Abstract Details

Title BHV-2100, a First-in-class TRPM3 Antagonist for the Treatment of Pain

Topic Pain

Presentation(s) S13 - Pain Research (11:27 AM-11:39 AM)

Poster/Presentation
Number 002

Background Transient Receptor Potential Melastatin 3 (TRPM3) is a nonselective cation channel expressed in rodent and human nociceptive neurons. Preclinical models and human genetics implicate TRPM3 in pain signaling. BHV-2100 is a small-molecule TRPM3 antagonist.

Objective Assess in vitro activity and in vivo efficacy and safety of BHV-2100.

Design/Methods Activity of BHV-2100 against TRPM3 and selectivity towards other ion channels was evaluated using whole-cell patch-clamp experiments and microfluorimetric calcium measurements in transfected HEK293 cells, rodent dorsal root ganglion neurons, and human stem cell-derived sensory neurons. Implantable sensors monitored the effect of BHV-2100 in rats on body core temperature (BCT) and heart rate (HR). In vivo target engagement was evaluated as the ability of BHV-2100 to inhibit pain responses following intraplantar injection of TRPM3 agonist pregnenolone sulfate (PS) in rodents. Analgesic potential was evaluated in different rodent neuropathic pain models.

Results BHV-2100 inhibited human, mouse, and rat TRPM3 with IC50 values between 1-10 nM, showing >1000-fold selectivity over a large panel of other ion channels and receptors. BHV-2100 exhibited high oral bioavailability in rodents, without noticeable lethargy or effects on BCT or HR. BHV-2100 inhibited PS-evoked pain responses in mice and rats with an ED50 of 1.3 mg/kg and 2.5 mg/kg, respectively, and showed dose-dependent efficacy in the sciatic nerve ligation, chemotherapy-induced neuropathic pain, and diabetic neuropathy models.

Conclusions BHV-2100 is a potent and selective TRPM3 antagonist that reduces pain in preclinical models without thermoregulatory or sedative effects. These findings support the advancement of BHV-2100 to human trials as a novel potential treatment for pain.

Authors/Disclosures
Bruce D. Car (Biohaven Pharmaceuticals) PRESENTER	No disclosure on file
Joris Vriens	No disclosure on file
Jean-Christophe Vanherck (CISTIM)	No disclosure on file
Arnaud MARCHAND (CISTIM Leuven vzw)	No disclosure on file
Gene Dubowchik	No disclosure on file
Reese Caldwell	No disclosure on file
Volkan Granit, MD (University of Miami, Miller School of Medicine)	Dr. Granit has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Dr. Granit has stock in Biohaven. Dr. Granit has received personal compensation in the range of $10,000-$49,999 for serving as a Faculty Member with University of Miami. Dr. Granit has a non-compensated relationship as a collaborator in clinical trial design with Cartesian Therapeutics that is relevant to AAN interests or activities.
Lawrence Marcin (Biohaven)	No disclosure on file
David Pirman (Biohaven Pharmaceuticals)	No disclosure on file
Patrick Chaltin (KU Leuven R&D)	No disclosure on file
Thomas Voets (VIB-KU Leuven Center for Brain and Disease Research)	No disclosure on file