Phase 2 Migraine Study of TRPM3 Antagonist BHV-2100 Commences

Author(s):

The phase 2 study, expected to include 575 patients with acute migraine, will use percentage of participants with freedom from pain and freedom from the most bothersome symptom as the coprimary end points.

Richard B. Lipton, MD

Biohaven recently announced the initiation of a new phase 2 trial NCT06603623) assessing its investigational agent BHV-1200, a first-in-class, potent, selective, orally administered TRMP3 antagonist, as a potential therapy for the acute treatment of migraine. The study, which tests 2 doses (75 mg and 150 mg) of BHV-2100, is expected to enroll approximately 575 patients across 60 sites in the United States.¹

The phase 2 trial, a randomized, double-blind, placebo-controlled study, will use change in pain freedom and freedom from the most bothersome symptom (MBS) as the coprimary end points. In addition, the trial will also include several secondary end points, such as percentage of participants with pain relief at 2 hours, returning to normal function, sustained pain relief, freedom from photophobia, and percentage of participants with rescue medication use.

In the study, patients with acute migraine will be randomly assigned to either BHV-2100 in doses of 75 mg or 150 mg, or placebo, with outcomes observed mainly after 2 hours. In addition to the aforementioned end points, the study will also report on plasma concentration in treated patients, number of adverse events (AEs), serious AEs, and number of patients with clinically significant laboratory abnormalities. Investigators will also record the percentage of participants with freedom from nausea and the percentage of those with pain relapse from 2 to 48 hours post-dose.

"The burden of migraine remains high, and many patients experience inadequate relief or suffer from tolerability issues from existing therapies. There remains a need for novel treatments for migraine to lessen disease burden and disability,” Richard B. Lipton, MD, director of the Montefiore Headache Center, said in a statement.¹ "The TRPM3 ion channel has been implicated in the pathophysiology of migraine, and this trial is the first to assess efficacy and tolerability of a novel agent targeting this mechanism in migraine."

Transient receptor potential (TRP) channels include several cationic channels with pleiotropic functions and ubiquitous distribution in various cells and tissues. Some members of the TRP channel family, such as the ankyrin 1 (TRPA1), vanilloid 1 and 4 (TRPV1 and TRPV4, respectively), and TRMP3, are abundantly expressed in primary sensory neurons and are recognized as sensors of chemical-, heat-, and mechanical-induced pain, and play a primary role in several models of pain diseases, including inflammatory, neuropathic cancer pain, and migraine pain. Furthermore, TRP channel stimulation results in calcitonin gene-related peptide release, which can be activated or sensitized by various endogenous and exogenous stimuli, some of which have been proven to trigger or worsen migraine attacks.²

BHV-2100 was previously assessed in a randomized, placebo-controlled, single-ascending dose (SAD), early-stage study of 39 healthy volunteers. Presented at the 2024 World Congress of Pain, patients were randomly assigned 3:1 to a single dose of BHV-2100 (25, 75, 150, 250, or 500 mg) or placebo. At the conclusion of the trial period, there were no serious or severe AEs reported, and most AEs were mild and resolved spontaneously without treatment.

In the phase 1 study, 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. 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. 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.

"Biohaven has deep expertise in running clinical trials in migraine and this study will assess an important new potential therapy for patients," Beth Morris, vice president of clinical operations, Biohaven, said in a statement.¹ "I am proud of our clinical operations team for efficiently advancing this trial into Phase 2 after completing the initial Phase 1 trial earlier this year. Days matter for patients and if this study is positive, we will be one step closer to delivering another novel treatment option to better meet the needs of people with migraine: to resolve symptoms and to return to their lives quickly."

REFERENCES
1. Biohaven initiates pivotal trial of novel investigational drug for treatment of migraine. News release. Biohaven. September 30, 2024. Accessed October 4, 2024. https://www.prnewswire.com/news-releases/biohaven-initiates-pivotal-trial-of-novel-investigational-drug-for-treatment-of-migraine-302261939.html
2. Iannone LF, De Logu F, Geppetti P, De Cesaris F. The role of TRP ion channels in migraine and headache. Neurosci Letters. 2022;768:136380. doi:10.1016/j.neulet.2021.136380
3. 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