Kv7.2

Results demonstrated statistically significant effects on biomarkers that predict ALS disease progression and severity Evidence of brain penetration, target engagement, and potential anti-seizure effects demonstrated through biomarkers for TMS-EMG and EEG Safety and tolerability profile consistent with previously reported results for QRL-101 QurAlis intends to advance QRL-101 into proof-of-concept studies as a potentially best-in-class treatment for both ALS and epilepsy CAMBRIDGE, Mass., March 12, 2025 /PRNewswire/ -- QurAlis Corporation ("QurAlis"), a clinical-stage biotechnology company driving scientific breakthroughs into powerful precision medicines that have the potential to alter the trajectory of neurodegenerative and neurological diseases, today announced positive topline data from QurAlis' Phase 1 proof-of-mechanism (PoM) clinical trial of QRL-101 in healthy volunteers evaluating biomarkers related to amyotrophic lateral sclerosis (ALS) and epilepsy. Topline results demonstrated a dose-dependent, statistically significant decrease in motor nerve excitability threshold tracking (mNETT) strength-duration time constant (SDTC), the co-primary endpoint of the trial related to ALS. SDTC is a well-established electrophysiological biomarker of peripheral motor excitability related to ALS, where elevation of SDTC has been clinically shown to predict faster disease progression and mortality. The decrease in SDTC observed with QRL-101 in this study was approximately 50% greater than previously reported for the Kv7 potassium channel opener ezogabine in a single-dose study in people with ALS. Additional observations for multiple secondary and exploratory endpoints related to motor nerve excitability were also significantly impacted. The clinical trial demonstrated a statistically significant impact on multiple secondary and exploratory endpoints related to epilepsy. These included transcranial magnetic stimulation electromyography (TMS-EMG) intracortical facilitation which indicates effective inhibition of cortical excitability, as well as significant increases in electroencephalography (EEG) spectral power in beta and gamma spectral bands further demonstrating cortical target engagement and brain penetration. There was minimal to no impact on the slower delta and theta EEG bands, which suggests a low potential for GABA-A receptor activation and sedation. The study did not reach statistical significance on the co-primary endpoint of TMS-EMG motor evoked potential (MEP) amplitude, another measure of corticospinal excitability. Results also demonstrated that the safety and tolerability profile of QRL-101 was consistent with previously reported study results evaluating QRL-101 to date. There were no serious adverse events or discontinuations due to adverse events reported observed in the study. "We are excited by these topline data from our biomarker study in healthy participants which suggest that QRL-101 has the potential to provide a therapeutic effect for both ALS and epilepsy," said Kasper Roet, Ph.D., CEO and co-founder of QurAlis. "Loss of Kv7.2/7.3 function from the mis-splicing of the KCNQ2 gene leading to hyperexcitability-induced neurodegeneration was one of the first genetic breakthroughs from human ALS motor neuron stem cell models made by our founders at Harvard. QurAlis was started to develop a best-in-class Kv7 ion channel opener for the treatment of hyperexcitability-induced disease progression in ALS, which occurs in about half of all people living with ALS. Elevated SDTC has been clinically linked to faster disease progression and mortality, underscoring the need for an effective treatment for this population." Dr. Roet continued, "The decrease in SDTC observed with QRL-101 in this study was approximately 50% greater than previously reported for the Kv7 opener ezogabine in a single-dose study in people with ALS. QRL-101 has the potential to be a promising therapeutic, especially considering the encouraging results from a previous study with ezogabine in ALS patients showing positive effects on both SDTC and the disease progression biomarker compound muscle action potential (CMAP). Further, based on the strong clinical validation of Kv7.2/7.3 ion channel openers in seizure reduction, the TMS-EMG intracortical facilitation together with the EEG data from this study suggest QRL-101 may have the potential to reduce both frequency and severity of seizures in people living with epilepsy without causing sedation. We are encouraged by these results and look forward to advancing the clinical program for QRL-101 in both ALS and epilepsy so that we can fulfill our mission of bringing much-needed precision medicine options to patients." Kv7.2/7.3 is a voltage-gated potassium channel whose role is crucial for the regulation of both neuronal excitability and membrane potential. QRL-101 is a potentially best-in-class selective Kv7.2/7.3 ion channel opener for the treatment of hyperexcitability-induced disease progression in ALS, which occurs in both sporadic and genetic forms of ALS, with the majority caused by the mis-splicing of the KCNQ2 gene in the pre-mRNA. Kv7 is also a clinically validated target to regulate the hyperexcitable state in epilepsy. In vivo and in vitro studies have demonstrated that QRL-101 is more potent in threshold track studies and exhibits the potential for fewer clinical adverse events that ezogabine, a less selective, first-generation, Kv7.2/7.3 channel opener. The Phase 1 PoM study (QRL-101-05, NCT06681441) was a randomized, double-blind, placebo-controlled, three-way crossover trial. The study was conducted at the Centre for Human Drug Research, an early-phase Contract Research Organization based in Leiden, The Netherlands. The study evaluated two dose levels of QRL-101 versus placebo in healthy volunteers, assessing: Co-primary endpoints: Motor nerve excitability (mNETT SDTC; ALS biomarker) Cortical excitability (TMS-EMG MEP amplitude; epilepsy biomarker) Secondary endpoints: Additional TMS-EMG cortical excitability measures Resting-state pharmaco-EEG Safety, tolerability, and pharmacokinetics (PK) Additional QRL-101 clinical trials include: QRL-101-01 (NCT05667779) was a first-in-human, single-ascending dose clinical trial in 88 healthy participants. In this clinical trial, QRL-101 was shown to be well tolerated. The study completed in late 2023 and results from QRL-101-01 supported a tolerable dose range for subsequent studies. QRL-101-03 (NCT06532396) is a randomized, double-blind, placebo-controlled, multiple-ascending dose clinical trial evaluating the safety, tolerability, and PK of QRL-101 in up to 60 healthy participants. QRL-101-04 (NCT06714396) is a Phase 1 PoM single-dose, placebo-controlled clinical trial designed to evaluate the safety and tolerability of QRL-101 in people living with ALS. QRL-101-04 is expected to enroll approximately 12 participants with ALS and will evaluate the impact of QRL-101 on mNETT. QRL-101-06 is a Phase 1 randomized, open-label, single dose, cross-over study to evaluate the PK of three formulations of QRL-101 in a fasted condition or in the presence of a high fat meal in healthy participants. More information about the QRL-101 clinical trials can be found at . About QurAlis Corporation At QurAlis, we are neuro pioneers on a quest to cure, boldly seeking to translate scientific breakthroughs into powerful precision medicines. We work collaboratively with a relentless pursuit of knowledge, precise attention to craft, and compassion to discover and develop medicines that have the potential to transform the lives of people living with neurodegenerative and neurological diseases. QurAlis is the leader in development of precision therapies for amyotrophic lateral sclerosis (ALS). In addition to ALS, QurAlis is advancing a robust precision medicine pipeline to bring effective disease-modifying therapeutics to patients suffering from severe diseases defined by genetics and clinical biomarkers. For more information, please visit or follow us on X @QurAlisCo or LinkedIn. SOURCE QurAlis WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Reported expanded safety results from BHV-7000 Phase 1 multiple ascending dose studies, including the once-daily extended-release formulation being evaluated in ongoing Phase 2 and 3 clinical studies, demonstrating excellent tolerability at all doses evaluated without central nervous system (CNS) adverse effects typically associated with other anti-seizure medications (ASMs), such as somnolence and cognitive/mood disturbances. Qualitative assessment of online social media platforms and forums provided a unique perspective of the unmet needs that people with epilepsy are vocalizing outside of the clinical setting, including the negative impact that ASM associated adverse events have on their quality of life. Additional nonclinical data presentations included characterization of BHV-7000 using optical electrophysiology as well as beneficial effects of BHV-7000 on pathogenic developmental epileptic encephalopathy-associated KCNQ2 variants NEW HAVEN, Conn., Dec. 6, 2024 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) announced today that it is presenting expanded safety data from BHV-7000 multiple-dose studies at the American Epilepsy Society (AES) 2024 Annual Meeting, taking place December 6-10, 2024, in Los Angeles, California. Additional poster presentations highlight BHV-7000 nonclinical data and unmet needs that persist for people living with epilepsy, including the negative impact of adverse effects associated with current ASMs. Jason Lerner, M.D., Medical Director and Epilepsy Clinical Lead at Biohaven, commented, "We are very excited to share the expanded safety results with the once-daily extended-release formulation being evaluated in ongoing Phase 2 and 3 clinical studies. We are encouraged to see BHV-7000 continue to demonstrate favorable safety and tolerability without dose-limiting toxicities or CNS adverse events commonly associated with other ASMs, such as somnolence. These results paired with previously demonstrated CNS target engagement in our Phase 1 EEG study and a nonclinical profile showing BHV-7000 is a selective Kv7.2/7.3 activator that dials out GABAA activation provide compelling rationale for why BHV-7000 offers a differentiated profile from other treatments currently available or in development." Dr. Lerner continued, "The evidence to date with BHV-7000 represents a potential paradigm shift in the treatment of epilepsy as many patients continue to be burdened by adverse events and do not achieve adequate seizure control with existing medications. As we continue advancing 5 ongoing pivotal Phase 2/3 trials with BHV-7000, including studies in focal epilepsy and idiopathic generalized epilepsy, Biohaven remains committed to developing novel, efficacious, and well-tolerated therapies for people living with epilepsy." In addition to 4 poster presentations at AES, Biohaven will be presenting 1 poster at the Partners Against Mortality (PAME) 2024 Conference in Los Angeles on Thursday, December 5th highlighting the patient-centric Phase 2/3 BHV-7000 study in idiopathic generalized epilepsy. American Epilepsy Society 2024 Annual Meeting Presentation Highlights: Poster 1.486: Phase 1 Multiple Ascending Dose Studies Demonstrate Safety and Tolerability of BHV-7000, a Novel Kv7 Potassium Channel Activator BHV-7000 is a selective Kv7.2/7.3 activator that was safe and well-tolerated at dose levels up to 120 mg daily for 15 days with no dose-limiting toxicities; 120 mg exceeds the doses being evaluated in ongoing Phase 2 and 3 clinical studies of up to 75 mg daily in focal epilepsy, idiopathic generalized epilepsy, bipolar mania, and major depressive disorder. There were low rates of CNS-related adverse events and no somnolence or cognitive/mood disturbances reported. Most AEs were mild and resolved spontaneously; and there were no serious adverse events or severe adverse events. New data with the BHV-7000 once-daily extended-release formulation demonstrated excellent tolerability. Poster 1.512: A Qualitative Assessment of the Epilepsy Patient Experience Through Social Media and Web-based Forums While seizure freedom remains the primary goal of epilepsy treatment, additional unmet needs of people living with epilepsy were assessed by investigating the patient experience directly through social media and online platforms where patients discuss epilepsy outside of a clinical setting. Patient perspectives and unmet needs were identified across 3 areas: antiseizure medication-associated adverse events, mental health, and stigma. The 4 most frequently discussed ASM associated adverse events included: sleepiness, insomnia, mood changes, and cognitive effects; comments from patients captured the negative impact these adverse events have on their quality of life. People with epilepsy also reported a range of challenges with mental health, and the stigma associated with epilepsy pressured patients to remain silent about their struggles. Poster 1.534: Pharmacological Characterization of BHV-7000, a Novel and Selective Activator of Kv7 Channels, Using All-optical Electrophysiology The acute and chronic pharmacological effects of BHV-7000 on the excitability of primary rat cortical neurons were evaluated using the all-optical electrophysiology platform Optopatch (Quiver Biosciences), which measures neuronal activity with single-cell and single action potential resolution. Concentration-dependent dampening of neuronal excitability was observed, consistent with previous data with BHV-7000 in other experimental paradigms. 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 neuronal excitability near action potential threshold. Poster 1.431: BHV-7000 Is a Potent M-current Activator with Efficacy on Multiple Epilepsy-associated KCNQ2 Variants This in vitro study assessed the effects of BHV-7000 on 50 loss-of-function KCNQ2 variants. BHV-7000 rescued current density in all tested pathogenic KCNQ2 variants. Current density was restored to wild-type (WT) levels with BHV-7000 for most variants. These findings support the potential therapeutic value of BHV-7000 in KCNQ2-related epilepsy associated with a wide range of pathogenic KCNQ2 variants. Partners Against Mortality (PAME) 2024 Conference Highlights: PAME Poster 41: 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 (IGE) With Generalized Tonic–Clonic Seizures (SHINE) Epilepsy studies have traditionally been double-blind, placebo-controlled, change-from-baseline endpoint studies; in these studies, subjects receiving placebo for a fixed treatment duration remain at risk for continued seizures, injury, and Sudden Unexpected Death in Epilepsy (SUDEP). SHINE (NCT06425159) is an innovative, ongoing registrational study in IGE with the selective Kv7 activator BHV-7000 with an efficient, patient-centric design utilizing an FDA-endorsed time to event endpoint that decreases time on placebo, potentially reducing the risk of exposure to additional seizures, injury, and SUDEP. Full posters will be available on the Posters and Presentations page at: . About BHV-7000 BHV-7000 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 is being developed 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 may translate to improved tolerability by reducing the typical dose dependent side effect profile often seen in patients receiving ezogabine and other anti-seizure medications. About Biohaven Biohaven is a biopharmaceutical company focused on the discovery, development, and commercialization of life-changing treatments in key therapeutic areas, including immunology, neuroscience, and oncology. The company is advancing its innovative portfolio of therapeutics, leveraging its proven drug development experience and multiple proprietary drug development platforms. Biohaven's extensive clinical and nonclinical programs include Kv7 ion channel modulation for epilepsy and mood disorders; extracellular protein degradation for immunological diseases; TRPM3 antagonism for migraine and neuropathic pain; TYK2/JAK1 inhibition for neuroinflammatory disorders; glutamate modulation for OCD and SCA (spinocerebellar ataxia); myostatin inhibition for neuromuscular and metabolic diseases, including SMA and obesity; antibody recruiting bispecific molecules and antibody drug conjugates for cancer. For more information, visit . 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; 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. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] +1 (201) 248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE Biohaven Ltd. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Kv7 is a clinically validated target to regulate hyperexcitable state in epilepsy QurAlis’ Phase 1 study in healthy volunteers of QRL-101 to evaluate biomarkers of both ALS and epilepsy also underway CAMBRIDGE, MA, USA I December 4, 2024 I QurAlis Corporation (“QurAlis”), a clinical-stage biotechnology company driving scientific breakthroughs into powerful precision medicines that have the potential to alter the trajectory of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative and neurological diseases, today announced that the first patient with ALS has been dosed in a Phase 1 clinical trial evaluating QRL-101 in people living with ALS (QRL-101-04). QRL-101 is a first-in-class selective Kv7.2/7.3 ion channel opener for the treatment of hyperexcitability-induced disease progression in ALS, which is present in approximately 50 percent of ALS patients. Kv7 hyperexcitability occurs in both sporadic and genetic forms of ALS, with the majority caused by the mis-splicing of the KCNQ2 gene pre-mRNA. Kv7 is also a clinically validated target to regulate the hyperexcitable state in epilepsy. QurAlis recently announced the company has expanded the development program for QRL-101 to include epilepsy. “QRL-101 is the only Kv7 ion channel opener being actively studied for the treatment of hyperexcitability-induced disease progression in ALS. The dosing of the first patient with ALS in the clinical development program of QRL-101 is a significant milestone,” said Kasper Roet, Ph.D., CEO and co-founder of QurAlis. “Kv7 is implicated in ALS as well as epilepsy. We believe that the data from this study, along with the data from our Phase 1 study evaluating biomarkers of ALS and epilepsy in healthy volunteers, will be valuable as we advance the clinical program for QRL-101 in ALS so that we can bring a much-needed therapeutic option to patients rapidly.” “Preclinical models of QRL-101 show its strong potential to control motor neuron hyperexcitability-induced neurodegeneration with an attractive side effect profile,” said Leonard H. van den Berg, M.D., Ph.D., professor of neurology and chair, TRICALS. “ALS is a devastating, fatal neurodegenerative disease and there are currently no therapies that can significantly extend patients’ lives. We look forward to results from this Phase 1 study in ALS patients.” QRL-101-04 (NCT06714396) is a Phase 1 proof-of-mechanism (PoM) single-dose, placebo-controlled clinical trial designed to evaluate the safety and tolerability of QRL-101 in people living with ALS. The study is expected to enroll approximately 12 participants with ALS and will evaluate the impact of QRL-101 on excitability biomarkers including on the strength-duration time constant (SDTC), a known predictor of survival in ALS patients. QurAlis is also conducting a Phase 1 PoM biomarker clinical trial (QRL-101-05; NCT06681441) to evaluate biomarkers of ALS and epilepsy of QRL-101 in healthy volunteers. These PoM studies together will inform QurAlis’ future development program, including dose levels for proof-of-concept studies. QurAlis anticipates reporting topline data from the QRL-101-04 Phase 1 clinical trial in the first half of 2025. More information about the QRL-101 Phase 1 clinical trials can be found at www.clinicaltrials.gov . About Amyotrophic Lateral Sclerosis (ALS) Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease impacting nerve cells in the brain and spinal cord, reducing muscle function and control. ALS can be traced to mutations in more than 25 different genes and is often caused by a combination of multiple sub-forms of the condition. Cases usually cannot be predicted, although a small percentage are inherited. ALS has a devastating impact on patients and families. ALS patients’ average life expectancy is three years; after diagnosis patients only have two years to live. There is currently no cure for the disease. About Kv7 Kv7.2/7.3 is a voltage-gated potassium channel whose role is crucial for the regulation of neuronal excitability and membrane potential. Kv7.2 is mis-spliced in sporadic amyotrophic lateral sclerosis (ALS) leading to loss of function and abnormal electrical activity in the spinal cord and brain. The activation of this channel shows the potential to decrease spinal and cortical/motor neuron excitability and to positively affect CMAP (compound muscle action potential), a disease progression biomarker for ALS. This suggests that this may be an effective therapeutic approach for ALS patients suffering from hyperexcitability-induced motor neuron degeneration. About QurAlis Corporation At QurAlis, we are neuro pioneers on a quest to cure. We work with a relentless pursuit of knowledge, a precise attention to craft, and an optimistic mindset to discover and develop effective precision medicines that have the potential to alter the trajectory of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative and neurological diseases. Founded by an internationally recognized team of neurodegenerative biologists from Harvard Medical School and Harvard University, QurAlis is advancing a robust precision medicine pipeline with therapeutic candidates aimed at modifying severe disease pathology in defined patient populations based on both disease-causing genetic mutation(s) and clinical biomarkers. For more information, please visit www.quralis.com or follow us on X @QurAlisCo or LinkedIn . SOURCE: QurAlis