Thursday, March 13, 2008

When Life Gives You Lemons, Make Lemonade (Caution: side effects may include forgetting you made lemonade)

Developing drugs that block the pain receptor TRPV1 just got a whole lot more complicated.

A study published in today's issue of the journal Neuron suggests these drug candidates may interfere with learning and memory, and that this action may be responsible for the reported psychiatric side effects of Sanofi-Aventis' rimonabant, as well.

A quick search through our Strategic Transactions Database throws up at least two recent TRPV1 deals--by Eli Lilly and Wyeth--to gain access to inhibitors of the receptor (which goes by the full and catchy name of transient receptor potential vanilloid 1). Lilly paid Glenmark $45 million up front plus milestones for access to the TRPV1 inhibitor GRC6211 just last November and Wyeth teamed up with Mochida Pharmaceuticals in January (naturally, Deals of the Week! was there to cover these for you in real-time). Activation of TRPV1 causes pain associated with inflammation and is triggered by molecules like capsaicin, which is found in chili peppers.

Wyeth and Lilly and others (such as NeurogesX, Pfizer, and Merck) aren't intending to mess with the brain, of course, they're targeting the receptor in the peripheral nervous system to ease pain associated with osteoarthritis, neuropathy, and other maladies. But the researchers, led by Brown University's Julie Kauer, working with slices of rat brain demonstrated for the first time the function of TRPV1 receptors in the CNS, where they appear to be part of the neural circuits of learning and memory in the hippocampus.

From the press release accompanying the paper:

“The broad distribution of TRPV1 receptors in the brain suggests that these receptors could play a similar role in synaptic plasticity throughout the CNS.” ... The researchers said their findings suggest that drugs targeting TRPV1 could act not only on pain receptors in the PNS, but in the brain as well. They also wrote that their findings and those of other researchers “indicate that drugs that bind to CNS TRPV1 receptors are likely to influence more than just pain-related functions.”
Kauer and colleagues also noted that TRPV1 was inhibited by rimonabant, possibly introducing new headaches for Sanofi-aventis and other -abant hopefuls like Merck & Co. (the latter has yet to officially comment on the abstract referring to some poor Phase III data due to be presented later this month at the big ACC meeting in Chicago).

But wait, you say, we understood there was to be lemonade? Fair enough. Despite the fact that Kauer's findings "have important implications for the development of drugs targeting TRPV1," and that they "cloud the prospects of TRPV1 analgesics," there may be some good news, according to the authors of a preview of the paper (also in Neuron), Benedict Alter and Robert Gereau, from the pain center at the Washington University School of Medicine.

Apparently, TRPV1 inhibitors that act both in the periphery and in the brain actually work pretty well at soothing pain. And what's more the drugs could find uses in other brain disorders, such as epilepsy, Alter and Gereau write.

Pain is a notoriously tricky clinical space that is nevertheless receiving quite a bit of pharma attention--Pfizer devoted more time to pain at its recent analyst day than to any other therapeutic area, to our surprise. Though this is just one study, in rats, and concerns just one target, it's another reminder that the science of pain and pain relief is complex, and in its early days.

Hat tip: Reuters

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