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Drug Criteria & Outcomes
The dangerous fight against plaque: The use of natalizumab in the treatment of multiple sclerosis
By Alison R. McGriff, PharmD Candidate
McWhorter School of Pharmacy, Samford University, Homewood, AL
A chronic inflammatory disease that affects the central nervous system, multiple sclerosis (MS) is one of the leading causes of neurologic disability in young and middle-aged adults. Although approximately 350,000 people in the United States are afflicted with this degenerative disease, much is still unknown about MS.1,2
MS is typically diagnosed between the ages of 20 and 45 years, with women being more commonly affected than men (ratio of approximately 2:1). Men typically present with signs of the disease at a later age than women. Furthermore, the course of MS in males is more likely to be progressive.1,2
MS is one of a broad category of demyelinating diseases that affect the central nervous system (CNS). It is theorized that MS results from an autoimmune attack, mediated by T-helper cells, against the myelin sheath located in the CNS.1,2 The myelin sheath is a fatty material that insulates the neuronal axon and allows it to transmit an impulse rapidly.3 In this disease the myelin sheath is stripped from around the neuronal axons in multiple areas of the CNS. This demyelination, coupled with an inflammatory response, leads to the formation of the characteristic MS lesions.1 These characteristic lesions appear as hardened, sclerotic (scarred) plaques and are found primarily in the brain, spinal cord, and optic nerves. MS plaques cause disruption of the transmission of nerve impulses, which results in a neurological deficit.1,3
Symptoms and Clinical Course
The presentation of symptoms of the disease is dependent on the exact location of the scarring.1,3 These signs and symptoms are usually divided into three categories: primary, secondary, and tertiary symptoms.
Primary symptoms are directly caused by the demyelination and axonal damage occurring in the CNS and tend to reflect the areas that have been damaged. Some examples of primary symptoms are gait difficulties, spasticity, tremor, bowel and bladder disturbances, major depressions, sexual dysfunction, fatigue, and sensory motor symptoms.
Secondary symptoms are difficulties that result from primary symptoms. An example of a secondary symptom would be multiple broken bones resulting from repeated falls due to the primary symptom of gait disturbance.
Finally, tertiary symptoms refer to the effect of MS on a patient's quality of life. Although a cure for this devastating disease is still unavailable, many advances have been made in treating and managing the complications associated with MS.1
The clinical course of MS is divided into four categories: relapsing-remitting, primary-progressive, secondary-progressive, and progressive-relapsing. When the disease process begins, most patients have attacks (acute exacerbations) followed by remissions. An MS attack is defined as new symptoms lasting at least 24 hours and separated from other new symptoms by at least 30 days. These attacks are referred to as relapses, and this course of the disease is referred to as relapsing-remitting MS (RRMS).
Early in the disease, neurologic recovery after an attack is often quite good; however, after repeated relapses, recovery usually is less complete. Most RRMS patients will enter a progressive phase of the disease in which attacks and remissions are hard to distinguish. This is known as secondary-progressive MS (SPMS). During this phase disability tends to accumulate more significantly.
Some patients never experience the acute attacks and remissions that are commonly seen at the outset of the disease, but experience a progressive form of the disease from the start. This is known as primary-progressive MS (PPMS). With this disease course, symptoms may worsen rapidly or slowly and an accumulation of disability is seen over time.
Finally, some patients may have a mixture of both progression and relapses. This is referred to as progressive relapsing MS (PRMS).1
Treatment of MS is divided into three categories: management of symptoms, treatment of acute attacks, and therapies designed to modify the disease process.
Symptomatic therapy is extremely important in this disease. Control of the pain; spasticity; bowel, bladder, and erectile dysfunction; emotional liability; depression; fatigue; etc, can greatly improve the patient's quality of life. It is also imperative to treat the severe exacerbations that occur in MS patients. Treatment of acute exacerbations will shorten the duration and possibly decrease the severity of the attack. It appears, however, that the most crucial part of the treatment for MS is with disease-modifying agents. Disease-modifying therapies alter the course of the illness and are most important to slow progression of disability over time.1,2
When a patient is diagnosed with relapsing MS, many physicians begin disease-modifying therapy with Betaseron® (interferon-b-1b), Rebif® (interferon-b-1a), Avonex® (interferon-b-1a), or Copaxone® (glatiramer acetate).1 These drugs are given either subcutaneously or intramuscularly from once to seven times weekly.1,2 All four of these agents reduce the rate of relapse by approximately one-third; however, neither interferon-b-1b nor glatiramer acetate has significant effects on the progression of disability in patients with relapsing disease.4
If progression of the disease continues while a patient is on one of these agents, an immunosuppressive drug may be tried. Novantrone® (mitoxantrone) is approved for use in SPMS, PRMS, and worsening RRMS to reduce neurologic disability and the frequency of clinical relapses. Other therapies that are currently utilized and have been shown to produce a modest effect in MS patients are cyclophophamide, cyclosporine, azathioprine, and methotrexate.1 Although these drugs are the first-line treatment of choice for relapsing MS, a promising new treatment option has become available over the last few years.
Tysabri® (natalizumab), a once-monthly infusion, was approved by the FDA in November 2004 for the treatment of relapsing forms of MS.5,6 Natalizumab belongs to a new class of drugs known as adhesion-molecule inhibitors.4,6 In MS, the inflamed demyelinated lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier. Natalizumab is a humanized monoclonal antibody that blocks the essential interaction that must occur before the T-lymphocytes can cross the blood-brain barrier.7 The ability of this drug to suppress T-lymphocyte entry into the CNS is what mediates its benefit in MS.6
In a randomized, placebo-controlled clinical trial of natalizumab for relapsing MS (AFFIRM study), natalizumab significantly reduced the risk of sustained progression of disability and the annualized rate of clinical relapse over two years of treatment. At one year, natalizumab reduced the annualized relapse rate to 0.26, as compared with 0.81 relapse per year in the placebo group (P < 0.001). After two years of treatment, the cumulative probability of disease progression was 17% in the natalizumab group and 29% in the placebo group (hazard ratio, 0.58; 95% confidence interval, 0.43-0.77; P < 0.001).4,7 The onset of natalizumab's therapeutic effect appears to occur at approximately six weeks, and the most common adverse effects encountered were fatigue and allergic reaction.4,6
Although natalizumab appeared to be a groundbreaking new drug, on March 1, 2005, all investigational and commercial administration of this dug was stopped by the manufacturer, Elan and Biogen Idec, when they were notified of the development of two cases of progressive multifocal leukoencephalopathy (PML) in patients treated with this drug for MS.4,8 PML is a demyelinating disease caused by the human polyomavirus JC virus, and is most frequently encountered in patients with immunodeficiency.5 Both patients who presented with PML had received more than two years of therapy with natalizumab in combination with interferon-b-1a in a separate trial. An additional case of PML was later identified in a patient with Crohn's disease who had received eight infusions of natalizumab as montherapy.4,8
After a detailed review of more than 3,700 patients treated with natalizumab failed to disclose additional cases of PML, the drug was re-released as monotherapy for patients with relapsing MS in July 2006 — with a black box warning about PML and some modified prescribing guidelines. The prescription of natalizumab is now restricted to only those pharmacies and infusion centers participating in the TOUCH program, a mandatory education, monitoring, and reporting program managed by the manufacturer.4
Although natalizumab is now back on the market as monotherapy, no formal guidelines for its place in MS therapy have been provided. For now, this drug should be suggested only for patients with: 1) active inflammatory disease (one or more relapses within the previous year) and 2) documented evidence that alternative medications have been ineffective or poorly tolerated. Although natalizumab appears to be a promising new drug, the standard treatment modalities for MS should be tried before considering this new drug as an option. Also, patients beginning treatment with natalizumab should have taken no immunosuppressive medications in the previous three months, they should have no immunodeficiency disorders, and their leukocyte counts should be normal.6
Although further clinical trials need to be conducted to continue to evaluate the safety of this drug and help determine its place in MS treatment, natalizumab has the potential to improve the quality of life for numerous patients. With this innovative new drug back on the market, patients suffering with multiple sclerosis may have a brighter future ahead.