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SAN FRANCISCO--(BUSINESS WIRE)--InCarda Therapeutics, Inc.: Analysis of the results of the RESTORE-1 Phase 3 trial following its premature termination demonstrated statistically significant cardioversion of PAF with orally inhaled flecainide, providing compelling rationale for the continued development of FlecIH-103 in the target population of PAF patients. — The RESTORE-1 trial was stopped prematurely due to lower-than-expected efficacy and plasma flecainide levels during a blinded review of the data — There were no safety concerns associated with the administration of FlecIH-103 A novel drug delivery platform has shown the potential to enable efficient and reliable delivery of flecainide to the heart through the lung, appropriate for both hospital and home use Bridging Phase 1 study data to date establishes a path for future registration trials Today, InCarda, a privately held biopharmaceutical company developing an inhaled flecainide acetate inhalation solution (FlecIH-103) for the acute conversion of paroxysmal atrial fibrillation (PAF) to sinus rhythm (SR), announced significant progress made on several fronts: 1) Results of the RESTORE-1 Phase 3 trial were presented at the 2024 European Society of Cardiology meeting in London 1 on September 2, 2024, and demonstrated strong “patient proof of concept” data for the safe and effective cardioversion of patients with PAF who were administered inhaled flecainide. These results were particularly striking in light of the fact that the trial was stopped prematurely. 2) Transition to a novel and more efficient drug-delivery platform is supported by recent in vitro and Phase 1 clinical data. 3) Preliminary interim results from a Phase 1 clinical study designed to establish the dose and dosing regimen with the new drug delivery platform warrant continuation of the study for the potential advancement of FlecIH-103 into registrational trials. RESTORE-1 Phase 3 results RESTORE-1 was a randomized, placebo-controlled, Phase 3 trial, employing a commercially available jet nebulizer, to assess the efficacy and safety of FlecIH-103 for the treatment of patients with PAF. The trial was stopped prematurely after 54 of the planned 400 patients had been enrolled due to an unexpectedly low rate of blinded cardioversion compared to the experience in the Phase 2 study (INSTANT). The rate of cardioversion in RESTORE-1 was 31% in the treated group versus 47% in the Phase 2 INSTANT study. This outcome was caused by lower-than-expected flecainide plasma levels and unexpected drug-device incompatibility not previously observed in the Phase 2 clinical trial. The premature halting of the trial was not due to any safety concerns. Despite the early termination of the trial and a small sample size (n=54), an analysis showed that the 31% cardioversion rate was statistically significant in FlecIH-103-treated patients compared to placebo (p=0.04), with a median time to restoration of normal sinus rhythm (NSR) of approximately 13 minutes from the start of dosing. The study captured statistically significant pharmacoeconomic benefits from early restoration of SR following administration of FlecIH-103: a) 80% of patients whose AF converted to sinus rhythm were eligible for discharge from the hospital within 2 hours of dose administration, compared to only 30% of patients whose PAF did not convert (p=0.002) b) 83% of patients who converted from PAF to NSR within 90 min of dosing were symptom-free, while only 28% of patients whose PAF did not convert to SR were symptom-free (p<0.0001) c) The need for electrical cardioversion to restore sinus rhythm was 49% in the active arm vs. 83% in the placebo arm (p<0.05). There were no safety concerns or SAEs associated with the administration of FlecIH-103 in this study and no patients discontinued the study due to an adverse event (AE) or had an AE that required treatment. In summary, these results indicate that orally inhaled flecainide can provide safe and rapid restoration of sinus rhythm in patients presenting to the emergency room with symptomatic acute PAF. We believe FlecIH-103 delivered via oral inhalation has the potential to be clinically meaningful and address the important unmet medical need for the estimated one million U.S. patients who visit ERs with PAF each year. Improved drug-delivery platform The lower-than-expected flecainide plasma levels observed in RESTORE-1 using a jet nebulizer motivated the transition to Aerogen’s novel, high-performance drug-delivery platform that enables more efficient and reliable inhaled delivery of FlecIH-103. This platform includes: a) A novel vibrating-mesh aerosol generation engine proven to deliver drugs to the deep lungs for rapid systemic absorption, provided by Aerogen Ltd., a world leader in acute care aerosol drug delivery located in Galway, Ireland, and b) A unique patient-facing breath-synchronized dosing system that helps optimize the patient’s breathing for the inhalation of FlecIH-103. The Aerogen drug-delivery platform employs the PDAP (Photo Defined Aperture Plate) technology, a breakthrough patented vibrating mesh for medical aerosol delivery developed by Aerogen Ltd. The PDAP technology effectively aerosolizes our flecainide formulation (FlecIH-103) into a fine-mist aerosol. In addition, the patient is guided by the dosing system to synchronize their breathing with the generation of the aerosol. We believe this increases the efficiency of the delivery of FlecIH-103 to the heart and may enable a low nominal dose needed for rapid and safe cardioversion. Bridging Phase 1 clinical data Preliminary interim results from a Phase 1 study being conducted in Australia with FlecIH-103 administered with this new delivery platform show encouraging results: a) Peak flecainide plasma concentrations (C max ) similar to those achieved in the Phase 2 (INSTANT) clinical trial, which showed a conversion rate of ~ 50% b) One-third of the amount of FlecIH-103 was needed in the inhaler to achieve similar C max when compared to the amount needed with the commercial jet nebulizer used in RESTORE-1, and c) Electrocardiographic (ECG) changes that are transient and consistent with the pharmacokinetics (PK) of the inhaled flecainide and are within a safe range [Max ΔQRS duration < 30 msec] No new safety signals have been observed, no SAEs reported and all AEs resolved without sequelae; the FlecIH-103 safety pro consistent with that observed in prior studies. We believe the novel delivery platform will easily be adaptable in all patient care settings including the hospital and at-home settings. Future plans InCarda plans to complete the ongoing Phase 1 study, including the investigation of additional dose regimens such as administration of a booster dose similar to current approved products for treating cardiac arrhythmias. Inhaled flecainide is being developed for use in both a medically supervised setting (e.g., in-hospital, emergency rooms and clinics) and as a portable treatment for self-administration outside the hospital. InCarda plans to reinitiate safety and efficacy trials in patients with PAF in 2025. Dr. Luiz Belardinelli, MD, InCarda’s Chief Medical Officer, said, “We believe that inhaled flecainide has the potential to be a valuable treatment for patients with recent-onset episodes of PAF. While RESTORE-1 did not achieve the level of efficacy desired and the trial was terminated early, the analysis showed a statistically significant higher conversion rate in the active arm compared to the placebo for the 54 patients evaluated, and the continued encouraging safety and tolerability pro FlecIH-103 suggest that this treatment could become an important option for patients with acute episodes of recent-onset of PAF. The trial also indicated that patients whose PAF converted to NSR had their symptoms relieved, required fewer interventions, and were discharged earlier from the ER, thus suggesting attractive pharmacoeconomic benefits of orally inhaled flecainide.” Carlos Schuler, Ph.D., co-founder and CEO of InCarda, said, “I am very excited by the ability of the new drug-delivery platform to deliver flecainide reliably. Given the positive Phase 1 results to date, I am optimistic that we will be able to achieve commercially attractive efficacy and safety and demonstrate pharmacoeconomic benefits in the registrational studies currently being planned.” About Atrial Fibrillation (AF) Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (abnormal heart rhythm) and is characterized by rapid and irregular heartbeats often resulting in palpitations and other symptoms that can be debilitating. A chronic, progressive condition, AF is estimated to affect six million people in the U.S., with that number expected to double by 2050 2 . This expected increase is partially due to the correlation between AF prevalence and an aging population, with approximately 9% of those aged 65 and older affected by the condition 2 . AF is associated with significant morbidity and a substantial reduction in quality of life, with the condition potentially resulting in exercise intolerance, congestive heart failure, tachycardia-induced cardiomyopathy, and stroke. The annual cost of AF to the U.S. healthcare system is estimated at more than $26 billion 2 . Paroxysmal AF (PAF) is a self-terminating type of AF in which episodes occur intermittently and resolve spontaneously in fewer than seven days. Approximately 25% of PAF patients progress to the permanent form of AF within five years 3 . Common symptoms of PAF can include a racing heartbeat, chest pain or pressure, a fluttering feeling in the chest, weakness, fatigue, dizziness, sweating, and lightheadedness. Current treatments for patients with PAF rely upon either chronic administration of oral antiarrhythmic drugs or acute hospital-based procedures such as intravenous drug administration of rate-control medicines and electrical cardioversion, neither of which adequately address the unmet need of patients for a rapid-acting treatment that can be administered whenever an episode of PAF occurs. There are currently no approved treatments that can be self-administered by patients whenever or wherever an episode of PAF occurs. About Inhaled Flecainide Inhaled Flecainide is a novel inhaled therapeutic candidate designed to rapidly deliver flecainide, a well-established oral antiarrhythmic agent, to the heart via the lungs to restore normal sinus rhythm and relieve the patient’s symptoms following the onset of new or recurrent episodes of paroxysmal AF (PAF). Previously completed Phase 1 clinical studies in healthy volunteers demonstrated that orally inhaled flecainide can rapidly and safely deliver the drug and result in ECG changes consistent with the potential to restore sinus rhythm in patients with PAF. A previously completed Phase 2 trial (INSTANT) in patients with recent-onset PAF showed that inhaled flecainide with an administration regimen of approximately eight minutes can safely and rapidly convert recent-onset PAF to normal sinus rhythm. InCarda started RESTORE-1, a Phase 3 clinical trial, but halted the study as mentioned above. With intellectual property protection now potentially extendable through 2045 with the inclusion of the new delivery system, orally inhaled flecainide continues to have potential as a first-in-class treatment for acute management of PAF. We estimate over a billion-dollar market potential for this product, in addressing this significant unmet medical need. About InCarda Therapeutics InCarda Therapeutics, Inc. is a privately held, clinical-stage biopharmaceutical company developing first-of-their-kind inhaled therapies for acute cardiovascular diseases and conditions. The company is leveraging the ability of inhaled therapy to deliver medicine in the “first pass” to cardiac tissue, presenting a ‘small,’ but effective dose of the drug directly to affected regions of the heart. This permits rapid-onset, lower off-target tissue exposure of the drug, lower exposure to cardiac tissue, and has the potential to be patient self-administered in an ambulatory care setting (e.g., at home care). InCarda employs a de-risked approach by using approved drugs as candidates for the new dosing paradigm via inhalation. The company’s lead development product, orally inhaled flecainide, is in development to treat acute episodes of symptomatic PAF, a prevalent cardiac arrhythmia. For more information, please visit: . LinkedIn: Twitter: @InCardaThera References: RESTORE-1 abstract, Dr. M. Rienstra, MD (Netherlands), ESC, London, Sep 02, 2024 J Am Coll Cardiol. 2014 Dec 2;64(21):2305-7 Am Heart J. 2005 Mar; 149(3):489-96 Contacts Carlos Schuler, Ph.D. CEO and Co-founder Email: schuler.carlos@incardatherapeutics.com Phone: 510-422-5522

Submitted a new drug application (NDA) for troriluzole in Spinocerebellar Ataxia Type 3 (SCA3) to U.S. FDA in 2Q2023, marking the team's fourth NDA in approximately 3 years Released additional data from Kv7 platform, including Phase 1 safety data by dose groups for BHV-7000 that further validates differentiated profile Projected Phase 3 Spinal Muscular Atrophy trial to complete enrollment in 2023 Initiated Phase 1 study of brain penetrant TYK2/JAK1 inhibitor, BHV-8000, and anticipate beginning Phase 2 trial in Parkinson's disease next year Highlighted robust pipeline with multiple INDs planned to be filed within the next year, including pan IgG degrader for multiple immune-mediated diseases in 2023 NEW HAVEN, Conn., May 31, 2023 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) ("Biohaven"), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating diseases, including ultra-rare disorders, will provide an overview of clinical progress, regulatory updates, and pipeline developments at an in-person R&D Day today, concurrently with the Yale Ventures' Innovation Summit 2023 taking place on May 31-June 1. Members of Biohaven's senior management team and key opinion leaders will meet with investors and research analysts. The clinical progress, regulatory updates, and pipeline developments to include: Troriluzole in SCA: Submitted New Drug Application (NDA) to the U.S. FDA for troriluzole for the treatment of spinocerebellar ataxia type 3 (SCA3), an ultra-rare, genetically-defined, neurodegenerative disease associated with progressive disability, frequent falls, loss of ambulation, speech and swallowing impairment, and premature death that is the most common SCA genotype worldwide. NDA supported by consistent treatment benefits observed in patients with genotype SCA3 in Study BHV4157-206 across multiple outcome measures including the change from baseline f-SARA at Week 48, CGI-I total score at Week 48, and a robust reduction in fall risk over the study period. A rigorous analysis by genotype was possible as patients were randomized by genotype strata at baseline prior to randomization in the pivotal Phase 3 48-week, double-blind, placebo-controlled phase of Study BHV4157-206. SCA3 represented 41% of study participants, consistent with being the most common subtype. SCA3 affects approximately 10,600 people in North America and in the EU and Japan. NDA further supported by a composite scale development (SCACOMS) and analysis of Study BHV4157-206, and confirmatory evidence of efficacy provided by data from the 3-year, long-term open-label (OLE) extension phase of two studies (BHV4157-206 and BHV4157-201) using a Matching Adjusted Indirect Comparison (MAIC) to an external control group. Biohaven has previously received Fast-Track and Orphan drug designation (ODD) from the FDA, and ODD from the European Medicines Agency, for troriluzole in SCA. Kv7 Platform: Highlighted progress and broad potential of Kv7 platform, including ongoing and planned development of BHV-7000 (Kv7.2/3 activator): Phase 1 EEG study with BHV-7000 in 1H2023. Pivotal studies with BHV-7000 in focal epilepsy and bipolar disorder planned to initiate in 2H2023. Burgeoning evidence for therapeutic benefits of targeting Kv7 in diverse, high unmet need indications. Bispecific Platform: Provided updates regarding planned INDs for targeted extracellular protein degradation franchise (including IgG, IgA, and autoantibody-specific degrader programs) and next-generation antibody-drug conjugate (ADC) technologies; IND application for novel IgG degrader, BHV-1300, on track for submission in 2023. TYK2/JAK1 Inhibition in Immune-Mediated Brain Disorders: Began dosing with BHV-8000 (an oral, brain-penetrant, dual TYK2/JAK1 inhibitor) in a ­­­Phase 1 study in normal healthy volunteers. Taldefgrobep Alfa: In Spinal Muscular Atrophy: Enrollment of approximately 225 patients in global Phase 3 trial now anticipated to complete in 2023. In Metabolic Disorders: Planned Phase 2 trial initiation in 2H2023. Vlad Coric M.D., CEO and Chairman of Biohaven, commented, "Today's R&D Day review of our robust pipeline highlights Biohaven's continued dedication to advance novel therapeutics for brain disorders and builds upon our team's successes with the prior approvals of Nurtec® ODT and Zavzpret™ that have changed the treatment paradigm in migraine." "The NDA we submitted for troriluzole for SCA3 represents approximately seven years of effort by the Biohaven team to bring forward a potentially new treatment for this ultra-rare disease. Advancing a new investigational drug for a rare disease that has no current therapy is a multi-year process that is the culmination of not only our own internal efforts but also close coordination with patient advocacy groups including the National Ataxia Foundation (NAF), leading academic researchers and regulatory agencies. Rare brain diseases are particularly challenging to research given relatively small populations of patients to run / participate in clinical trials, the need to rely on real-world data and often a lack of standardized ratings scales or biomarkers. We could not have advanced the SCA program this far without the leadership from the National Ataxia Foundation that has supported basic science research as well as the development of natural history cohorts in SCA that serve as an external control for longitudinal studies. The Biohaven clinical trials in SCA were a first of its kind in this area and utilized a newly developed rating scale (the functional SARA or f-SARA) that was developed in close consultation with the FDA using standard regulatory pathways to elucidate this new scale. We look forward to interactions with the US FDA, EMA and other regulatory agencies across the globe as our submissions advance in the review process," Dr. Coric added. "We are pleased that our decades-long investment in ataxia research and understanding of disease progression has accelerated treatment development for SCA," said Andrew Rosen, Executive Director of the National Ataxia Foundation. "Thank you to all NAF members who participated in these important trials." Bruce Car PhD, Biohaven's CSO, stated, "Given the lack of efficacious therapies for many brain disorders, we must urgently evaluate new mechanisms and approaches to change the treatment paradigm in this therapeutic area. Our R&D Day today demonstrates the commitment that we have given to this effort with exciting new approaches ranging from our submission of a glutamate modulator in SCA to immune modulation using small molecule degraders to ion channels targeting agents for epilepsy and mood disorders, as well as a biologic treatment to enhance muscle growth in SMA. Our scientific and clinical team is poised to file multiple new INDs from our deep pipeline and complete late-stage clinical trials in the next couple of years. It is an exciting time at Biohaven for our passionate employees, patients and investors as we advance these novel investigational drugs in our pipeline." The Research & Development Day presentations will be made available following the conclusion of the program on . About Biohaven Biohaven is a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating diseases, including rare disorders. 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 disorder and schizophrenia. The company is advancing a pipeline of therapies for diseases with little 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 brain-penetrant TYK2/JAK1 inhibition for immune-mediated brain 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 degrader platform technology (MoDE™) with potential application in neurological disorders, cancer, and autoimmune diseases. 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 Food and Drug Administration; 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 new 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] +1 (201) 248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE Biohaven Ltd.

SEOUL, South Korea, March 16, 2023 /PRNewswire/ -- OliPass Corporation, an RNA therapeutics platform company, disclosed that OLP-1002, a selective inhibitor of Nav1.7 sodium ion channel, showed strong analgesic efficacy and long therapeutic duration according to interim findings from a placebo-controlled double blind multicenter Phase 2a study in chronic osteoarthritis patients with moderate to severe pain in Australia. In the Phase 2a study designed to evaluate 90 osteoarthritis (OA) patients in total, patients are subjected to pain assessment for 6 weeks following a single subcutaneous injection of 1 microgram (mcg) OLP-1002, 2 mcg OLP-1002 or placebo (vehicle only). An interim analysis was carried out for the first 30 patients (10 patients per group) completed the pain assessment primarily by WOMAC Pain and VAS. The average WOMAC Pain score of 2 mcg group gradually decreased and reached the lowest in day 43 (6 weeks) post dose. The observed % decrease in day 43 was 55% from the baseline. In the meantime, placebo effect peaked in day 15 (2 weeks) post dose and then gradually subsided to a decrease of 26% from the baseline in day 43. Consequently, 2 mcg group and placebo started differentiating from day 22 (3 weeks) post dose. The observed difference between 2 mcg OLP-1002 and placebo in day 43 is regarded quite large compared to conventional pain killer's efficacies in OA pain studies. The difference was either slightly short of significance (p-value 0.07 by t-test) or significant (p-value 0.011 by Wilcoxon test). The current sample size (10 patients per group) of this interim analysis would be too small for OA pain trials to draw reliable conclusions by statistical analysis. VAS scores showed a similar trend to WOMAC Pain scores. Taken these interim findings together, 2 mcg is the therapeutic dose eliciting strong efficacy with an injection frequency of once every two months. "The ongoing Phase 2a study has been estimated to be statistically fully powered, once the study is completed in 90 patients as initially planned," said Dr. Shin Chung, CEO of OliPass. "Given that OLP-1002 possesses disease-modifying activity to down-regulate neuropathic hypersensitization, the analgesic efficacy of OLP-1002 shall increase upon repeated dose," added Dr. Chung. OLP-1002 is being evaluated to pin down the therapeutic dose in OA patients which is translated further into the therapeutic dose for peripheral pain in general. OLP-1002 is still considered ideal for a broad range of chronic or refractory pain, to name a few, diabetic neuropathic pain, trigeminal neuralgia, chemotherapy-induced pain, fibromyalgia, cancer pain, and so on. People with a null mutation in the SCN9A gene encoding Nav1.7 sodium ion channel subtype were found insensitive to pain but with other sensory functions undisturbed. A selective inhibitor of Nav1.7 has been implicated to safely treat pain. Unfortunately, there are ca 10 sodium channel subtypes structurally indistinguishable with small molecule inhibitors. Inhibition of Nav1.5 subtype, for example, may cause life-threatening heart arrhythmia. Nav1.7 selectivity really matters to safety. Despite a huge number of Nav1.7 selective small molecule inhibitors have been evaluated, none have manifested strong efficacy and good safety in patients. OLP-1002 would be the first Nav1.7 selective inhibitor manifesting strong efficacy and good safety. Lack of safe and effective pain killers triggered the outbreak of opioid crisis. Opioid crisis is getting worse and taking lives of more than 100,000 victims each year. "The urgency and importance of identifying safe and effective pain killers can never be overemphasized," noted Dr. Chung. Hundreds of millions are still painfully suffering from chronic or refractory pain. OLP-1002 has been estimated to create a market potential exceeding 50 billion USD per year owing to its strong efficacy, excellent safety, and vast therapeutic scope. [About OLP-1002] OLP-1002 is an SCN9A antisense PNA and selectively inhibits the expression of Nav1.7 sodium channel in neuronal cells. OLP-1002 replicates much of the phenotype of people with a null mutation in the SCN9A gene. OLP-1002 shows an attomolar (10-18M) in vitro potency and broadly distributes to tissues, which would be responsible for its very small therapeutic dose and long therapeutic duration as seen in the ongoing Phase 2a trial. Unlike small molecule inhibitors of Nav1.7, OLP-1002 possesses disease-modifying activity by down-regulating neuropathic hypersensitization. [About OliPass Corporation] OliPass Corporation is a public biotech company listed in KOSDAQ in South Korea (ticker: KQ244460). The company is developing RNA therapeutics based on its proprietary oligonucleotide platform called OPNA (Olipass Peptide Nucleic Acid). OPNA was derived from PNA by rational chemical modifications to show good cell permeability and ultra-strong affinity for RNA. For therapeutic intervention, OPNA potently binds to target pre-mRNA, induces exon skipping, and yields mRNA splice variant. Unlike other types of RNA therapeutics, OPNA does not require formulational aid for in vivo therapeutic activity. SOURCE OliPass Corporation