedly
`reduced in the 2-CdA group to almost zero. 47
`Bone marrow suppression was observed in
`
`some patients who received 2-CdA, and signifi(cid:173)
`cant thrombocytopenia developed in a few.
`Two cases of herpes zoster also occurred in
`the cladribine group. 46
`
`NONPHARMACOLOGIC INTERVENTIONS
`Although this review focuses on pharma(cid:173)
`cotherapy, several nonpharmacologic treat(cid:173)
`ments intended to limit demyelination have
`also been investigated and are noted briefly
`here.
`Total lymphoid irradiation (TLI), generally
`considered a relatively safe method for achiev(cid:173)
`ing sustained immunosuppression, temporarily
`interrupted disease progression in patients with
`progressive MS, but deterioration resumed at a
`median of 3 years after treatment.48
`A recent study suggests that TLI in combi(cid:17