October 5, 2007 �?A newly developed DNA vaccine appears to fundamentally alter the disease course of multiple sclerosis in patients with relapsing remitting multiple sclerosis (RRMS).

Phase 2 results of the investigational drug BHT 3009 (Bayhill Therapeutics, Palo Alto, California), a tolerizing vaccine encoding full-length human myelin basic protein (MBP), induced a 50% to 60% reduction in gadolinium-enhancing brain lesions as well as volume reductions in T2 volumes and T1 black holes in MS patients treated with 0.5 mg of the drug, compared with placebo.

Furthermore, the investigators observed statistically significant reductions in several cerebral spinal fluid (CSF) autoantibodies in the BHT 3009 0.5-mg group. The CSF analysis also revealed that the highest impact of BHT 3009 occurred in those with the highest tier of anti-MBP autoantibodies.

"This is a significant step in advancing one of the first antigen specific therapies for use in the clinic. We're a step closer to providing MS patients with a treatment that fundamentally alters the course of the disease," vaccine inventor Hideki Garren, MD, PhD, from Stanford University, in Palo Alto, California, and Bayhill Therapeutics, told Medscape.

Major Advantages Over Traditional Treatment

Invented by Dr. Garren and 3 other colleagues at Stanford, BHT 3009 offers several advantages over established MS treatments such as beta interferon. Most important, rather than targeting the entire immune system, BHT-3009 targets only disease-causing antigen-specific T-cells that attack the myelin.

In addition, he said, the drug's dosing schedule is only once per month. In contrast, beta interferon treatment protocols range from every other day to once per week. Furthermore, adverse effects, including flulike symptoms, associated with beta interferon can make it difficult to tolerate. In contrast, he said, the tolerability of BHT 3009 is "excellent."

The study will be presented at the American Neurological Association 132nd Annual Meeting on October 9 in Washington, DC and again at the 23rd Congress of the European Committee for Treatment and Research on October 12 in Prague, Czech Republic.

The multicenter randomized, placebo-controlled trial, which was predominantly conducted at more than 40 centers in Eastern Europe, included 289 RRMS patients, the vast majority of whom had never been treated with disease-modifying therapy.

Low-Zone Tolerance

Inclusion criteria included Expanded Disability Status Scale (EDSS) score of 0 to 3.5. In addition, patients were required to have a minimum of 1 relapse within the year prior to study enrollment and 5 or fewer gadolinium-enhancing brain lesions.

Exclusion criteria were individuals with greater than 5 brain lesions and who had received more than a lifetime total of 180 days of previous disease-modifying therapy.

Study subjects were randomized to 1 of 3 study groups �?placebo, 0.5-mg BHT 3009, or 1.5-mg BHT 3009 administered monthly by intramuscular injection for 1 year.

The trial's primary end point was the reduction in the number of gadolinium-enhancing lesions. Secondary end points included various other magnetic resonance imaging (MRI) measures, including gadolinium lesion volume and T2 and T1 black hole volume. Other non-MRI secondary end points included relapses and disability.

Results of the study's secondary MRI end points were generally consistent with reductions seen in the primary end point, which was limited to patients in the 0.5-mg group.

"There was no effect with the higher dose of the vaccine. This finding is consistent with the hypothesis that lower doses, given chronically in MS, will tolerize the immune system, a phenomenon known as 'low-zone tolerance.' We did not see any worsening of the disease with the higher dose; there was just no effect," he said.

No Clinical Impact

In addition, the study showed no statistically significant clinical impact of lesion reduction with either dose of the vaccine.

"Unfortunately, we did not see an effect on disability or relapse rates. Although the overall relapse rate was relatively low [compared with trials of other therapies], the study was not sufficiently powered to reveal such an effect. We need another, much larger phase 3 trial to answer this question," said Dr. Garren.

He added plans are currently under way to conduct such a trial, which is expected to launch by the end of 2008.

"In this current trial, we've shown a reduction in lesions and an antigen-specific effect. In the next trial, we want to replicate these results and demonstrate clinical efficacy," he said.

The researchers are also looking at a second, similar experimental agent in type 1 diabetes.

"We have started a safety and proof-of-concept trial using another investigational agent, BHT-3021 in type 1 diabetic patients. We don't have any data to report as of yet, but the initial results are encouraging," he said.

The study was funded by Bayhill Therapeutics Inc. Dr. Garren discloses that he is cofounder of and has received salary, stock, and/or stock options from Bayhill Therapeutics, Inc.

American Neurological Association 132nd Annual Meeting: Abstract T84. Presented October 9, 2007.

23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis. Presented October 12, 2007.