Experimental MS Drug Shows Promise

February 13, 2008 News Office: Jennifer O'Brien (415) 476-2557

A drug therapy currently used to treat non-Hodgkin's lymphoma and rheumatoid arthritis had a significant effect in treating the most common form of multiple sclerosis in a small, short-term clinical trial.

Because the drug targets the immune system's B-cells, rather than the immune system's traditionally targeted T-cells — long considered the primary culprit — the finding provides a new insight into the cause of the disease, researchers say.

The study, reported in the Feb. 14 issue of the New England Journal of Medicine showed that the drug rituximab dramatically reduced the number of inflammatory lesions that form along nerve fibers in patients' brains — the hallmark of the disease. It also significantly decreased the clinical symptom of the disease — sporadic, temporary disruptions in certain neurological functions, such as mobility in a limb or vision in an eye. The study of the drug, which is administered by infusion, was a 48 week, phase II trial.

"The magnitude and rapidity of the drug's effect suggest that therapies targeting B-cells may provide an important treatment strategy if proved effective and safe in larger and longer-term clinical trials," said the principal investigator of the multi-center study, Dr. Stephen L. Hauser, a neurologist at UCSF Medical Center and chair of the Department of Neurology at UCSF. "These findings shift the perspective on the cause of MS and open up a new frontier for investigation."

Autoimmune Disease

MS is thought to be an autoimmune disease, a condition in which one or more types of cells of the immune system turn against a tissue of the body. MS specifically occurs when the immune system attacks myelin, the protective insulating sheath that surrounds nerve fibers in the central nervous system, leaving scars of hardened sclerotic patches called plaques in multiple places within the brain and spinal cord. Nerve fibers allow the transmission of electrical impulses between the nerve cells and damage to the myelin disrupts this transmission, affecting neurological function.

Since the early 1970s, scientists have focused on the role of T-cells in MS, and all currently available therapies target these cells, some quite successfully. Rituximab targets B-cells, specifically, those with a protein on their surface known as CD20.

B-cell Depletion

Hauser and his team, including Dr. Emmanuelle Waubant, proposed the clinical trial based on accumulating evidence by UCSF scientists and a handful of other teams during the last decade that CD20+ B-cells and related pathways played a central role in damaging the myelin sheath.

The discovery that B-cell depletion has such an impact on MS is "a beautiful proof of principal," Hauser said. "It signals a paradigm shift in our understanding of how MS develops."

Genentech Inc. and Biogen Idec, which market rituximab (Rituxan), sponsored the trial, co-designing the study and analyzing the data. The trial was conducted at 32 medical centers in the United States and Canada, and involved 104 patients, 69 of whom received the drug and 35 of whom received a placebo. It was a "double blind" study, meaning that neither the physicians nor patients knew who received rituximab and who received placebo.

The trial focused on patients with relapsing-remitting MS, the most common form of the disease. Patients with this condition have acute flare-ups of inflammation in the myelin sheath that lead to temporary neurological malfunctions. Once the attacks pass (usually within days or weeks), patients regain most, if not all of their previous function. However, residual damage (permanent scarring, loss of myelin, and injury to neurons' axons that together can result in the progressive loss of neurological function) remains and accrues with each attack, ultimately leading to a progression of disability.

Participants in the study received one course of rituximab, intravenously, and were examined regularly with brain scans and clinical evaluations. At the primary endpoint, week 24, those receiving the drug had a 91 percent reduction in inflammatory lesions and a 58 percent reduction in the number of relapses, compared to patients receiving placebo. Results were comparable at week 48. Adverse events were comparable between both groups.

While the mechanism by which the rogue CD20+ B cells exact their toll is unknown, their depletion had such a quick impact on the disease that they could not be acting by calling up their key ammunition — antibodies, Hauser said.

"There wouldn't have been time for the cells to produce these chemicals."

Rather, he says, B-cells circulating in the blood, probably in conjunction with T-cells, must be driving the inflammation causing the demyelination and scarring in the myelin sheath by some yet to be determined means.

Numbness

Numbness of the face, body or extremities (arms and legs) is one of the most common symptoms of MS. Often it’s the first symptom experienced by those eventually diagnosed with MS. The numbness may be mild or so severe that it interferes with the ability to use the affected body part. For example, a person with very numb feet may have difficulty walking. Numb hands may prevent writing, dressing, or holding objects safely.

Caution Advised Regarding Eating and Hot Objects

People with MS who have severe facial numbness should be very careful when eating or chewing, as they may unwittingly bite the inside of their mouth or tongue. People with numbness over other parts of the body should be careful around fires, hot water and other sources of heat, as they may suffer a burn without realizing it.

There are no medications to relieve numbness. Fortunately, however, most instances of numbness are not disabling, and tend to remit on their own. In very severe cases, a neurologist may prescribe a brief course of corticosteroids, which often can temporarily restore sensation.

What is Multiple Sclerosis?

Multiple sclerosis (or MS) is a chronic, often disabling disease that attacks the central nervous system (CNS), which is made up of the brain, spinal cord, and optic nerves. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another. Today, new treatments and advances in research are giving new hope to people affected by the disease.

MS is Thought to be an Autoimmune Disease

The body’s own defense system attacks myelin, the fatty substance that surrounds and protects the nerve fibers in the central nervous system. The nerve fibers themselves can also be damaged. The damaged myelin forms scar tissue (sclerosis), which gives the disease its name. When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing the variety of symptoms that can occur.

Most people with MS learn to cope with the disease and continue to lead satisfying, productive lives.

The Four Courses of MS

People with MS can typically experience one of four disease courses, each of which might be mild, moderate, or severe.

• Relapsing-Remitting MS
  People with this type of MS experience clearly defined attacks of worsening neurologic function. These attacks—which are called relapses, flare-ups, or exacerbations —are followed by partial or complete recovery periods (remissions), during which no disease progression occurs. Approximately 85% of people are initially diagnosed with relapsing-remitting MS.
• Primary-Progressive MS
  This disease course is characterized by slowly worsening neurologic function from the beginning—with no distinct relapses or remissions. The rate of progression may vary over time, with occasional plateaus and temporary minor improvements. Approximately 10% of people are diagnosed with primary-progressive MS.
• Secondary-Progressive MS
  Following an initial period of relapsing-remitting MS, many people develop a secondary-progressive disease course in which the disease worsens more steadily, with or without occasional flare-ups, minor recoveries (remissions), or plateaus. Before the disease-modifying medications became available, approximately 50% of people with relapsing-remitting MS developed this form of the disease within 10 years. Long-term data are not yet available to determine if treatment significantly delays this transition.
• Progressive-Relapsing MS
  In this relatively rare course of MS (5%), people experience steadily worsening disease from the beginning, but with clear attacks of worsening neurologic function along the way. They may or may not experience some recovery following these relapses, but the disease continues to progress without remissions.

Since no two people have exactly the same experience of MS, the disease course may look very different from one person to another. And, it may not always be clear to the physician—at least right away—which course a person is experiencing.

For more important information about MS, check out Just the Facts (.pdf)

Rituxan Joins List of Treatments

By KEITH J. WINSTEIN
April 15, 2008; Page B9
Rituxan, a top-selling drug from Genentech Inc. and Biogen Idec Inc., failed to slow the course of the most severe form of multiple sclerosis in a large study, the companies said.

The findings make Rituxan at least the sixth unsuccessful attempt to treat so-called primary-progressive MS, or PPMS. In the U.S., about 35,000 to 40,000 people have primary-progressive MS, out of roughly 350,000 to 400,000 total MS patients.

There are no approved treatments for PPMS. Genentech and Biogen had hoped that Rituxan -- which is approved for blood cancer and rheumatoid arthritis -- might become the first such treatment. The drug costs about $20,820 a year at the dosage used.

But in the companies' study, which followed 439 patients for 96 weeks, Rituxan didn't significantly slow the course of the disease, which gradually robs patients of motor function and causes tremors, tingling and fatigue. Secondary results -- like whether Rituxan improved MRI scans of patients' brains -- weren't released.

"We are disappointed in the outcome of the primary endpoint, but not surprised given the significant clinical challenges presented by PPMS," said Hal Barron, chief medical officer at Genentech, in a statement.

A successful result could have yielded $236 million to $359 million in annual sales to the two companies, according to a Bear Stearns estimate. Genentech gets 60% of the profits from Rituxan, with 40% going to Biogen. Total sales were $2.3 billion last year.

In a smaller study last year, Rituxan slowed down the less-severe form of MS, which has several approved drugs, including Biogen's Avonex and Tysabri. The companies have disagreed over what to do next. The matter is subject to an arbitration hearing this summer.

Rituxan is being studied in lupus, another immune-system disease with few treatment options. Genentech has said results may be released within a few weeks.

Write to Keith J. Winstein at keith.winstein@wsj.com

Diagnosing MS

At this time, there are no symptoms, physical findings, or laboratory tests that can, by themselves, determine if a person has MS. The doctor uses several strategies—including a careful medical history, a neurologic exam, and various tests—to determine if a person meets the long-established criteria for a diagnosis of MS and to rule out other possible causes of whatever symptoms the person is experiencing.

The Criteria for a Diagnosis of MS

In order to make a diagnosis of MS, the physician must:

• Find evidence of damage in at least two separate areas of the central nervous system (CNS), which includes the brain, spinal cord, and optic nerves AND
• Find evidence that the damage occurred at different points in time—at least one month apart AND
• Rule out all other possible diagnoses

In 2001, the International Panel on the Diagnosis of Multiple Sclerosis updated the criteria to include specific guidelines for using magnetic resonance imaging (MRI), visual evoked potentials (VEP), and cerebrospinal fluid analysisto speed the diagnostic process. These tests can be used to look for a second area of damage in a person who has experienced only one attack (also called a relapse or an exacerbation) of MS-like symptoms—referred to as a clinically-isolated syndrome (CIS). A person with CIS may or may not go on to develop MS.

The criteria were further revised in 2005 (now referred to as The Revised McDonald Criteria) to make the process even easier and more efficient.

The Tools for Making a Diagnosis

Medical History and Neurologic Exam

The physician takes a careful history to identify any past or present symptoms that might be caused by MS and to gather information about birthplace, family history, and places traveled that might provide further clues. The physician also performs a variety of tests to evaluate mental, emotional, and language functions, movement and coordination, vision, balance, and the functions of the five senses.

In many instances, the person’s medical history and neurologic exam provide enough evidence to meet the diagnostic criteria. Other tests are used to confirm the diagnosis or provide additional evidence if it’s necessary.

MRI

MRI is the best imaging technology for detecting the presence of MS plaques or scarring (also called lesions) in different parts of the CNS. It can also differentiate old lesions from those that are new or active.

The diagnosis of MS cannot be made solely on the basis of MRI because there are other diseases that cause lesions in the CNS that look like those caused by MS. And even people without any disease—particularly the elderly—can have spots on the brain that are similar to those seen in MS.

Although MRI is a very useful diagnostic tool, a normal MRI of the brain does not rule out the possibility of MS. About 5% of people who are confirmed to have MS do not initially have brain lesions on MRI. However, the longer a person goes without brain or spinal cord lesions on MRI, the more important it becomes to look for other possible diagnoses.

• Read more on MRI

Visual evoked potential (VEP)

Evoked potential (EP) tests are recordings of the nervous system's electrical response to the stimulation of specific sensory pathways (e.g., visual, auditory, general sensory). Because damage to myelin (demyelination) results in a slowing of response time, EPs can sometimes provide evidence of scarring along nerve pathways that does not show up during the neurologic exam. Visual evoked potentials are considered the most useful for confirming the MS diagnosis.

• Read more on visual evoked potentials

Cerebrospinal fluid analysis

Analysis of the cerebrospinal fluid, which is sampled by a spinal tap, detects the levels of certain immune system proteins and the presence of oligoclonal bands. These bands, which indicate an immune response within the CNS, are found in the spinal fluid of about 90-95% of people with MS. But because they are present in other diseases as well, oligoclonal bands cannot be relied on as positive proof of MS.

• Read more on celebrospinal fluid analysis

Blood tests

While there is no definitive blood test for MS, blood tests can rule out other conditions—including Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS—that cause symptoms similar to those of MS.

Other Conditions Cause Demyelination (Damage to Myelin)

• Demyelination in the Central Nervous System
  Although MS is the most common, other conditions can damage myelin in the CNS, including viral infections, side effects from high exposure to certain toxic materials, severe vitamin B12 deficiency, autoimmune conditions that lead to inflammation of blood vessels (the "collagen-vascular diseases"), and some rare hereditary disorders.
• Demyelination in the Peripheral Nervous System
  Demyelination of the peripheral nervous system (the nerves outside the brain and spinal cord.) occurs in Guillain-Barré Syndrome. After some injuries, the myelin sheath in the peripheral nervous system regenerates, bringing recovery of function.

Some demyelinating conditions are self-limiting, while others may be progressive. Careful (and sometimes repetitive) examinations may be needed to establish an exact diagnosis among the possible causes of neurologic symptoms.

Who gets MS?

In the United States today, there are approximately 400,000 people with multiple sclerosis (MS)—with 200 more people diagnosed every week. Worldwide, MS is thought to affect more than 2.5 million people. While the disease is not contagious or directly inherited, epidemiologists—the scientists who study patterns of disease—have identified factors in the distribution of MS around the world that may eventually help determine what causes the disease. These factors include gender, genetics, age, geography, and ethnic background.