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Distinguished member
Aug 14, 2006
Lost a loved one

LOS ANGELES–An experimental drug that regulates inflammation and showed a strong signal in a pilot study in patients with amyotrophic lateral sclerosis (ALS) failed to show a difference in a larger phase 2B study, researchers reported here at the AAN Annual Meeting.

"This is devastating news for patients," said Robert G. Miller, MD, FAAN, a clinical professor of neurology and neurological sciences at Stanford University Medical School and director of the Forbes Norris ALS Research Center at California Pacific Medical Center. "There was a lot of hope and expectation that this drug would work. I continue to feel that neuroinflammation does play a role in ALS. We don't know whether it's a primary role or a secondary role but neuroinflammation is an important target for therapy in ALS. Although this is a negative trial, it informs us how to refine our hunt for biomarkers to be used in future studies."

NP001, developed by Neuraltus Pharmaceuticals, blocks the activation of inflammatory macrophages. A phase 1 study found that the intravenous drug was safe and well-tolerated. A phase 2A study showed a signal in a subgroup of patients with systemic inflammation who seemed to stop declining on the ALS Functional Rating Scale (ALSFRS-R) and showed a slowing in their decline on vital capacity measures. In fact, 25 percent of the patients receiving high dose NP001 in the first trial stopped progressing during the study compared to 10 percent of those on placebo.

In this latest randomized double-blind study, Dr. Miller and researchers from 21 centers recruited 138 ALS patients who still had a functional vital capacity greater than 65 percent, high C-reactive protein levels (a biomarker for inflammation), and less than two years with symptoms. The patients were randomized to NP001 or placebo intravenously. The first cycle was five consecutive daily doses followed by five cycles of three consecutive daily doses at 28-day intervals. The primary outcome was a change in the ALSFRS-R from baseline; secondary outcomes included a change from baseline in slow vital capacity, ALSFRS-R slope, and inflammatory biomarkers.

Several patients dropped out of the study, but they still had enough patients — 55 on the active drug and 62 on placebo — to detect a 40 percent difference between the two groups.

But the drug didn't work in the newest analysis.The ALS-FRS decreased equally in both groups, as did all secondary measures. Fifteen patients seemed to have stopped progressing during the study, but there was no difference between those on the drug compared with those on the placebo.

"We couldn't believe it," said Stanley H. Appel, MD, FAAN, co-director of the Houston Methodist Neurological Institute and chair of neurology at Houston Methodist Hospital. Dr. Appel's medical center recruited patients into the study.

"One possibility is that the drug really suppressed inflammation and it didn't have an effect, and the other possibility is that the drug didn't hit the activated macrophage target," Dr. Appel said. "The only way to know whether the drug hit the target is to determine whether NP001 affected the inflammatory macrophage cytokine biomarkers in the serum."

"There is no question that there is a pro-inflammatory signal coming from macrophages," he added. "There are ways to explain the data without dismissing inflammation."

Commenting on the study, Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital and the Julieanne Dorn professor of neurology at Harvard Medical School, said: "It is so important to conduct clinical trials like this phase 2B NP001 trial so we get clear answers. We learn so much from these trials, and we need to know whether a drug is biologically active. There remains a lot of hope for people and families with ALS and we need to work closely to find answers and new treatments."


AAN Annual Meeting Abstract S38.004: Miller R, Katz J, Block G, and NP001-10-003 Study Group. Randomized phase 2B trial of NP001, a novel immune regulator in ALS.
well, bugger.
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