Caution Recommended Following Study On New Painkillers That Block A Receptor Called TRPV1

2008-03-13T04:10:00.000-07:00

A new class of painkillers that block a receptor called TRPV1 may interfere with brain functions such as learning and memory, a new study suggests. The experiments with rat brain found that the TRPV1 receptor regulates a neural mechanism called long-term depression, which is believed to be central to establishing memory pathways in the brain.

The researchers said their findings also suggest that the function of TRPV1 in neural tissue may explain reported side effects of the anti-obesity drug Acomplia, widely used outside the U.S. While Acomplia has been approved in Europe, the FDA denied U.S. approval because of concerns that the drug increases risk of depression and suicide. The researchers, led by Julie Kauer, published their findings in the March 13, 2008, issue of the journal Neuron, published by Cell Press.

TRPV1, or "transient receptor potential vanilloid 1," is a pain receptor whose activation causes the pain in inflammation. The receptor is also triggered by noxious chemicals such as the chili pepper compound capsaicin.

Drug companies have been testing TRPV1 receptor blockers to treat the pain of inflammation and nerve damage in the peripheral nervous system (PNS). However, besides being expressed in the PNS, TRPV1 is expressed in areas of the central nervous system (CNS), including the hippocampus, the brain's learning center. However, its function in the brain was not well established.

In their experiments with rat brain slices, Kauer and colleagues explored whether TRPV1 plays a role in long-term depression (LTD), which is a weakening of the signaling between neurons that takes place at the connections called synapses. LTD, and the counterpart strengthening of connections, called long-term potentiation, are key to the formation of neural pathways in learning, a process called plasticity.

The researchers found that they could block LTD in the brain slices using drugs that block TRPV1. Also, they could induce LTD using the TRPV1-activating compound capsaicin.

What's more, they found that genetically knocking out the TRPV1 receptor in mice drastically reduced LTD in the animals.

"In this study, we show for the first time that TRPV1 receptors are necessary and sufficient for a novel form of long-term depression at excitatory synapses," concluded the researchers. "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."

"Further work will help to ascertain whether hippocampal TRPV1 receptors could provide novel drug targets for neurological disorders," they wrote.

What's more, they concluded that their findings suggest a mechanism for the reported side effects of the anti-obesity drug Acomplia.

"A large percentage of patients stop taking this drug as a result of psychiatric side effects, and our findings suggest the possibility that some of the central effects of [Acomplia] result from the antagonism of TRPV1 receptors …," they wrote.

"The results from this study have important implications for the development of drugs targeting TRPV1," wrote Benedict Alter and Robert Gereau in a preview of the paper in the same issue of Neuron. They wrote that the Kauer study as well as others indicating widespread expression of the TRPV1 receptor, "cloud the prospects of TRPV1-targeted analgesics. If TRPV1 is important in hippocampal synaptic plasticity, as this study suggests, then systemic TRPV1 antagonists may interfere with many processes thought to rely on hippocampal synaptic plasticity, such as learning and memory."

However, wrote Alter and Gereau, "there is a silver lining to this cloud." Drugs targeting TRPV1 in both the peripheral and pain-processing regions of the central nervous system "actually produced greater analgesia than antagonists thought to primarily act in the periphery." Also, they noted, targeting TRPV1 may be useful in treating other neural disorders, such as epilepsy.

"Regardless of the uncertain future of TRPV1-targeted therapeutics," they wrote, such studies "are important not only for drug development but also for expanding our knowledge of synaptic function."

Array BioPharma Announces Positive Phase 2 Top-Line Results In Inflammatory Pain Clinical Trial

2008-03-05T12:48:00.000-08:00

Array BioPharma Inc. (NASDAQ: ARRY) announced positive top-line results from a Phase 2 clinical trial evaluating the efficacy of ARRY-797, a novel, orally administered, small molecule pan-cytokine inhibitor, in patients with post-surgical dental pain. ARRY-797 achieved its primary and secondary endpoints for analgesic efficacy and was well tolerated. Based on these results, Array is moving forward with a second Phase 2 acute inflammatory pain trial comparing various doses of ARRY-797 to placebo and to celecoxib. Array also plans to initiate a Phase 2 study of ARRY-797 in ankylosing spondylitis, a chronic, painful, inflammatory disorder known to respond to biologic TNF inhibitors.

The analgesic effect of 400 mg of ARRY-797, compared to placebo, was statistically significant based upon the primary endpoint of total pain relief over six hours post dose (p<0.0001). The analgesic effect was also statistically significant for total pain relief over three, eight, twelve and 24 hours post dose. Other analgesic endpoints, including total pain intensity, time to meaningful pain relief and time to analgesia were also significantly improved versus placebo. Peri-operative dosing with 200 mg before and 200 mg after surgery also resulted in a substantial reduction in total pain intensity. Array believes the efficacy observed in this study is due to the simultaneous inhibition of the pain mediator PGE2 and the inflammatory mediators TNF, IL-1 and IL-6. No serious adverse events were reported and non-serious adverse events were evenly balanced across the three groups. Complete trial results will be presented at an appropriate scientific conference later this year.

"These results demonstrate efficacy of ARRY-797 in the management of inflammatory pain," said John Yates, MD, Chief Medical Officer, Array BioPharma. "Together with our multiple-dose, 14-day trial in healthy volunteers, these data confirm the good safety and tolerability profile of ARRY-797. In particular, we have observed no evidence of any gastrointestinal, hepatic or skin toxicity due to ARRY-797. Therefore, we remain very excited about the potential of ARRY-797 to provide clinical benefit in a variety of inflammatory pain conditions."

Phase 2 Inflammatory Pain Study Design

The Phase 2 trial was a randomized, double-blind, placebo-controlled, parallel-group efficacy study of ARRY-797 in patients undergoing third molar extraction. This is a standard model for testing efficacy of analgesic agents. The study objective was to assess the analgesic efficacy, safety and tolerability of ARRY-797 dosed either after the operation (400 mg) or both before and after surgery (200 mg twice). The trial enrolled 103 patients and was conducted at two centers in the United States.

About ARRY-797 / Pan-cytokine Inhibitor

ARRY-797 is a highly selective p38-alpha inhibitor, which modulates the production of TNF, IL-1, IL-6 and PGE2 in human whole blood with nanomolar potency. ARRY-797 has unique properties, including high water solubility and tissue penetration, and was designed to limit distribution to the central nervous system.

In Phase 1 studies in healthy volunteers of up to 14 days dosing, ARRY-797 demonstrated linear increases in exposure with increasing oral doses from 25 to 400 mg. The drug was well-tolerated at all doses tested with no serious adverse events. In blood samples taken from these volunteers and with LPS, ARRY-797 dose-dependently inhibited the stimulated production of TNF, IL-1, IL-6 and PGE2.

About Pan-cytokine Inhibition for Inflammation and Pain

P38 is a kinase target that regulates the production TNF, IL-1 and IL-6 as well as PGE2. TNF, IL-1 and IL-6 are all clinically validated cytokines for controlling inflammation in rheumatoid arthritis and are prevalent in many forms of inflammation. PGE2 is an important mediator of inflammatory pain and the target of NSAIDs. Many forms of acute and chronic pain have inflammatory origins, and pan-cytokine suppression may treat both the inflammation and the resulting pain. Array believes modulation of all three cytokines plus PGE2 may be more effective than inhibition of any one in isolation for controlling both the underlying inflammation and the resulting symptoms such as pain.

About Array BioPharma

Array BioPharma Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer, inflammatory diseases and pain. Our proprietary drug development pipeline includes clinical candidates that are designed to regulate therapeutically important target proteins and are aimed at significant unmet medical needs. In addition, leading pharmaceutical and biotechnology companies collaborate with Array to discover and develop drug candidates across a broad range of therapeutic areas. For more information on Array, please go to http://www.arraybiopharma.com.

Clinical Trials Web

Caution Recommended Following Study On New Painkillers That Block A Receptor Called TRPV1

Array BioPharma Announces Positive Phase 2 Top-Line Results In Inflammatory Pain Clinical Trial