As described in an accompanying article by

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1 TREATING RELAPSING-REMITTING MULTIPLE SCLEROSIS I: THE PRIMARY DISEASE-MODIFYING DRUGS * Melody Ryan, PharmD, MPH, BCPS, CGP ABSTRACT Most patients with multiple sclerosis (MS) initially experience a clinical presentation that has been referred to as relapsing-remitting MS, which is defined by a pattern of acute episodes of impaired neurologic function and a return to normal or nearnormal function between episodes. A number of options are available to treat acute MS exacerbations or to reduce the likelihood of future episodes. Steroids, especially intravenous methylprednisolone, have been used to accelerate recovery from acute MS episodes. Two formulations of interferon beta-1a are approved for use in MS one is administered by intramuscular injection once weekly and one by subcutaneous injection 3 times per week. One formulation of interferon beta-1b is also administered by subcutaneous injection every other day. Glatiramer acetate is also used to prevent MS exacerbations. Randomized, controlled trials have demonstrated improvements in attack frequency and other clinical outcomes with interferon beta preparations and glatiramer acetate. The most common adverse events of MS preventive therapy include flu-like symptoms and injection-site reactions with interferon beta, and injection-site reactions and a postinjection reaction of transient chest pain or tightness with glatiramer acetate. (Adv Stud Pharm. 2007;4(11): ) *This article is based on a presentation at a roundtable on April 10, 2007, in San Diego, California. Associate Professor, Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Department of Neurology, University of Kentucky College of Medicine, Lexington, Kentucky. Address correspondence to: Melody Ryan, PharmD, MPH, BCPS, CGP, Associate Professor, Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Department of Neurology, University of Kentucky College of Medicine, 231D College of Pharmacy, 725 Rose Street, Lexington, KY maryan1@ .uky.edu. As described in an accompanying article by Dr Guthrie, most patients with multiple sclerosis (MS) initially present with relapsing-remitting MS (RRMS), which is characterized by acute episodes of MS that are separated by periods of normal or near-normal neurologic function. A number of medications are now available to treat patients with RRMS, including corticosteroids and potentially disease-modifying treatments such as interferon beta and glatiramer acetate. TREATING ACUTE EXACERBATIONS: STEROIDS Steroids have long been used to speed the functional recovery of patients with acute MS exacerbations. They are thought to suppress MS exacerbations by decreasing the release of inflammatory cytokines, the activation of T lymphocytes, and the migration of immune cells into the central nervous system (CNS). They may also stimulate the death of these activated immune cells. 1,2 Methylprednisolone is typically administered at a dose of 1 g/day intravenously (IV), either as a single dose or in divided doses, usually for a total of 3 to 5 days. Some clinicians, but not all, use a gradual taper before discontinuing treatment. Oral prednisone has also been used at very high doses (eg, 1250 mg every other day for 5 days). 3,4 Typically, adrenocorticotropic hormone has been used only in unusual circumstances (eg, during a methylprednisolone shortage). PREVENTING EXACERBATIONS: INTERFERONS AND GLATIRAMER ACETATE Immunomodulatory therapy is a mainstay for the prevention of MS exacerbations. Approved medications include glatiramer acetate and 3 interferon beta formulations interferon beta-1a intramuscular (IM), interferon beta-1a subcutaneous (SC), and interferon beta-1b. All of the interferons are assumed to share the 318 Vol. 4, No. 11 October 2007

2 same mechanisms of action in the treatment of MS, which include the preservation of myelin by the suppression of immune cells and inflammatory substances that cause myelin loss. 5,6 Interferon therapy decreases T-cell activation and secretion of inflammatory cytokines; prevents up-regulation of cell-surface adhesion molecules that are required for activated T cells to enter the CNS; suppresses the formation of tissueinjuring substances (eg, matrix metalloproteases); decreases the proliferation of phagocytic microglia cells, which are thought to damage myelin; and directs the maturation of helper T cells from the inflammatory Th1 type to the anti-inflammatory Th2 type. 5,6 In general, the effects of the 2 interferon beta-1a products in MS treatment are similar. Compared with placebo, both have been shown to decrease the frequency of exacerbations and the number of brain lesions visible on magnetic resonance imaging (MRI), and to increase the time before progression of disability (Figure 1) Interferon beta-1a is absorbed more slowly after IM injection than SC injection. Interferon beta-1a IM is administered at a dose of 30 µg once weekly, whereas interferon beta-1a SC is administered at a dose of 44 µg 3 times per week. Both products produce similar adverse effects, including flu-like symptoms and injection-site reactions. Less common effects include laboratory abnormalities (eg, decreased white blood cell count and elevated liver function tests), menstrual abnormalities, and depressed mood. More serious, but rare, adverse effects include hepatic failure and depression of all peripheral blood cells lines; for this reason, liver function tests and a complete blood count are recommended at 1, 3, and 6 months after starting therapy, then periodically thereafter. 12 Randomized clinical trials have shown that early administration of interferon beta-1a, in both IM and SC formulations, beginning after the first clinical attack, slows the progression of MS (Figure 2) Analyses of different patient subgroups revealed that patients who were the most likely to benefit from early interferon beta-1a therapy were those with the following characteristics: immunoglobulin G synthesis or oligoclonal bands in cerebrospinal fluid samples, 2 or more lesions on MRI, or symptoms that remained 2 months after their initial attack. 15 Interferon beta-1b is similar to interferon beta-1a in its mechanisms of action and efficacy. It has been shown to reduce the frequency and severity of MS exacerbations compared to placebo, and has also been shown to improve symptoms in patients with secondary progressive multiple sclerosis. 16,17 It is rapidly absorbed after SC injection, reaching a peak plasma concentration within 1 to 8 hours. Interferon beta-1b produces adverse events that are similar to the adverse events produced by interferon beta-1a, with flu-like symptoms and injection-site reactions occurring most often. The frequency of injection-site reactions for all of the subcutaneous products may be reduced by administering injections to the buttocks instead of the stomach, abdomen, or back of the arm; by using topical hydrocortisone cream 30 minutes before injection; rotating injection sites; and the application of ice or heat. 18,19 Patients should be counseled that flu-like symptoms usually remit after 2 to 3 months of treatment, and that symptoms may be prevented by using gradual dose increases and the use of acetaminophen or ibuprofen. A significant obstacle to the long-term efficacy of beta interferons is the formation of neutralizing antibodies (NABs). NABs usually appear after 12 to 18 months, and are more common with interferon beta- Figure 1. Treatment with Interferon Beta-1a Intramuscularly Prevents Neurologic Disability in Patients with Multiple Sclerosis Mean EDSS scores Baseline Study weeks In this randomized, double-blind, phase III clinical trial of 301 patients with multiple sclerosis, the mean EDSS scores for placebo (shaded bars) and interferon beta-1a (solid bars) are shown at baseline and each 6-month visit. The 2 groups were not significantly different at baseline. EDSS scores were significantly higher (indicating more disability) in the placebo group at week 78, week 104, and week 130 (P <.05). EDSS = Expanded Disability Status Scale. Reprinted with permission from Rudick et al. Neurology. 1997;49: University of Tennessee Advanced Studies in Pharmacy 319

3 1b (approximately 38% 47% of patients) than with interferon beta-1a SC (12% 28%) or interferon beta- 1a IM (2% 6%). 20 NABs may also disappear even with continued treatment. NABs exhibit cross-reactivity, and switching from one interferon beta product to another may not eliminate them. A consensus statement by the European Federation of Neurological Societies recommended antibody testing by specialized laboratories after 12 and 24 months of treatment. 21 Patients who are antibody positive should be retested every 3 to 6 months, and those with high antibody titers should discontinue treatment due to the likelihood of decreasing efficacy. A contrasting consensus statement from the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology determined that no recommendations could be made regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply for neutralizing antibodies. 22 In contrast with the interferon beta preparations, glatiramer acetate is thought to act by binding to the major histocompatibility complex class II molecule, preventing antigen presentation and T-cell activation, and directing the maturation of helper T cells from the proinflammatory Th1 type to the anti-inflammatory Th2 type. 5,6 In patients with RRMS, glatiramer acetate reduces the number of exacerbations compared to placebo (Figure 3). 23,24 It is administered at a dose of 20 mg (1 ml) SC daily. The most common adverse effects of glatiramer acetate include injection-site reactions and a postinjection reaction of transient chest pain or tightness and shortness of breath, which are often described by patients as similar to a panic attack. COMPARATIVE STUDIES A small number of clinical studies have directly compared the efficacy of the different agents in patients with RRMS, although none has used a prospective, randomized, double-blind design. The INCOMIN (Independent Comparison of Interferon) study was an open-label comparison of interferon beta-1a IM versus interferon beta-1b in 188 patients who were treated for 2 years. Interferon beta-1b was associated with a small but significantly lower rate of relapse (0.5 vs 0.7 per year). 25 Interferon beta-1b was also associated with fewer new lesions on MRI, but a higher incidence of NABs (22% vs 6% of patients). The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) trial was a randomized, openlabel study of 677 patients who were treated with interferon beta-1a SC or interferon beta-1a IM for 48 weeks. 26 Relapse rates and the number of active lesions on MRI were lower with the more frequent SC dosing regimen, and the number of patients with NABs was also greater. In an open-label extension phase, patients were allowed to switch to SC dosing, which resulted in a 50% relative reduction in relapse rate during the extension period. 27 An open-label, nonrandomized study in which 156 patients were assigned to whichev- Figure 2. Early Administration of Interferon Beta-1a Clinically definite MS, % Placebo Interferon beta-1a Months Interferon beta-1a group No. at risk Clinically definite MS Early withdrawal from study Followed until end of study Placebo group No. at risk Clinically definite MS Early withdrawal from study Followed until end of study Early administration of interferon beta-1a intramuscularly after a first episode of multiple sclerosis (MS) delays the progression to clinically definite MS, which requires, by definition, at least 2 episodes that are consistent with central nervous system demyelination. After 3 years, the percentage of patients who progressed to clinically definite MS was significantly lower among patients who received interferon beta-1a than placebo (P =.002). Reprinted with permission from Jacobs et al. N Engl J Med. 2000;343: Copyright 2000 Massachusetts Medical Society. All rights reserved. 320 Vol. 4, No. 11 October 2007

4 Figure 3. Improvement of Neurologic Status with Glatiramer Acetate Percentage of patients, % Glatiramer acetate Placebo P =.024 (RMA) P =.001 (BL to Last Visit) Improved Unchanged Worsened The figure shows the percentage of patients who improved or worsened by 1 or more steps on the Expanded Disability Status Scale, or who remained unchanged, after 24 months of daily treatment with glatiramer acetate or placebo. The results were analyzed using repeated measures analysis (RMA), which included assessments performed every 3 months during the trial, and for the change between baseline and the conclusion of the study (baseline [BL] to last visit). For both analyses, neurologic status was significantly better for patients who received glatiramer acetate than placebo. Reprinted with permission from Johnson et al. Neurology. 1998;50: er treatment they preferred compared interferon beta- 1a IM, interferon beta-1b, glatiramer acetate, or no treatment. 28 Compared to untreated patients, the mean number of relapses was significantly lower for patients in the glatiramer acetate and interferon beta- 1b groups, but not in the interferon beta-1a group. Finally, an open-label, nonrandomized, retrospective 2-year study examined clinical outcomes for patients who had received no treatment, interferon beta-1a IM, interferon beta-1a SC, interferon beta-1b, or glatiramer acetate. 29 The only statistically significant differences between active treatment groups were a lower number of relapses per year with glatiramer acetate than with the other therapies, and a lower rate of treatment discontinuation. CONCLUSIONS A 3-day to 5-day course of IV methylprednisolone is commonly used to treat acute MS exacerbations, and may be discontinued with or without a gradual taper. Options to prevent relapses in patients with RRMS include 3 interferon beta preparations and glatiramer acetate. The typical dosing, route of administration, and common adverse effects of these agents are summarized in the Table. 12,28-32 All of these agents have been shown to be superior to placebo in randomized controlled trials, but the different treatments have not been rigorously compared to one another. DISCUSSION HIGHLIGHTS Dr Guthrie: What is the clinical significance of NABs? Do the patients who develop NABs have a worse outcome? Dr Bennett: It is very controversial. The latest consensus statement from the American Academy of Neurology on neutralizing antibodies has not progressed very far from the initial statement in early High titer antibodies are not likely to go away. Antibodies usually start to appear after approximately 6 months, but they don t start to cause a clinical effect until roughly 18 to 24 months. It was only in the 4- year PRISM study that the effects of antibodies on clinical outcomes were apparent, and especially from years 3 to With shorter trials, due to the low rate of antibody formation during the first few months, the numbers of patients with clinical events is small, which makes it difficult to detect differences between those with and without NABs. I would say that there is no reason for prospective analysis of antibodies right now for patients with MS. Antibodies should not be assessed unless a patient is not doing well on treat- Table. Medications to Prevent Multiple Sclerosis Exacerbations Common Adverse Medication Dose Route Frequency Effects Interferon beta-1a 30 µg IM Weekly Flu-like symptoms Interferon beta-1a 44 µg SC 3 times Flu-like symptoms, per week injection-site reactions Interferon beta-1b 8 M IU SC Every other Flu-like symptoms, day injection-site reactions Glatiramer acetate 20 mg SC Daily Injection-site reactions, chest tightness Data from Khan et al 28 ; Haas and Firzlaff 29 ; Avonex (interferon beta-1a) [prescribing information] 30 ; Betaseron (interferon beta-1b) [prescribing information] 31 ; Copaxone (glatiramer acetate injection) [prescribing information]. 32 University of Tennessee Advanced Studies in Pharmacy 321

5 ment. In large clinical trials, including the interferon beta-1a IM 30 µg versus 60 µg trial and in the PRISMS trial, patients who develop antibodies in the first year actually appeared to respond better than other patients without antibodies. If you test these patients at 12 months and detect antibodies, but they have a good clinical response, are we going to discontinue the treatment? There are no long-term data to support that. Patients who are treated with interferon beta-1b, as mentioned in the presentation, exhibit a high degree of fluctuation in antibody positivity. One question that has not really been addressed is the question of whether all antibodies are neutralizing, or whether there are some that are only binding. Particularly with an agent like interferon beta-1b, the process of reconstituting the protein in solution may contribute to antibody fluctuation. Did all of it fold properly? Did you form aggregates? Did you form denatured proteins? Did you expose new epitopes that your immune system has never seen before? Did you make macromolecular complexes and form new epitopes? And, if you are not reconstituting the exact same way every time, then you may be stimulating your immune system with novel protein epitopes. As a result, you are making antibodies that are going to fluctuate as different protein epitopes come and go. And, I think that could be a best explanation for the higher rate of antibody formation and fluctuation with interferon beta-1b. Dr Cook: Is the distinction between neutralizing and binding antibodies important clinically? I m not sure that the clinical response would be different between the two, as any antibody marking another protein would be cleared by the reticuloendothelial system. Other antibodies that don t neutralize may still have an impact by reducing serum levels. Also, one of my concerns is that right now the only test is an indirect model that uses cell signaling in vitro. Dr Bennett: I think it s very important we have indirect assays of interferon efficacy, such as viral resistance, that we currently use for the identification of neutralizing antibodies. People want to test for interferon-induced genes, which right now don t correspond very well to clinical effects. The biggest problem is that we have no clear biologic measure of drug efficacy. Some people may respond to treatment even if their circulating interferon level was decreased by 50%, whereas someone else might need even more interferon to produce a biological effect. Dr Ryan: Some of these antibodies dissipate over time. Suppose that you have a patient who is starting to deteriorate clinically, and antibody testing reveals a high antibody titer. You switch them to glatiramer acetate, but they don t tolerate it very well. Could you now switch the patient back to interferon? Would you use a different formulation, such as the IM rather than SC formulation of interferon beta-1a? Dr Bennett: No one has done that exact experiment. One study enrolled some patients who had developed antibodies in an earlier clinical study of interferon beta-1b and started them on interferon beta-1a. Many of the patients lost their antibody titers with interferon beta-1a over time. 34 So, there is the possibility of losing antibodies even while still continuing to take interferon. This was a very small group of patients. I think that with the release of new agents, such as natalizumab, we have the opportunity in those patients who develop antibodies to go to something else. But obviously, there is a risk-benefit ratio that has to be evaluated with these new drugs. Although it is a real issue, the vast majority of our patients fail interferon therapy in the absence of neutralizing antibodies. I think that the most important pharmacoeconomic issue is that we need to understand what antibodies mean for a patient who is failing to respond. We need to know whether the patient is failing because of the antibodies, or whether the medication itself is ineffective. REFERENCES 1. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58: Sloka JS, Stefanelli M. The mechanism of action of methylprednisolone in the treatment of multiple sclerosis. Mult Scler. 2005;11: Morrow SA, Stoian CA, Dmitrovic J, et al. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63: Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry. 1993;56: Dhib-Jalbut S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology. 2002; 58(suppl 4):S3-S9. 6. Hartung HP, Bar-Or A, Zoukos Y. What do we know about the mechanism of action of disease-modifying treatments in MS? J Neurol. 2004;251(suppl 5):v12-v Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multi- 322 Vol. 4, No. 11 October 2007

6 ple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39: Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol. 1998;43: Rudick RA, Goodkin DE, Jacobs LD, et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1997;49: PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised, double-blind, placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352: Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon beta-1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis. Ann Neurol. 1999;46: Rebif (interferon beta-1) [prescribing information]. Rockland, Mass: Serono, Inc; Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343: Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357: Rieckmann P, Toyka KV, Bassetti C, et al. Escalating immunotherapy of multiple sclerosis new aspects and practical application. J Neurol. 2004;251: The IFNB Multiple Sclerosis Study Group, The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: Paty DW, Li DK. Interferon beta-1b is effective in relapsingremitting multiple sclerosis II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43: Rio J, Nos C, Bonaventura I, et al. Corticosteroids, ibuprofen, and acetaminophen for IFN beta-1a flu symptoms in MS: a randomized trial. Neurology. 2004;63: Bayas A, Rieckmann P. Managing the adverse effects of interferon-beta therapy in multiple sclerosis. Drug Saf. 2000;22: Hartung HP, Munschauer F 3rd, Schellekens H. Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference. Eur J Neurol. 2005;12: Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-ifn-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12: Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68: Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology. 1998;50: Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Mult Scler. 2000;6: Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359: Panitch H, Goodin D, Francis G, et al. Benefits of highdose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci. 2005;239: Schwid SR, Thorpe J, Sharief M, et al. Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study. Arch Neurol. 2005;62: Khan OA, Tselis AC, Kamholz JA, et al. A prospective, open-label treatment trial to compare the effect of IFN beta- 1a (Avonex), IFN beta-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing remitting multiple sclerosis: results after 18 months of therapy. Mult Scler. 2001;7: Haas J, Firzlaff M. Twenty-four-month comparison of immunomodulatory treatments: a retrospective open label study in 308 RRMS patients treated with beta interferons or glatiramer acetate (Copaxone). Eur J Neurol. 2005;12: Avonex (interferon beta-1a) [prescribing information]. Cambridge, Mass: Biogen-Idec; Betaseron (interferon beta-1b) [prescribing information]. Wayne, NJ: Bayer Healthcare Pharmaceuticals; Copaxone (glatiramer acetate injection) [prescribing information]. Kansas City, Mo: Aventis Pharmaceuticals, Inc; Vartanian T, Solberg Sorensen P, Rice G. Impact of neutralizing antibodies on the clinical efficacy of interferon beta in multiple sclerosis. J Neurol. 2004;251(suppl 2):II25-II Herndon RM, Rudick RA, Munschauer FE 3rd, et al. Eightyear immunogenicity and safety of interferon beta-1a Avonex treatment in patients with multiple sclerosis. Mult Scler. 2005;11: University of Tennessee Advanced Studies in Pharmacy 323