September 15, 2008

Controlling Multiple Sclerosis
By Kim M. Norton
For The Record
Vol. 20 No. 19 P. 28

An old cancer drug and several promising clinical trials have given hope to those fighting against the disease’s devastating effects.

Multiple sclerosis (MS) is a chronic disease of the central nervous system that destroys the myelin and leaves a wake of scar tissue that can destroy or interrupt the nerve impulses traveling to the brain, spinal cord, and optic nerves. It is not yet known what causes MS, but researchers believe it to be an autoimmune disease that can be tied to factors such as decreased sun exposure, low vitamin D levels, a vitamin B12 deficiency, diet issues, and industrial toxins in patients with certain genetic predispositions.

MS patients have near-normal life expectancies, and their condition can be managed effectively as the symptoms present. However, for the 400,000 MS sufferers in the United States—and the 200 more who are diagnosed each week—the road to diagnosis can be long and frustrating. While physicians perform test after test to eliminate other possible diseases, there is time for MS symptoms to progress and cause more damage, says John R. Richert, MD, a neurologist and the executive vice president of research and clinical programs for the National Multiple Sclerosis Society.

Meanwhile, researchers are working to halt MS’ progression in those diagnosed with the disease. A recent study from Johns Hopkins Medical Center in Baltimore reported success with using extremely high doses of cyclophosphamide. The therapy, dubbed HiCy, consisted of giving 50 milligrams per kilogram per day of cyclophosphamide intravenously for four consecutive days (200 milligrams per kilogram total), followed by 5 micrograms per kilogram per day of granulocyte colony-stimulating factor six days after HiCy treatment ended, until the absolute neutrophil count exceeded 1 X 109 cells per liter for two consecutive days.

“This amounts to roughly 3.5 grams of cyclophosphamide per day for four days [14 grams per cycle], an extremely high dose compared with the the previous cyclophosphamide used protocols. Cyclophosphamide was shown to be an effective therapy for those patients who have a severe disease and refractory to other therapies,” says Bianca Weinstock-Guttman, MD, an associate professor of neurology at the State University of New York at Buffalo. The goal of HiCy is to eradicate the lymphocytes (B and T cells) responsible for the disease while sparing the pluripotent (hematopoetic) blood stem cells.

Although HiCy uses similar high dosages of cyclophosphamide as hematopoietic stem cell transplantation, the procedure is less toxic and does not require additional interventions—stem cell mobilization and autoreactive lymphocyte reinfusion are often associated with increased side effects.

Cyclophosphamide is a drug that MS researchers have been visiting and revisiting in their search for better therapies and a possible cure. Since approximately 1983, the drug has been studied in varied dosages over time frames ranging from four days to a couple weeks. The Johns Hopkins results are significant because of the nine enrolled patients, eight had failed other conventional MS therapies and one had exceeded the criteria for other initial treatments.

In the study, success was defined as an improved score on the Expanded Disability Status Scale (EDSS). “The EDSS for MS patients is a zero to 10 scale with zero being normal and 10 being death. Inclusion in the [Johns Hopkins] study required the patient to have one exacerbation during the six months preceding the study entry or an increase with one point in EDSS over the last year, as well as the presence of at least two enhancing lesions in the baseline brain MRI,” says Weinstock-Guttman. Over the course of the two-year study, patients experienced about a 40% reduction in their EDSS scores and an 87% improvement in their scores on a composite test that measures physical and mental function, according to Johns Hopkins researchers.

“Researchers also reported that all patients experienced decreased enhancing lesions, with one patient showing no new lesions. Six patients had a full disease control for the length of the study without additional interventions. However, three patients had MRI-related activation, one having also a clinical relapse, suggesting that the benefit of this intervention may vary based on individual specific response,” says Weinstock-Guttman.

First Steps First
Controlling MS, reducing EDSS scores, and halting its progression all rely on the patient having been diagnosed with MS, which can be a time-consuming process of elimination. There is no definitive test for MS, nor is there a clear cut presentation of the disease. “You can have a room full of MS patients, and no two will have the same set of symptoms,” says Richert. Due to the disease’s unusual presentation and its ability to mimic many other diseases, it can take years before a proper diagnosis is established. Even after a patient has been diagnosed with MS, new diseases are discovered that must be routinely ruled out to know whether the patient truly has MS or another recently discovered disease, adds Richert.

To make an MS diagnosis, certain criteria must be met. There must be evidence of damage to at least two areas of the central nervous system, the damage must have occurred at least one month apart, and all other possible diagnoses must be ruled out, according to Richert.

If the patient is experiencing MS-like symptoms, the first step is for the physician to gather a complete medical and family history (which should include past or present symptoms) and conduct a battery of tests. Such evaluations should include mental, emotional, and language function; movement; coordination; balance; and the five senses, according to the MS society.

Depending on the person’s medical history and neurological exam, other tests may be used to confirm the diagnosis and provide additional evidence of central nervous system injury. MRI, visual evoked potential, cerebrospinal fluid analysis, and blood tests can offer evidence of MS, while also providing signs of secondary damage and ruling out other possible diseases.

MRI is currently the best technology for detecting MS lesions in different parts of the central nervous system and can differentiate between old lesions and new or active ones. The visual evoked potential test is also useful for confirming an MS diagnosis because it records the central nervous system’s electrical response to stimulation along visual pathways very often affected in MS. Because MS causes damage to the myelin, the electrical responses can slow the response time, which would provide additional support for an MS diagnosis. Cerebrospinal fluid analysis is the least reliable of these tests because other immunological diseases will also be present in the spinal fluid, making an MS diagnosis inexact. Lastly, blood tests can assist with ruling out other diseases and conditions that are similar in nature, such as Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS, according to the MS society.

Types of MS
“Symptoms run the whole gamut from decreased motor function such as weakness to paralysis, pins and needles to loss of sensation, vision problems from blurred vision to blindness, and coordination problems from bad tremors to loss of bowel, bladder, sexual, and reduced cognitive function,” says Richert. Fatigue, muscle spasms, and neurogenic pain are also common in MS, he adds.

There are two separate forms of the disease with different types within each form. Relapse-remitting, which is characterized by a series of attacks followed by remission, affects 85% of those diagnosed. “The patient will have stability between flare-ups with some transient progression and may experience some neurological deficit,” says Richert.

About one half of those patients diagnosed with relapse-remitting MS will progress to secondary-progressive MS. In this form of the disease, there are less periods of stability and increased periods of active MS. “In this progressive form of the disease, the patient is difficult to treat, and it is my impression that for patients with an aggressive course of relapse-remitting disease, HiCy could be used as a second-line therapy when other therapies fail,” says Richert.

The other less common forms of MS are primary-progressive, which accounts for 10% of patients diagnosed, and the rarer progressive-relapsing MS, which accounts for only 5% of those diagnosed. With progressive-relapsing MS, the primary progressive patient will experience a slow worsening without remissions and infrequent acute exacerbations, says Richert.

Treatment
When managing MS, the goal is to control how the disease progresses and to modify its course, if possible. There are currently six disease-modifying, FDA-approved drugs for patients with relapse-remitting disease. Richert explains what each type of drug does and how it is used to modify the progression of the disease:

• Glatiramer acetate, a noninterferon that is a synthetic protein, simulates myelin basic protein, a component of the myelin that insulates nerve fibers in the brain and spinal cord. This drug seems to block myelin-damaging T cells by acting as a myelin decoy.

• Mitoxantrone belongs to a group of medicines called antineoplastics. Before its approval for MS, it was used to treat certain forms of cancer. It acts in MS by suppressing the activity of T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath.

• Natalizumab, a laboratory-produced monoclonal antibody, is designed to hamper the movement of potentially damaging immune cells from the bloodstream across the “blood-brain barrier” into the brain and spinal cord.

• There are two interferon beta-1a and one interferon beta-1b medications that are manufactured from naturally occurring interferons. The drugs appear to delay the time between exacerbations, reduce the number of active lesions, and possibly lessen the severity of the exacerbations.

Controlling the disease’s progression is only one component of the treatment plan. The symptoms accompanying the disease are crippling and can affect patients’ work and social lives, leaving them isolated and susceptible to depression. “Symptomatic therapies are essential in treating the MS patient because controlling the oftentimes debilitating symptoms of the disease can greatly improve the patient’s quality of life,” says Richert.

These therapies can include antispastic drugs to reduce painful muscle spasms and improve ambulation due to stiffness. “Fatigue is also a debilitating aspect of the disease; however, there are no FDA-approved drugs, and we do not have any large placebo controlled studies to refer to,” says Richert. Over-the-counter medications and off-label drugs are thought to be helpful for pain associated with MS and to assist in controlling incontinence, he adds.

For progressive MS, there are currently no FDA-approved disease-modifying drugs, according to the MS society.

Hope in the Pipeline
At this April’s American Academy of Neurology meeting, researchers from around the world came together to present their findings on possible MS breakthroughs. Although still in the pipeline, there are a number of drugs in phase 2 and 3 studies that have impressive data.

Among them is the immune-suppressing monoclonal antibody alemtuzumab for patients with relapse-remitting MS who have never taken any other disease-modifying therapies. The data indicate a 73% reduction in the risk of MS relapse compared with those on interferon beta-1a and a 71% reduction in the risk for sustained accumulation of disability. “This particular study compared alemtuzumab with a high dose of the interferon, and alemtuzumab appears to offer a very sizable environmental benefit to MS patients,” says Richert.

Another promising experimental drug that is entering a large phase 3 trial is fingolimod, which, according to Weinstock-Guttman, works on specific receptors to keep active lymphocytes trapped in the lymph nodes and spleen to keep them from migrating to the brain and spinal cord. “The added benefit of fingolimod is that it is an oral therapy, which patients welcome,” she adds.

Phase 2 results demonstrated that 73% of patients who began the study on 5 milligrams of fingolimod remained free from relapses after three years, and 68% of those who began the study on 1.25 milligrams of fingolimod remained relapse free. Results also showed an average annualized relapse rate of 0.2 (meaning one relapse in five years), and 89% were free of active brain lesions on MRI (vs. 84% at two years), according to the study abstract.

Other drugs that have promising study data include fumerate derivatives (ie, BG12), which is in a phase 3 clinical trial, and the oral medication laquinimod, also in a phase 3 trial. Rituximab is another drug that has impressive phase 2 data and is entering another trial as a slightly modified drug, which is more humanized, explains Richert.

— Kim M. Norton is a New Jersey-based freelance writer specializing in healthcare-related topics for various trade and consumer publications. She can be contacted at kim_norton1@hotmail.com.