KCNQ2-related epileptic encephalopathy

Biohaven reported full results from the BHV-7000 Phase 1 study examining doses up to 120 mg daily, demonstrating BHV-7000 was well-tolerated at all doses studied without the typical central nervous system (CNS) adverse effects associated with other anti-seizure medications (ASMs), such as somnolence and cognitive/mood disturbances. In a Phase 1 electroencephalogram (EEG) biomarker study, BHV-7000 demonstrated dose-dependent target engagement in the brain as measured by changes in EEG spectral power across all brain regions. Additional poster presentations at the American Epilepsy Society Annual Meeting will include: BHV-7000 preclinical data, health-related quality of life in patients with focal epilepsy, and functional impairments in patients with KCNQ2‐associated developmental and epileptic encephalopathy (KCNQ2-DEE). NEW HAVEN, Conn., Dec. 1, 2023 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) announced today that it is presenting expanded EEG and safety data for BHV-7000 at the 2023 American Epilepsy Society (AES) Annual Meeting, taking place December 1-5, 2023, in Orlando, Florida. The presentations include results from the BHV-7000 Phase 1 EEG biomarker study and additional BHV-7000 safety and tolerability data from Phase 1 single ascending dose (SAD) / multiple ascending dose (MAD) studies. Additional posters showcase BHV-7000's preclinical data, findings from a systematic literature review on health-related quality of life (HRQoL) in patients with focal epilepsy, and results from a cross-sectional survey assessing functional impairments in patients with KCNQ2-DEE. Jason Lerner, M.D., Medical Director and Epilepsy Clinical Lead at Biohaven, commented "Selective Kv7 activators are one of the most exciting new drug targets for the treatment of epilepsy, and BHV-7000 has shown a favorable and differentiated profile in preliminary Phase 1 studies to date. We are pleased to see favorable safety and tolerability with BHV-7000 dosed up to 120 mg daily for 15 days, without the CNS adverse effects typically associated with other ASMs, such as somnolence. Together with the preclinical data showing BHV-7000 is a selective Kv7.2/7.3 channel opener lacking GABAA activation and the results from our Phase 1 EEG study confirming target engagement, we are excited to advance BHV-7000 into late-stage development in epilepsy patients." Dr. Lerner added, "The robust BHV-7000 data presentations at the AES meeting underscore Biohaven's progress and commitment to developing novel, efficacious and well-tolerated therapies for people living with epilepsy." In addition, both the systematic literature review and parental survey illustrated the importance of Health-Related Quality of Life issues among patients with focal epilepsy and developmental manifestations of KCNQ2-DEE that are relevant to parents, such as communication, eating abilities, and motor impairments. Presentation Highlights: Poster 2.510: Novel, Selective Kv7.2/7.3 Potassium Channel Activator, BHV-7000, Demonstrates Dose-Dependent Pharmacodynamic Effects on EEG Parameters in Healthy Adults In this Phase 1 study, pharmacodynamic activity of BHV-7000 in the brain of healthy adults was demonstrated by dose-dependent increases in EEG spectral power. Unlike prior reports where EEG effects of a Kv7.2/7.3 activator showed the greatest power increase in the delta frequency band (Biondi et al. 2022), the highest spectral power increases with BHV-7000 were seen in alpha, beta, and gamma frequency bands. While changes in spectral power were observed across all frequency bands with BHV-7000, the minimal impact on slower frequencies (i.e., delta) is consistent with the low incidence of CNS adverse events, in particular somnolence, seen in the BHV-7000 Phase 1 SAD/MAD studies. EEG delta activity is associated with somnolence, an undesirable CNS adverse event often seen with other ASMs. Poster 3.265: A First in Human Phase 1 Study Evaluating the Safety and Tolerability of BHV-7000, a Novel, Selective Kv7.2/7.3 Potassium Channel Activator, in Healthy Adults BHV-7000 was safe and well-tolerated at single doses up to 100 mg and multiple doses up to 120 mg daily for 15 days No serious adverse events or severe treatment emergent adverse events were reported Adverse events typically associated with other ASMs, such as somnolence and cognitive/mood disturbances, were not reported Poster 2.249: Characterization of BHV-7000: A Novel Kv7.2/7.3 Activator for the Treatment of Seizures BHV-7000 is a potent activator of Kv7.2/7.3 channels, impacting both deactivation kinetics and voltage dependence of activation BHV-7000 requires the Kv7.2 W236 residue for channel activity No significant activation of the GABAA receptor with BHV-7000 BHV-7000 is potent in the maximal electroshock seizure (MES) test without impact on neurobehavior or motor (rotorod) behavior Poster 1.487: Determinants of Health-Related Quality of Life of Patients with Focal Epilepsy: A Systematic Literature Review This systematic literature review identified multiple factors associated with lower HRQoL in patients with focal epilepsy Depression and anxiety were among the most significant and frequent determinants of HRQoL change Other relevant and frequent determinants of HRQoL change included cognition, ASM adverse events, seizure freedom, and employment A comprehensive understanding of the modifiable determinants of HRQoL is relevant to patient health and well-being and can inform clinical practice and observational/interventional studies Poster 2.451: Functional Impairments in Patients with KCNQ2-DEE: Associations Among Key Clinical Features Data obtained from a cross-sectional survey (2018-2020) of parents of children aged ≥2 years with KCNQ2-DEE was analyzed Among individuals with KCNQ2-DEE, there is a hierarchy of impairments wherein communication is the most sensitive domain and is often affected in isolation from others Gross and fine motor skill impairments tend to be correlated Hand use impairment is closely correlated with multiple other functional impairments Full posters will be available on the Posters and Presentations page at: . Reference Biondi A, et al. Sci Rep. 2022 Feb 4;12(1):1919. About BHV-7000 BHV-7000, the lead asset from Biohaven's Kv7 platform, is a novel and selective activator of Kv7.2/Kv7.3, a key ion channel involved in neuronal signaling and in regulating the hyperexcitable state, that Biohaven is developing for the treatment of epilepsy and mood disorders. BHV-7000 was rationally developed as a potent activator of heteromeric Kv7.2/7.3 potassium channels, the molecular substrate that underlies the M-current (IKM). BHV-7000 is highly differentiated from ezogabine (known as retigabine in Europe), a Kv7 activator that was previously approved for adjunctive treatment of partial-onset seizures in adults. In comparison with ezogabine, BHV-7000 belongs to a significantly different structural class and differentiates from ezogabine in key properties, including pharmacology, plasma stability and stability to photooxidation. In addition, BHV-7000 does not exhibit GABAA receptor positive allosteric molecular activity as seen with ezogabine and similar compounds, which may contribute to the poor tolerability of ezogabine. This lack of GABAA receptor activity potentially gives BHV-7000 a wide therapeutic window which, based on dose-dependent clinical responses seen in other ASM clinical trials, should translate to improved efficacy without the typical dose dependent side effect profile often seen in patients receiving ezogabine and other anti-seizure medications. About Biohaven Biohaven is a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies to treat a broad range of rare and common diseases. Biohaven's experienced management team brings with it a track record of delivering new drug approvals for products for diseases such as migraine, depression, bipolar and schizophrenia. The company is advancing a pipeline of therapies for diseases, many of which have limited or no treatment options, leveraging its proven drug development capabilities and proprietary platforms, including Kv7 ion channel modulation for epilepsy and neuronal hyperexcitability, glutamate modulation for obsessive-compulsive disorder and spinocerebellar ataxia, myostatin inhibition for neuromuscular diseases and metabolic disorders, and brain-penetrant TYK2/JAK1 inhibition for neuroinflammatory disorders. Biohaven's portfolio of early- and late-stage product candidates also includes discovery research programs focused on TRPM3 channel activation for neuropathic pain, CD-38 antibody recruiting, bispecific molecules for multiple myeloma, antibody drug conjugates (ADCs), and targeted extracellular protein degradation platform technology (MoDE™) with potential application in neurological disorders, cancer, and autoimmune diseases. Forward-looking Statements This news release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The use of certain words, including "continue", "plan", "will", "believe", "may", "expect", "anticipate" and similar expressions, is intended to identify forward-looking statements. Investors are cautioned that any forward-looking statements, including statements regarding the future development, timing and potential marketing approval and commercialization of development candidates, are not guarantees of future performance or results and involve substantial risks and uncertainties. Actual results, developments and events may differ materially from those in the forward-looking statements as a result of various factors including: the expected timing, commencement and outcomes of Biohaven's planned and ongoing clinical trials; the timing of planned interactions and filings with the FDA; the timing and outcome of expected regulatory filings; complying with applicable U.S. regulatory requirements; the potential commercialization of Biohaven's product candidates; the potential for Biohaven's product candidates to be first in class therapies; and the effectiveness and safety of Biohaven's product candidates. Additional important factors to be considered in connection with forward-looking statements are described in Biohaven's filings with the Securities and Exchange Commission, including within the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations". The forward-looking statements are made as of the date of this news release, and Biohaven does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. MoDEs is a trademark of Biohaven Therapeutics Ltd. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] 201-248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] 312-961-2502 SOURCE Biohaven Ltd.

Company Presents Additional Positive Data from Open Label Extension of Phase 2b ‘X-TOLE’ Clinical Trial for Focal Onset Seizures XEN1101 Phase 3 Program to be Showcased at Scientific Exhibit Taking Place on Sunday, December 4, 2022 BURNABY, British Columbia, Dec. 02, 2022 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neurology-focused biopharmaceutical company, today announced it will provide updates on its proprietary, neurology programs at the Annual Meeting of the American Epilepsy Society (AES 2022). In addition, the Company is presenting results from the open label extension (OLE) and sub-analyses of data from the XEN1101 Phase 2b X-TOLE clinical trial. Mr. Ian Mortimer, Xenon’s President and Chief Executive Officer stated, “We continue to advance our portfolio of neurology-focused programs. Xenon will have a significant presence at AES this year with seven poster presentations and a scientific exhibit showcasing our recently launched XEN1101 Phase 3 program and our planned clinical trials in focal onset seizures and primary generalized tonic clonic seizures. We also look forward to meeting with leading epileptologists, including Xenon trial investigators, as well as patient advocacy groups at this important meeting.” Mr. Mortimer continued, “Importantly, we have a scientific poster outlining additional data from the open-label extension of the XEN1101 Phase 2b X-TOLE study. This interim analysis shows XEN1101 continues to be generally well-tolerated, yielding long-term efficacy at the 20 mg once-daily dose, with patients experiencing continued seizure reduction during the OLE and extended periods of seizure freedom. Two other XEN1101-related posters outline additional sub-analyses of the X-TOLE data that suggest a rapid onset of efficacy of XEN1101, with statistically significant reduction in focal onset seizures within one week for all doses studied when compared to placebo. Further, based on the number of concomitant ASMs, baseline seizure frequency, and number of failed anti-seizure medications, the X-TOLE study enrolled more ‘difficult-to-treat’ patients than other similar focal onset seizure studies. We believe this is important as it suggests that the efficacy of XEN1101 may be robust in patients with less severe disease, which may represent the most common use of XEN1101 if commercially approved. With these promising data, we have now initiated our XEN1101 Phase 3 program, where we hope to confirm these encouraging results and continue to execute on our goal to deliver a new, differentiated therapeutic that could potentially play a key role in treating patients with epilepsy.” XEN1101 AES Poster Highlights Poster No. 2.235 (French et al.) “XEN1101, a Novel Potassium Channel Modulator: Interim Data From an Ongoing, Long-Term, Open-Label Extension of a Phase 2B Study (X-TOLE) in Adults With Focal Epilepsy” During the OLE, there was a sustained monthly reduction in seizure frequency (80%–90% seizure reduction as measured by MPC) from the double-blind period (DBP) baseline, as of the analysis cutoff date of September 22, 2022. Seizure freedom for ≥6-month and ≥12-month consecutive durations was achieved in 17.5% and 10.5% of patients, respectively. XEN1101 continues to be generally well-tolerated in the OLE with adverse events (AEs) consistent with prior results and other anti-seizure medications (ASMs). At the end of the first year in the OLE, patients recorded a mean (SD) weight gain of 1.1 (5.9) kg. To date, two AEs of urinary retention occurred in the OLE possibly related to study drug; both patients continued in the study without requiring intervention. Although not seen to date, Xenon continues to monitor for the emergence of the tissue discoloration that was associated with long-term exposure to ezogabine. Poster No. 2.236 (Kenney et al.) “Rapid Onset of Efficacy of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: Results From a Phase 2b Study (X-TOLE)” X-TOLE met the primary and key secondary efficacy endpoints with XEN1101 demonstrating a statistically significant, dose-dependent reduction from baseline in monthly focal onset seizure (FOS) frequency compared to placebo. The rapid onset of efficacy for XEN1101 was associated with starting at an effective, therapeutic and well-tolerated dose. There was a statistically significant reduction in median FOS frequency within 1 week for all doses compared with placebo. The rapid onset of efficacy after 1 week and sustained efficacy of XEN1101, if confirmed in the Phase 3 clinical trials, suggests that XEN1101 may offer a compelling option for patients seeking adjunctive therapy. Poster No. 2.233 (Leung et al.) “The Impact of Disease Severity on Efficacy From a Phase 2b Study of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy (X-TOLE)” X-TOLE met the primary and key secondary efficacy endpoints with XEN1101 demonstrating a statistically significant, dose-dependent reduction from baseline in monthly FOS frequency compared to placebo in a difficult-to-treat population. Based on the number of concomitant ASMs, baseline seizure frequency, and number of failed ASMs, the X-TOLE study enrolled more difficult-to-treat patients than other FOS studies. In the 25 mg dose group, XEN1101 reduced seizure frequency in sub-groups of patients with ≤ 8.5 seizures/month, and in patients that failed ≤ 6 ASMs or were on 1-2 concomitant ASMs by 70.6%, 58.0% and 60.9%, respectively, compared with placebo (18.8%, 20.0% and 14.2%, respectively). These post hoc analyses suggest that efficacy may be more robust in patients with less severe disease, which may represent the most common clinical use of XEN1101 if commercially approved. Xenon’s Scientific Exhibit and Booth In addition to the posters noted above, Xenon is hosting a scientific exhibit at AES 2022 providing an overview of its clinical and research programs on Sunday, December 4, 2022 from 2-5 pm CT in Room 207 C, Level 2 of Music City Center. The exhibit will feature an overview of the XEN1101 Phase 3 trial designs, including X-TOLE2 and X-TOLE3 for FOS and X-ACKT for primary generalized tonic clonic seizures, as well as the Phase 2 study design for X-NOVA for major depressive disorder. Other poster presentations will cover additional programs within Xenon’s neurology-focused pipeline. Xenon is also hosting a booth (#1028) in the Exhibit Hall, which is scheduled to open at 12 pm CT on Saturday, December 3, 2022 and run to 2 pm CT on Monday, December 5, 2022. Other AES Poster Highlights Other Xenon posters at AES 2022 include clinical work related to Xenon’s XEN496 program and its ongoing Phase 3 EPIK clinical trial in pediatric patients with KCNQ2 developmental and epileptic encephalopathy: Poster 1.370 (Grayson et al.) “Genetic Burden of KCNQ2 in Neonates With Epilepsy” Poster 1.372 (Harden et al.) “An Online Survey of Caregivers of Patients With KCNQ2 Developmental and Epileptic Encephalopathy” Poster 2.334 (Butterfield et al.) “Real-World Evidence of KCNQ2 Disease Management as Generated Through a Novel Data Platform” Xenon is also presenting pre-clinical work from its discovery efforts related to the exploration of NaV1.1 potentiators for the treatment of Dravet Syndrome: Poster 3.049 (Goodchild et al.) “Molecularly Selective NaV1.1 Potentiators Increase PV+ Fast-Spiking Interneuron Excitability and Restore Motor Performance in a Mouse Model of Dravet Syndrome” Posters will be added to the Xenon website consistent with AES 2022 conference guidelines. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (NASDAQ:XENE) is a clinical stage biopharmaceutical company committed to developing innovative therapeutics to improve the lives of patients with neurological disorders. We are advancing a novel product pipeline of neurology therapies to address areas of high unmet medical need, with a focus on epilepsy. For more information, please visit . Safe Harbor Statement This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our development programs; the timing and results of our interactions with regulators; our ability to successfully develop and obtain regulatory approval of XEN1101 and our other product candidates; and anticipated enrollment in our clinical trials and the timing thereof. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including XEN1101 may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; the impact of the ongoing COVID-19 pandemic on our research and clinical development plans and timelines and results of operations, including impact on our clinical trial sites, collaborators, regulatory agencies and related review times, and contractors who act for or on our behalf, may be more severe and more prolonged than currently anticipated; the impact of the COVID-19 pandemic on our business; the impact of unstable economic conditions in the general domestic and global economic markets; adverse conditions from geopolitical events; as well as the other risks identified in our filings with the Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. Investor/Media Contact: Jodi Regts Xenon Pharmaceuticals Inc. Phone: 604.484.3353 Email: investors@xenon-pharma.com

Biohaven Pharmaceuticals has set a new course following its acquisition by Pfizer with a focus on developing therapeutics that modulate the Kv7 Ion Channel for the treatment of neurological and neuropsychiatric diseases. The company officially launched Tuesday as a new spin-off entity with more than 13 clinical and preclinical programs. Biohaven’s primary focus will be developing treatments for neurological and rare disorders including epilepsy, pain and mood disorders, obsessive-compulsive disorder, spinocerebellar ataxia and spinal muscular atrophy. The new Biohaven launches with approximately $257.8 million in cash. The seeds for this new path were established earlier this year with the acquisition of Channel Bio, a subsidiary of Knopp Biosciences. This brought in the experimental epilepsy treatment BHV-7000, which targets the Kv7 ion pathway. BHV-7000 is currently in Phase I development for multiple indications. Additionally, the company licensed rights to an experimental spinal muscular atrophy drug from Bristol Myers Squibb. That asset, an anti-myostatin adnectin, is expected to enter late-stage development later this year. The new company will continue to be helmed by Vlad Coric as chairman and chief executive officer. Other established members of the leadership team include Irfan Qureshi as chief medical officer, and Tanya Fischer, who serves as chief development officer and head of translational medicine. Bruce Car joins the company as chief scientific officer. Car most recently served as CSO of Agios Pharmaceuticals where he focused on genetically defined diseases and oncology. He previously held leadership roles at BMS and Dupont. A New Therapeutic Focus Biohaven will focus on developing therapeutics based on its proprietary technology platforms. This includes BHV-7000, a lead program in Kv7 Ion Channel Modulation for epilepsy and other central nervous system disorders associated with pathological hyperactivity. BHV-7000 is being assessed for the treatment of KCNQ2 developmental and epileptic encephalopathy, a rare and debilitating disease that manifests in infants and children as early-onset seizures. It is also being studied for encephalopathy due to a defect in the function of the Kv7.2 channel caused by pathogenic mutations in the KCNQ2 gene. Kv7 Ion Channel Modulation targets subunits involved in neuronal signaling. It also plays a role in regulating the “hyperexcitable state” in epilepsy and could potentially play a role in other central nervous system disorders. In its announcement, Biohaven pointed to multiple clinical development programs that include Glutamate modulation for spinocerebellar ataxia and obsessive-compulsive disorder. The company also has a program aimed at inhibition of myostatin in neuromuscular diseases. This could also play a role in diabetes and weight loss, according to the company. Biohaven is also developing a novel immune modulation platform that targets CD-38 for multiple myeloma. Biohaven’s initial focus will be to advance Kv7 ion channel activation across multiple therapeutic indications, as well as TRPM3 ion channel activation for neuropathic pain. The company also intends to develop degrader platforms that target immunology and oncology inflammatory disorders and antibody linker technologies. Beyond these, Biohaven is keeping an eye on potentially targeting disease adjacencies, which can include pain, smooth muscle disorders and immunological disease, according to the Tuesday statement. Biohaven’s experimental ALS treatment verdiperstat, which recently missed the mark in the Healey ALS trial, was not mentioned. When the data was announced last week, Biohaven reported it would continue to assess the trial information. Pfizer Retains 3% Stake Under terms of the Pfizer acquisition, the pharma giant retains Biohaven’s calcitonin gene-related peptide (CGRP) receptor antagonist products, which includes Nurtec ODT, a treatment for acute and episodic prevention of migraine in adults. Additionally, Pfizer will hold onto the potential migraine treatment zavegepant, which has been submitted to the FDA for potential approval. A PDUFA date has not yet been set. Pfizer will also retain a portfolio of pre-clinical CGRP assets. Even as Biohaven sets a new course as an independent company, Pfizer will retain a 3% investment in the new entity.