Laurie Barclay, MD, May 2005

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system. Damage to the myelin sheath, which coats nerve fibers, interferes with their ability to transmit impulses to each other and to other parts of the body, causing problems with muscle control, coordination, walking, vision, balance, sensation, thinking, and bowel and bladder function.

MS is the most common, non-traumatic, neurological disease in young adults, affecting approximately 400,000 Americans and two million people worldwide. Age of onset is typically between 20 and 40 years, and women are more likely to be affected than men. The relapsing-remitting form of MS, characterized by flares interspersed with symptom-free periods for up to 10 years, accounts for about 90% of cases. The remaining 10% are primary progressive, meaning that neurologic impairment and disability continue to worsen. Even in relapsing-remitting MS, however, the exacerbations may not clear completely, and each relapse tends to increase the patient's residual level of disability.

About 70% of people with MS are still able to work five years after the onset of symptoms. Complications may include urinary infections, pneumonia, malnutrition because of swallowing impairment, depression, and dementia in the late stages.

Although the exact cause of MS is unknown, it is thought to be an autoimmune disease, possibly triggered by viral infections, genetic factors, and/or other environmental factors such as climate.

Diagnosis is usually by clinical history of dissemination in time (two or more episodes of neurological symptoms) and in space (involvement of more than one part of the central nervous system). Other tests that may be helpful include magnetic resonance imaging (MRI) showing characteristic white matter lesions, cerebrospinal fluid analysis for protein and anti-myelin antibodies, and visual and other evoked potential testing.

Although there is no cure for MS, disease-modifying drugs affect the course of the disease, helping to reduce relapses. These include steroids such as prednisolone, interferon beta-1a (Avonex or Rebif), interferon beta-1b (Betaferon), and glatiramer acetate (Copaxone). Long-term complications of steroids may include gastrointestinal bleeding, immunosuppression, and psychosis. Adverse effects of the interferons may include pain at the injection site, flu-like symptoms, diarrhea and insomnia, whereas glatiramer acetate may cause side effects such as flushing and breathlessness after injection.

Drugs that control symptoms include muscle relaxants for spasms, and specific treatments for incontinence, constipation and sexual dysfunction. Physiotherapy, exercise, and attention to diet and lifestyle also play a role in management.

CenterWatch has identified a pipeline of 17 drugs in various phases of development for MS. These include interferons and other immune system modulators, as well as a few drugs aimed at symptomatic relief.

GW Pharmaceuticals has submitted a new drug application (NDA) in the UK and Canada for Sativex (GW-1000, Tetranabinex), but queries from UK regulators have repeatedly delayed approval. This whole plant medicinal cannabis extract is administered via oral spray to target MS symptoms such as pain and spasm. The Cannabinoids in Multiple Sclerosis Research (CAMS) group compared cannabinoid treatment over 15 and 52 weeks in patients with MS, and long-term data released in September 2004 suggest that chronic use of cannabinoids is more effective in relieving MS symptoms than short-term use.

Although cannabis is illegal, estimates suggest that about 10% to 30% of MS patients in Europe smoke cannabis to relieve symptoms. Sativex contains tetranabinex (THC) and nabidiolex (cannabidiol; CBD), but to avoid intoxication, it does not contain the active substance found in recreational cannabis. Phase III placebo-controlled trials in about 350 patients with MS suggest that Sativex sublingual spray is safe and effective, with improvement in spasticity compared with placebo (P < .05).

In collaboration with Serono, IVAX is in Phase III development of Mylinax (cladribine), an orally administered adenosine deaminase inhibitor. This purine nucleoside analogue interferes with activity and proliferation of lymphocytes involved in the immunological basis of MS. A two-year, double-blind, placebo-controlled study enrolling more than 1,200 patients with relapsing forms of MS is now underway. Endpoints in this multicenter, international study will include assessments of relapses, progression of disability, and serial MRI scans. Earlier trials using a parenteral formulation of cladribine suggested clinical benefits and reduction in new MRI lesions.

BioMS Medical is in Phase II/III testing of MBP8298, a synthetic Myelin Basic Protein (MBP) peptide which reduces production of MBP-antibody by B lymphocytes. It consists of 17 amino acids linked in a sequence identical to that of a portion of human myelin basic protein (MBP). This sequence is the point of attack in MS patients with HLA haplotypes DR-2 or DR-4, which account for 65% to 75% of all MS patients. When administered in high doses intravenously, MBP8298 appears to induce or restore tolerance to ongoing immune attack at this specific molecular site. A Phase II clinical trial showed statistically significant clinical benefit in patients with HLA haplotypes DR-2 or DR-4.

Rituximab, in Phase II/III development by Genentech, is a monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant B lymphocytes. In a recent study in the Archives of Neurology (2005;62:258-264), four patients with primary progressive MS received rituximab and underwent analysis of cerebrospinal fluid (CSF) and peripheral blood. Rituximab temporarily suppressed the activation state of B cells in CSF, but the B cells in CSF were not depleted to the extent that B cells were depleted in peripheral blood. Furthermore, the remaining B cells multiplied after rituximab treatment.

Antisense Therapeutics is in Phase IIa testing of ATL1102, a second generation antisense inhibitor targeting production of Very Late Antigen-4 (VLA-4), a receptor on the surface of lymphocytes. VLA4 mediates adhesion of immune cells to blood vessel walls and subsequent migration of lymphocytes into the tissue, which is a pivotal event in inflammatory diseases. In MS, excessive amounts of VLA4 are thought to allow the inappropriate entry of lymphocytes into the central nervous system. In earlier studies, blocking VLA4 has reportedly been associated with a reduction of new MRI lesions in patients with MS.

In August 2003, Antisense Therapeutics began Phase I testing of ATL1102 in 54 healthy volunteers. This double-blind, dose-escalation, placebo-controlled, randomized study suggested that 6mg/kg/week of ATL1102 appeared to be well tolerated and would be an appropriate dose for Phase II development. Trials were temporarily suspended pending a TYSABRI safety issue. However, in December 2004, Antisense announced their intention to conduct a Phase Iia, multicenter, double-blinded trial of ATL1102 in approximately 60 patients with relapsing-remitting MS. These subjects are to be randomized to receive subcutaneous ATL1102 twice weekly at a dose of 400 mg per week, or placebo, over eight weeks, and efficacy is to be evaluated with monthly MRI.

Alferon N, or interferon alfa-n3, is in Phase Iia testing by Hemispherx Biopharma. This form of interferon is derived from human leukocytes and contains at least 14 alpha interferon molecules. In a retrospective, uncontrolled study, brain MRI with gadolinium contrast enhancement was performed in 69 patients treated with MS, including 38 who declined treatment with interferon alfa-n3, and 31 who were treated with subcutaneous interferon alfa-n3 for three to six months. MRI revealed gadolinium enhanced lesions in two of 31 patients (6%) treated with interferon alfa-n3, and in 14 of 38 patients (37%) in the untreated group. During a mean follow-up of 11 months, mean Expanded Disability Status Scale (EDSS) score decreased in the interferon alfa-n3 treated group from 4.8 to 3.4, reflecting less disability, but mean score in the untreated group increased from 3.8 to 4.5. However, prospective, controlled trials are needed to obtain regulatory approval.

Acorda Therapeutics has completed Phase II testing of Fampridine SR, an oral, sustained-release tablet formulation of 4-aminopyridine (4-AP), which is a potassium channel blocker enhancing conduction in damaged nerves. In the laboratory, Fampridine has improved impulse conduction in demyelinated nerve fibers. In Phase II clinical trials in MS, treatment with Fampridine-SR has been associated with faster walking and improved leg strength on standard neurological assessments. Most of the adverse effects, including insomnia, paresthesias (numbness/tingling), dizziness and nausea, were rated as mild to moderate. At higher doses than those used in the most recent trials, a few patients had seizures.

Active Biotech/Teva Pharmaceutical has completed Phase II development of the oral immunomodulatory agent laquinimod (SAIK-MS). In a Phase II study in MS, 24 weeks of treatment with laquinimod was associated with a statistically significant 28% to 44% reduction in new brain MRI lesions, and a very favorable safety profile. Patients with active disease when beginning treatment had a 52% decrease in new lesions.

ABT-874, a fully human anti-interleukin-12 (IL-12) monoclonal antibody, is a protein mediating inflammatory response and present in MS lesions. Abbott Laboratories has begun a Phase II, randomized trial in North America and Europe to evaluate the efficacy of ABT-874 in reducing MS brain lesions. The 48-week study will consist of a 24-week, placebo-controlled phase followed by a 24-week active open-label extension.

Genzyme is in Phase II testing of Campath-1H (alemtuzumab), a lymphocyte-depleting humanized monoclonal antibody targeting CD52, and thereby killing T cells thought to initiate the pathological processes underlying MS. In 27 patients with secondary progressive MS (SPMS), Campath-1H treatment was associated with no new MRI lesions for at least eighteen months. Although 14 of these patients had stable disease during that time, the remaining 13 had continued worsening of MS symptoms despite the absence of new MRI lesions. The latter group had the greatest amount of existing lesions and brain atrophy at baseline, leading the investigators to conclude that Campath-1H therapy is more effective of given early in the course of MS. A new clinical trial in 180 patients with early relapsing-remitting MS will compare low- and high-dose Campath-1H with high-dose Rebif. Preliminary findings are anticipated in 2006.

Surprisingly, Campath-1H appears to be reasonably well tolerated even though it destroys T cells. In studies thus far, there have been few serious infections and no deaths. However, one third of subjects developed Graves disease, an autoimmune form of thyroid disease relatively easily managed with thyroid supplements. Another drawback is that most study subjects reported a transient worsening of symptoms immediately following the first Campath-1H injection.

Also in Phase II testing is NeuroVax (IR208), a synthetic T-cell receptor (TCR) peptide vaccine developed by Immune Response Corporation. In a multicenter, three-arm, randomized 24-week trial enrolling 60 subjects, 94% of patients treated with NeuroVax had a statistically significant, peptide-specific immune response response compared with those receiving three peptides in saline (7%) or adjuvant alone (0%). NeuroVax was well tolerated with no serious adverse effects.

Pirfenidone, in Phase II development by InterMune, is an inhibitor of Tumor Necrosis Factor-alpha (TNF-alpha). In an open-label, two-year study in 20 patients with chronic progressive MS, three patients dropped out early because of gastrointestinal adverse reactions, and another three patients dropped out for personal reasons after one year. However, the remaining 14 patients completed the study and did not report any other drug-related adverse reactions or complications. Most patients had improvement or stabilization at about three months, which was sustained at six, 12 and 24 months, and MRI did not reveal any new lesions.

Zenapax (daclizumab), manufactured by Protein Design Labs, is an intravenously administered immunosuppressive monoclonal antibody targeting the alpha chain of the human interleukin-2 (IL-2) receptor. A Phase II trial sponsored by the National Institute of Neurological Disorders and Stroke is currently recruiting patients with relapsing-remitting MS. By blocking the activity of IL-2, Zenapax interferes with the growth of T lymphocytes that damage myelin.

Recent advances in molecular biology and genetics have paid dividends for research in MS therapeutics. By targeting specific pathways thought to be involved in myelin destruction, one or more of these agents may ultimately prove to be a "silver bullet" reducing or preventing relapses while maintaining a reasonably good safety and tolerability profile. For the agents in earlier phases of development, only time will tell to what extent these disease-modifying drugs may accomplish these goals.