TRPM3 Antagonist BHV-2100 Shows Safe Profile as Potential Therapy for Migraine

Volkan Granit, MD, MSc

New data from a randomized, placebo-controlled sequential single-ascending dose (SAD) study showed that treatment with BHV-2100 (Biohaven), a TRPM3 antagonist, was safe and well tolerated at single doses up to 500 mg. All told, the therapy was rapidly absorbed with a highly favorable pharmacokinetic profile, further supporting its future development into clinical trials for pain and migraine as a novel non-opioid treatment.^1,2

Presented at the 2024 World Congress on Pain, held August 5-9 in Amsterdam, the Netherlands, the SAD portion of the trial included 39 healthy individuals who were randomly assigned 3:1 a single dose of to BHV-2100 (25, 75, 150, 250, or 500 mg) or placebo. At the conclusion of the trial period, there were no serious or severe adverse events (AEs) reported, and most AEs were mild and resolved spontaneously without treatment. In addition, there were no dose-limiting toxicities observed as well.

BHV-2100 is a first-in-class, orally administered, highly selective, potent, small molecule TRPM3 antagonist currently in development for the treatment of migraine and other pain disorders. TRPM3 is a novel druggable calcium channel in the transient receptor potential channel family. This channel is expressed in the trigeminovascular system, where it drivers neurogenic inflammation and sensitization/activation of nociceptors, and TRPM3 normalizes nociceptor function. In addition, TRPM3 gene mutations/variants have been shown to be associated with migraine risk and pain sensitivity in humans.

Presented by lead investigator Volkan Granit, MD, MSc, a clinical researcher and drug developer at Biohaven, the analysis summarized the blinded safety data and described initial pharmacokinetic results from the SAD cohort. Of note, the multiple-ascending dose (MAD) portion of the study was ongoing at the time of the abstract submission. Following the completion of each dose level prior to dose escalation, a safety review committee assessed the safety, tolerability, and pharmacokinetic data of BHV-2100 in treated patients.

In the study, which comprised of mainly patients who were male (97%) and white (80%), no clinically significant trends in vital signs, laboratory values, or electrocardiograms were observed. Maximal drug concentrations (Tmax) were achieved after approximately 1.5 to 2 hours; and the mean terminal elimination half-life ranged between approximately 8 to 12 hours. Of note, the pharmacokinetics of BHV-2100 were approximately dose-proportional at doses up to 150 mg.

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Biohaven expects to initiate a phase 2 study assessing BHV-2100 in acute migraine in the second half of 2024. One of several agents in Biohaven’s clinical pipeline, BHV-2100 is also expected to undergo an additional trial in neuropathic pain later this year.

Additional data from the study revealed that dosing with food or an acid-reducing agent did not have a significant impact on BHV-2100 pharmacokinetics, as observed with the 150 mg dose. At the lowest dose evaluated of 25 mg, plasma concentrations achieved EC90 by 30 minutes, and 2x EC90 by Tmax; and, at a dose of 150 mg, plasma concentrations achieved 4x EC90 by 30 minutes and 7x EC90 by Tmax.

Earlier this year, at the 2024 American Academy of Neurology Annual Meeting, investigators presented a preclinical study assessing in vitro and in vivo efficacy and safety of BHV-2100. Activity of the therapy 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. All told, results showed that 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.²

In the preclinical study, BHV-2100 exhibited high oral bioavailability in rodents, without noticeable lethargy or effects on body core temperature or heart rate. In addition, the agent inhibited pregnenolone sulfate-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.

REFERENCES
1. Granit V, Bertz B, Lucas A, et al. Safety, tolerability, and pharmacokinetics of BHV-2100, a first-in-class TRPM3 antagonist for pain. Presented at: 2024 World Congress on Pain; ABSTRACT WE725
2. Vriens J, Vanherck JC, Marchand A, et al. BHV-2100, a first-in-class TRMP3 antagonist for the treatment of pain. Presented at: 2024 AAN Annual Meeting; ABSTRACT S13.002.