Axonyx' Phase III candidate phenserine could be the first novel disease-modifying agent for Alzheimer's disease filed at FDA as companies look to move beyond the symptom relief offered by current therapies.

Phenserine is an acetylcholinesterase inhibitor that also modulates the messenger RNA involved in the transcription of beta-amyloid precursor protein, which leads to the production of the toxic beta-amyloid plaques associated with the disease. The drug is being tested in a Phase III cognition trial in Europe designed to be a pivotal study for both Europe and the U.S.

A concurrent Phase IIb study aims to elucidate phenserine's mechanism of action. Along with cognitive function measurements, Axonyx will analyze cerebrospinal fluid in a subgroup of 75 patients to measure occurrence of beta-amyloid, CEO Marvin Hauseman told a Biotechnology Industry Organization CEO & Investor Conference panel on age-related central nervous system disorders Feb. 24 in New York. Another subgroup analysis will use brain scans.

Both trials are slated for completion in December of 2004. Axonyx hopes to demonstrate a slowing in the rate of cognitive decline for phenserine compared to placebo, along with correlations between cognitive slowing and toxic beta-amyloid levels, Hauseman said.

The Axonyx exec maintained that phenserine's dual mechanism of action is "unique" and is not found in other AChE inhibitors, such as Pfizer/Eisai's Aricept (donepezil) and Novartis' Exelon (rivastigmine).

Beta-amyloid plaques, which appear to lead to neuronal cell death, are a primary target for disease-modifying drugs to treat Alzheimer's disease, Institute for the Study of Aging Executive Director Howard Fillitt, MD, told the panel. Currently approved drugs, including the AChE inhibitors and Forest/Merz' NMDA antagonist Namenda (memantine), provide only short-term symptom relief, he noted.

"With the cholinesterase inhibitors we have seen two-thirds of patients at one year either better or the same, but then the curves begin to parallel, and so it doesn't look like a disease-modifying agent," Fillitt said.

The other later-stage agents targeting beta amyloid are testing slightly different mechanisms of action.

Neurochem's Alzhemed , which is expected to enter Phase III in the second quarter, is an oral beta-amyloid fibrillogenesis inhibitor. Prana Biotechnology's metal protein-attenuating compound PBT-1 binds to copper and zinc present in high concentrations in damaged brain regions to decrease beta-amyloid levels.

Myriad Genetics' single-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen (MPC-7869) is designed to decrease brain levels of a subtype of beta-amyloid - amyloid beta-42.

The potential neuroprotective properties of approved NSAIDs are also being explored. However, in the wake of a National Institute on Aging study showing that naproxen and Merck's Vioxx (rofecoxib) did not slow the rate of cognitive decline in mild-to-moderate AD, reported in June 2003, the focus of NSAID research has turned to delaying or preventing onset of AD.

Pfizer's COX-2 inhibitor Celebrex (celecoxib) and naproxen are in a Phase III NIA trial in patients with age-associated memory impairment, while Rofecoxib is being tested in earlier-stage NIH studies in combination with other agents in similar populations.

Calcium-channel blockers may also have potential to prevent progression of dementia: the recent Syst-Eur trial found a 50% reduction in incidence of dementia after three years of CCB treatment for hypertension.

Statins are another marketed drug class being investigated for AD disease modification. Past trials have hinted that statins may slow the rate of decline or prevent AD. Current studies include Phase II trials of Pfizer's Lipitor (atorvastatin), co-sponsored by NIA, and NIA-sponsored Phase III trials of Merck's Zocor .

Additional drugs in the clinic to slow AD progression include Voyager Pharmaceuticals' anti-gonadotropin leuprolide, Sanofi-Synthelabo's "neurotrophic" SR-57667, and interferon-alpha 2a, being studied by Pfizer in combination with Aricept, according to FDC Reports' The NDA Pipeline. All three agents are in Phase II.

Fillitt predicted that cognitive measurements will continue to be the primary endpoint for demonstrating AD drugs' disease-modifying properties at FDA because surrogate markers such as beta-amyloid levels in the brain or spinal fluid have not yet been validated.

"I don't think FDA at this point can use [surrogate markers] as approval mechanisms, I really think it's going to be slowing the curve of cognition," Fillitt said.

- Alla Rutstein Bobbitt

Axonyx’ Phenserine Could Be First Alzheimer’s Agent Targeting Beta-Amyloid Plaques To Reach FDA

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