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Multiple Sclerosis: Current Status and Strategies for the Future (2001)
Institute of Medicine (IOM)

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387
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Page 387

Appendix E

Drugs Used in the Treatment of MS

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387

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Page 387 Appendix E Drugs Used in the Treatment of MS

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Page 388 APPROVED DISEASE-MODIFYING MEDICATIONS Generic Name Trade Name Company Indication Mechanism of Action Potential Side Effects Beta-Interferon-1a Avonex, Rebifa Biogen, Serono RRMS Beta-interferon-1a is believed to suppress the autoimmune destruction of myelin. Slows accumulation of disability and decreases the frequency of clinical exacerbations. Interferon-β-1a is involved in the regulation of activation, proliferation, migration, and suppressor cell function of T-cells, the modulation of the production of cytokines, including down-regulation of proinflammatory cytokines and up-regulation of inhibitory, antiinflammatory cytokines. Flu-like symptoms, muscle aches, fever, chills and weakness, pain from intramuscular injection Beta-Interferon-1b Betaseron Berlex Labs (Distributor) Chiron (Manufacturer) RRMS Possesses both antiviral and immunoregulatory activities, mediated through interactions with specific cell receptors, which results in the expression of interferon-induced gene products. Redness, pain and swelling and discoloration at injection site, flu-like symptoms, depression, anxiety, depersonalization, suicide attempts

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Page 389 Glatiramer acetate Copaxone Teva Marion Partners RRMS Blocks myelin-specific autoimmune responses. Non-steroidal, non-interferon. Mechanism uncertain, but it is thought that glatiramer acetate, consisting of the acetate salts of synthetic polypeptides, resembles myelin basic protein (mbp) and serves as a decoy that blocks myelin damaging T cells. Redness, pain and swelling and discoloration at injection site, flushing, chest pain, weakness, infection, pain, nausea, joint pain, anxiety and muscle stiffness, Immediate postinjection reaction characterized by chest tightness with heart palpitations and difficulty breathing Note: Avonex, Betaseron, Copaxone, and Rebif are “orphan drugs.” The 1983 Orphan Drug Act (ODA) provides incentives for sponsors to develop products for rare diseases or conditions, by guaranteeing the developer of an orphan product seven years of market exclusivity following the approval of the product by the FDA. The definition of “rare disease or condition” in the Orphan Drug Act: “...the term rare disease or condition means any disease or condition which (a) affects less than 200,000 persons in the U.S. or (b) affects more than 200,000 persons in the U.S. but for which there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered from sales in the U.S. of such a drug.” aRebif has been approved by the European Commission for the treatment of relapsing-remitting multiple sclerosis. The FDA has upheld the Orphan Drug Act and has not granted approval to Rebif. The FDA also had questions about the data filed in the marketing application, which prevented granting tentative approval. If tentative approval is received, Rebif could enter the US market in 2003, when the exclusivity periods for Avonex and Betaseron end.

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Page 390 AVAILABLE AND EMERGING DISEASE-MODIFYING THERAPIES a GLOBAL IMMUNOSUPPRESSION Medication Options Status as of 1999 Putative Mechanisms Of Action Cyclophosphamide Off label use in the U.S. and Europe Global reduction of T-cell population Azathioprine Off label use in the U.S. and Europe As above Glucocorticosteroids Off label use in the U.S. and Europe As above Methotrexate Off label use in the U.S. and Europe As above Total lymphoid irradiation Off label use in the U.S. and Europe As above Paclitaxel Phase II Clinical Trials As above 2-Chlorodeoxyadenosine Phase III Clinical Trials As above Mitoxantrone Phase III Clinical Trials As above IMMUNOMODULATION Therapeutic Strategy Medication Options Status as of 1999 Putative Mechanisms Of Action 1) Inhibit T-cell receptor/peptide/MHC-II interaction Altered peptide ligands Phase I/II Block or compete with the binding of encephalitogenic peptides to the MHC-II molecule Copolymer Approved for relapsing forms of MS in the U.S. and Europe Block or compete with the binding of encephalitogenic peptides to the MHC-II molecule TCR vaccination and TCR peptide vaccination Phase I Generation of antibodies against peptides within the TCR IL-10 , TGF b Phase I/II Immunomodulation; reduce MHC-II molecule expression Interpheron Beta Approved for relapsing forms of MS in the U.S. and Europe Immunomodulation; reduce MHC-II molecule expression 2) Induction of T-cell anergy Antibodies to B7 or molecules Preclinical testing T cells are anergised when TCR/peptide/ MHC-II interaction occurs in the absence of co-signalling aAdapted from Waubant and Goodkin 1997.

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Page 391 Soluble MHC-II/ peptide complexes Phase I T cells are anergised when TCR/peptide/ MHC-II interaction occurs in the absence of co-signalling 3) Deletion of autoreactive T cells Anti-CD4, anti-CD52 Phase I/II Depletion of T cells targeted by the antibodies 4) Reduce T-cell trafficking across blood-brain-barrier (BBB) Glucocorticosteroids Unlabelled use in the U.S. and Europe Decrease the expression of adhesion molecules on T cells and vascular endothelial cells TGF b Phase I/II Decrease the expression of adhesion molecules on T cells and vascular endothelial cells Interpheron Beta Approved for relapsing forms of MS in the U.S. and Europe Decrease the expression of adhesion molecules on T cells and vascular endothelial cells Antibodies to adhesion molecules (Antegren, antiCD11/CD18) Phase II Decrease the attachment of T cells to vascular endothelial cells Matrix metalloprotease inhibitors Phase I Inhibit proteases that facilitate T-cell trafficking across BBB 5) Alter the balance of pro-inflammatory (Th1) and immunomodulatory (Th2) cytokines Antibodies to TNFa, IL-1 Phase I/II Reduce proinflammatory (Th1) cytokine activity Soluble IL-2 or TNFa receptors Phase I/II Reduce proinflammatory (Th1) cytokine activity Antagonists to IL-1 receptor Preclinical testing Reduce proinflammatory (Th1) cytokine activity

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Page 392 Oral myelin Testing discontinued; phase III trial revealed no difference between active and placebo groups Increases immunomodulatory (Th2) cytokine production Interpheron Alpha Phase I Antagonise production of proinflammatory cytokines induced by IFNg Interpheron Beta Approved for relapsing forms of MS in the U.S. and Europe Reduce Th1 cytokine secretion and macrophage function Glucocorticosteroids Unlabelled use in the U.S. and Europe Reduce Th1 cytokine secretion and macrophage function Matrix metalloprotease inhibitors Phase I Block cleavage of pro-TNF to TNF Methotrexate Unlabelled use in the U.S. and Europe Reduces level of soluble IL-2 receptor Intravenous immunoglobulin Unlabelled use in the U.S. and Europe, Phase III Reduction of proinflammatory cytokines Anti-CD40 ligand Preclinical testing Blocks Th1 differentiation and effector function, inhibits IFNg production Roquinimex (Linomide) Testing discontinued; phase III trial revealed an increase in heart attacks associated with this drug Inhibits TNF production 6) Neuroprotection Riluzole, Insulin-like growth factor (IGF-1) Eliprodil Phase I Preclinical testing Prevent neuronal death Prevent neuronal death 7) Reduces gliosis Pirfenidone Phase I Prevents gliosis, blocks TNF synthesis

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Page 393 8) Promote remyelination IGF-1 Phase I Promotes oligodendrocyte survival and maturation of precursors in vitro Intravenous immunoglobulin Unlabelled use in the U.S. and Europe, Phase III Promote remyelination Oligodendrocyte grafts Preclinical testing Promote remyelination Eliprodil Preclinical testing Promote remyelination

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Page 394 ONGOING CLINICAL TRIALS FOR MEDICATIONS IN DEVELOPMENTAS OF AUGUST 2000 Trade Name Generic Name Company Phase a About the trial Source Anergix HLA-DR2 MHC II Corixa I Anergix consists of complexes of MHC Class II molecules, called Soluble DR2-MBP84-102 Complexes. The complexes contain autoantigenic peptides that shut down the MBP reactive T cells that damage myelin components, without compromising other T cells required for immune protection of the individual taking the drug. The phase I trial in chronic progressive MS was completed by Anergen in 1998. Anergix was shown to be safe and well tolerated with no signs of generalized immune suppression. Corixa is looking for a partner to initiate Phase II. PhRMA (Pharmaceutical Research and Manufacturers of America) Database b Antegren Natalizumab Elan CorporationAthena Neurosciences II Antegren is a humanized antibody that blocks a receptor on leukocytes and thus blocks their migration into the brain. This can reverse paralysis and reduce myelin destruction in the EAE animal model of MS. Ongoing phase II testing has shown that patients treated with Antegren showed a significant reduction in new brain lesions over 12 weeks. PhRMA Database, UCSF MS Center c Fampridine d Neurelan 4-Amino pyridine Acorda Therapeutics II Fampridine's major action is to block specialized potassium channels on axons. In a demyelinated axon, large numbers of potassium channels are exposed, and nerve transmission is impaired. Fampridine has been shown to increase nerve conduction in impaired and demyelinated axons, and to result in improved neurological function in animal and in vitro studies. A phase II trial was successfully completed in 1998, and additional phase II trials are underway. FDA—Office of Orphan Products Development

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Page 395 Leukarrest HU23F2G recombinant humanized MAb ICOS II Leukarrest is a humanized antibody that impedes white blood cell movement from the blood stream to the surrounding tissue by binding to CD 11 and CD 18 on the white blood cell surface. Two phase II trials were recently completed in patients with acute symptomatic episodes of MS. PhRMA Database Leustatin 2-CDA / Cladribine Ortho Biotech III Cladribine is a potent immunosuppressive drug that has been shown to decrease total lymphocyte count and CD4, CD8 and CD19 subsets. Cladribine may benefit people with Chronic Progressive MS, according to the results of a pilot study, but toxicity is a concern. PhRMA Database, FDA Myotrophin Insulin-like growth factor I (IGF-I) Cephalon I IGF-1 promotes the proliferation, differentiation and survival of oligodendrocytes, and reduces inflammation and TNF-alpha induced oligodendrocyte and myelin damage. IGF-I treatment has been shown to reduce lesion severity and promote myelin regeneration in the experimental autoimmune encephalomyelitis (EAE) model. Cephalon is developing Myotropin for use in amyotrophic lateral sclerosis (ALS), and is exploring the drug's potential for use in MS. ClinicalTrials.gov Database, e UCSF MS Center Novantrone Mitoxantrone Immunex III Novantrone suppresses T cells and B cells, which are key components of the immune system and multiple sclerosis. Immunex has filed a new drug application (NDA) with the FDA for approval to label Novantrone for use in treatment of secondary progressive MS. The FDA has assigned priority review status to the application, indicating that the FDA will act on the application within 6 months of the June 7, 1999 filing date. On January 28, 2000, the FDA Peripheral and Central Nervous System Drugs Advisory Panel unanimously recommended that Novantrone be approved. PhRMA Database Deskar Pirfenidone Marnac I Pirfenidone is an anti-fibrotic agent which is also in clinical trials for pulmonary fibrosis. It acts to inhibit the production of tumor necrosis factor (TNF), and reduces gliosis and astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. UCSF MS Center

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Page 396 Rebif Recombinant interferonbeta-1a Serono Laboratories III Rebif has been approved by the European Commission for the treatment of Relapsing Remitting Multiple Sclerosis. The FDA has upheld the Orphan Drug Act and has not granted approval to Rebif. The FDA also had questions about the data filed in the marketing application, which prevented granting tentative approval. If tentative approval is received, Rebif could enter the US market in 2003, when the exclusivity periods for Avonex and Betaseron end. PhRMA Database Rilutek Riluzole Rhone Pulenc Rorer I Rilutek is neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. In in vitro tests, Riluzole protected cultured rat motor neurons from the excitotoxic effects of glutamic acid and prevented the death of cortical neurons induced by anoxia. UCSF MS Center Taxol Paclitaxel Angiotech II Paclitaxel is an immuno suppress ant. According to preliminary results from the treatment extension phase of the phase I/II clinical study of paclitaxel for the treatment of secondary progressive multiple sclerosis, patients showed a significant improvement in all tests undertaken. Study measures included functional testing, quality of life measures and changes in the amount of brain tissue scarring demonstrated by magnetic resonance imaging (MRI). A 189 patient, phase II clinical study is underway. UCSF MS Center

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Page 397 TM27 ATM027 humanized Mab Astra Zeneca/ Avant Immuno-Therapeutics I/II T Cell Receptor Monoclonal Antibody (MAb) under development. Astra Zeneca has discontinued the development of this T cell antigen receptor monoclonal antibody because results of a phase II trial suggested that the reduction of disease activity in the trial was not sufficient to warrant further study. The company is considering whether to development the T cell antigen receptor peptide as a MS vaccine. PhRMA Database Thalidomide Thalomid Andrulis Pharmaceuticals II Thalidomide suppresses the production of cytokines that are found in the cerebrospinal fluid of patients with MS, and especially Chronic Progressive MS. PhRMA Database Zenapax Daclizumab Interleukin-2 Receptor Alpha humanized Mab Hoffman-La Roche, Inc. I/II Zenapax binds to protein receptors on lymphocytes, keeping them from interacting with interleukin-2, a substance necessary for their growth. As a result, the T lymphocytes are unable to attack the myelin sheath. Zenapax was developed as an immune modulating drug for use after transplantation. In two Phase III clinical trials, Zenapax was effective in reducing the incidence of acute rejection episodes within six months of kidney transplantation, the primary endpoint, when administered with standard immunosupressive drug regimens. ClinicalTrials.gov Database BB-3644 British Biotech/ Schering Plough I BB-3364 is a matrix metalloproteinase (MMP) inhibitor that also inhibits leukocyte migration to the CNS. Its development is based on the theory that MMPs may contribute to the pathology of MS. BB-3644 also inhibits tumor necrosis factor production. UCSF MS Center IR 208 therapeutic vaccine Immune Response Corporation I The vaccine consists of an immunostimulant, Incomplete Freund's Adjuvant, combined with synthetic peptides. The vaccine is designed to halt the T-cell attack on myelin by shutting down specific T cells and inhibit further damage. PhRMA Database

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Page 398 MSP-771 Neurocrine Biosciences/ Novartis II MSP-771 is an altered peptide ligand based on the immunodominant epitope of human MBP. Immune responses directed against this epitope may be involved in the pathogenesis of MS. In vitro, MSP-771 fails to induce T-cell proliferation and selectively reduces the production of inflammatory cytokines by pathogenic T cells. In the EAE model, MSP-771 markedly reduces the severity of disease and induces a specific T-cell response that down-regulates the inflammatory process. The molecule was well tolerated in a phase I study, with the most common side effect being local, transient injection site reactions. The primary endpoint in current clinical trials is the progression or regression of lesions in the brains of these patients as measured by MRI. As a secondary endpoint, clinical investigators will look for the generation of a protective immune response as shown in the Phase I trials. PhRMA Database Interleukin-10 (IL-10) Schering-Plough I/II IL-10 has a number of inhibitory functions such as inhibiting interferon g production, antigen presentation, and the production by macrophages of the cytokines IL-1, IL-6 and TNFa. UCSF MS Center DEFINITIONS Preclinical testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety. Phase I. Tests that involve about 20 to 80 normal, healthy volunteers. The tests study a drug's safety profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, metabolized, and excreted as well as the duration of its action. Phase II. Controlled trials of approximately 100 to 300 volunteer patients (people with the disease) assess a drug's effectiveness. Phase III. Tests involving 1,000 to 3,000 patients in clinics and hospitals. Physicians monitor patients closely to confirm efficacy and identify adverse events.

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Page 399 aClinical trial phases are defined at the end of this table. bThe PhRMA (Pharmaceutical Research and Manufacturers of America) Database lists only clinical trials being conducted in private firms in the U.S. Clinical trials at academic health centers and universities are not included. chttp://mscenter.ucsf.edu dListed as an orphan drug by FDA, http://www.fda.gov/orphan. e The ClinicalTrials.gov Database contains clinical studies sponsored primarily by the National Institutes of Health. In the future, additional studies from other Federal agencies and the pharmaceutical industry will be included.

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Page 400 Drugs Used to Treat Various Symptoms: Overview Bladder Control Capsaicin Desmopressin Detrol Dicyclomine hydrochloride Hyoscyamine Imipramine Oxybutynin chloride Propantheline bromide Depression Amitriptyline Bupropion hydrochloride Imipramine Nortriptyline Paroxetine Fluoxetine hydrochloride Sertraline Dysesthesia-Paresthesia, trigeminal neuralgia, pruritis Amitriptylene Carbamazepine Gabapentin Hydroxyzine Phenytoin Erectile Dysfunction-Impotence Sildenafil citrate Alprostadil Papaverine Fatigue Amantadine Fluoxetine hydrochloride Modafinil Pemoline Inflammation Azathioprine Dexamethasone Methylprednisolone Prednisone Optic Neuritis Methylprednisolone Prednisone Decadron Seizures Carbamazepine Klonopin Gabapentin Phenytoin Spasticity and Tremor Baclofen Botulinum Toxin A Klonopin Dantrolene Gabapentin Urinary Tract Infections Methenamine Vertigo Meclizine hydrochloride

Representative terms from entire chapter:

phase iii