February 2008

In the February 2008 issue of the journal Amyotrophic Lateral Sclerosis (see Publications, below), the investigators say the following:

The 30-person, nine-month study, there were statistically nonsignificant declines in the slopes of two functional rating scales.

In the dose-escalation study, all participants increased their daily (R+)pramipexole dosage to 100 milligrams three times a day. Blood plasma levels of the drug increased with dose increases. Scores on the ALS Functional Rating Scale did not change, but forced vital capacity (FVC, a respiratory measurement) improved.

In the open-label extension study, changing from 30 milligrams to 60 milligrams per day of (R+)pramipexole was associated with a statistically nonsignificant reduction of 17 percent in the slope of decline on the ALS Functional Rating Scale. The drug was tolerated well long-term at 30 and 60 milligrams per day.

In February, James Bennett Jr., M.D., Ph.D., at the University of Virginia Health System in Charlottesville, said the team is collecting functional clinical data in the 300 milligram per day study but that they don’t have enough data points to draw any conclusions yet. They expect to finish that study late this summer.

In their paper, the investigators say their findings support longer-term testing of higher doses of (R+) pramipexole as a potential therapy for sporadic ALS.

September 2007

The details of this study have changed over time. As of April 2007, the investigators say the following:

• A 30-person, nine-month study of 30 milligrams per day of R(+)pramipexole in early ALS is now complete. The drug was well tolerated. Data analysis showed small improvements in the course of ALS that were not statistically significant. Based on these findings future, they decided that future studies would use higher drug doses.
• A 10-person study of R(+)pramipexole at a variety of increasing dosages (“dose-escalation” study) has also been completed. The drug was well tolerated in daily doses from 30 to 300 milligrams per day. Target drug levels in blood plasma were reached in some patients. The short duration of this study did not allow for any effectiveness data to be analyzed. No adverse effects on ALS symptoms were observed.
• A 10-person, six-month, early phase 2 study has been started in which participants will take 300 milligrams per day for six months. This study is “open label,” meaning participants know what they were taking. Results are expected in mid-2008.
• The investigators have offered (R+)pramipexole to everyone who participated in any of these studies, and they have provided the drug to an additional 30-35 people around the United States on an open-label basis. They treat this as an “open-label safety study.” The daily dose in these open-label studies has gradually increased.

Pramipexole was synthesized in the 1980s with the hope that it would mimic a brain chemical called dopamine, needed by patients with Parkinson’s disease. The studies resulted in the development of two forms of pramipexole that are mirror images of each other in their chemical structures: R(+) pramipexole and S(-) pramipexole.

The S(-) form was found to be a good mimic of dopamine and went on to be developed into the drug Mirapex, which is used to treat Parkinson’s.

The R(+) form was not a good dopamine mimic, but it penetrates well into brain tissue; is an antioxidant, which means it combats free radicals (toxic byproducts of cellular metabolism); and can enter mitochondria, the energy-producing miniature organs (organelles) inside cells. These activities would be likely to enhance nerve cell survival in adverse conditions, such as those found in ALS-affected cells.

A pilot study of 15 ALS patients taking 30 milligrams of R(+) pramipexole a day for eight weeks showed that the drug was well tolerated.

The results of a study to test this dose did not show significant improvements in ALS symptoms. A subsequent short-term dose-escalation study showed that a 300 milligrams per day dose was well tolerated and produced drug levels in blood plasma that could protect nerve cells in culture (in laboratory dishes) from dying.

The hypothesis of the phase 2 study is that treatment with R(+) pramipexole at 300 milligrams per day will alter the rate of decline in early ALS, as measuring by a functional rating scale, over the course of six months.

ALS patients at an early stage of the disease will take increasing daily doses of R(+) pramipexole over five weeks to reach the target dose of 300 milligrams a day. Their daily dose will be adjusted upwards or downwards as a function of their drug levels in blood plasma. They will stay on this high drug dose for six months. Spinal fluid will be collected at the beginning and near the end of the study.

The goals of the study are to determine if a high drug dose is tolerated for longer periods, what drug levels are reached in blood plasma and spinal fluid, and whether antioxidant effects can be seen in blood plasma and spinal fluid. The ALS Functional Rating Scale-Revised will be used to measure disease progression.

Inclusion Criteria

Participants must

• have an established diagnosis of ALS
• have a forced vital capacity (respiratory measurement) of more than 60 percent of normal without being ventilated
• be able to swallow
• be able to walk, with or without assistive devices

Exclusion Criteria

Participants must not

• have had ALS for more than three years
• have advanced ALS with a predicted survival time of less than six months
• have active cardiovascular disease
• have dementia (disorientation, poor thinking ability)
• have a history of psychosis or hallucinations
• have had prior exposure to R(+) pramipexole
• have orthostatic hypotension (a significant drop in blood pressure when assuming a standing position)
• have abnormal baseline lab values that would jeopardize safety