Hyperkinesis

- PRODUODOPA® (foslevodopa/foscarbidopa) is the first-and-only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of advanced Parkinson's disease - PRODUODOPA demonstrated sustained improvements in "Off" time (when symptoms return between medication doses), "On" time (when symptoms are controlled) without dyskinesia (involuntary movement), and morning akinesia ("Off" time upon waking) NORTH CHICAGO, Ill., Jan. 9, 2024 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced the launch of PRODUODOPA® (foslevodopa/foscarbidopa) in the European Union for the treatment of advanced Parkinson's disease with severe motor fluctuations and hyperkinesia (excessive movement) or dyskinesia (involuntary movement), and when available combinations of Parkinson's medicinal products have not given satisfactory results.1 PRODUODOPA is the first-and-only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of severe motor fluctuations in people living with advanced Parkinson's disease whose symptoms are inadequately controlled by other therapies. The continuous delivery of PRODUODOPA provides levodopa 24-hours a day which may help patients by extending the period when symptoms are well-controlled, often referred to as "On" time.2 AbbVie was granted marketing authorization of PRODUODOPA through the Decentralized Procedure in the third quarter of 2022. The VYAFUSER™ pump for the subcutaneous delivery of PRODUODOPA received Conformité Européenne (CE) Mark in November of 2023. Parkinson's disease is a chronic, progressive neurodegenerative disorder affecting approximately 6.1 million people globally3 and is expected to double by 2040. Parkinson's disease is characterized by tremor, muscle rigidity, slowness of movement and difficulty with balance.4 As the disease progresses, the severity of symptoms increases5, and patients tend to experience greater disability and an impaired ability to perform activities of daily living6, as well as the reemergence of symptoms as standard treatment wears off.7 Characteristics of advanced Parkinson's disease may include needing help with performing daily activities, increased motor fluctuations (changes in the ability to move referred to as "On-Off" times), difficulty swallowing, recurrent falls, dementia, dyskinesia (involuntary movements) and other symptoms.5 "People living with Parkinson's disease experience daily challenges and uncertainty, especially as their disease progresses and symptoms are no longer adequately controlled," said Roopal Thakkar, Senior Vice President, Development and Regulatory Affairs and Chief Medical Officer, AbbVie. "This approval is an example of our unwavering commitment to this community by developing new, transformative therapeutic options for people experiencing advanced Parkinson's disease, their families, and care partners." The launch was supported by three studies: the Phase 3, 12-month open label study (M15-741 study) which evaluated the long-term safety, tolerability, and efficacy of continuous subcutaneous infusion of PRODUODOPA8, the Phase 3, 12-week study (M15-736 study) which compared the efficacy and safety of PRODUODOPA to oral levodopa/carbidopa2, and a Phase 1 pharmacokinetic comparability study.9 Findings from the M15-741 safety and tolerability study showed a favorable benefit/risk profile and demonstrated sustained improvements in "Off" time and "On" time without dyskinesia, and morning akinesia as measured by the percentage of patients in early morning "Off" time as recorded by PD diary.8 The majority of adverse events (AEs) with PRODUODOPA were non-serious and mild or moderate in severity. The most frequent AEs (greater than or equal to 10 percent) were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.1 "This approval represents a significant advancement for those with Parkinson's disease who have historically had limited treatment options for advanced stages," said Angelo Antonini, MD, PhD, Professor of Neurology at the Department of Neuroscience, University of Padua, Italy. "When oral treatment no longer sufficiently helps with improvement in motor fluctuations, patients need alternative options. PRODUODOPA's around-the-clock infusion allows for continuous delivery of levodopa, the gold standard of treatment." "As Parkinson's progresses, it can take a significant physical and emotional toll not only on the person but also on their family and care partners, who often play a critical role in their daily lives," said Josefa Domingos, President, Parkinson's Europe. "It is vital that the Parkinson's community have more options that can help them manage their symptoms." About the Phase 3 M15-741 Study8 The Phase 3, single arm, open-label study evaluated the safety and tolerability, and efficacy of 24-hour daily exposure of continuous subcutaneous infusion of PRODUODOPA in people with advanced Parkinson's disease whose motor symptoms were inadequately controlled by their current treatment. The primary endpoint was to evaluate the safety and tolerability of PRODUODOPA. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, and total scores from quality-of-life surveys. The study was conducted at 58 sites across 13 countries (Australia, Belgium, Canada, Denmark, Germany, Italy, Japan, Netherlands, Russia, Spain, Sweden, United Kingdom, and United States). Eligible patients included adults 30 years or older diagnosed with levodopa-responsive idiopathic Parkinson's disease experiencing an average of greater than or equal to 2.5 hours of "Off" time per day, as assessed by patient's Parkinson's disease diaries. Reduction in motor fluctuations was observed as early as one week and persisted through week 52. The percentage of patients experiencing morning akinesia dropped from 77.7 percent at baseline to 27.8 percent at week 52. Indicators of sleep and quality of life were assessed from baseline through week 52 as published in the Journal of Neurology & Therapy (). More information on the study can be found on (NCT03781167). About the Phase 3 M15-736 Study2 The Phase 3 randomized, double-blind, double-dummy, active-controlled study compared the efficacy, safety and tolerability of PRODUODOPA to oral immediate-release levodopa/carbidopa (LD/CD) in patients with advanced Parkinson's disease. Participants were provided with a home diary (the PD Diary) to assess their motor state during the day. The primary endpoint was "On" time without troublesome dyskinesia. The study included 141 participants who were randomly assigned and received treatment at 65 centers in the U.S. and Australia. Participants were randomized one to one to receive either the PRODUODOPA solution as a continuous delivery under the skin (subcutaneous) plus oral placebo capsules for LD/CD or oral capsules containing immediate-release LD/CD plus continuous subcutaneous delivery of placebo solution for PRODUODOPA. The treatment duration was 12 weeks. The increase in "On" time without troublesome dyskinesia at week 12 was an average of 2.72 hours for PRODUODOPA versus 0.97 hours for oral LD/CD (p= 0.0083). Improvements in "On" time were observed as early as the first week and persisted throughout the 12 weeks. This study also assessed changes from baseline to week 12 in motor experiences of daily living, morning akinesia, sleep, and quality of life indicators, however results did not achieve statistical significance. More information on the study can be found on (NCT04380142) and in The Lancet Neurology ((22)00400-8). About the Phase 1 Pharmacokinetic study9 A Phase 1, open label, randomized, two period cross over study was conducted to compare the pharmacokinetics (PK) of levodopa from 24-hour continuous subcutaneous infusion of PRODUODOPA (foslevodopa/foscarbidopa) to the PK of levodopa from 16-hour levodopa-carbidopa intestinal gel (LCIG), followed by two night-time oral levodopa/carbidopa (LD/CD) doses. The levodopa exposures following subcutaneous infusion of PRODUODOPA over 24 hours were similar (less than 8 percent difference) to those of LCIG mg LD/CD administered over 16 hours, followed by two oral doses at 18 and 21 hours after the start of LCIG delivery. The study concluded that 24-hour continuous subcutaneous infusion of PRODUODOPA provides levodopa exposures comparable to LCIG throughout the day. More information on the study can be found on (35339102) and in Science Direct (). About PRODUODOPA® (foslevodopa/foscarbidopa) PRODUODOPA® (foslevodopa/foscarbidopa) is a solution of levodopa and carbidopa prodrugs for 24-hour continuous subcutaneous infusion for the treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. PRODUODOPA® (foslevodopa and foscarbidopa solution for infusion) Indication and Summary of Important Treatment Considerations1 Indication Treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. Contraindications PRODUODOPA is contraindicated in patients with hypersensitivity to the active substances or to any of the excipients, narrow-angle glaucoma, severe heart failure, acute stroke, severe cardiac arrhythmia, co-medication with selective MAO type A inhibitors and nonselective MAO inhibitors, conditions contraindicated for adrenergics (e.g. pheochromocytoma, hyperthyroidism, and Cushing's syndrome), and suspicious undiagnosed skin lesions or history of melanoma. Select special warnings and precautions for PRODUODOPA Special warnings and precautions for PRODUODOPA Several warnings and precautions below are generic for levodopa and, therefore, also for PRODUODOPA. Not recommended for the treatment of drug-induced extrapyramidal reactions. Caution use in patients with: severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or of convulsions. History of myocardial infarction with residual atrial nodal or ventricular arrhythmias, cardiac function should be monitored during the initial dosage adjustments. Monitor all patients for the development of mental changes, depression with suicidal tendencies, and other serious mental changes. Caution with past or current psychosis and antipsychotics used concomitantly with dopamine receptor-blocking properties (observe for loss of antiparkinsonian effect). Higher frequency of hallucinations may occur with dopamine agonists and/or other dopaminergic treatments including PRODUODOPA. Monitor patients regularly for the development of impulse control disorders, for example Dopamine Dysregulation Syndrome (DDS). Before initiation of treatment, warn patients and caregivers of the potential risk of developing DDS. The dose of PRODUODOPA may need to be adjusted downwards in order to avoid levodopa induced dyskinesias. Caution in chronic wide-angle glaucoma; monitor for intra-ocular pressure changes. PRODUODOPA may induce orthostatic hypotension and should be given cautiously in patients taking other medicinal products that may cause orthostatic hypotension. Concomitant use of selegiline and levodopa/carbidopa has been associated with serious orthostatic hypotension. Levodopa may induce somnolence and sudden sleep: caution should be exercised when driving and operating machines. Risk of symptoms resembling Neuroleptic Malignant Syndrome following abrupt dose reduction or discontinuation. Infusion site events (see section 4.8) have been reported in patients receiving PRODUODOPA. Follow aseptic techniques and frequently rotate the infusion site to reduce the risk. In clinical studies, few patients who reported infusion site reactions also experienced infusion site infections. Therefore, monitor for serious infusion site reactions and infusion site infections. Patients with Parkinson's disease have a higher risk of developing melanoma. Monitor patients for melanomas on a regular basis when using PRODUODOPA. Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with PRODUODOPA. PRODUODOPA contains hydrazine (foscarbidopa degradation product), that can be genotoxic and probably carcinogenic. The approximately median exposure of hydrazine is 0.2 mg/day, with a maximum of 0.5 mg/day. The clinical significance of this hydrazine exposure is not known. Reduced ability to handle the delivery system can lead to complications. In such patients a caregiver should assist the patient. A sudden or gradual worsening of bradykinesia may indicate an obstruction in the device for whatever reason and needs to be explored. Polyneuropathy has been reported; evaluate for history/signs of and known risk factors before starting therapy. PRODUODOPA is high in sodium; considered especially in patients on a low salt diet. Caution is needed in concomitant administration of PRODUODOPA with the following medicinal products: Antihypertensives, antidepressants, COMT inhibitors, dopamine antagonists, MAO inhibitors, amantadine. Sympathomimetics may increase cardiovascular adverse events related to levodopa. Foscarbidopa is a potential inducer of CYP1A2 in vitro. Care should be taken when prescribing PRODUODOPA in combination with sensitive CYP1A2 substrates (e.g. caffeine). Review section of interactions with other medicinal products in SmPC for further details about these and a complete list of interactions. Fertility, pregnancy and lactation PRODUODOPA is not recommended during pregnancy. Breast-feeding should be discontinued during treatment with PRODUODOPA. Undesirable effects Summary of the safety profile The most frequent adverse reactions (≥10%) reported in all Phase 3 studies in patients exposed to PRODUODOPA were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety. This is not a complete summary of all safety information. Globally, prescribing information varies; please refer to your country specific product labeling for complete product prescribing and safety information. About AbbVie in Neuroscience At AbbVie, our commitment to preserving personhood of people around the world living with neurological and psychiatric disorders is unwavering. With more than three decades of experience in neuroscience, we are providing meaningful treatment options today and advancing innovation for the future. AbbVie's Neuroscience portfolio consists of approved treatments in neurological conditions, including migraine, movement disorders, and psychiatric disorders, along with a robust pipeline of transformative therapies. We have made a strong investment in research and are committed to building a deeper understanding of neurological and psychiatric disorders. Every challenge makes us more determined and drives us to discover and deliver advancements for those impacted by these conditions, their care partners, and clinicians. For more information, visit . About AbbVie AbbVie's mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at . Follow @AbbVie on X (formerly Twitter), Facebook, Instagram, YouTube, and LinkedIn Forward-Looking Statements Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions and uses of future or conditional verbs, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2022 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law. References 1 PRODUODOPA® (foslevodopa/foscarbidopa solution for infusion) Summary of Product Characteristics. November 2023. 2 Soileau, M., et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial. The Lancet Neurology. December 2022. 3 Armstrong, MJ. and Okun, MS. (2020). Diagnosis and Treatment of Parkinson Disease. A Review. JAMA 2020; 323(6): 548-560. 4 "What is Parkinson's?" Parkinson's Foundation. Available at: . Accessed: August 29, 2023. 5 Luquin M-R et al. Parkinson's Dis. 2018; 4047392. 6 Malaty IA et al. (2022). Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries. Gainsville: BCM Neurology. 7 "Wearing off and motor fluctuations". Parkinson's Europe. Available at . Accessed November 6, 2023. 8 Aldred, J., et al. Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study. Journal of Neurology & Therapy. August 2023. 9 Rosebraugh, M., et al. Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum. Science Direct. April 2022. SOURCE AbbVie

Territorial expansion for a product candidate previously exclusively targeting the U.S.Kye Pharmaceuticals to register and commercialize in Canada Liège, Belgium – 24 October 2023 – 7AM CET – Non-regulated information - Hyloris Pharmaceuticals SA (Euronext Brussels: HYL), a specialty biopharma company committed to addressing unmet medical needs through reinventing existing medications, today announces it has out-licensed its product candidate atomoxetine oral liquid for the treatment of attention deficit hyperactivity disorder (ADHD) in Canada to Kye Pharmaceuticals. ADHD is one of the most common neurobehavioral disorders, affecting 4-6% of adults and 5-7% of children in Canada, or approximately 1,8 million Canadians1. It is a chronic condition for most patients, with approximately 60 to 80% of the symptoms of ADHD persisting into adulthood2. Global prevalence of ADHD has increased significantly in recent years3, leading to an increased usage of ADHD therapies such as the well-established medication atomoxetine. In 2022, the Canadian market amounted to 17 million capsules (CAGR of 7,4% in the period 2020-2022)4 of atomoxetine. Atomoxetine is currently not available as an oral liquid formulation in Canada. Considering the added value, significant market share penetration was often observed in countries when an oral liquid became available in this drug category5. Kye Pharmaceuticals is targeting a regulatory submission in 2024, and will be the exclusive partner for commercialization in Canada. The territorial expansion for atomoxetine oral liquid should not result in additional product-related investments for Hyloris. Stijn Van Rompay, Chief Executive Officer of Hyloris, commented: “We are proudly partnering with this local champion focused on commercializing therapies within pediatrics and neurosciences. Partnering atomoxetine oral liquid outside of the U.S. underlines our capability to bring innovative treatments to patients on a global scale, and unlock the hidden value in our existing pipeline of reformulated and repurposed product candidates.” John McKendry, President of Kye, commented: “Many Canadians with ADHD are unable to take solid tablets as prescribed, and alternative formulations which have been available internationally are not readily available in the Canadian market. This partnership expands our growing portfolio of innovative ADHD treatments and will ensure Canadian patients have access to a liquid formulation of atomoxetine, a well-established non-stimulant medication.” Under the terms of the agreement, Hyloris will be eligible to receive attractive sales-related milestone payments (totalling up to USD 7,5 million), and a substantial share of the revenue generated in Canada. About Attention Deficit Hyperactivity Disorder (ADHD) ADHD is a chronic mental childhood-onset disorder characterized by developmentally inappropriate and impaired inattention, motor hyperactivity, and impulsivity, with difficulties often continuing into adulthood. Children and adolescents suffering from ADHD experience challenging key formative years. Because of impulsive behaviour and slower rates of processing information, they perform poorly on standardized tests, score lower grades and are more likely to drop out of school. About Atomoxetine oral liquid Atomoxetine is a non-stimulant prescription medication used to treat ADHD symptoms in adults and children over the age of 6. For patients up to 70kg body weight, administration of Atomoxetine is initiated as a total daily dose of 0.5 mg/kg/day up to a target total daily dose of approximately 1.2 mg/kg either as a single daily dose or as evenly divided doses. An easy-to-swallow oral liquid formulation of atomoxetine could facilitate accurate dosing through titration. In addition, it could offer improved patient compliance and convenience, particularly in patients with dysphagia (who have difficulty swallowing capsules). Due to the pediatric use for this product candidate, Hyloris deployed an innovative taste masking strategy targeting a preferred taste for young patients. For the U.S. market, a pivotal clinical study is in preparation as previously announced. About HylorisHyloris is a specialty biopharma company focused on innovating, reinventing, and optimizing existing medications to address important healthcare needs and deliver relevant improvements for patients, healthcare professionals and payors. Hyloris has built a broad, patented portfolio of 16 reformulated and repurposed value-added medicines that have the potential to offer significant advantages over available alternatives. Outside of its core strategic focus, the Company also has 3 high barrier generic products in development. Two products are currently in initial phases of commercialization with partners: Sotalol IV for the treatment of atrial fibrillation, and Maxigesic® IV, a non-opioid post-operative pain treatment. The Company’s development strategy primarily focuses on the FDA’s 505(b)2 regulatory pathway, which is specifically designed for pharmaceuticals for which safety and efficacy of the molecule have already been established. This pathway can reduce the clinical burden required to bring a product to market, and significantly shorten the development timelines and reduce costs and risks. Hyloris is based in Liège, Belgium. For more information, visit www.hyloris.com and follow-us on LinkedIn. About KYE PharmaceuticalsKYE Pharmaceuticals is a private company headquartered in Canada focused on bringing medications to the Canadian market which fulfill clinically significant and unmet needs. KYE has licensed many innovative products and was founded on an entrepreneurial spirit that optimizes our team's strengths and brings unique value to our partners, Canadian healthcare professionals, and most importantly, our patients. For more information please visit www.kyepharma.com.For more information, contact Hyloris:Stijn Van Rompay, CEOstijn.vanrompay@hyloris.com+32 (0)4 346 02 07Jean-Luc Vandebroek, CFOjean-luc.vandebroek@hyloris.com+32 (0)478 27 68 42Sven Watthy, Investor Relations & Communications managerSven.watthy@hyloris.com+32 (0)499 71 15 29Disclaimer and forward-looking statementsHyloris means “high yield, lower risk”, which relates to the 505(b)(2) regulatory pathway for product approval on which the Company focuses, but in no way relates or applies to an investment in the Shares. Certain statements in this press release are “forward-looking statements.” These forward-looking statements can be identified using forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. These statements relate to future events or the Company’s future financial performance and involve known and unknown risks, uncertainties, and other factors, many of which are beyond the Company’s control, that may cause the actual results, levels of activity, performance or achievements of the Company or its industry to be materially different from those expressed or implied by any forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law. 1 https://caddac.ca/about-adhd/2 https://journals.sagepub.com/doi/10.1177/10600280135106993 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616454/4 IQVIA5 IQVIA Attachment Atomoxetine Canada out-licensing FINAL

DUBLIN, Dec. 5, 2022 /PRNewswire/ -- Jazz Pharmaceuticals plc (NASDAQ: JAZZ) today announced new real-world data from the BECOME (BEhavior, COgnition, and More with Epidiolex ®) Caregiver Survey that showed a substantial proportion of caregivers of adult and pediatric patients with Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS) prescribed Epidiolex ® (cannabidiol) oral solution reported improvements in patients' seizure and non-seizure outcomes across all age groups.1,2 These data were presented at the 2022 American Epilepsy Society (AES) annual meeting taking place December 2–6, 2022, in Nashville, TN. "At Jazz, we strive to continually deepen our understanding of the benefits of Epidiolex across the patient experience. The data from the BECOME Caregiver Survey provide important insights into the reported effects of Epidiolex on both seizure and non-seizure outcomes," said Kelvin Tan, MB BCh, MRCPCH, senior vice president and chief medical officer of Jazz Pharmaceuticals. "These data expand our understanding of the multifaceted experience of people living with epilepsy and their caregivers and could ultimately refine the Epidiolex treatment paradigm across age groups. The BECOME study ensures that patients and caregiver lived experience is front and center in clinical research." Epidiolex, a pharmaceutical formulation of highly purified cannabidiol (CBD), is the first and only prescription, plant-derived, cannabis-based medicine approved by the U.S. Food and Drug Administration. It is indicated for the treatment of seizures associated with LGS, DS, and tuberous sclerosis complex (TSC) in patients aged one year and older. "Severe, childhood-onset epilepsies like LGS and DS are lifelong conditions that have significant, long-term impacts on both caregivers and patients. These results are critical in broadening the knowledge base of the potential benefits of Epidiolex treatment across all age groups and identifying additional seizure and non-seizure outcomes to explore in future studies," said lead author and investigator Timothy B. Saurer, Medical Affairs Director of Jazz Pharmaceuticals. "We look forward to additional insights from the BECOME survey as we work to further characterize the specific effects of Epidiolex in both adult and pediatric patients living with rare, treatment-resistant epilepsy conditions." Results The results from both poster presentations suggest that a substantial proportion of the caregivers of people with LGS or DS treated with Epidiolex reported improvements in many patients' seizure and non-seizure outcomes, regardless of age group (patients aged >18 years). Limitations to the survey included retrospective caregiver accounts, post-hoc analyses that were not pre-specified, and selection bias due to study design. In addition, the studies were not blinded and there were no comparator arms. Seizure-Related Outcomes by Age (Poster 3.428) The seizure-related outcome analysis found a large majority of caregivers reported patient seizure improvements as measured by decreased frequency in at least one seizure type (84% aged >18 years) and severity (77% aged >18 years).1 Respondents reported patient improvements in specific seizure types: convulsive seizures (72% each), drop seizures (71% each), non-convulsive/non-drop seizures (66% aged >18 years) and night-time seizures (61% and 63%).1 Many respondents also reported reductions in use of rescue medications (57%), emergency room visits (56% and 51%), hospitalizations (55% and 50%) and occurrence of seizure-related injuries (48% and 49%).1 Non-Seizure-Related Outcomes by Age (Poster 3.429) A substantial proportion of caregivers of patients with LGS or DS, regardless of age, reported improvements in alertness, cognition and executive function, emotional and social function, language and communication, physical function, sleep, and daily activities since initiating Epidiolex treatment.2 A significant proportion of respondents in both age groups (patients aged >18 years) reported any improvement (possible, minor, definite) in one or more questions regarding the following non-seizure outcome areas: Alertness, cognition, and executive function (87% and 81%) and emotional and social function (82% and 80%).2 In patients aged >18 years, the most frequently reported improvement was in alertness (70%).2 Rates of worsening varied by behavior and ranged from 0% to 20% of respondents.2 The most common side effects for Epidiolex include: sleepiness, decreased appetite, diarrhea, increase in liver enzymes, feeling very tired or weak, rash, sleep problems, fever, vomiting and infections.3 The AES abstracts are available online at https://www.aesnet.org/education/annual-meeting/aes-abstract-search. About the BECOME (BEhavior, COgnition, and More with Epidiolex) Caregiver Survey The U.S.-based survey, BECOME (global outcomes survey assessing changes in BEhavior, Cognition, and More with Epidiolex®), characterized and quantified real-world seizure and non-seizure outcomes in patients with LGS (80 percent) or DS (20 percent) treated with Epidiolex for three or more months. The investigators conducted an online survey of 498 caregivers (97 percent parents). The caregivers were asked to compare the past month to the period prior to initiation of Epidiolex treatment by answering questions with answers that were multiple choice or ranked on worsening-to-improving scales. All of the questions were based on those from validated measures and other previously published caregiver reports. Epidiolex-associated adverse events were not assessed in this survey. Limitations to the survey included retrospective caregiver accounts and selection bias due to study design. About Tuberous Sclerosis Complex Tuberous sclerosis complex (TSC) is a rare genetic condition.4 The condition causes mostly benign tumors to grow in vital organs of the body including the brain, skin, heart, eyes, kidneys and lungs5 and is a leading cause of genetic epilepsy.6 People with TSC may experience a variety of seizure types. One of the most common is infantile spasms that typically present in the first year of life; focal (or partial) seizures are also very common.7 TSC is associated with an increased risk of autism and intellectual disability8 and the severity of the condition can vary widely. In some children the disease is very mild, while others may experience life-threatening complications.4 Epilepsy is present in about 85 percent of patients with TSC and may progress to become intractable to medication.4,9,10 More than 60 percent of individuals with TSC do not achieve seizure control11 with standard treatments such as antiepileptic drugs, epilepsy surgery, ketogenic diet, or vagus nerve stimulation8 compared to 30-40 percent of individuals with epilepsy who do not have TSC who are drug resistant.12,13 About Dravet Syndrome Dravet syndrome (DS) is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms).14 Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with (DS) typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others. About Lennox-Gastaut Syndrome Lennox-Gastaut syndrome (LGS) begins in childhood. It is characterized by multiple types of seizures. People with LGS begin having frequent seizures in early childhood, usually between ages 3 and 5.15 More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with LGS develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with LGS require help with usual activities of daily living. About Epidiolex®/Epidyolex® (cannabidiol) EPIDIOLEX/EPIDYOLEX is a prescription, plant-derived cannabis-based medicine administered as an oral solution which contains highly purified cannabidiol (CBD). Cannabidiol, the active ingredient in EPIDIOLEX, is a cannabinoid that naturally occurs in the Cannabis sativa L. plant. The precise mechanisms by which EPIDIOLEX exerts its anticonvulsant effect in humans are unknown. Epidiolex was approved by the U.S. Food and Drug Administration (FDA) for use in the U.S., the European Commission (EC) for use in Europe, the Medicines and Healthcare products Regulatory Agency (MHRA) for use in Great Britain, the Therapeutic Goods Administration for use in Australia, Swissmedic for use in Switzerland, and the Food & Nutrition Services of the Israel Ministry of Health for use in Israel, is an oral solution which contains highly purified cannabidiol (CBD). In the U.S., Epidiolex is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) or tuberous sclerosis complex (TSC) in patients one year of age and older. Epidiolex has received approval in the European Union under the tradename Epidyolex for adjunctive use in conjunction with clobazam to treat seizures associated with LGS and DS in patients two years and older, and for adjunctive use to treat seizures associated with TSC, in patients two years of age and older. Epidyolex has received Orphan Drug Designation from the European Medicines Agency (EMA) for the treatment of seizures associated LGS, DS and TSC. Important Safety Information & Indications CONTRAINDICATION: HYPERSENSITIVITY EPIDIOLEX (cannabidiol) oral solution is contraindicated in patients with a history of hypersensitivity to cannabidiol or any ingredients in the product. WARNINGS & PRECAUTIONS Hepatocellular Injury: EPIDIOLEX can cause dose-related transaminase elevations. Concomitant use of valproate and elevated transaminase levels at baseline increase this risk. Transaminase and bilirubin levels should be obtained prior to starting treatment, at one, three, and six months after initiation of treatment, and periodically thereafter, or as clinically indicated. Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX, reduction of EPIDIOLEX and/or concomitant valproate, or without dose reduction. For patients with elevated transaminase levels, consider dose reduction or discontinuation of EPIDIOLEX or concomitant medications known to affect the liver (e.g., valproate or clobazam). Dose adjustment and slower dose titration is recommended in patients with moderate or severe hepatic impairment. Consider not initiating EPIDIOLEX in patients with evidence of significant liver injury. Somnolence and Sedation: EPIDIOLEX can cause somnolence and sedation that generally occurs early in treatment and may diminish over time; these effects occur more commonly in patients using clobazam and may be potentiated by other CNS depressants. Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including EPIDIOLEX, increase the risk of suicidal thoughts or behavior. Inform patients, caregivers, and families of the risk and advise to monitor and report any signs of depression, suicidal thoughts or behavior, or unusual changes in mood or behavior. If these symptoms occur, consider if they are related to the AED or the underlying illness. Withdrawal of Antiepileptic Drugs: As with most AEDs, EPIDIOLEX should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. Adverse Reactions: The most common adverse reactions in patients receiving EPIDIOLEX (≥10% and greater than placebo) include transaminase elevations; somnolence; decreased appetite; diarrhea; pyrexia; vomiting; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder and poor-quality sleep; and infections. Hematologic abnormalities were also observed. Pregnancy: EPIDIOLEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who are taking EPIDIOLEX during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Drug Interactions: Strong inducers of CYP3A4 and CYP2C19 may affect EPIDIOLEX exposure. EPIDIOLEX may affect exposure to CYP2C19 substrates (e.g., clobazam, diazepam, stiripentol), orally administered P-gp substrates, or other substrates (see full Prescribing Information). Consider dose reduction of orally administered everolimus, with appropriate therapeutic drug monitoring, when everolimus is combined with EPIDIOLEX. A lower starting dose of everolimus is recommended when added to EPIDIOLEX therapy. Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations. Pneumonia was observed more frequently with concomitant use of EPIDIOLEX and clobazam. Dosage adjustment of EPIDIOLEX or other concomitant medications may be necessary. Indications: EPIDIOLEX (cannabidiol) oral solution is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older. Please refer to the EPIDIOLEX full Prescribing Information for additional important information here. About Jazz Pharmaceuticals plc Jazz Pharmaceuticals plc (NASDAQ: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseases—often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. Within these therapeutic areas, we are identifying new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science. Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. Please visit www.jazzpharmaceuticals.com for more information.