Is an oral disease-modifying drug on the horizon?

For over a decade now, we have had the benefit of FDA-approved disease-modifying drugs: the beta interferons (Betaseron, Avonex, and Rebif), glatiramer acetate (Copaxone), and, more recently, mitoxantrone (Novantrone) All are injected under the skin, into muscle, or into a vein. Natalizumab (Tysabri), which is currently under a new FDA review, is also injected. People with MS have been eagerly awaiting the development of oral tions that might take their places.

There are several oral immune-modulating agents in various stages of clinical testing. Novartis' FTY720 is entering into phase III trials in relapsing-remitting MS and results may be available sometime in 2008. This medication targets a cellsurface molecule called the sphingosine-1-phosphate receptor on immune cells.

In so doing, it causes the immune cells to remain in the body's lymphatic tissue and hinders them from entering sites of inflammation in the central nervous system or other tissues.

Fumarate therapy, consisting of a mixture of fumaric acid esters, referred to as BG00012, produced by Fumapharm AG, has been used in Europe as a treatment for psoriasis for decades. Psoriasis is mediated by overactive immune cells, and this medication, in pill form, has been shown to inhibit the function of a key immune-system molecule. Investigators who studied this medication last year in a preliminary open-label trial in people with relapsing-remitting MS reported that it achieved a reduction in disease activity as measured by MRI. Open-label studies must be confirmed by "blinded" studies with control groups. Double-blind, randomized, placebo-controlled studies are currently in progress.

Temsirolimus, produced by Wyeth Pharmaceuticals, had promising results in a phase II trial in relapsing forms of MS last year. Temsirolimus is an enzyme inhibitor that blocks a specific T-cell function.

An oral form of the chemotherapeutic agent cladribine (Mylinax), produced by IVAX and Serono, has been tested preliminarily to determine if the oral form can achieve the blood levels obtainable with an intravenous preparation. Several years ago studies of the IV form demonstrated a beneficial effect on MRI measures of disease activity. A phase III trial with oral cladribine has been started.

As with the injectable disease modifying agents, National MS Society-funded research helped bring some of these oral agents to their current state. For example, a Society research grant enabled Edward Goetzl at the University of California San Francisco Medical Center to study the T-cell receptors for sphingosine-1-phosphate and helped clarify the role they play in the control of the immune response to myelin.

No one can say how soon we will have MS medications that don't need to be injected, but it is clear that the progress of the last 15 years has absolutely changed the world of MS. Research has greatly improved our ability to manipulate immune processes with new therapies.

Researchers are currently striving to improve these therapies, in terms of both efficacy and ease of administration. At the moment, oral drug candidates appear to be moving ahead quickly. Work is also proceeding on inhaled therapies.

I hope that people will remember that such advances would not occur without volunteers with MS who are willing to take part in clinical trials. Information on trials that are currently recruiting participants can be found on our Web site at nationalmssociety.org/Research-trialsrecruiting.asp. Medical professionals are invited to call our Professional Resource Center at 866-MS-TREAT (866-678-7328) for details that they may discuss with their patients.

Only well-conducted clinical trials can prove the efficacy and safety of agents that look so promising in pre-clinical studies. When the hoped-for results materialize, they are truly the product of the combined efforts of researchers, pharmaceutical/biotech manufacturers, funding agencies, and people with MS.

Dr. John Richert is vice president of Research and Clinical Programs at the National MS Society.