ENVIVO PHARMACEUTICALS: A SMARTER BRAIN

Kees Been, president and CEO, EnVivo Pharmaceuticals

The cognitive-enhancement market is estimated to be worth $20 billion. Although FDA currently shows no sign of smiling upon the use of "smart pills" for patients with no health problems, the working assumption is that consumer demand will eventually force the agency to create some kind of mechanism for approval.

EnVivo's pipeline boasts five early-stage agents, most bought from Bayer when the German drug firm was selling off its entire CNS group. EnVivo's chief scientific officer, Gerhard Koening, had headed dementia research at Bayer, "so we kind of had the inside track," says Been.

The demographics and dynamics of Alzheimer's remain devastating. In the developed world, rates of Alzheimer's in people 65 and over range from 5 to 10 percent; the annual cost of treatment is close to $100 billion in the US, to say nothing of its psychological burden on caregivers.

Alzheimer's R&D is intense, with more than 500 clinical trials ongoing. Yet little about its medical profile is clear. There are two competing hypotheses regarding cause, based on the two hallmarks of its pathogenesis: amyloid plaques (deposits of the amyloid beta protein between brain cells) and neurofibrillary tangles (twisted forms of the protein tau in the cells). The standard treatment, acetylcholinesterase inhibitors, led by Aricept (which nets about $2.5 billion in global sales) works by blocking the enzyme that breaks down the neurotransmitter acetylcholine. While these drugs can help slow the symptoms of memory loss, they don't make a dent in disease progression.

EnVivo had good news to report at July's International Conference on Alzheimer's Disease. Its lead product, a nicotinic alpha-7 acetylcholine receptor agonist, showed positive Phase Ib/IIa results on six of eight standard cognition measures. The alpha-7 nicotinic receptor has emerged as a popular target for cognitive enhancement because it plays a role in the transmission of messages between neuronal synapses. The nicotine chemical stimulates these receptors. "In Alzheimer's patients, who are typically diagnosed after they've already lost half their brain, the drug can make the remaining brain fire harder," Been says.

Accordingly, Big Pharmas have teamed up with alpha-7 biotechs in the race to market. Last November, Roche snapped up Memory Pharmaceuticals, whose alpha-7 candidate was the first to reach proof-of-concept. AstraZeneca recently inked a deal to co-develop several of Targacept's neuronal nicotinic receptors, while Mitsubishi is helping EnVivo with it's alpha-7 trials in Japan.

EnVivo is testing four other compounds in Alzheimer's, including a second alpha-7 and a gamma-secretase modulator (GSM) that also targets the amyloid beta protein, reducing the number of longer pieces while increasing the shorter ones. This down-with-the-bad, up-with-the-good mechanism may prove to be disease modifying, although the first-in-class GSM, codeveloped by Myrial Genetics and Lundbeck, crashed and burned in Phase III last year.

The biotech is also working on a phosphodiesterase-10 (PDE 10) inhibitor for schizophrenia that fuels neurotransmission from the cell membrane to the nucleus, which may translate in the clinic to decreasing the delusions and other so-called positive symptoms of the disease.

Further along is a histone-deacetylase (HDAC) inhibitor, which shows evidence of improving memory by increasing synaptic plasticity and possibly by targeting the tau protein. EnVivo has exclusive rights to the neurodegenerative corner of the HDAC inhibitor field, which it licensed from MethylGene, complete with biomarkers.

Yet EnVivo's fate will likely be determined by its alpha-7's performance. Next up for the nicotine drug are Phase IIb efficacy trials in both Alzheimer's and schizophrenia, at a cost of $10 million to $30 million per disease. "We are debating about whether to partner—it depends largely on the specifics of the deal," says Been.

The biotech also put its most profitable asset on the auction block: its collection of flies. EnVivo started in CNS drug-discovery in 2001 with transgenic fruit flies, whose genome is easy to manipulate. Been spun it off as a fee-for-service gadget after he came onboard, and now the collection may help bankroll the company's next big push into the smart-drug market.