Understanding How Existing and Emerging MS Therapies Work

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1 Understanding How Existing and Emerging MS Therapies Work This is a promising and hopeful time in the field of multiple sclerosis (MS). Many new and different therapies are nearing the final stages of research. Some may soon be approved for treating MS patients in the United States. Learning how MS treatments work may help you better understand your current therapies or help you make an informed decision if alternative options become available. How does MS cause damage in the body? The brain and spinal cord make up the central nervous system (CNS). There, information is passed between nerve cells (neurons) along tiny fibers, a bit like electrical wiring. These nerve fibers have a protective coating known as myelin. The myelin is necessary for messages between nerves to be transmitted correctly. In MS, damage is believed to be caused by a malfunction of the immune system, which includes white blood cells (including T cells and B cells) that fight invaders such as infections. For unknown reasons, in people with MS these cells enter the CNS. In MS, immune cells attack the myelin coating of the nerve fibers, or axons, and cause swelling, or inflammation. If the inflammation is severe, the axon or nerve fiber may be damaged, and the nerve cell dies. Nerve function is important to the functioning of the entire body. In MS, nerve damage can affect vision, thought processes, bowel and bladder function, muscle and motor function, sensation, and many other body systems. The immune system: Going a bit deeper MS is called an autoimmune disease because the body basically attacks itself. Although we don t know exactly why immune cells attack necessary parts of the body, researchers have learned much about the way certain immune cells behave. T cells and B cells, the main immune cells involved in MS, have several subtypes. For example, the category of T cells includes helper T cells, regulatory T cells, cytotoxic T cells, and others. All T and B cells originate in the bone marrow. When the body senses an invader, immune cells are recruited from the bone marrow. They circulate through the bloodstream to the site where they are needed. Certain changes can occur within the immune cells, causing them to become activated. This affects their behavior in relation to an invader and other types of cells. For immune cells to attack myelin, they must first cross the blood brain barrier, a cellular barrier in the circulatory system that helps protect the brain and nervous system. Many types of bacteria, viruses, and drugs are incapable of crossing the blood 1

2 brain barrier; they can exist in the bloodstream, but not reach the tissues of the brain or spinal cord. How do current MS treatments work? The way a particular drug works is called its mechanism of action. In MS, there are many sites in the body where the disease process can be interrupted. Most MS drugs work by more than one mechanism. The exact mechanisms at work in MS are not completely understood. Interferons Drugs for MS in the category of interferons include: Interferon beta-1a, intramuscular Interferon beta-1a, subcutaneous Interferon beta-1b An interferon is a protein that occurs naturally in the body. Interferons are thought to work by reducing inflammation in the CNS (Table 1). Interferons used to treat MS are made by duplicating these proteins. People who take interferons need regular blood tests to check their blood cell count and liver and thyroid function. Glatiramer acetate This medicine is an antigen-based therapy for MS. An antigen is one of the substances that triggers an immune response in the body. T cells and B cells have receptors for certain antigens on their surfaces. Like interferons, glatiramer acetate reduces inflammation in the CNS. With any injectable therapy for MS, skin reactions and other injection-related problems can occur. These can be minimized by practicing proper injection technique. Natalizumab Natalizumab is the first monoclonal antibody (mab) to be approved for MS. (It is approved for relapsing forms of MS and is generally used as a second-line treatment). In the body, the role of antibodies is to recognize and fight a foreign invader by recognizing the antigen in the infected cell. In MS, mabs reduce or eliminate specific targets to limit the attack on myelin. Risk of infection has been the main safety concern with natalizumab, particularly the risk for a rare and dangerous viral infection of the brain called progressive multifocal leukoencephalopathy (PML). People who are taking this drug must be monitored carefully for signs of PML and other safety risks. Immunosuppressants During a flare-up or relapse of MS, or if the disease appears to be getting worse, treatments may be used to further suppress immune function. These include: Oral steroids (prednisolone or prednisone) Intravenous (IV) steroids such as methylprednisolone Mitoxantrone, a form of chemotherapy Cyclophosphamide, also a form of chemotherapy; not approved for MS by the US 2

3 Food and Drug Admistration (FDA), but occasionally used to treat progressive forms of MS Immunosuppressants often have more side effects, such as an increased risk of infection, that limit their long-term use. Bone marrow transplant Immune cells are formed in the bone marrow. Removing bone marrow and allowing new cells to regrow should, ideally, reset the immune system. This is the basic theory behind bone marrow transplant (BMT) in MS. In this procedure: The patient s own stem cells are harvested Intensive chemotherapy is used to destroy immune cells Harvested stem cells are transplanted back into the patient to reboot the immune system Research is beginning to show that BMT holds promise as a treatment for MS. Larger, long-term studies are needed to show how BMT affects MS patients over time. Emerging therapies for MS Several new medicines for MS are under development. Several are awaiting FDA approval, a designation which means that the safety and efficacy of these drugs has been established. Although the approval process may seem to take too long, it is necessary to help protect patients from possible harm. Oral therapies for MS Each of the oral therapies being studied in MS works in a different way to modify the immune system. Some therapies are taken alone and others are used along with an injected MS drug. Table 2 shows some of the oral therapies under study and how they are thought to work. Monoclonal antibodies In addition to natalizumab, other mabs are being studied. Some may be highly effective for treating MS but also have serious safety concerns. A few of the mabs being studied for use in MS are listed in table 2. Weighing the risks and benefits of emerging therapies If new treatments are approved, deciding which treatment is right for each person may be challenging. Newer drugs do not have the long-term safety record of existing medicines. Over time, unforeseen problems and risks could appear with these newer agents. Some may require careful monitoring, involving regular blood tests. Every person with MS is different there is no one-size-fits-all in the treatment for this disease. As we learn more about the way new treatments work, it may be possible to tailor therapy to each patient. In the meantime, patients with MS must work with their healthcare providers to decide which treatment is best suited to their unique situation. 3

4 Table 1: Approved Treatments for MS Drug name Taken as: Thought to work by: Main safety concerns: Interferon beta-1a Intramuscular Injection 1 time/week Interferon beta-1a Subcutaneous injection 3 times/week Preventing activation of immune cells that attack myelin Injection-site reactions, including complications related to injection; flu-like symptoms Interferon beta-1b Subcutaneous injection every other day Preventing immune cells from crossing the blood brain barrier Liver and thyroid function and blood counts must be monitored Glatiramer acetate Subcutaneous injection every day Modifying T cells specific to myelin to prevent attack Skin and injectionsite reactions Enhancing helper T cells Natalizumab Intravenous infusion every 4 weeks Preventing immune cells from crossing the blood brain barrier Increased infection risk, including PML (dangerous and potentially fatal viral infection of the brain) 4

5 Table 2: Experimental Treatments for MS Drug name Taken as: Thought to work by: Main safety concerns: ORAL DRUGS Cladribine Oral, 2 to 4 cycles per year Depleting T cells by causing cell death Infections, reproductive risks, malignancies Fingolimod Oral, daily Trapping T and B cells temporarily in lymph nodes Fumarate Oral, daily Suppressing cell reaction that destroys nerve cells Teriflunomide Oral, daily Decreasing T and B cells Laquinimod Oral, daily Promoting antiinflammatory cell development Cardiac problems (slowed heartbeat), breathing problems, infections Mainly digestive (diarrhea, vomiting), headache, fatigue Reproductive risks Increases in liver enzymes MONOCLONAL ANTIBODIES Alemtuzumab IV infusions (optimal cycle in MS to be determined) Targets a surface antigen on many immune cells to neutralize their effect Autoimmune thyroid disease; disrupted blood clotting, including serious blood platelet disorder; infections; infusion reactions Ocrelizumab (Variation of rituximab) IV infusions (optimal cycle in MS to be determined) Binds to a surface antigen on B cells to temporarily deplete them Fever, breathing problems, fast heart rate, rash; infection risk including PML Daclizumab IV infusions every 4 weeks Binds to IL-2, an immune signaling cell, to deplete T and B cells Skin reactions; possible increased severity of common infections 5

6 Resources Multiple Sclerosis Association of America. All About MS. Available at National Multiple Sclerosis Society. MS Learn Online Feature Presentation Research News on Oral Therapies. Available at National Multiple Sclerosis Society. What We Know About MS: Treatments. Available at: National Multiple Sclerosis Society. Bulletins from clinical trials of new MS therapies. Available at 0 National Multiple Sclerosis Society. About MS. Available at Coyle PK, Halper J. Living With Progressive Multiple Sclerosis: Overcoming the Challenges. Second Edition. Demos Medical Publishing: New York Book available at 6