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Disease-Modifying Alzheimer's Drugs Chart Unsteady Course

Staff Writer

It was "two steps forward and one step back" for disease-modifying Alzheimer's drugs at this week's International Conference on Alzheimer's Disease (ICAD), Cowen and Co. LLC analyst Ian Sanderson told BioWorld Today.

Existing treatments boost memory and cognition but cannot slow the progression of the Alzheimer's, which affects an estimated 26 million people worldwide. A disease-modifying approach is seen as the Holy Grail in the $4 billion Alzheimer's market.

Front and center at ICAD, held this week in Chicago, was the monoclonal antibody bapineuzumab (Elan Corp. plc and Wyeth). The much-anticipated drug failed to hit its endpoints in a Phase II trial last month, and although subgroup data looked promising, side effect data turned out to be less encouraging. (See story in this issue.)

Amyloid Beta Alive and Well

Bapineuzumab is designed to rid the brain of amyloid beta, the peptide responsible for forming the hallmark plaques associated with Alzheimer's disease. Other amyloid-targeting drugs to face setbacks recently include Neurochem Inc.'s small-molecule amyloid beta antagonist Alzhemed (tramiprosate) and Myriad Genetics Inc.'s selective amyloid beta-lowering agent Flurizan (tarenflurbil). Both drugs failed Phase III trials seeking to improve ratings on the Alzheimer's Disease Assessment Scale, cognitive subpart (ADAS-cog). (See BioWorld Today, Aug. 28, 2007, and July 1, 2008.)

Myriad presented full data from its Phase III trial at ICAD, stating that ADAS-cog scores for patients in both the treatment and placebo arms had declined by approximately 7 points by the end of the 18 month trial.

Another amyloid approach to bite the dust was Elan's Alzheimer's synthetic amyloid-beta peptide vaccine. Elan shelved the project after researchers reported last month that although the vaccine had cleared amyloid plaques, that clearance had not prevented the progressive neurodegeneration and cognitive decline of Alzheimer's disease. (See BioWorld Today, July 18, 2008.)

Yet Sanderson maintained that amyloid beta is "alive and well."

At ICAD, Eli Lilly and Co. presented Phase II data with its anti-amyloid beta monoclonal antibody LY2062430. Lilly said patients receiving the drug had increased amyloid beta in their blood and cerebrospinal fluid for several weeks, indicating that the drug dissolved plaques in the brain and may have disease-modifying potential. There was no change in ADAS-cog scores, which Lilly said is typical for a 12-week trial, and Lilly pointed out that there was no evidence of the treatment-related brain inflammation that plagued Elan and Wyeth's antibody. Phase III trials are set to start next year.

Prana Biotechnology Ltd. also presented 12-week data with an amyloid-targeting drug at ICAD. In a Phase IIa trial, the higher dose of the company's PBT2, which is designed to block aggregation of amyloid into plaques, had a significant effect on biomarkers and on certain components of the Neuropsychological Test Battery. Again, there was no change in ADAS-cog scores.

Tau Takes Center Stage

But amyloid plaques aren't the only target in Alzheimer's disease. Kimberly Lee, analyst with Pacific Growth Equities LLC, called Phase II data with TauRx Therapeutics Ltd.'s tau aggregation inhibitor Rember (methylthioninium chloride) "pretty interesting." Tau proteins are responsible for forming the neurofibrillary tangles that have been associated with dementia in Alzheimer's.

In the 24-week Phase II trial, TauRx said there was not enough of a decline in the placebo group to assess the primary endpoint of ADAS-cog scores in the overall patient population. However, when the trial was continued through a 60-week extension, analysis at 50 weeks showed that Rember stabilized disease progression, with an ADAS-cog effect of -6.8 compared to a decline of 7.8 in the control arm (p < 0.0001).

A mixed effects slope analysis showed an 81 percent reduction in cognitive decline over 50 weeks (p < 0.0001), and TauRx said the effect was continued through the full 84-week trial.

Also targeting tau is Allon Therapeutics Inc.'s AL-108. Phase IIa data presented at ICAD showed a statistically significant, dose-dependent, durable improvement in endpoints measuring short-term memory recall. There was no affect on cognitive functions, which the company said was to be expected in a short-term trial in mildly impaired patients.

A Plethora of New Approaches

Other Alzheimer's approaches in the clinic include Accera Inc.'s Ketasyn (AC-1202), which targets defects in glucose utilization and lipid metabolism, and Pipex Pharmaceuticals Inc.'s Coprexa (tetrathiomolybdate), which seeks to lower copper levels. Even earlier in development are start-ups like Mithridion Inc., which is developing small molecules to protect neurons from amyloid beta, and Kinexis Inc., which is targeting prefibrilar oligomers upstream of amyloid plaques.

At ICAD, Medivation Inc. presented data showing that its Phase III Alzheimer's drug Dimebon (dimebolin) works by improving mitochondrial function that is impaired in Alzheimer's disease, leading to loss of brain cell function. The company also presented data showing that patients treated in a 12-month Phase II trial maintained their function through a six-month extension phase. In the 12-month trial, the drug had generated a 6.9 point ADAS-cog improvement over placebo. (See BioWorld Today, Jan. 29, 2008.)

Although the Dimebon data indicated disease-modifying potential, Lee noted that Medivation is "not going for a disease-modifying label yet."

Also at ICAD, EPIX Pharmaceuticals Inc. presented data from select patients who received extended treatment after the Phase IIa trial with 5-HT4 agonist PRX-03140. Initial data from the monotherapy arm of the trial showed a statistically significant mean 5.7 point ADAS-cog improvement, boosting the company's stock. (See BioWorld Today, Dec. 19, 2007.)

Trial Design Challenges Persist

Moving forward, Sanderson said it's going to take Phase III trials to prove if most of these disease-modifying drugs work. And since a disease-modifying Alzheimer's drug has yet to gain FDA approval, there is no clear regulatory path.

Many companies have blamed clinical trial failures on a strong placebo effect caused by the use of approved concomitant medications. Yet an analysis of 87 randomized, double-blind, placebo-controlled Alzheimer's trials that lasted for at least six months found no changes in the amount of cognitive decline across the 15-year time period of the trials.

Researchers from the University of Southern California Keck School of Medicine and the USC Leonard Davis School of Gerontology presented their analysis at ICAD. They did identify several factors that seem to be associated with cognitive decline in placebo groups, and recommended that companies maximize their chances of showing efficacy against placebo by including at least 200 patients in the placebo arm, using English-speaking trial sites and assessing ADAS-cog scores at least four times over the course of the trial to reduce variance.

Published; July 31, 2008