Editors’ note: PRF member Michel Paré is president and co-founder of PhylogenX, a contract research organization in Montreal, Canada. Paré submitted the following comment about a new TRPV1 blocker entering clinical study. We invited PRF member Arpad Szallasi, who studies TRP channels at Monmouth Medical Center, Long Branch, New Jersey, US, to add his thoughts, which appear after Paré’s comment. We invite our readers to submit their own comments below.
The first generation of TRPV1 blockers tested for analgesic efficacy demonstrated undesirable side effects such as dysregulation of core body temperature (AMG517; AZD1386; ABT-102; MK-2295) or loss of sensitivity to heat pain (ABT-102, MK-2295). These side effects, which are also found in preclinical studies, are hypothesized to depend on the specific TRPV1 gating modalities (heat, pH, and capsaicin) targeted by the antagonists (Lehto et al., 2008; Reilly et al., 2012). New chemical entities were developed based on the idea of modality-specific antagonism. Such a compound, NEO6860, which is being advanced by NEOMED, a public-private organization in Montreal developing early-stage drug discovery projects, is now entering clinical study [download PDF below].
In vitro data demonstrated that NEO6860 blocks capsaicin activation of the human TRPV1 channel but does not inhibit heat- or pH-evoked responses. In primate dorsal root ganglion (DRG) neurons, NEO6860 was found to selectively antagonize capsaicin-evoked currents, sparing the heat response, and did not increase heat thresholds of primate unmyelinated C-fibers.
Hopefully, this compound will provide the first human test of the modality-specific TRPV1 blocker hypothesis, and can avoid hyperthermia and burn injury side effects and provide validation of preclinical data supporting this view. Most importantly, the compound will hopefully be shown to maintain analgesic properties.
Comments
Arpad Szallasi, Monmouth Medical Center
NEO6860, A “Modality-Specific
NEO6860, a “Modality-Specific” TRPV1 Antagonist: An Elegant Solution or Another Disappointment?
With 50-plus pharmaceutical companies filing over 1,000 patents and spending an estimated US$1 billion on drug development, TRPV1 is arguably the most expensive therapeutic target ever. Although a number of small molecule TRPV1 antagonists have been advanced to clinical trials, so far none has progressed beyond Phase 2 due to a combination of dose-limiting side effects like hyperthermia and impaired heat pain sensation.
An attractive approach is to eliminate the undesirable side effects of TRPV1 antagonists by chemical modification of the pharmacophore. Indeed, in the rat it was feasible to eliminate hyperthermia while preserving anti-hyperalgesia by differential modulation of distinct modes of TRPV1 activation (Lehto et al., 2008). Subsequently, several companies described so-called “modality-specific” TRPV1 antagonists that do not raise body temperature in the rat (Watabiki et al., 2011; Reilly et al., 2012).
“Modality specificity” is an attractive concept. Site-directed mutagenesis experiments furnished strong evidence that point mutations can selectively eliminate TRPV1 activation mechanisms. For example, the Y511A mutant responds to heat and protons but not capsaicin (Jordt et al., 2000). Conversely, the T633A mutant shows normal capsaicin activation but does not respond to heat or protons (Ryu et al., 2007). These findings imply that such modality-selective antagonists that leave heat sensing intact may be synthesized.
NEO6860 is a promising representative of this new generation of modality-specific TRPV1 antagonists. In primate sensory neurons, it selectively blocks capsaicin-evoked responses, leaving heat sensation intact. The major outstanding question is whether this modality specificity also translates into clinically meaningful pain relief. Unfortunately, it is not known what operates TRPV1 under painful conditions. If this putative “endovanilloid” targets the capsaicin-recognition domain, NEO6860 may provide pain relief without compromising heat pain sensing. However, if the analgesic activity requires the blockade of the proton and/or heat activation sites, NEO6860 may disappoint. Clinical trials are ongoing. One has to lean back and wait until the results are disclosed.
PRF Team, Harvard NeuroDiscovery Center
Editor's note: NEOMED has
UPDATE: NEOMED has received approval from Health Canada to begin a phase II clinical trial of NEO6860, its TRPV1 antagonist, for the treatment of osteoarthritis pain. Read more at http://neomed.ca/en/neomed-to-initiate-its-first-phase-ii-clinical-trial-in-canada/