Research News
Tysabri® (Natalizumab) Update
Tysabri is Released and Subsequently Suspended From the Market
Tysabri is the latest drug approved for the treatment of MS, having been released for use in the United States in November 20041. Tysabri is a humanized monoclonal antibody and is designed for patients with relapsing forms of multiple sclerosis. It prevents the inflammatory phase of MS by blocking activated leukocytes from crossing the blood-brain barrier (BBB).
Biogen Idec and Elan Pharmaceuticals, the companies licensed to manufacture and commercialize Tysabri®, voluntary suspended marketing of the drug2 on February 28, 2005. The decision to voluntarily suspend the marketing of Tysabri was based on reports of dramatic events occurring in two patients who were treated with both Tysabri and Avonex (interferon beta-1a). Both patients were confirmed as having Progressive Multifocal Leukoencephalopathy (PML), and one of the patients died.
PML is a viral disease occurring in immuno-suppressed patients. Both patients were enrolled in a long-term clinical trial, receiving Tysabri in combination with Avonex for more than two years. More recently, a third person who was a patient in an open label Crohn's disease clinical trial was diagnosed with PML postmortem. This latter case is still under investigation.
Biogen Idec and Elan Pharmaceuticals are currently conducting an extensive evaluation of all patients treated with Tysabri in clinical trials for multiple sclerosis, Crohn's disease (an inflammatory disease of the small intestine and colon), and rheumatoid arthritis. The result of this analysis will decide Tysabri's future. Biogen Idec and Elan could reconsider the dosage of Tysabri, change the elective patients for the treatment, or remove the drug from the market. The pharmaceutical companies reported no cases of PML in patients treated only with Avonex.
Progressive Multifocal Leukoencephalopathy
Progressive Multifocal Leukoencephalopathy (PML) is a fatal viral disease of the Central Nervous System (CNS), which consists of the brain and spinal cord. PML is characterized by demyelination in white matter, or destruction of the oligodendroglial cells which make the myelin sheath covering of the nerve cells of the brain. This demyelination occurs at the same time at numerous locations in the brain (multifocal).
Symptoms of PML include vision loss, speech disturbances, ataxia (inability to coordinate movements), paralysis, and ultimately coma. PML affects patients with suppressed immune systems, including patients with cancers such as leukemia or lymphoma.
The cause of PML is the activation of the polyoma virus known as "JC Virus." As many as 80 percent of healthy adults could be carriers of the inactivated (latent) form of the JC Virus. When a carrier becomes immuno-compromised, the virus has the opportunity to become activated.
What is Tysabri?
Tysabri is an immunomodulator, which is an agent that reduces the body's immune responses. It was the sixth disease-modifying treatment approved by the FDA to treat the inflammatory phase of multiple sclerosis.
Tysabri is a humanized monoclonal antibody, engineered and produced in the laboratory. Originally derived from a mouse antibody, Tysabri is 80 percent human in sequence. Tysabri is also known as a laboratory-produced immunoglobulin (Ig). Naturally occurring immunoglobulin is a protein that is manufactured in the blood by lymphocytes (a type of leukocyte, which is a white blood cell that helps to fight disease).
Immunoglobulins function as antibodies, which are molecules that react only to a specific substance called an antigen. Antigens are present on the surface of bacteria and toxins that enter the body. Each antigen induces a specific immune response.
The monoclonal antibody Tysabri specifically identifies a region of the integrins alpha4 beta1 (a4b1) known as the alpha4 (a4) subunit. Alpha4 integrin is a cell-surface protein present on the surface of all leukocytes (except a type called neutrophils).
How does Tysabri work?
Tysabri's strategic design is based on the following observation: during MS exacerbations, lymphocytes and monocytes (two types of leukocytes) from the blood stream cross the blood-brain barrier (BBB) and enter the central nervous system (CNS). With MS, these leukocytes migrate into the CNS, where they begin an attack on the body's own myelin (nerve covering) and nerves, causing inflammation.
In order for lymphocytes and monocytes to cross the BBB, they need to recognize a specific site on the wall of the blood vessel. Among them is the "vascular cell adhesion molecule-1" (VCAM-1). By binding a4-integrin (located on the leukocytes' surface) and VCAM-1 (located on the vascular endothelial cells' surface), leukocytes are able to latch onto and then penetrate through the BBB.
By analogy, a4-integrin is the key and VCAM-1 is the lock. Working together, they open the door from the blood stream, across the BBB, and into the CNS. Once in the CNS, the leukocytes initiate an inflammatory cascade leading to the release of inflammatory molecules and the recruitment of additional lymphocytes and monocytes. This subsequently causes an increase in inflammation and eventual demyelization.
The mission of Tysabri is to block the key (a4-integrin) on the leukocytes' surface. By doing so, Tysabri prevents the disease-fighting cells from crossing the BBB to the brain and spinal cord. Instead, the leukocytes remain in the blood stream and therefore the inflammatory cascade is interrupted. As a result, this process may reduce or prevent the formation of new sclerosis (or damage to the nerves).
How Tysabri Differs from Other Disease-Modifying Agents Approved for MS
Before the release of Tysabri, five drugs were available to the practitioner to prescribe to his or her patients. Four are immunomodulatory drugs: Betaseron® (interferon beta-1b), Rebif® and Avonex® (interferon beta-1a), and Copaxone® (glatiramer acetate).
The immunomodulators, by various approaches, regulate the immune activation involved during the inflammatory process of an attack. In contrast to Tysabri, these drugs are not pharmacologically focused on one event of the attack, but rather contribute to affect several aspects of the exacerbation and immune responses to the disease.
The fifth drug available for MS is Novantrone® (mitoxantrone), which is a chemotherapeutic agent. As a chemotherapeutic drug, Novantrone indiscriminately destroys all rapidly dividing cells in the organism, including those in the immune system. It is seen as an immunosuppressant; usually prescribed for worsening disease in spite of treatments with the immunomodulating drugs.
Tysabri's action is quite different from the other immunomodulator drugs. Tysabri was designed to reduce new lesion formation and to limit the progress of evolving lesions, acting before the irreversible destruction of the CNS tissue occurs. Tysabri is a pharmacological agent specifically targeting the lymphocytes and monocytes involved in inflammation, by preventing them from reaching the CNS. More specifically, Tysabri is targeting the alpha4 beta1 integrin present at the lymphocytes surface.
The Consequences of Tysabri's Withdraw
While the contribution of Tysabri remains unknown on the development of PML, Tysabri's withdraw jeopardizes the future of eleven other drugs under development which use alpha4 beta1 integrin as a target. Five of these are designed to fight MS.
Drugs targeting the alpha4 beta1 integrin have been studied since 1995. This strategy seemed to be very promising and generated lots of excitement in the pharmaceutical industry. If the Tysabri withdraw becomes permanent, then the development and approval of other alpha4 beta1 integrin antagonists would be more difficult.
After the investigation, should Tysabri be shown to cause PML, Biogen Idec and Elan Pharmaceuticals may still ask the FDA if Tysabri may go back on the market with a "black box" on its label. This would warn doctors and patients that the medication could cause fatal complications in a certain percentage of patients. The black box warning allows doctors and consumers to decide what risks they are willing to take.
Written by Christian CD Poncet, PhD
Comments and questions are welcome.
References:
1. The FDA is reporting this suspension at www.fda.gov (search for natalizumab)
2. Tysabri's Website: www.tysabri.com;
Biogen Idec help line: (800) 456-2255
