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`Merck 2037
`Hopewell v Merck
`IPR2023-00480
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`ReprintsDesk | 3/16/2023 8:13:03 PM
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`&
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`and bladder disorders. Neurologic abnormalli-
`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.’
`Disability attributable to MS is usually mea-
`sured by the Expanded Disability Status Scale
`(EDSS) developed by Kurtzke.’ 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-
`ability in halfpoint increments ranging from 0
`(normal neurologic findings) to 10 (death
`due to MS).
`Magnetic resonance imaging (MRI) pro-
`vides the most accurate assessment of disease
`‘burden, identifying multifocal cerebral white
`matter lesions in more than 90% of people
`with MS.? Even when there are no clinical
`signs, serial MRI studies of patients with
`relapsing-remitting MS can identify develop-
`ing lesions.” In fact, it is now well established
`that new lesions as identified by MRI occur 5
`to 10 times more often than clinical changes."
`Recent refinements in MRI, such as gadolin-
`ium enhancement, magnetization transfer,
`and magnetic resonance spectroscopy, have
`improved the sensitivity of detecting MS-asso-
`ciated lesions.!!
`
`TREATMENT OF MULTIPLE SCLEROSIS
`Current therapy for MS includesrelief of
`symptoms, amelioration of exacerbations, and
`reduction in the numberof exacerbations and
`subsequent progression of neurologic disabil-
`ity. Symptomatic treatment addresses both the
`physical and psychologic needs of the patient.
`It includes pharmacotherapy, diet, energy con-
`servation, physical therapy, patient and family
`counseling, support groups, mechanical
`devices, and surgery.’*"* Exacerbations are usu-
`ally treated with corticosteroids or corti-
`cotropin (ACTH), and administration of high
`doses of intravenous methylprednisolone
`(IVMP) has becomeparticularly widely used."
`The third area of MS therapy, preventing
`exacerbations and progression of neurologic
`disability associated with the disease, has stim-
`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-
`duction in demyelinated fibers.’ The remain-
`der of this review discusses each of these thera-
`peutic strategies and the specific treatments
`that have been developed, or are in develop-
`ment, in response to each approach.
`EFFORTSTO 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.°
`
`Interferon beta
`The first agent shown to alter the natural
`course of MS by reducing the frequency of
`clinical exacerbations is interferon beta-1b
`(IFNB-1b [Betaseron]), a recombinant inter-
`feron-beta produced in Escherichia coli. IFNB-
`lb differs from natural interferon-B in thatit
`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."
`Although the overall mechanisms by which
`IFN6-lb exerts its actions are unknown, it is
`believed to bind to the same cell surface
`receptor as interferon-alpha and natural inter-
`feron-f8." It induces the expression of a num-
`ber of proteins, via transcription factors, that
`mediate its immunologic, antiproliferative,
`and antiviral effects." The immunomodula-
`tory effects of IFNB-1b are believed to play the
`major role in reducing the numberand fre-
`quency of exacerbations in patients with
`MS.,!617
`A double-blind, randomized, placebo-con-
`trolled, multicenter phase III trial was con-
`ducted in which 372 patients with relapsing-
`remitting MS received placebo (n = 123) or
`either 1.6 million IU (n = 125) or 8 million IU
`(n = 124) of IFN®-1b subcutaneously, every
`other day, for 2 years.'*"® Eligibility criteria
`included clinically evident MS of at least 1
`year’s duration and at least two exacerbations
`in the 2 years precedingthetrial without an
`exacerbation in the preceding month. Other
`inclusion criteria were an EDSS score of 5.5 or
`less (ambulatory withoutaids) and clinically sta-
`ble disease at study entry. Patients who had
`received previous immunosuppressant therapy
`were excluded, and those needing more than
`
`368 April1997 »* SOUTHERN MEDICAL JOURNAL © Vol. 90, No. 4
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`three brief courses of corticosteroids during a
`2, and 2% in year 3; antibody positivity, which
`12-month period were withdrawn from the
`was sporadic in somepatients and sustained in
`study. At the end of 2 years, 80% of patients
`others, was associated with an increased exac-
`remaining in the study elected to continue
`erbation rate comparable to-that in the
`treatment under double-blind conditions.
`placebo group."
`Some patients were treated for as long as 5%
`The approval of IFNB-1b has had a notice-
`years.
`able effect on patients with MSandtheir fami-
`After 2 years of treatment, the annual exac-
`lies, neurologists, and clinical investigators
`erbation rates in patients who received
`and has brought about a new sense of thera-
`placebo or 1.6 million or 8 million IU IFNB-1b
`peutic optimism.”
`were 1.27, 1.17, and 0.84 peryear, respectively.
`A second recombinantinterferon-8, IFNB-
`Thelowerrate in the group given 8 million IU
`la (Avonex), a natural sequence, glycosylated
`represents a 34% decrease from the placebo
`IFN-8 produced in Chinese hamster ovary
`exacerbation rate and is highly significant
`cells, is now marketed for the treatment of
`(P= .0001). After 3 years, the exacerbation
`relapsing MS. IFNB-la also has been tested in
`rate in the high-dose group (0.84) compared
`a phase III randomized, placebo-controlled,
`with that in the placebo group (1.21) wasstill
`double-blind multicenter trial, in which 301
`significantly reduced (P= .0004)."
`patients received placebo (n = 143) or 6 mil-
`There was also a significant difference in
`lion IU IFNB-la (n = 158) intramuscularly,
`the proportion of exacerbation-free patients
`once a weekfor 2 years.” In contrast to the
`among the treatment groups. After 2 years,
`IFNB-1b phase III trial, the primary outcome
`the percentage of patients without exacerba-
`measure in the IFNf-la trial was progression
`tions in the 8 million IU IFN®-1b group
`of disability rather than exacerbationrate.
`(31%) was almost twice that in the placebo
`Progression of disability was measured by the
`group (16%) (P= .007). At 3 years, 22% of
`time taken for an increase to occur in the
`patients in the high-dose group were exacer-
`EDSSscore of 1.0 unit above baseline persist-
`bation free, compared with 14% in the
`ing for at least 6 months. Secondary outcome
`placebo group, but the difference was no
`measures included timeto first exacerbation,
`longerstatistically significant (P= .097)."
`exacerbation rate, proportion of patients
`Serial annual MRIs showed nosignificant
`remaining exacerbation free, and change in
`progression in lesion burden in the 8 million
`disease burden as measured by MRI.”
`IU IFNB-1b group in each successive year,
`Time to sustained progression of disability
`whereas there was a highlysignificant increase
`wassignificantly greater in the IFNB-la group
`in lesion area in the placebo group
`than in the placebo group (P= .02)."! The pro-
`(P= .0001)."
`portion of patients with progression of disabil-
`ity at 2 years was 21.9% in the IFN6-la group
`Of the 124 patients who received IFNB-1b
`compared with 34.9% in the placebo group.”
`therapy at the recommendeddoseof 8 million
`In addition, patients receiving IFNB-la had
`IU every other day duringclinicaltrials, 76%
`one third fewer exacerbations andasignifi-
`reportedaflu-like symptom complex." Over 3
`cant reduction in the numberoflesions as
`years, the incidence of these events declined,
`with only 4% of patients experiencing the
`detected by gadolinium (Gd)-enhanced MRI,
`complex during the last 6 months. Other com-
`as comparedwith placebo.”
`mon. adverse clinical and laboratory events
`As in the IFN6-1b clinical trial, the mostfre-
`associated with IFNB-1b therapy include injec-
`quent adverse effects in patients receiving
`tion site reactions and menstrual disorders.
`IFNB-la were flu-like symptoms, injection site
`The formerare generally mild, but in approxi-
`reactions, and menstrual disorders. However,
`mately 5% of patients, skin necrosis may
`in contrast to IFNB-1b,local skin irritation and
`occur. This has occasionally required surgical
`necrosis do not occur. Serum neutralizing
`treatment. Absolute neutrophil count less
`anti-IFN activity was observed in 14% of
`than 1,500/mm', white blood cell countless
`patients receiving IFNB-la at week 52, in 21%
`than 3,000/mm*, and AST and ALT levels
`of patients at week 78, and in 22% ofpatients
`greater than 5 times baseline value may occur
`at week 104; the majority of patients remained
`on occasion." Neutralizing antibodies to IFNB-
`positive for neutralizing activity on repeattest-
`lb developed in 27% of patients in the 8 mil-
`ing.”' It is not yet clear whetherthis will affect
`lion IU groupin year 1, 6% of patients in year
`clinical efficacy.
`;
`
`Miller
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`IVMP, frequently used to treat the exacerba-
`Other Interferons
`tions of MS, did not have a prolonged effect
`Early clinical trials of both natural and
`on the immunologic abnormalities associated
`recombinant JFN-« in patients with MS were
`with the disease and thus had:no long-term
`not too promising.” This is surprising, since
`therapeutic value in patients with relapsing-
`both IFN-8 and IFN-a bind to the samecell
`remitting or chronic-progressive MS.
`surface receptor and have similar immunoreg-
`ulatory functions." It is possible that the rela-
`However, a recent study by the Optic
`tively small doses and the frequency and route
`Neuritis Study Group to evaluate the effect of
`corticosteroid therapy on the developmentof
`of administration used in the early trials were ©
`suboptimal. A recent 6-month randomized,
`definite MS in patients treated for optic neuri-
`double-blind, placebo-controlled pilot trial
`tis, often the first manifestation of MS, had a
`involving 20 patients with relapsing-remitting
`positive outcome.” Within 2 years, definite MS
`developed in 7.5% of patients treated with
`MS had more promising results.* Patients
`1,000 mg of IVMP for 3 days and in 16.7% of
`receiving 9 million IU of IFNa-2a (Roferon-A)
`intramuscularly every other day for 6 months
`those in the placebo group,a statistically sig-
`had a significant reduction in exacerbation
`nificant difference (P = .006).* Interestingly,
`rate (P< .03), and a higher proportion
`the beneficial effect of 'VMP occurred most in
`remained exacerbation free (P< .02) com-
`patients at greatest risk for developing clini-
`pared with the placebo group.In addition, the
`cally definite MS, as judged by the multifocal
`median time to first exacerbation was approxi-
`lesions seen on their MRI scans.* This study
`mately twice as long in the IFNa-2a group as
`may encourage clinicians to administer IVMP
`in the placebo group (111 days versus 58
`for the first episode of optic neuritis, or any
`days).** MRI studies done before and after
`other neurologic abnormality that might sig-
`treatment revealed only one active lesion in
`nal the onset of MS,in an attemptto favorably
`the IFNa-2a group compared with 27 lesions
`alter the course of the disease.” In patients
`in the placebo group—asignificant difference
`whose MS has progressed further, cortico-
`(P< .01). Thus, the MRI data verified the clini-
`steroids may be most valuable when they are
`cal information regarding the benefits of
`used in conjunction with other immunologic
`IFNa-2a treatment.”
`agents.”’ In patients with progressive MS,
`IVMP did not seem to affect the natural pro-
`As with all interferon compounds, IFNa-2a
`gression of the disease.”
`caused moderate side effects, mainlyaflu-like
`complex and some mild laboratory abnormali-
`In addition to this study, a 2-year clinical
`ties similar to those observed with IFNB-la
`trial comparing the relative benefits of
`and IFNB-1b.'?!4 JFN-y has also been tested in
`bimonthly pulses of 10 mg versus 500 mg of
`clinical trials of MS, but it causes significant
`IVMPis now in progress, and a separate stud
`increases in disease activity.”
`comparing the benefits of IVMP and IFNB-1b
`is being planned.” There is evidence from one
`study” that 1,000 mg of IVMP daily for 10 con-
`secutive days significantly reduced the relapse
`rate over an average of 2.6 years in patients
`with relapsing-remitting or progressive-relaps-
`ing MS (compared with rates | year before
`study entry [P< .0001]).
`
`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-
`tion, reducing intrathecal immunoglobulin G
`synthesis, and inducing immunosuppression
`by the steroid-mediated blockade of cytokine
`gene expression.” Despite their established
`role in managing exacerbationsof MS,the use
`of corticosteroids and corticotropin (ACTH)
`to prevent acute attacks and favorably alter dis-
`ease progression: has not been thoroughly
`investigated.” Early trials showed that neither
`low doses of oral prednisolone” nor intramus-
`cular ACTH®had any benefits after 18 months
`of treatment when compared with placebo.
`In one study, Compston and colleagues”’
`concluded that a short course of high-dose
`
`370 April 1997 * SOUTHERN MEDICAL JOURNAL » Vol. 90, No. 4
`
`Azathioprine
`Azathioprine, a purine analogue that sup-
`presses cell-mediated hypersensitivity reactions
`and alters antibody production,” has been used
`in clinical trials of patients with MS. Results of
`22 such trials have been published.” Seven of
`these, two single-blind and five double-blind
`studies, were reviewed in a meta-analysis by
`Yudkin et al.”' This analysis evaluated data from
`793 patients with relapsing-remitting, progres-
`sive, or progressive-relapsing MS, 459 of whom
`had been treated for at least 3 years.*) Mean
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`&
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`changesin Kurtzke disability scores, reported in
`six of the trials, indicated increased neurologic
`impairmentafter 1, 2, and 3 years; although the
`degree of neurologic impairmentwas less than
`that observed in the control groups, it was not
`statistically significant." Azathioprinesignifi-
`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-
`turbances, abnormal liver function, and skin
`rash.*! Despite lingering concerns that cancer
`may develop after long-term administration,
`this association has not been substantiated.”
`Although azathioprine remains an investiga-
`tional agent for the treatment of MS andits
`clinical benefit appears to be modest, it is the
`most commonly used form of immunosup-
`pressant therapy for this disease.” It is proba-
`ble that azathioprine will continue to have a
`limited role in the management of patients
`with MS becauseof its relatively acceptable
`toxicity, favorable cost, and comparative ease
`of administration.”
`
`Cyclophosphamide
`Administration of cyclophosphamide, an
`alkylating agent with cytotoxic as well as
`immunosuppressive effects, reduces the num-
`bers of helper T cells and suppressor T cells.
`This reduction is more pronouncedin the for-
`mene
`Manytrials have confirmed thattheclinical
`benefits of cyclophosphamide therapy for MS
`are restricted to the short term and are mar-
`ginal at best, with toxicity being a major prob-
`lem.” Acute toxicity includes nausea and vom-
`iting, alopecia, hemorrhagic cystitis, and
`myelosuppression, whereas long-term toxicity
`may involve induction of leukemia or bladder
`cancer, Accordingly, cyclophosphamideis an
`unlikely candidate for long-term therapy for
`patients with MS.*** However,a recent study in
`which patients with MS were given pulse IV
`cyclophosphamide therapy in combination
`with monthly IVMP suggested a clinical bene-
`fit due to a shift from a Thl-type to a Th2-type
`cytokine profile (IFN-y, lymphotoxin versus
`IL-4, IL-5).
`
`Cyclosporine
`‘Cyclosporine (cyclosporin A), which is
`widely used to prevent graft rejection after
`
`organ transplantation, is an immunosuppres-
`sive agent with a relatively specific, but
`reversible, inhibitory effect on helper T
`cells." 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 autoimmunediseases in humans,its
`possible therapeutic role in MS has been inves-
`tigated.”
`The Multiple Sclerosis Study Group con-
`ducted a placebo-controlled, double-blind
`trial of 554 patients with progressive MS in
`which 273 patients received a daily dose of
`oral cyclosporine for 2 years.Patients in the
`treatment group hada statistically significant
`delay in disease progression, but the clinical
`effects of treatment wereslight. Furthermore,
`the nephrotoxicity and hypertensive effects of
`the drug outweighed its benefits. Adverse
`effects were also a cause for concern in a mul-
`ticenter, double-blind, randomizedtrial of
`cyclosporine versus azathioprine involving 194
`patients, the majority of whom hadrelapsing-
`remitting MS.” Nosignificant differences in
`exacerbation rates or disability progression
`were shown over 2years, and more than twice
`as many side effects were reported in the
`cyclosporine group as in the azathioprine
`group.
`
`Methotrexate
`Becauseofits anti-inflammatory and im-
`munomodulatory actions, in addition to its
`beneficial effect in rheumatoid arthritis,
`another autoimmunedisease, methotrexate is
`now underinvestigation for the treatment of
`progressive MS.™ In a double-blind, placebo-.
`controlled phase II study, 60 patients with an
`EDSSscore of 3.0 to 6.5 received weekly
`placebo or 7.5 mg of oral methotrexate. A com-
`posite of outcome measuresreflecting both
`upperandlower extremity function was used to
`measure efficacy of treatment. At the end of
`the 2-year study period, progression of neuro-
`logic impairment wassignificantly less in the
`group given methotrexate (P= .011), and
`adverse effects were minimal.*
`
`Roquinimex
`The synthetic immunomodulator roquin-
`imex (Linomide) has shown promise in
`patients with relapsing-progressive MS.
`Roquinimex increases natural killer cell activ-
`ity and stimulates other lymphocyte subpopu-
`lations.”It also interferes with antigen presen-
`
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`the earlier pilot trial, the therapeutic effect of
`COP 1 appeared to be more pronouncedin
`patients with minimal disability (EDSS score of
`0 to 2). Also, in both trials irritation at the injec-
`tion site and rare transient reactions character-
`ized by chest tightness or flushing combined,at
`times, with dyspnea, palpitations, or anxiety
`were the only side effects noted."
`
`tation, inhibiting T-cell activation early
`enough so that induction of generalized
`immunosuppression does not occur.” Because
`roquinimex was extremely effective in limiting
`the clinical and pathologic signs of experi-
`mental allergic encephalomyelitis in mice, a
`recent double-blind, placebo-controlled study
`involving 30 patients with relapsing:progres-
`sive MS (EDSSscoresof 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 T1 Gd-
`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 enhancinglesions
`(P< .021) than patients who received placebo.
`Side effects were mild and included myalgia,
`arthralgia, and edema.” A large, multicenter
`phaseIII trial in patients with progressive MS
`was begun in 1996.
`
`Monoclonal Antibodies
`The use of lymphocytotoxic monoclonal
`antibodies against specific T-cell subpopula-
`tionsin patients with MSis another promising
`avenue of therapy. Two types of monoclonal
`antibody are underinvestigation: humanized
`and chimeric. In humanized monoclonalanti-
`bodies, only the complementary determining
`regions (also known as hypervariable regions) .
`are nonhuman; in chimeric monoclonal anti-
`bodies, the complete Fab portion is nonhu-
`man and has been fused onto a humanFc por-
`tion.” It is believed that these antibodieswill
`be less immunogenic than complete mouse
`Copolymer 1
`monoclonal antibodies and thus can be used
`Copolymer 1 (COP 1, Copaxone) is a syn-
`repeatedly in patients to reducethe activity of
`thetic polypeptide composed of L-alanine,
`specific lymphocyte populations. In prelimi-
`L-glutamic acid, L-lysine, and L-tyrosine, amino
`nary studies using the humanized antibody
`acids commonly found in myelin basic protein
`CAMPATH-1H, which is directed against the
`(MBP). COP 1 is a mixture of polymers, the
`lymphocyte surface antigen CDw52,** seven
`sequence and length of which vary randomly.
`ambulatory patients with chronic-progressive
`It was originally developed as an MBP ana-
`MS had rapid and profound lymphopenia.*
`logue, and like MBPitself, COP 1 inhibits
`Gadolinium-enhanced MRI showed a substan-
`experimental allergic encephalomyelitis in sev-
`tial reduction in new lesion formation,
`eral mammalian species.
`although someactive lesions foundat the start
`In a double-blind, placebo-controlled pilot
`of treatment continued to develop for approx-
`trial, 50 patients with relapsing-remitting MS
`imately 3 months. Several patients had tran-
`self-injected 20 mg of COP 1 or placebo sub-
`sient but marked neurologic changes, includ-
`‘ cutaneously daily for 2 years. Over the 2 years,
`ing deterioration in vision, inability to walk,
`an average of 2.7 exacerbations occurred per
`and bilateral internuclear ophthalmoplegia.
`patient in the placebo group and an average
`These temporary effects were attributable to
`of 0.6 in the GOP 1 group."!
`substantially increased levels of circulating
`COP 1 has recently been underevaluation in
`tumor necrosis factor-a, interferon-y, and
`an 1l1-center, phase III double-blind clinical
`interleukin-6; values returned to normal
`trial in the United States, involving 251 patients
`within 18 hours.
`with relapsing-remitting MS. Results indicate a
`The potentially hazardous effects of CAM-
`significant reduction of 29% in the exacerba-
`PATH-1H on the immunesystem indicate that
`tion rate over the 2 years of study in the COP
`this particular form of monoclonal antibody
`1-treated patients compared with that in the
`therapy should be regarded only asaclinical
`placebo-treated patients (P = .007).# The
`experiment.” However,it is likely that investi-
`median timeto first relapse was longer in COP
`gation of monoclonalantibody therapy for MS
`1-treated patients (287 days) than in placebo-
`will continue.*
`treated patients (198 days), and the percentage
`of COP 1-treated patients remaining exacerba-
`tion free was higher than that of placebo-
`treated patients (33.6% vs 27.0%); these last
`results approachedstatistical significance.® Like
`
`T-Cell Receptor Peptides
`Studies in rodents have shownthat vaccina-
`tion with attenuated encephalitogenic T cells
`specific for MBP inducescell-mediated protec-
`
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`tion against experimental allergic enceph-
`some patients who received 2-CdA,andsignifi-
`alomyelitis. Moreover, experimentalallergic
`cant thrombocytopenia developed in a few.
`encephalomyelitis can be treated and pre-
`Two cases of herpes zoster also occurred in
`vented by vaccination of the animals with cer-
`the cladribine group.”
`tain peptides from the antigen-recognizing
`NONPHARMACOLOGIC INTERVENTIONS
`portion of T-cell receptors (T'CRs) expressed
`Although this review focuses on pharma-
`by MBP-specific T cells.”
`cotherapy, several nonpharmacologic treat-
`These results have led to a recently reported
`ments intended to limit demyelination have
`double-blind, placebo-controlled pilot study to
`also been investigated and are noted briefly
`evaluate the clinical and immunologic effects
`here.
`of TCR peptide vaccination in 23 patients with
`Total lymphoid irradiation (TLI), generally
`progressive MS. A native peptide (n = 8) with
`consideredarelatively safe method for achiev-
`the V85.2 sequence expressed in MS plaques
`ing sustained immunosuppression, temporarily
`and on MBP-specific T cells and a substituted
`interrupted disease progression in patients with
`peptide (n = 9) were tested. Treatment con-
`progressive MS, but deterioration resumed at a
`sisted of 100 pg of peptide or placebo adminis-
`median of 3 years after treatment.
`tered weekly for 4 weeks, then monthly for an
`A recent study suggests that TLI in combi-
`additional 10 months, by intradermal injec-
`nation with low-dose prednisone may inhibit
`tion. Response to vaccination, defined as
`the rate of disease progression in patients with
`increased frequency of TCR peptide-reactive T
`progressive MS, since there was a significant
`cells, was accompanied by decreased fre-
`difference in EDSS scores between patients
`quency of MBP-specific T cells (P< .001); 6 of
`receiving the active treatment and those
`the 17 peptide recipients responded to vacci-
`receiving placebo (P< .005).”
`nation, | in response to the native peptide and
`5 in response to the substituted peptide. All 6
`Plasmapheresis done in conjunction with
`immunosuppressive therapy has been used
`vaccine responders remained clinically stable
`with some success to treat patients with MS,
`or showed improvement over the course of
`although the beneficial effects were limited to
`the trial, without any reported side effects; in
`contrast, 10 of the 17 nonrespondersreceiving
`less than 1 year. The results could not be
`replicated in a Canadian study.”
`either peptide or placebo progressedclinically
`(P = .019). Further study of the TCR peptide
`EFFORTS TO ENHANCE REMYELINATION
`:
`vaccination approach and development of
`Although it is not yet known whether
`more sensitive techniques may enable more
`remyelination can -be promoted in humans.
`widespread application to MS as well as other
`with MS, this approach is being actively investi-
`tissue-specific autoimmunediseases involving
`gated.* Histologic studies show that remyelina-
`T cells.*
`tion occurs in the early postinflammatory
`- Jesion but that most or all areas of inflamma-
`tion eventually mature into demyelinated
`areas in which oligodendrocytes have been
`lost. This is probably due to a recurrence in
`inflammation.” For the most part, axons are
`unaffected by this destructive process." When
`natural remyelination does occur, the remyeli-
`natingcell is a glial precursor. Unlike a mature
`oligodendrocyte, these progenitorcells retain
`their ability to proliferate, migrate, survive,
`and differentiate.”
`Onepotential approach to remyelinationis
`transplantation of purified oligodendrocyte-
`type-2-astrocyte progenitor cells into the
`demyelinated areas. This has been done
`experimentally in rats.” Progenitor cells,
`obtained from optic nerves of 7-day-old rats
`and grown in culture in the presence of basic
`fibroblast growth factor (bFGF) andplatelet-
`
`Cladribine
`The highly specific antilymphocyte/anti-
`monocyte immunosuppressive nucleoside,
`cladribine (2-chlorodeoxyadenosine [2-CdA]),
`has been shownin preliminary investigations
`to have potential value in altering the clinical
`course of chronic-progressive MS." In a dou-
`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 EDSSscores 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).” After 2 years,
`the numberof active lesions was markedly
`reduced in the 2-CdA group to almost zero.”
`Bone marrow suppression was observed in
`
`Miller
`
`* MULTIPLE SCLEROSIS: ALTERING THE COURSE
`
`373
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`
`derived growth factor (PDGF), were trans-
`planted into demyelinating lesions in the
`spinal cord of adult rats. Three weeks after
`transplantation, microscopic examination of
`the treated areas showed clear evidence of
`remyelination in 8 of 10 animals. Although
`this study indicates that large populations of
`cells that are suitable for transplantation can
`be produced, it remains to be determined
`whether the remyelinated axon will function
`normally.”
`In light of this and related studies, some
`argue that sufficient data now exist to support
`the intracranial administration of PDGF and
`bFGFin laboratory animals with experimen-
`tally induced chronic demyelinative disorders.
`It is believed that this will lead to the develop-
`ment of protein growth factor—based treat-
`ments to repair lesions in patients with MS."
`
`EFFORTS TO IMPROVE CONDUCTIONIN
`DEMYELINATED FIBERS
`It is possible that demyelinated axons in MS
`lesions may be capable of conducting
`impulses.™ Studies have shown that the con-
`duction block in demyelinated fibers is partly
`due to the appearance of aminopyridine-sensi-
`tive potassium channels in demyelinated
`areas.” Preclinical studies using the potassium
`channel blockers 4-aminopyridine (4AP) and
`3,4-diaminopyridine (DAP) resulted in
`improved conduction in experimentally
`demyelinated nerves and thus warrants clini-
`cal trials in patients with MS.
`Manytrials, reviewed by Bever,™ have shown
`that 4-AP and DAP can improve neurologic
`function in MSpatients, as measured by vision
`testing, neurologic examination, or EDSS, and
`so may be beneficial in the symptomatictreat-
`ment of MS. Onestudy suggests that approxi-
`mately 30% of MSpatients arelikely to have a
`significant clinical response at the outset of 4-
`AP therapy and that 80% to 90% of: these
`patients will continue to benefit during long-
`term administration.™
`A potential obstacle to the therapeutic use
`of 4-AP and DAPis their safety profile.
`Althoughparesthesia, gait instability, dizziness,
`and abdominal pain have been reported, the
`most serious concernis seizures.*! Seizures
`have rarely occurred at the doses used in MS
`trials, but they occur commonly at higher
`doses and have been reported in patients
`receiving doses as low as 100 mg per day of
`DAP and 50 mgperday of 4-AP.
`
`CONCLUSION
`It appears likely that intensive and diverse
`efforts will continue to be directed toward the
`developmentof therapies to prevent the exac-
`erbations and progression of neurologic dis-
`ability associated with MS. Atthe level of basic
`research, possible participants involved in
`myelin destruction, such as tumornecrosis fac-
`tor-a and other cytokines, will probably
`receive attention. Investigations of new
`immunosuppressive therapies will continue
`the quest for efficacious agents with greater
`selectivity and thusa better safety profile.
`Because monoclonal antibody therapy
`offers a meansof achieving rapid and substan-
`tial anti-inflammatory effects, new agents with
`a more favorable safety profile than CAM-
`PATH-1H will almostcertainly be investigated.
`Evaluationof the use of protein growth factors
`to enhance remyelinationis likely to inten-
`sify.343,53
`cur-
`With respect to IFNB-la and IFN€-1b,
`rently the only approved medications shown
`to favorably alter the course of MS, the devel-
`opment of biologic products that may
`enhance this effect in patients with relapsing-
`remitting MS will be explored.” The finding
`that thereis a synergistic effect between IFN-8
`and COP 1 in controlling MBP-active T cells in
`vitro suggests one promising avenue of
`approach.”
`
`References
`1. Bastianello S, Pozzilli C, Bernardi S, et al: Serial study of
`gadolinium-DPTA MRI enhancement in multiple sclerosis.
`Neurology 1990; 40:591-595
`2. Antel JP, Arnason BGW: Demyelinating diseases, Harrison’s
`Principles of Internal Medicine. Wilson JD, Braunwald E,
`IsselbacherKJ, et al (eds). New York, McGraw-Hill, 12th Ed,
`1991, pp 2038-2045
`3. Whitaker JN: Rationale for immunotherapy in multiple
`sclerosis. Ann Neurol 1994; 36(supp!):S103-S107
`4. Lublin FD, Reingold SC: Defining the clinical course of
`multiple sclerosis: results of an internationa