opakalim (BHV-7000) / Biohaven - LARVOL DELTA

Expanding the toolkit: An update on the evolution of new therapies for Lennox-Gastaut Syndrome. (PubMed, Semin Pediatr Neurol) - "The purpose of this paper is to address three such aspects of treatment evolution for LGS: (1) To review data supporting the repurposing of existing drugs for use in LGS, specifically, perampanel and cenobamate. (2) To present recent (soticlestat), ongoing (carisbamate, bexicaserin, clemizole) and upcoming (opakalim) clinical drug trials for LGS...With the richness of recent trial development for LGS combined with the nascence of clinical trials for specific genetic epilepsies comes a new era in which treatment options for LGS will continue to expand. Increasing understanding of the underlying genetic and molecular underpinnings of LGS should enable development of unique therapies, with the continued aims of sustained, durable seizure control and additional positive impact on central nervous system outcomes and beyond."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy

A Phase 1b Study of BHV-7000 in Participants With Inherited Erythromelalgia (clinicaltrials.gov) - P1 | N=5 | Not yet recruiting | Sponsor: Biohaven Therapeutics Ltd.

New P1 trial

RISE 3: Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset Epilepsy (clinicaltrials.gov) - P2/3 | N=390 | Recruiting | Sponsor: Biohaven Therapeutics Ltd. | Trial primary completion date: Jan 2026 ➔ May 2026

Trial primary completion date • CNS Disorders • Epilepsy

Opakalim (BHV-7000) Potentiates the Activity of Kv7.2/Kv7.3 Channels Containing a Single Copy of the Kv7.2 DEE-Causing Mutation, G281E (AES 2025) - "Since the patient is heterozygous for Kv7.2 G218E, it is likely that the channel population is comprised of ~25% WT channels, 50% channels containing one copy of Kv7.2 G281E, and 25% channels containing two copies of Kv7.2 G281E. Since both the first-generation activator and opakalim could activate the Kv7.2 G281E-containing channels and the patient responded favorably to replacement of the first-generation activator with opakalim, it is likely that therapeutic benefit arises from potentiation of both WT and Kv7.2 G281E-containing channels and underscores the potential value of opakalim for treatment of other patients with Kv7.2 mutant-associated DEE."

Late-breaking abstract • CNS Disorders • Dystonia • Epilepsy • Movement Disorders

Compassionate Use of Kv7.2/7.3 Potassium Channel Activator Opakalim (BHV-7000) in a Child with KCNQ2 Developmental and Epileptic Encephalopathy: Early Promising Results (AES 2025) - "Opakalim demonstrates early tolerability and initial improvement in seizures followed by return to baseline seizure frequency, with no worsening compared to prior treatment with another potassium channel activator despite a history of severe exacerbation with attempts to wean. He also showed encouraging improvement in alertness. Follow-up evaluations will determine additional changes in EEG or clinical status."

Clinical • Late-breaking abstract • CNS Disorders • Dystonia • Epilepsy • Movement Disorders

BHV-7000 Responsive Neurostimulation System (RNS) Study (clinicaltrials.gov) - P1 | N=5 | Recruiting | Sponsor: Yale University | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

RISE 2: A Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset Epilepsy (clinicaltrials.gov) - P2/3 | N=390 | Recruiting | Sponsor: Biohaven Therapeutics Ltd. | Trial completion date: Sep 2025 ➔ Dec 2026 | Trial primary completion date: Aug 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Efficacy and Safety Study of BHV-7000 Monotherapy in Major Depression (clinicaltrials.gov) - P2 | N=300 | Active, not recruiting | Sponsor: Biohaven Therapeutics Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RISE 3: Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset Epilepsy (clinicaltrials.gov) - P2/3 | N=390 | Recruiting | Sponsor: Biohaven Therapeutics Ltd. | Trial completion date: Sep 2025 ➔ Feb 2026 | Trial primary completion date: Aug 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

BHV-7000 Responsive Neurostimulation System (RNS) Study (clinicaltrials.gov) - P1 | N=5 | Not yet recruiting | Sponsor: Yale University

New P1 trial • CNS Disorders • Epilepsy

BHV-7000 Open-Label Extension Bipolar Mania Study (clinicaltrials.gov) - P2 | N=94 | Terminated | Sponsor: Biohaven Therapeutics Ltd. | N=200 ➔ 94 | Trial completion date: Apr 2026 ➔ Apr 2025 | Enrolling by invitation ➔ Terminated | Trial primary completion date: Mar 2026 ➔ Apr 2025; Business Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry

Efficacy and Safety Study of BHV-7000 Monotherapy in Major Depression (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Biohaven Therapeutics Ltd. | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: May 2025 ➔ Nov 2025

Monotherapy • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Biohaven Presents Data Across Innovative Neuroscience Portfolio at the 2025 American Academy of Neurology (AAN) Annual Meeting (PRNewswire) - "Biohaven Ltd....announced today that it will present 13 abstracts at the 2025 American Academy of Neurology (AAN) Annual Meeting, taking place from April 5 to April 9, 2025 in San Diego, California. The presentations highlight Biohaven's innovative neuroscience pipeline across multiple early and late-stage development programs including Kv7 ion channel modulation, extracellular protein degradation, TRPM3 antagonism, TYK2/JAK1 inhibition, and glutamate modulation."

Clinical data • Migraine • Parkinson's Disease

Biohaven Reports Recent Business Developments and Fourth Quarter and Full Year 2024 Financial Results (PRNewswire) - "IgG MoDE Degraders (1300/1310): BHV-1300 Phase 1 with the optimized subcutaneous formulation completing in 1H 2025. BHV-1310 completion of preclinical testing prior to anticipated FIH study initiating 1H 2025...Phase 1 with BHV-1400 and BHV-1600 expected to be completed in 1H 2025...Kv7 Activator (BHV-7000): Pivotal major depressive disorder topline results expected in 2H 2025. Focal epilepsy study topline results expected in 1H 2026."

Clinical data • Preclinical • Trial completion date • Epilepsy • IgA Nephropathy • Immunology • Major Depressive Disorder

A Modern Design for a Phase 2/3 Randomized, Double-blind, Placebo-Controlled Study to Evaluate Efficacy and Safety of BHV-7000 in Idiopathic Generalized Epilepsy with Generalized Tonic-Clonic Seizures (AAN 2025) - P2/3 | "SHINE is an innovative registrational study in IGE with the differentiated Kv7 activator BHV-7000. This patient-centric study utilizes a TTE endpoint that decreases time on placebo, potentially reducing the risk of exposure to additional seizures, injury, and SUDEP."

Clinical • P2/3 data • CNS Disorders • Epilepsy • Mental Retardation • Psychiatry

Phase 1 Multiple Ascending Dose Studies Demonstrate Favorable Safety and Tolerability of BHV-7000, a Novel Kv7 Potassium Channel Activator (AAN 2025) - "BHV-7000 was safe and well tolerated in multiple-dose Phase 1 studies across all doses evaluated for up to 15 days. Adverse events typically associated with other ASMs, such as somnolence and cognitive/mood disturbances, were not reported at equivalent doses to those currently being dosed in Phase 3 trials in focal epilepsy, generalized epilepsy, major depressive disorder, and bipolar disorder."

Clinical • P1 data • Back Pain • Bipolar Disorder • CNS Disorders • Cognitive Disorders • Constipation • Depression • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Major Depressive Disorder • Mental Retardation • Mood Disorders • Musculoskeletal Pain • Pain • Psychiatry

BHV-7000 Acute Treatment of Bipolar Mania (clinicaltrials.gov) - P2/3 | N=274 | Completed | Sponsor: Biohaven Therapeutics Ltd. | Active, not recruiting ➔ Completed

Trial completion • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry

Targeting Kv7 Potassium Channels for Epilepsy. (PubMed, CNS Drugs) - "Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae...Another Kv7.2/3 activator, BHV-7000, has completed phase I studies in healthy subjects, with excellent tolerability at plasma drug concentrations that exceed the median effective concentrations in a preclinical model of anticonvulsant activity, but no efficacy data in patients with epilepsy are available to date. Among other Kv7.2/3 activators in clinical development as potential antiseizure medications, pynegabine and CB-003 have completed phase I safety and pharmacokinetic studies, but results have not been yet reported. Overall, interest in targeting Kv7 channels for the treatment of epilepsy and for other indications remains strong. Future breakthroughs in this area could come from exploitation of mechanistic..."

Journal • Review • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Pediatrics • Psychiatry

BHV-7000 Acute Treatment of Bipolar Mania (clinicaltrials.gov) - P2/3 | N=256 | Active, not recruiting | Sponsor: Biohaven Therapeutics Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry

Phase 1 Multiple Ascending Dose Studies Demonstrate Safety and Tolerability of BHV-7000, a Novel kv7 Potassium Channel Activator (AES 2024) - "BHV-7000 was well tolerated in multiple-dose Phase 1 studies across all doses evaluated, without AEs typically associated with other anti-seizure medications. These findings support the continued clinical development of BHV-7000 as a novel ASM with the potential to reduce seizures while minimizing AEs. Patients are currently being enrolled in multiple Phase 2/3 studies evaluating the efficacy and safety of BHV-7000 in focal and generalized epilepsy as well as neuropsychiatric disorders."

Clinical • P1 data • CNS Disorders • Cognitive Disorders • Epilepsy • Mental Retardation • Psychiatry

Pharmacological Characterization of BHV-7000, a Novel and Selective Activator of kv7.2/kv7.3 Channels, Using All-optical Electrophysiology (AES 2024) - "Overall, BHV-7000 demonstrated potent in vitro effects to reduce neuronal activity impacting a diverse set of Optopatch functional features across the stimulus protocol, including spike timing and spike shape features in different stimulus periods, which indicates lower excitability near action potential threshold. Compound effects were more pronounced (additional altered features detected) under the more Chronic Regimen A compared to Regimen B, suggestive of neuronal remodeling with longer treatment. Lastly, the fraction of neurons staying completely silenced during a long gentle blue stimulus period can effectively distinguish ASMs treated wells from DMSO wells in a parallel neuronal excitability assay using human iPS cell-derived cortical excitatory ("NGN2") neurons, suggesting relevance of this measure for predicting an efficacious ASM."

CNS Disorders • Epilepsy • Mood Disorders • Psychiatry

New kv7 Channel Opener Chemistry for Treatment of Seizures (AES 2024) - "Kv7 channel opening is a validated target for epilepsy with the approval of ezogabine (EZG) in 2011 as a first-in-class molecule; it was removed from the market in 2017. Kv7 openers BHV7000 and azetukalner (XEN1101) are currently in clinical development... In vivo, PO efficacy in rodent MES is >10-fold over aztukalner (ED50 > 4 mg/kg) and BHV7000 (full protection at 3 mg/kg). It is anticipated that the lead molecule, based on an in vivo minimum effective brain concentration of >20 nM for MES in mice and rats, a half maximal voltage shift of ~7 mV at 0.7 in rodents, may be effective at a plasma conc. of 30 nM, as a threshold conc., for clinical seizure protection in humans."

CNS Disorders • Depression • Epilepsy • Mood Disorders • Psychiatry

BHV-7000 Is a Potent M-current Activator with Efficacy on Multiple Epilepsy-associated KCNQ2 Variants (AES 2024) - "BHV-7000, a selective M-current activator restored current density in all tested pathogenic KCNQ2 variants. For most of the tested variants, current density was restored to near WT levels with 1 μM BHV-7000. The calculated BHV-7000 EC50 values were similar to WT for the majority of the variants tested."

Clinical • CNS Disorders • Epilepsy

Effects of BHV-7000 on human iPSC-derived sensory neurons from IEM patients (IASP 2024) - "This study demonstrated that BHV-7000 hyperpolarized the resting membrane potential, increased the rheobase, and decreased the action potential firing rate at 3X rheobase from iPSC-SNs using standard patch-clamp recordings. In IEM-iPSC-SNs from 2 IEM patients, multi-electrode-array recordings demonstrated potent inhibition of spontaneous firing with BHV-7000. In addition, current-clamp recording from one IEM-iPSC cell line demonstrated that BHV-7000 hyperpolarized iPSC-SN resting membrane potential."

Clinical • CNS Disorders • Epilepsy • Pain • NAV1

Long-term Safety Study of BHV-7000 in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P2 | N=480 | Enrolling by invitation | Sponsor: Biohaven Therapeutics Ltd. | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry