BHV-2100, A First-In-Class TRPM3 Antagonist for the Treatment of Neuropathic Pain

Background & Aims

The transient receptor potential (TRP) superfamily act as molecular sensors of painful stimuli (1). Indeed, molecules that adequately and safely target these channels have the potential to suppress pain at its origin (2). Among the TRP channels, TRPV1, TRPA1, and TRPM8 have been the most studied targets to develop new analgesic drugs (3).
Transient Receptor Potential Melastatin 3 (TRPM3) is a calcium-permeable, nonselective TRP channel expressed in somatosensory neurons, including nociceptors of rodents and humans (4,5). Preclinical models and human genetics implicate a key role of TRPM3 in pain signaling. TRPM3 plays a key role in acute heat sensing, and its function is upregulated in animal models of inflammatory or neuropathic pain (6-8). Moreover, TRPM3-deficient mice do not develop pathological hypersensitivity (5,6,9,10). TRPM3 is also functional in trigeminal nerve fibers innervating mouse meninges, and TRPM3 agonist evoke trigeminally induced pain (11,12).

Methods

The activity of BHV-2100 against TRPM3 was evaluated in a range of experimental paradigms including whole-cell patch-clamp experiments and microfluorimetric calcium measurements in TRPM3-overexpressing HEK293 cells, rodent dorsal root ganglion neurons, and human stem cell-derived sensory neurons. In vivo, target engagement in rodents was confirmed by measuring the ability of BHV-2100 to inhibit pain responses following intraplantar injection of the TRPM3 agonist, pregnenolone sulfate (PS). The analgesic effects of BHV-2100 were assessed in clinically relevant rodent models of pain (i.e., nerve injury, diabetic peripheral neuropathy and chemotherapy induced peripheral neuropathy).

Results

In patch clamp experiments, BHV-2100 was a potent inhibitor of human, mouse, and rat TRPM3 in HEK293 cells with IC50 values between 1-10 nM. BHV-2100 induced dose-dependent inhibition (IC50 value = 10.9 ± 0.4 nM) of PS-induced [Ca2+]i influx in human stem-cell derived sensory neurons. BHV-2100 exhibited >1000-fold selectivity over related TRP channels and a broad range of other targets. Oral administration of BHV-2100 inhibited PS-evoked pain responses in a dose-dependent manner in mice and rats with ED50 values of 1.3 mg/kg and 2.5 mg/kg, respectively. Furthermore, BHV-2100 showed robust efficacy in rodent models of neuropathic pain, without adverse effects.

Conclusions

BHV-2100 is a potent, selective, peripherally restricted, orally administered, first-in-class TRPM3 antagonist that reverses pain in a spectrum of animal models without causing the sedative effects that severely limit current standard of care treatments for pain. Importantly, in preclinical models, BHV-2100 does not cause the adverse thermoregulatory effects that have prohibited the pharmacological targeting of other TRP family ion channels. These findings provide a compelling rationale for the advancement of BHV-2100 into currently ongoing human clinical trials as a potentially novel, highly effective, and non-sedating non-opioid treatment for pain.

References

1Rosenbaum, T., Morales-Lazaro, S. L. & Islas, L. D. TRP channels: a journey towards a molecular understanding of pain. Nat Rev Neurosci 23, 596-610 (2022). https://doi.org/10.1038/s41583-022-00611-7
2Bamps, D., Vriens, J., de Hoon, J. & Voets, T. TRP Channel Cooperation for Nociception: Therapeutic Opportunities. Annu Rev Pharmacol Toxicol 61, 655-677 (2021). https://doi.org/10.1146/annurev-pharmtox-010919-023238
3Julius, D. TRP channels and pain. Annu Rev Cell Dev Biol 29, 355-384 (2013). https://doi.org/10.1146/annurev-cellbio-101011-155833
4Vangeel, L. et al. Functional expression and pharmacological modulation of TRPM3 in human sensory neurons. Br J Pharmacol 177, 2683-2695 (2020). https://doi.org/10.1111/bph.14994
5Vriens, J. et al. TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 70, 482-494 (2011). https://doi.org/10.1016/j.neuron.2011.02.051
6Aloi, V. D. et al. TRPM3 as a novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain. Pain 164, 2060-2069 (2023). https://doi.org/10.1097/j.pain.0000000000002906
7Mulier, M. et al. Upregulation of TRPM3 in nociceptors innervating inflamed tissue. Elife 9 (2020). https://doi.org/10.7554/eLife.61103
8Vanneste, M. et al. TRPM3 Is Expressed in Afferent Bladder Neurons and Is Upregulated during Bladder Inflammation. Int J Mol Sci 23 (2021). https://doi.org/10.3390/ijms23010107
9Alkhatib, O. et al. Promiscuous G-Protein-Coupled Receptor Inhibition of Transient Receptor Potential Melastatin 3 Ion Channels by Gbetagamma Subunits. J Neurosci 39, 7840-7852 (2019). https://doi.org/10.1523/JNEUROSCI.0882-19.2019
10Su, S., Yudin, Y., Kim, N., Tao, Y. X. & Rohacs, T. TRPM3 Channels Play Roles in Heat Hypersensitivity and Spontaneous Pain after Nerve Injury. J Neurosci 41, 2457-2474 (2021). https://doi.org/10.1523/JNEUROSCI.1551-20.2020
11Kelemen, B. et al. The TRPM3 ion channel mediates nociception but not itch evoked by endogenous pruritogenic mediators. Biochem Pharmacol 183, 114310 (2021). https://doi.org/10.1016/j.bcp.2020.114310
12Krivoshein, G., Tolner, E. A., Maagdenberg, A. V. D. & Giniatullin, R. A. Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists. J Headache Pain 23, 4 (2022). https://doi.org/10.1186/s10194-021-01383-8

Presenting Author

Joris Vriens

Treatment/Management: Pharmacology: Non-opioid

BHV-2100, A First-In-Class TRPM3 Antagonist for the Treatment of Neuropathic Pain

Background & Aims

Methods

Results

Conclusions

References

Presenting Author

Joris Vriens

Poster Authors

Joris Vriens

Jean-Christophe Vanherck

Arnaud Marchand

Bruce Car

Gene Dubowchik

Reese Caldwell

Volkan Granit

Lawrence Marcin

David Pirman

Patrick Chaltin

Thomas Voets

Topics

IASP 2024 World Congress on Pain