ALS Research Roundup June 2008

by Margaret Wahl and Amy Labbe on Sun, 2008-06-01 09:16
Article Highlights:

Research Roundup updates as of May 2008:

MDA-funded lithium trial is now open

Participant for Lithium trial
The MDA-funded trial is designed so that all participants will receive lithium.

Neurologist Robert Miller, director of the Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco, has begun testing the drug lithium carbonate in an MDA-funded trial that expects to include 100 participants with ALS at 10 U.S. sites.

Recruitment of participants is under way through the coordinating site in San Francisco (see below) and is expected to be under way soon at centers located in Arizona, California, Kansas, Missouri, Oregon, Pennsylvania, Texas and Utah.

Another study of lithium in ALS, coordinated by researchers at Massachusetts General Hospital in Boston, also is on the drawing board.

In February, an Italian study of lithium carbonate and riluzole in people with ALS showed the combination of the two drugs slowed progression of the disease. The results, published online Feb. 4 in Proceedings of the National Academy of Sciences, prompted Miller to plan and begin the new study, which aims to confirm or refute the effectiveness of lithium carbonate both in combination with riluzole and alone. (See Research Roundup, March 2008.)

Miller said the results of the Italian study are “important” and “the most positive ever reported for ALS” but that questions still exist for which the U.S. study should provide answers.

Participants in the new study will take twice-daily doses of lithium, designed to replicate the same blood serum levels tested in the Italian group, for one year.

Researchers hope positive results from an Italian study can be replicated in a U.S. trial of lithium.

The investigators will assess lithium’s safety and measure changes in general function (as detected by the ALS Functional Rating Scale – Revised), pulmonary function, quality of life and survival time. These measurements will be compared with those in people who participated in a recent ALS study but received only a placebo. This “historical control” design allows all participants in the current trial to receive the study drug.

Although investigators will “take all comers,” Miller says that because approximately 50 percent of people with ALS in the United States take riluzole, he expects to see roughly the same percentage of study participants taking the drug as well. The trial design will enable investigators to determine not only the effects of lithium, but any synergistic effect of the combination of riluzole and lithium.

“If riluzole is having a significant impact, it should be apparent,” he said.

Contact Dallas Forshew at (415) 600-3938 or, and/or see

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Phase 2 study of KNS-760704 is open

Knopp Neurosciences, a Pittsburgh drug-discovery company, has announced the opening of a phase 2, 20-center trial of its experimental compound KNS-760704 in 80 people with ALS.

Disease Diagram
Knopp Neurosciences is following up on studies that showed (R+) pramipexole (KNS-760704), a mirror image of a Parkinson disease drug, might be effective in ALS.

The KNS-760704 molecule is a mirror image of (S-) pramipexole (Mirapex), a drug used to treat Parkinson disease. The mirrorimage compound, known as (R+) pramipexole, initially was developed for ALS at the University of Virginia in Charlottesville. It’s designed to have some of the characteristics of the original molecule, but not others.

(S-) pramipexole mimics the actions of dopamine, a carrier of signals in the brain, which is desirable for treating Parkinson disease but would be toxic in ALS at the doses that may be needed. However, it has antioxidant and anti-cell-death properties that are preserved in the mirror-image (R+) molecule and may benefit ALS patients. (See Research Roundup, November-December 2007.)

In February, the journal Amyotrophic Lateral Sclerosis reported that patients with earlystage ALS who took part in an exploratory, 30-person, nine-month study of (R+) pramipexole at the University of Virginia showed a slowing of their decline in function described as “encouraging but statistically nonsignificiant.”

The work at the University of Virginia has been “very valuable in pioneering a potentially promising approach to the treatment of patients with ALS,” said Tom Petzinger, executive vice president of Business Development, Strategy and Public Affairs at Knopp. “We’re encouraged by the early safety experience with (R+) pramipexole at UVA and by the data suggesting a hint of effectiveness.”

Now, he said, Knopp has developed a purified tablet formulation of (R+) pramipexole with its KNS-760704 compound and is on a path toward its commercial development for the treatment of ALS.

“The milestone we have achieved now is having completed a phase 1 study in 80 healthy subjects,” Petzinger said, in which KNS-760704 “demonstrated excellent levels of safety and tolerability.” The phase 2 study will test the drug in ALS patients.

Petzinger said Knopp will move on to a much larger study later this year if there are no safety or tolerability problems.

See, or contact Tom Petzinger at (412) 488-1776 or

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High-dose coenzyme Q10 showed no benefit

Petra Kaufmann

Petra Kaufmann, principal investigator, said the results of the high-dose coenzyme Q10 were disappointing but that they free patients from believing they have to buy the supplement and free resources to test other drugs.

High-dose coenzyme Q10 (coQ10) is not promising enough to warrant further study as a treatment for ALS, reported principal investigator Petra Kaufmann from Columbia University Medical Center in New York at the 60th annual meeting of the American Academy of Neurology in April. (For more news from this meeting, see “Researchers Gather at AAN meeting” under What’s New at

Kaufmann, with colleagues at 19 U.S. centers and funding from the National Institutes of Health, tested coQ10 at dosages up to 2,700 milligrams per day against an inactive substance (placebo) in 185 people with ALS.

“The difference between the 2,700-milligram coQ10 group and the placebo group was not large enough to suggest that one would find a meaningful difference in a future phase 3 [large-scale] trial,” Kaufmann said. She added, however, that the study didn’t address the question of whether coQ10 might be helpful in combination with other drugs.

Kaufmann said the result was disappointing because they didn’t find a drug that helps people with ALS. However, she noted, it frees ALS patients from believing they have to buy coQ10, and it frees resources to test other drugs rather than conducting an expensive, phase 3 trial of coQ10.

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Leaks in blood-spinal cord barrier come before nervous-system damage in mice with SOD1 ALS

A research team that included MDA grantees M. Kerry O’Banion at the University of Rochester (N.Y.) Medical Center and Severine Boillee at the University of California-San Diego has found that leaks in the blood vessels of the spinal cord precede damage to the nervous system in ALS in mice with the SOD1-related form of the disease.

Berislav Zlokovic at the University of Rochester and colleagues, who published their findings in the April issue of Nature Neuroscience, found that mice with mutated SOD1 genes had disruptions in the barrier between the spinal cord and bloodstream that normally protects the central nervous system from toxins and injury.

In these mice, the blood-spinal cord barrier was disrupted because of reduced levels of three of the so-called “tight junction” proteins that normally keep it together, the investigators noted.

The disruptions resulted in inflammation, as well as reductions in blood flow and, in some areas, small hemorrhages with release of toxins.

The researchers said their study demonstrates that an increase in the permeability of the spinal-cord blood vessels probably makes an important contribution to degeneration of the muscle-controlling nerve cells (motor neurons), which is the hallmark of ALS.

They also noted that damage to these blood vessels is among the earliest events in a “toxic cascade” set in motion by SOD1 gene mutations. (Research published last year showed damage to these blood vessels in mice with SOD1-related ALS, but the investigators couldn’t determine whether the damage came before or after damage to nerve cells.) “Genetic or pharmacologic interventions targeted specifically to the endothelium [lining of blood vessels] will help to determine both the causality between the blood-spinal cord barrier leakage and motor neuron degeneration and how such damage may [affect] disease onset and/or progression,” the researchers note. (The University of Rochester Medical Center says the team is currently testing a compound that may help seal leaky blood vessels.)

A caveat is that these experiments were conducted in mice with SOD1-related ALS. Their meaning for ALS resulting from other causes (the most common kind) isn’t known.

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Letter to the editor:

I would like to thank Bill Norman for his article “ALS and Vets: Searching for Connections” (March 2008).

As a Gulf War vet with PLS (primary lateral sclerosis), I’m glad this is getting some attention. I just got a book called Gulf War Syndrome: Legacy of a Perfect War by Alison Johnson (MCS Information Exchange, February 2001). The book gives a whole chapter to ALS. At the time of printing, there were 28 confirmed cases, out of a group of around 700,000 vets. Not sure what the number is now.

Thanks again,
David Miller
Cumming, Ga.

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