Phenserine - Next Generation AChE Inhibitor for Alzheimer's Disease (AD)

Under development by Axonyx, a US biopharmaceutical company that focuses on treatments for dementia, phenserine is a next generation acetylcholinesterase (AChE) inhibitor indicated for the treatment of AD. Unlike currently marketed AChE inhibitors, it has a dual mechanism of action that also includes anti-amyloid activity, which may confer disease-modifying effects in patients with AD. If this is substantiated in an ongoing clinical trial then phenserine may open the door to an entirely new type of treatment for AD.

Phenserine is Axonyx's lead investigational compound in a series of drugs under development for the treatment of AD and other types of dementia.

NEW TREATMENTS NEEDED TO HALT RISING PREVALENCE OF AD

It is estimated that somewhere between 12 and 15 million people worldwide have AD, with 4.5 million people affected in the US alone. Because AD is primarily a disease of the elderly, these figures are projected to rise significantly as the proportion of elderly in the world's population increases. Indeed, by 2025 there are likely to be more than twice as many people with AD than there are today unless more effective treatments are discovered. Among those aged 85 years and older the prevalence of AD may be as high as 50%.

Currently available anti-dementia drugs provide modest symptomatic improvement but do not address the underlying pathology of AD. Furthermore, their effects on cognition, executive functioning and behaviour are only temporary. None is considered to have disease-modifying effects that can halt the progression of the disease and stop cognitive decline - the hallmark of AD. Many patients also fail treatment with first-line anti-dementia drugs because of poor efficacy, safety and adherence to treatment.

There is an urgent need to find drugs that can address the underlying pathology of AD and help halt the inexorable rise in the prevalence of the most common form of dementia to afflict the elderly.

ANTI-AMYLOID AGENTS MAY HAVE DISEASE-MODIFYING EFFECTS

At postmortem the brains of patients who have died from AD have a number of distinct pathological features: amyloid plaques, first described by Alois Alzheimer in 1906, neurofibrillary tangles and a loss of cortical neurones and synapses.

The discovery that the amyloid plaques in the brains of AD patients contained an accumulation of insoluble toxic beta-amyloid (Β -amyloid42), derived from amyloid precursor protein (APP), led to the search for compounds that could either prevent the deposition of toxic beta-amyloid in the brain or eliminate existing amyloid plaques. After drugs that target cholinergic neurotransmission, anti-amyloid therapies represent the next largest group of compounds in development for AD. The hope is that by targeting what is believed to be a key step in the pathogenesis of AD, such compounds will have a disease-modifying effect.

PHENSERINE ADVANCES TO PHASE III DEVELOPMENT

Early evidence of clinical efficacy, safety and tolerability was demonstrated in a phase II randomised, double-blind, placebo-controlled trial in 72 AD patients conducted in the US. Completed in 2001, this phase II trial showed that phenserine was well tolerated, with a lower incidence of adverse events than traditionally seen with marketed AChE inhibitors: the incidence of nausea and vomiting with phenserine was <8.5%. The rapid clearance of phenserine from the blood may account for its improved tolerability. Although not adequately powered to assess efficacy, the trial nonetheless provided evidence that treatment with phenserine improved cognition, memory and functioning in patients with AD.

Phenserine is currently undergoing evaluation in two phase III registration trials as well as a phase IIb trial designed to assess its ability to lower levels of beta-APP and beta-amyloid in the plasma and CSF of patients with mild to moderate AD. The latter should provide early and valuable information on the potential of phenserine to modify disease progression in AD.

In the phase III randomised, placebo-controlled double-blind studies the safety and efficacy of phenserine (10mg and 15mg twice daily) is being evaluated in 375 and 450 patients respectively with mild to moderate AD. Efficacy assessment over the six-month trial period will include standard memory and cognition tests (ADAS-Cog, CIBIC-Plus) that are the required efficacy endpoints for drug approval. A six-month open-label extension study is planned for both the phase III and IIb trials. It is hoped that data from these will form the basis of an NDA submission.

MARKETING COMMENTARY

The current market for anti-dementia therapies is in its infancy with among the highest growth dynamics in the CNS market, fuelled by a growing elderly population and the need for better treatments.

Analysts are bullish about the prospects for Axonyx's phenserine, especially if the drug proves to have disease-modifying effects in addition to protecting cholinergic function. The outcome of the ongoing phase IIb trial described above is awaited with interest.

If the promising results seen in the initial clinical study are confirmed in the current registration trials then phenserine is likely to reach the market by 2006 and may become the first disease-modifying drug for AD. Securing a strong co-development and marketing partner for phenserine will be essential if it is to compete effectively against the products that dominate today's anti-dementia market.

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