Background & Aims
TRPM3 is a calcium-permeable, nonselective TRP channel expressed in somatosensory neurons, including nociceptors of rodents and humans (1,2). When activated by noxious heat or chemical ligands, TRPM3 evokes pain (1). TRPM3-deficient mice do not develop pathological mechanical or thermal hypersensitivity (1,3,4). TRPM3 expression and activity are markedly increased in sensory neurons innervating inflamed tissues (5). Preclinical models and human genetics implicate a key role of TRPM3 in pain signaling (5-7). TRPM3 genetic polymorphisms are also associated with migraine and cluster headache (8,9).
BHV-2100 is a first-in-class, oral, peripherally-restricted TRPM3 antagonist in development for pain and migraine that has demonstrated potent pain reversal in preclinical models. We conducted a first-in-human Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses (SAD and MAD) of BHV-2100.
Methods
This was a randomized, placebo-controlled, sequential SAD/MAD study. Healthy adult males and females ages 18-55 years were enrolled. In the SAD cohorts, participants were randomized 3:1 to a single dose of BHV-2100 (25, 75, 150, 250, or 500 mg) or placebo under fasting conditions; the 150 mg dose was also tested for effects of food and an antiacid agent (famotidine). In the MAD cohorts, participants were randomized 3:1 to BHV-2100 or placebo and treated for 14 days. This analysis summarizes blinded safety data and describes initial PK results from the SAD cohorts; the MAD portion of the study was ongoing at the time of abstract submission. Safety evaluations throughout the study included adverse event (AE) monitoring, clinical laboratory tests, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale (C-SSRS). A Safety Review Committee assessed the safety, tolerability, and PK data after the completion of each dose level prior to dose escalation.
Results
In the SAD portion of the study, 39 subjects were treated with BHV-2100 or placebo. The mean age of the SAD population was 35 years; the majority of subjects were male (97%) and white (80%). Blinded safety data demonstrated a favorable safety and tolerability profile. No serious or severe AEs were reported. Most AEs were mild and resolved spontaneously without treatment. No clinically significant trends in vital signs, laboratory values, or ECGs were observed. There were no dose-limiting toxicities. 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. The PK of BHV-2100 was approximately dose-proportional at doses up to 150 mg. Data at 150 mg suggests dosing with food or an acid-reducing agent will not have a significant impact on BHV-2100 PK. 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.
Conclusions
TRPM3 represents a novel target for the treatment of pain and migraine. BHV-2100 is a potent, selective, orally administered, first-in-class TRPM3 antagonist that was safe and well tolerated at single doses up to 500 mg in this first-in-human study. BHV-2100 did not cause thermoregulatory side effects observed with other TRP antagonists or sedation and gastrointestinal side effects associated with standard-of-care pain medications. BHV-2100 was rapidly absorbed with a highly favorable PK profile, achieving projected efficacious concentrations within 30 min. These findings provide a compelling rationale for the advancement of BHV-2100 into clinical trials for pain and migraine as a novel non-opioid treatment. The MAD portion of the study will provide additional safety and PK data to inform clinical development plans.
References
1.Vriens J, et al. Neuron. 2011;70(3):482-494.
2.Vangeel L, et al. Br J Pharmacol. 2020;177(12):2683-2695.
3.Alkhatib O, et al. J Neurosci. 2019;39(40):7840-7852.
4.Su S, et al. J Neurosci. 2021;41(11):2457-2474.
5.Mulier M, et al. Elife. 2020;9:e61103.
6.Aloi VD, et al. Pain. 2023;164(9):2060-2069.
7.Lötsch J, et al. Int J Mol Sci. 2020;21(12):4367.
8.Patent application WO2022152715A1.
9.Biohaven data on file.
Presenting Author
Volkan Granit
Poster Authors
Volkan Granit
MD, MSc
Biohaven, New Haven, CT, USA
Lead Author
Richard Bertz
PhD
Biohaven Pharmaceuticals
Lead Author
Andrew Lucas
PharmD
PumasAI
Lead Author
Eric Ashbrenner
MS
Biohaven Pharmaceuticals
Lead Author
Mary Donohue
MS
Biohaven Pharmaceuticals
Lead Author
Patricia Mydlow
BS
Mydlow Consulting, LCC
Lead Author
Christopher Jensen
PharmD
Biohaven Pharmaceuticals
Lead Author
Joris Vriens
Laboratory of Ion Channel Research, KU Leuven
Lead Author
Thomas Voets
PhD
Laboratory of Ion Channel Research, KU Leuven; IB Center for Brain & Disease Research
Lead Author
Beth Emerson
MD
Biohaven Pharmaceuticals
Lead Author
Irfan Qureshi
MD
Biohaven Pharmaceuticals
Lead Author
Vladimir Coric
MD
Biohaven Pharmaceuticals
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Migraine
- Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral