CONTEMPORARY AND NEW IMMUNOMODULATORY THERAPY FOR MULTIPLE SCLEROSIS Richard A. Rudick, M.D. Cleveland, Ohio

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1 CONTEMPORARY AND NEW IMMUNOMODULATORY THERAPY FOR MULTIPLE SCLEROSIS Richard A. Rudick, M.D. Cleveland, Ohio JNTR.ODUCTION This presentation will focus on imrnunomodulatory drugs that have become available for multiple sclerosis over the past seven years. In addition, promising investigational therapies will be reviewed briefly. The presentation will focus on use of these drugs in patients with relapsing remitting MS, with less emphasis on drugs used in the secondary progressive stage of the disease. In a companion presentation, we will discuss the rationale for early, proactive use of disease monitorjng drugs. The emphasis on early proactive therapy results from increasing evidence that the MS disease process is continuously active in many patients from early in the disease, and that the pathologic process in includes irreversible tissue injury and diffuse axonal pathology. AVAILABLE DRUGS FOR RELAPSING REMITTING MS Recombinant interferon B-1 b (IFNB-1 b, Betaseron, recombinant interferon B-1a (IFNB-la, Avonex and Rebif ) and glatiramer acetate.(copaxone ) (Table 1) have been shown to be safe and effective in relapsing remitting MS. Avonex and Rebif are recombinant interferon beta preparations that are glycosylated and amino acid identical with natural human beta interferon. Betaseron is produced by E. Coli and is consequently non-glycosylated. It has a serine for cysteine substitution at the 17 amino acid position. Copaxone is a polymer of 4 basic amino acids that was originally synthesized as a mimic of myelin basic protein. The. drugs were tested in separate multicenter, placebo-controlled, double-masked clinical trials. Key elements ofthe studies are summarized in Table 2. Table 1: Available Disease Modifying Drugs For RR-MS Drug Description Possible Mechanisms IFN6-la (Avonex) Recombinant IFNB, glycosylated, AA Immunomodulatory; inhibits IFN6-la (Rebif) IFN6-lb (Betaseron) Glatiramer acetate (Copaxone) identical with natural IFNB Recombinant IFNB, Non glycosylated, Cysteine Serine substitution Random polymer of basic amino acids cell migration and cellmediated inflammation. Antiviral effects May inhibit T cell recognition of myelin antigens. May induce myelin reactive regulatory cells Betaseron was tested in 372 patients given 8 million international units (MIU) (250 ug), 1.6 MIU (50 ug), or placebo by SC injection every other day for up to five years 1 2 The primary outcome measure was drug effect on relapse rate. Treatment with the higher dose reduced the relapse rate by 33%, increased the proportion of relapse-free patients from 16% to 31%, and reduced by two-fold the number of patients having moderate or severe relapses. Beneficial effects were maintained for patients who elected to remain m the blinded trial for up to 5 years. There was a statistically nonsignificant trend suggesting that patients in the 8 MIU arm were less likely to experience worsening by at least 1 point from the baseline Expanded Disability Status Scale (EDSS) sustained for at least three months. A vonex was tested in 301 patients given weekly IM injections (6 MIU,30 ug) or placebo for up to two years 3.4. The primary outcome measure was time to onset of sustained disability progression, defmed as deterioration from baseline by at least 1.0 point on the Expanded Disability Status Scale (EDSS) persisting for at least six months. Treatment with A vonex resulted in a significantly lower probability of sustained disability progression, and significantly fewer IFNB-1a recipients became severely disabled, defined as 6 month sustained worsening at least to the EDSS 4.0 or EDSS 6.0 levels 5. Patients at EDSS 6.0 require assistance to walk, and at this EDSS score, most patients have evolved into secondary progressive MS (SP-MS). This finding suggests that IFNB therapy can prevent or delay transition from RR-MS to SP-MS in some patients. Treatment with Avonex also reduced the relapse rate by 169

2 32% in the cohort of patients treated for 2 years, and by 18% in all patients regardless of the time in the study 4 Rebif was tested in 560 patients given 12 million international units (MID) ( 44 ug), 6 MIU (22 ug), or placebo by SC injection three times weekly for 2 years 6 The primary outcome measure was drug effect on total relapse number per patient. Treatment with the lower dose reduced the relapse rate by 29% and treatment with the higher dose reduced the relapse rate by 32% after two years. Treatment with Rebif increased the proportion of relapse-free patients from 16% to 27% (lower dose) and 32% (higher dose). Treatment with Rebif reduced the number of severe relapses the number of steroid courses, and the number of hospital admissions for MS. There were statistically significant benefits on EDSS change between baseline and 2 years, and in the time to 3-month sustained worsening from the baseline EDSS. Both IFNB-1b and IFNB-1a had beneficial effe ts the disease process measured by cranial MRI c Betas~ron resu~ted.in si~ficantly fewer new: 0 enlargmg T2 les10ns m 52 patj.ents studied at one of thr clinical sites with MRI scans every 6 weeks e fi ' and s1gm cant y ess annua accumu ation of T2 lesions... the entire study group 7 In a separate study, Betaselil reduced the frequency of brain lesions that enhan~o~ with gadolinium (Gad+) 8 In the phase ill trial, Avone significantly reduced Gad + brain lesions after 1 ande~ years of treatment, and decreased the number of new and enlarging T2 lesions after 1 and 2 years 4 9 These studies indicate that IFNB inhibits new brain lesion formation, Rebif also has prominent beneficial effects on MRI parameters, particularly gadolinium enhancing lesions and new and enlarging T2 lesions. TABLE 2: Pivotal Trials of Drugs for RR- MS Avonex 4 Rebif 6 Betaseron 10 Copaxone 11 Sample Size PLC 142 RX 158 PLC 187 RX,6 MIU 189 RX, 12MIU 184 PLC 12 3 RX,l.6MIU 12 5 RX, 8 MIU 12 4 PLC 126 RX 125 EDSS MinRR Age (2 in 3 yrs) (2 in 2 yrs) (2 in 2 yrs) (2 in 2 yrs) Dosage 1 Outcome 1 Result Adverse Events 30 ug (6MIU) IMweek:l~ Sustained disability Delay in sustained EDSS worsening Flu-like symptoms (first 2-3 months) 22 ug (6 MIU) SC TIW 44 ug {12 MIU) SC TIW Relapse Count 29%,!, (6 MIU) and 32%,!, (12MIU) Flu-like syniptoms Skin reactions Decreased WBC, increased transaminases 250 ug (8 MIU) SCQOD RelaEse Rate 33%,!, (8 MIUvs PLC) Flu-like symptoms (first 2-3 months) Skin reactions, occasionally severe 20mg SCQD RelaEse Rate 29%,!, Mild skin reactions Rare systemic reaction with flushing, sweating, palpitations Neutralizing Antibodies (NAB) Phase ill study: 14% NAB+ after 12 months; 22% after 24mnths 4 Open label study: 7% NAB+ after months; Decreased in vivo response to injections 12 Phase ill study: 6 22 ug dose: 23.8% positive 44 ug dose: 12.5% positive Phase ill study: 38% NAB+ after 24 months Decreased clinical efficacy 13 Open label study: 35%NAB+Abs after months % binding Abs; significance unknown. There is no methodology to determine neutralizing activity. 170

3 The significance of the prominent effects of IFNB on uadolinium enhancement remains uncertain, because of ~!he lack of a documented relationship between gadoli~ium ~ lesions ~d subsequ~nt neurologic disabihty 14 This may be clanfied as stud1es focus more on the effects of IFNB on destructive pathologic process, as measured by the volume of T1 holes, or brain atrophy (see below). Nevertheless, the prominent effect of IFNB preparations on gadolinium positive lesions suggests that IFNB therapy reduces brain inflammation. This conclusion was supported by the Avonex study, which found significantly reduced CSF cellularity among Avonex recipients after two years oftherapy 15 Two studies were completed that tested IFNB for efficacy at the first clinical episode in patients at high risk for developing MS. These studies enrolled patients with optic neuritis, transverse myelitis, or brainstem syndromes who had at least 2 periventricular T2 lesions. A von ex was shown to decrease the probability of converting to clinically definite MS by 50%, and markedly reduced :MRI disease progression 15 a. Rebif, in the dose tested, was also effective, but the results were considerably more modest. In aggregate, the studies suggest that early therapy with IFNB can inhibit destructive brain pathology. Results from these studies will be discussed. All 3 IFNB preparations cause transient flu-like symptoms. Headache, myalgia, fever, malaise, and occasionally increased MS symptoms commorily last hours after each injection; the severity of these symptoms typically lessens after 6-12 weeks of therapy. -Betaseron causes redness and swelling at the injection site and skin necrosis in 5% of the patients. In the phase ill clinical trials, neutralizing antibodies to IFNB were observed in 38% ofbetaseron recipients 13, 22% of Avonex recipients\ 23.8% of Rebif recipients (low dose) and 12.5% of Rebif recipients (high dose) 6 The presence of neutralizing activity in the Betaseron study was associated with reduced clinical and MRI efficacy. In an open label study, a single biological assay was used to determine titers of neutralizing antibodies in patients treated clinically with Betas~ron or Avonex 12 After months of treatment, neutralizing antibodies were observed in 35% of patients treated with Betaseron, and 7% of patients treated with A vonex. This raises the possibility that IFNB-1b is more immunogenic than IFNB-1a. Interferon B induces expression of many genes, so the mechanisms of action in MS are likely complex (reviewed in 16). Putative mechanisms include: 1) Inhibition of autoreactive T cells 17 ; 2) inhibition ofmhc class IT expression 18 with reduced antigen presentation within the CNS; 3) inhibition of metalloproteases 19 ' 20 or altered expression of cell-associated adhesion molecules 2 \ leading to reduced cellular migration into the CNS; 4) induction of inlmunosuppressive cytokines 22 and inhibition of proinflammatory cytokines 23, leading to resolution of the inflammatory process. Glatiramer acetate (Copaxone) is a polypeptide consisting of. a random arrangement of 4 basic amino acids. The drug is thought to mimic myelin basic protein, and is postulated to _induce myelin-specific suppressor T -cells and to inhibit myelin-specific effector T cells u. Copaxone was tested in 251 patients given daily subcutaneous injections of Copaxone, 20 mg or placebo for two years. The primary outcome measure. was drug effect on the relapse rate. In the original 2-year study, Copaxone reduced the relapse rate by 29%. At the. end of 2-years of therapy, patients were offered entry to an extension study, which was continued in a double-masked manner for about 1 additional year. The large majority of patients continued in the extension study, and the beneficial effect on relapse rate was maintained 24 No significant effect was observed on sustained changes on EDSS, either in the original study or the extension study. Copaxone was well tolerated. Mild swelling and redness occurred at each injection site and 15% of patients experienced brief episodes of flushing, chest tightness, palpitations, dyspnea, and anxiety. MRI scans were not included as part of the Copaxone phase ill study, but 27 cases had serial MRI scans at one of the sites 25 There was a trend toward reduced Gad+ lesions favoring Copaxone, and a significant benefit in favor of Cop axone on a measure of brain volume loss 26 A similar trend in favor of Copa.Xone on Gad+ lesions was found in a small study in 10 patients 27 A large study was recently completed to determine the effect of glateramir on MRI disease activity. Relapsing remitting MS patients were required to have at least one gadolinium enhancing lesion to enroll in the study. 485 patients were screened and 239 enrolled. After a baseline MRI scan, patients were randorrily assigned to glatiramer acetate or placebo, and followed in a double-blind protocol with monthly MRI scans for 9 months. During the 9 month double-blind phase, there was a statistically significant 35% reduction in the total number of gadolinium-enhancing lesions in the glatiramer group compared with placebo (G. Comi, personnal communication). Interestingly, the therapeutic effect was first observed 3-4 months after treatment was initiated. This is considerably slower than the rapid-onset inhibitory effect of IFNB on gadolinium enhancing brain lesions. 171

4 AVAILABLE DRUGS FOR SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS IFNB-1b (Betaseron) and ifnb-1a (Rebif) were tested for efficacy in patients with secondary progressive MS. The European Study Group conducted a randomized, double blind, placebo controlled trial of Betaseron 9 MIU SC QOD vs placebo 28 Patients at 32 centers in 12 European countries were randomized to Betaseron (n-360) or placebo (n=358). Patients had definite MS in the SP phase, 2 relapses or a 1 EDSS-point progression in the 2 years prior to study entry, and EDSS score between The primary endpoint was time to confirmed progression, defined as an increased EDSS score, sustained for 3 months. Time to confirmed progression was significantly prolonged in the Betaseron treated ann (p<0.001). The time until40% of the cases progressed on the primary endpoint was delayed for 12 months. fu this study, there was a significant effect on disability progression in patients with or without relapses during the study. There was also significant benefits seen on a number of secondary endpoints, including progression to EDSS 7.0 (32% reduction), relapse rate on study (32% reduction), change in T2 lesion volume between baseline and year 1 and year 2, and the number of newly e:rihancing lesions. Another study of IFNB-lb, done in North America studied 939 patients in 35 centers in the US and Canada. Patients were randomized to receive Betaseron 8 MIU SC QOD (n=317), 5 MIU/M 2 (n=314), or placebo (n=308). Patients had definite SP-MS with at least 1 documented relapse during the course of MS, entry EDSS between 3.0 and 6.5, and 1 EDSS-point progression in 2-years prior to study entry. The primary outcome measure was time to confirmed progression, defined as sustained increase in EDSS score lasting at least 6 months. The study showed no difference between study arms on the primary study outcome, although there were significant benefits on some of the secondary outcomes. Relapse rate was decreased by 43% (p<0.01) in the 8 MIU ann, and by 29% (p<0.05) in the 5 MIU/m 2 arm. There was no significant difference between the doses on relapse rate. Change in T2 lesion area from baseline Was significantly decreased in both treatment arms (p<0.001), and agafu. there was no dose effect. Newly enhancing lesions were reduced by 64% in the 8 MIU arm and by 76% in the 5 MIU/m 2 arm. Both were statistically significant, but there were no significant dose effects. A randomized controlled trial of interferon beta 1a (Rebif) was completed in Europe. 618 patients with definite SP-MS were randomized to receive Rebif at 22 meg by s11bcutaneous injection three times per week (n=209), 44 meg three times per week (n=204) or placebo (n=205). Patients had EDSS between 3.0 and 6.5, and had worsened by at least 1 EDSS point prior two years. T_he ~rim~ry. ~utcome was tirne. co~ed progression m disability, defmed as EDs worsenmg for at least 3 months of 1 point for pati. S entering at 5.0 or below, or 0.5 points for patients entermg at 55. or a b ove. T. Ime to sustamed disab ents Tty progression did not differ significantly between I~ study arms. As with the North American Betaser e study, there were significant benefits of treatment fo on number of secondary variables. Both the low and hi~~ dose groups showed a 30% reduction in relapse rate (p<o.ol) and there. was no dose effect. There were significant benefits in favor of either ann in number of steroid courses, and hospitalizations for relapses. There were_ also significant benefits in new and enlarging T2 lesions, gadolinium enhancing lesions, and change in T2 lesion volume. The beneficial MRI effects were greater at the higher dose. A post-hoc analysis in this study showed a treatment-by-gender effect, in which women benefited more than men. fu contrast to the European Betaseron study, the presence of prestudy relapses was associated wit greater therapeutic effects during the. clinical trial. The results of IFNB trials in patients with SP-MS have thus been mixed. This is particularly striking with the two Betaseron studies, which appear superficially quite similar and use an identical IFNB product,. given with the same dose schedule. The European study showed a highly significant, though modest, benefit on disability progression, while the North American Study showed no differences. This discrepancy has led to comparison between the two study populations. The North American population was significantly older at entry, had a longer disease duration, fewer relapses in the prior 2 years, greater change in EDSS in the 2 years prior to study entry, and less gadolinium enhancing lesions at study entry. These differences suggest that the North American population showed less inflammation and possibly more noninflammatory axonal degeneration. While speculative, this analysis would conclude that IFNB therapy is most effective in the earlier, inflammatory stage of MS, and increasingly less effective in later stages characterized by progressive disability. PROMISING NEW APPROACHES FOR IMMUNOMODULATORY THERAPY Altered peptide ligands: Productive interaction between antigen and T cell requires an MHC class II molecule on the surface of an antigen presenting cell, together with cognate antigen and T cell receptor. All 3 elements contribute to the specificity of the immune response, and also to the down-stream events resulting from T cell activation. For example, the nature of c.ostimulatory molecules may determine whether a T 172

5 ell develops into a memory cell, or is tolerized to that c articular antigen. Considerable work in EAE has ;) defined immunodominant epitopes of myelin basic protein; and b) defmed the therapeutic potential of altered peptides that both fail to induce EAE and also protect treated animals from active or passive EAE induction. One such "altered peptide ligand" (APL) is CGP77116, an altered peptide ofmbp 83~99. In one study, patients with defmite MS were randomized into a placebo-controlled, double blind phase IT study. ~e study was discontin~ed by a safety monitoring committee because 9% of patients developed hypersensitivity reactions. There were no increases of clinical relapses or new enhancing lesions in any patient, and a secondary analysis suggested that the volume and number of enhancing lesions was reduced at the highest dose tested- 5 mg. 29 A second study of this same APL was discontinued early as well 30 ' In this case, 3 patients had relapses of MS. Two of them also had markedly increased reactivity to myelin basic protein. The study raised a concern about the risk of antigen therapy generally. At the present time, the future of antigen-specific immunotherapy is uncertain for a number of reasons. There is significant variability iri myelin recognition. between patients 3 \ significant change in myelin recognition within patients over time , and inadequate information about reliable methodologies to induce protective rather than inflammatory T cell responses. Trafficking (e.g. Antegren): Movement of cells across endothelial barriers and into tissues requires a number of important molecular interactions. These include interaction between selectins and their receptors, integrins on leukocytes and their Ig-family receptors on endothelial cells, chemokines and their receptors, and various enzymes such as metalloproteinases. Inhibition of leukocyte trafficking is an attractive therapeutic strategy. The future of chemokine based therapy is bright, but has not yet emerged in the MS field. Inhibition ofvla-4, an a4bl integrin, has emerged as a potential therapeutic strategy in MS. A randomized, double-blind, placebo-controlled trial of a humanized monoclonal antibody to VLA-4 (Antegren, Elan Pharmaceuticals) was conducted in 72 patients with active RR or SP-MS 34 Each patient received 2 infusions of Antegren or placebo 4 weeks apart, and was followed for 6 months with serial MRI and clinical assessments. The treated group exhibited significantly fewer new enhancing lesions compared with the 'placebo group during the first 12 weeks of the study. There was no effect of treatment on relapses, but the study was not designed to look at a clinical outcome. Inhibition of leukocyte integrins, e.g. Antegren, represents an appealing therapeutic strategy, and the Antegren study provides proof of principal that this. can be effective. Future directions related to adhesion molecule therapy will be discussed. Costimulatory molecules (e.g. CD40L mab, CTLA4Ig). Two reagents targetting costimulatory molecules are currently in the planning stages. The first molecule that is being targetted is CD40 ligand (CD =154), and the reagent is a humanized monoclonal anti-cd40l. Two companies have anti-cd40l antibodies in early clinical trials - Biogen, Inc., and IDEC Pharmaceuticals. Both companies have early phase Illl programs under way. The IDEC molecule has been tested in a phase I dose-fmding study. The IDEC molecule will be tested in a phase n trial with gadolinium enhancement as the target. Biogen has planned a phase II trial of anti-cd40l in MS patients, but the trial has not started because of concerns about possible thrombotic complications of anti-cd40l that have arisen in other studies. Another promising target of immunomodulatory therapy is CTLA4Ig. This fusion protein binds CD28 and effectively tolerizes T cells. 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