Jun 19, 2008

Laquinimod Results Published: Oral Drug Reduces Disease Activity in Phase 2 Study

Treatment with oral laquinimod (Teva Pharmaceutical Industries) reduced disease activity by 40.4% compared with inactive placebo in a phase 2 study of 306 people withrelapsing-remitting MS*. Laquinimod is believed to affect the immune attack on the brain and spinal cord that occurs in MS. Giancarlo Comi, MD (Scientific Institute San Raffaele, Milan) and colleagues, who originally reported the results at the Annual Meeting of the American Academy of Neurology in 2007, now publish these results in the Lancet (2008; 371: 2085–92). Aphase 3 studyof laquinimod is underway in 1000 people with relapsing-remitting MS.

Background:

Multiple sclerosis involves immune-system attacks against the central nervous system. Currently approved therapies for MS involve injections or infusions. Having an effective therapy in pill form would be a big step forward for people with MS. Laquinimod is an oral therapy that is thought to shift the balance of immune cells away from inflammation. The drug is related in structure to linomide, which showed early promise but in phase 3 clinical trials caused significant adverse events including cardiac toxicity.

The Study:

Dr. Comi and colleagues randomly assigned 306 people with MS to receive placebo, .3 mg/day, or laquinimod .6 mg/day. Participants underwent monthly brain MRI scans and clinical examinations from week 12 to week 36. The primary outcome tested was the number of active lesions (areas of active disease activity or damage) as observed on MRI.

The Results:

The cumulative average number of active lesions was significantly reduced by 40.4% in the group taking .6 mg compared with those taking placebo, but no benefit was seen in the .3 mg group. No significant reductions were seen in relapses; however the study was not designed to detect these differences.

Both doses were considered well tolerated, and heart problems were not seen at either dose. Increases in liver enzymes occurred in 23.4% of the .6 mg group, 33% of the .3 mg group, and in 10.8% of the placebo group, with two patients in the .3 mg group discontinuing treatment due to these abnormalities. One patient in the .6 mg group developed Budd-Chiari syndrome (a partial blockage of blood outflow from the liver) after one month on treatment. This person had a pre-existing tendency toward blood clots, and the authors note that the possibility that such patients might be at increased risk of serious adverse events should be explored in further studies.

In an accompanying editorial, B. Mark Keegan, MD, and Brian Weinshenker, MD (Mayo Clinic, Rochester, MN), write that this study may have been too short to reveal reductions in MS relapses, and that the two-year, phase 3 study should clarify this issue. They also suggest that head-to-head studies are needed to directly compare laquinimod with approved MS therapies to determine if the convenience of oral therapy is adequately matched by the drug’s effectiveness.

“We are encouraged by the MRI data from this publication,” says John R. Richert, MD, Executive Vice President of Research & Clinical Programs for the National MS Society. “We look forward to seeing further clinical and safety data from the phase 3 study, which will help to determine if this treatment can be used safely and effectively in people with MS.”