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A novel study has identified a range of metabolic biomarkers that could help predict the risk of cancer. A novel study from the University of South Australia has identified a range of metabolic biomarkers that could help predict the risk of cancer. Deploying machine learning to examine data from 459,169 participants in the UK Biobank, the study identified 84 features that could signal increased cancer risk. Several markers also signalled chronic kidney or liver disease, highlighting the significance of exploring the underlying pathogenic mechanisms of these diseases for their potential connections with cancer. The study, "Hypothesis-free discovery of novel cancer predictors using machine learning," was conducted by UniSA researchers: Dr Iqbal Madakkatel, Dr Amanda Lumsden, Dr Anwar Mulugeta, and Professor Elina Hyppönen, with University of Adelaide's Professor Ian Olver. "We conducted a hypothesis-free analysis using artificial intelligence and statistical approaches to identify cancer risk factors among more than 2800 features," Dr Madakkatel says. "More than 40% of the features identified by the model were found to be biomarkers -- biological molecules that can signal health or unhealthy conditions depending on their status -- and several of these were jointly linked to cancer risk and kidney or liver disease." Dr Amanda Lumsden says this study provides important information on mechanisms which may contribute to cancer risk. "After age, high levels of urinary microalbumin was the highest predictor of cancer risk. Albumin is a serum protein needed for tissue growth and healing, but when present in your urine, it's not only an indicator of kidney disease, but also a marker for cancer risk. "Similarly, other indicators of poor kidney performance such as high blood levels of cystatin C, high urinary creatinine (a waste product filtered by your kidneys), and overall lower total serum protein were also linked to cancer risk. "We also identified that greater red cell distribution width (RDW) -- or the variation in size of your red blood cells -- is associated with increased risk of cancer. "Normally, your red blood cells should be about the same size, and when there are discrepancies, it can correlate with higher inflammation and poorer renal function. As this study shows, also higher risk of cancer." Additionally, the study found that high levels of C-reactive protein -- an indicator of systemic inflammation -- were connected to increased cancer risk, as were high levels of the enzyme gamma glutamyl transferase (GGT)- a liver stress-related biomarker. Chief investigator, Professor Elina Hyppönen, Centre Director of the Australian Centre for Precision Health at UniSA, says the strength of this study lies in the machine learning. "Using artificial intelligence, our model has shown that it can incorporate and cross-reference thousands of features and identify relevant risk predictors that may otherwise remain hidden," Prof Hyppönen says. "It is interesting that while our model incorporated information on thousands of features, including clinical, behavioural, and social factors, so many were biomarkers, which reflect the metabolic state before cancer diagnoses. "While further studies are needed to confirm causality and clinical relevance, this research suggests that with relatively simple blood tests it may be possible to gain information about our future risk of cancer. This is important as it can then allow us to act early, at a stage when it may still be possible to prevent the disease."

Analysis published in the Journal of Comparative Effectiveness Research shows ropeginterferon alfa-2b-njft provided a cost-effective benefit in quality-adjusted life years compared to a commonly used treatment pathway BURLINGTON, Mass.--(BUSINESS WIRE)-- PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced the publication of a cost-effectiveness analysis of ropeginterferon alfa-2b-njft (marketed as BESREMi®) in the Journal of Comparative Effectiveness Research. The analysis, titled “Cost-Effectiveness of Ropeginterferon Alfa-2b-njft for the Treatment of Polycythemia Vera,” showed that ropeginterferon alfa-2b-njft provided a cost-effective benefit for a broad range of patients with polycythemia vera (PV) versus first-line hydroxyurea followed by ruxolitinib. Cost effectiveness was demonstrated in a modeled population including both low- and high-risk patients receiving first- or second-line treatment with ropeginterferon alfa-2b-njft. “PV is a chronic blood cancer that requires lifelong therapy, which can prevent or delay negative clinical outcomes, but is also associated with additional costs to patients and payers. These new data demonstrate ropeginterferon alfa-2b-njft’s value not only to people living with PV, but also to the healthcare system at large,” said Dr. Aaron Gerds, MD, MS, Medical Director at Case Comprehensive Cancer Center and lead study author. “This study shows ropeginterferon alfa-2b-njft is a cost-effective treatment option over the modeled lifetime and that earlier initiation of treatment of PV with effective therapy can translate to more favorable cost to benefit ratios.” PV is the most common myeloproliferative neoplasm (MPN) and a long-term, potentially life-threatening disease with limited approved treatment options. Patients with PV are at risk for disease progression to myelofibrosis (post-PV MF) or transformation to blast phase (MPN-BP) which is akin to acute myeloid leukemia1-3. Patients are also at an increased risk for arterial and venous thromboembolic events (TEs) which are associated with higher mortality, lower quality of life, and higher healthcare costs4-7. This new study used an economic model developed from the United States healthcare system perspective. Inputs were informed by the data from randomized clinical trials, including the PROUD-PV and CONTINUATION-PV studies, and from real-world sources. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line therapy versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. To reflect the long-term consequences of treating PV, results were presented over a lifetime horizon. Findings from the study conclude ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea. Of note: These data show that over the modeled lifetime, patients who receive ropeginterferon alfa-2b-njft have more years alive (0.4), higher quality-adjusted life years (QALYs) (0.4), and higher cost ($60,175) as compared to the alternative treatment pathway. Weighing the additional costs versus the additional QALY gains results in a cost per QALY of $141,783. This cost per QALY is less than a standard willingness to pay threshold of $150,000 per QALY8. In this study, treating patients at a younger age or those with low-risk disease led to more cost-effective results, suggesting that earlier initiation of treatment of PV with effective therapy can translate to more favorable cost to benefit ratios. The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates. “Ropeginterferon alfa-2b-njft has demonstrated safety and efficacy in studies including both low- and high-risk patients and patients with and without prior cytoreductive treatment with HU. Recently, the National Comprehensive Cancer Network (NCCN) updated their treatment guidelines to include ropeginterferon as a preferred treatment regimen for both low- and high-risk PV patients9. As ropeginterferon continues to be more widely used in clinical practice, this study was imperative to demonstrate the cost-effectiveness of ropeginterferon alfa-2b-njft for a broad range of patients with PV,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs at PharmaEssentia. “This analysis also underscores the importance of treating low-risk patients and patients early in their disease journey to help minimize more severe events and their corresponding costs to the healthcare system.” The full benefits of ropeginterferon alfa-2b-njft may not be fully captured in the model, and in particular, data on disutility of phlebotomy are lacking. Although some patients may tolerate regular phlebotomies, others can experience iron deficiency which can negatively impact quality of life. While the results from a scenario analysis incorporating a small decrement in utility had minimal impact on the cost-effectiveness results, due to the lack of data in this area, this estimate remains conservative. This study took a U.S. healthcare perspective, and the results may not generalize to other countries given the differences in healthcare resource use, costs and cost-effectiveness thresholds. Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates. About Polycythemia Vera (PV) Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.10 About BESREMi® (ropeginterferon alfa-2b-njft) BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients. BESREMi has orphan drug designation for the treatment of polycythemia vera (PV) in adults in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has recently received approval in Taiwan and South Korea. The drug candidate was invented by PharmaEssentia and is manufactured in the company’s Taichung plant, which was cGMP certified by TFDA in 2017 and by EMA in January 2018. PharmaEssentia retains full global intellectual property rights for the product in all indications. Indication BESREMi is indicated for the treatment of adults with polycythemia vera. Important Safety Information WARNING: RISK OF SERIOUS DISORDERS Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy. CONTRAINDICATIONS Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi. Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment History or presence of active serious or untreated autoimmune disease Immunosuppressed transplant recipients WARNINGS AND PRECAUTIONS Depression and Suicide: Life-threatening or fatal neuropsychiatric reactions have occurred in patients receiving interferon alfa-2b products, including BESREMi. These reactions may occur in patients with and without previous psychiatric illness. Other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products. Closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue BESREMi therapy. Endocrine Toxicity: These toxicities may include worsening hypothyroidism and hyperthyroidism. Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease. Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi. Cardiovascular Toxicity: Toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation and coronary artery ischemia. Patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease, (e.g., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction. Decreased Peripheral Blood Counts: These toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). Monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase. Monitor patients for signs and symptoms of infection or bleeding. Hypersensitivity Reactions: Toxicities may include serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment. Pancreatitis: Pancreatitis has occurred in 2.2% of patients receiving BESREMi. Symptoms may include nausea, vomiting, upper abdominal pain, bloating, and fever. Patients may experience elevated lipase, amylase, white blood cell count, or altered renal/hepatic function. Interrupt BESREMi treatment in patients with possible pancreatitis and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis. Colitis: Fatal and serious ulcerative or hemorrhagic/ischemic colitis have occurred in patients receiving interferon alfa products, some cases starting as early as 12 weeks after start of treatment. Symptoms may include abdominal pain, bloody diarrhea, and fever. Discontinue BESREMi in patients who develop these signs or symptoms. Colitis may resolve within 1 to 3 weeks of stopping treatment. Pulmonary Toxicity: Pulmonary toxicity may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment. Ophthalmologic Toxicity: These toxicities may include severe eye disorders such as retinopathy, retinal hemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness. During BESREMi therapy, 23% of patients were identified with an eye disorder. Eyes disorders ≥5% included cataract (6%) and dry eye (5%). Advise patients to have eye examinations before and during BESREMi therapy, specifically in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension. Evaluate eye symptoms promptly. Discontinue BESREMi in patients who develop new or worsening eye disorders. Hyperlipidemia: Elevated triglycerides may result in pancreatitis. Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. Consider discontinuation of BESREMi in patients with persistently, markedly elevated triglycerides. Hepatotoxicity: These toxicities may include increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and bilirubin. Liver enzyme elevations have also been reported in patients after long-term BESREMi therapy. Monitor liver enzymes and hepatic function at baseline and during BESREMi treatment. Discontinue BESREMi in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage) during treatment. Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi if severe renal impairment develops during treatment. Dental and Periodontal Toxicity: These toxicities may include dental and periodontal disorders, which may lead to loss of teeth. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with BESREMi. Patients should have good oral hygiene and regular dental examinations. Dermatologic Toxicity: These toxicities have included skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis. Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs. Driving and Operating Machinery: BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence or hallucination during BESREMi therapy should avoid driving or using machinery. Embryo-Fetal Toxicity: Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended in females of reproductive potential prior to treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose. ADVERSE REACTIONS The most common adverse reactions reported in > 40% of patients in the PEGINVERA study (n=51) were influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain. In the pooled safety population (n=178), the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%). DRUG INTERACTIONS Patients on BESREMi who are receiving concomitant drugs which are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs. Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression. Avoid use with narcotics, hypnotics or sedatives and monitor patients receiving the combination for effects of excessive CNS toxicity. USE IN SPECIFIC POPULATIONS Pregnancy: Based on mechanism of action and the role of interferon alfa in pregnancy and fetal development, BESREMi may cause fetal harm and should be assumed to have abortifacient potential when administered to a pregnant woman. There are adverse effects on maternal and fetal outcomes associated with polycythemia vera in pregnancy. Advise pregnant women of the potential risk to a fetus. Lactation: There are no data on the presence of BESREMi in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from BESREMi, advise women not to breastfeed during treatment and for 8 weeks after the final dose. Females of Reproductive Potential: BESREMi may cause embryo-fetal harm when administered to a pregnant woman. Pregnancy testing prior to BESREMi treatment is recommended for females of reproductive potential. Advise female patients of reproductive potential to use effective contraception during treatment with BESREMi and for at least 8 weeks after the final dose. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy. Please see accompanying full Prescribing Information, including Boxed Warning. About PharmaEssentia PharmaEssentia (TPEx: 6446), headquartered in Taipei, Taiwan, is a global and rapidly growing biopharmaceutical innovator. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2003 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan. For more information about PharmaEssentia USA, visit the website, LinkedIn or Twitter. Forward Looking Statement This press release may contain forward-looking statements, including statements about a cost-effectiveness analysis involving BESREMi and the expected impact of BESREMi on healthcare outcomes. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and similar legislation and regulations under Taiwanese law. These forward-looking statements are based on management expectations and assumptions as of the date of this press release, and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include changes in healthcare policies and regulations, the availability and acceptance of BESREMi in the market, changes in reimbursement that may impact the acceptance and adoption of BESREMi, and competition from other products. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. © 2023 PharmaEssentia Corporation. All rights reserved. BESREMi and PharmaEssentia are registered trademarks of PharmaEssentia Corporation, and the PharmaEssentia logo is a trademark of PharmaEssentia Corporation. 1 McKinnell Z, Karel D, Tuerff D, Sh Abrahim M, Nassereddine S. Acute Myeloid Leukemia Following Myeloproliferative Neoplasms: A Review of What We Know, What We Do Not Know, and Emerging Treatment Strategies. J Hematol, 11(6), 197-209 (2022). 2 Masarova L, Bose P, Daver N et al. Patients with post-essential thrombocythemia and post polycythemia vera differ from patients with primary myelofibrosis. Leuk Res, 59, 110-116 (2017). 3 Finazzi G, Caruso V, Marchioli R et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood, 105(7), 2664-2670 (2005). 4 Griesshammer M, Kiladjian JJ, Besses C. Thromboembolic events in polycythemia vera. Ann Hematol, 98(5), 1071-1082 (2019). 5 Tefferi A, Rumi E, Finazzi G et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia, 27(9), 1874-1881 (2013). 6 Marchioli R, Finazzi G, Landolfi R et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol, 23(10), 2224-2232 (2005). 7 Parasuraman SV, Shi N, Paranagama DC, Bonafede M. Health Care Costs and Thromboembolic Events in Hydroxyurea-Treated Patients with Polycythemia Vera. J Manag Care Spec Pharm, 24(1), 47-55 (2018). 8 2020–2023 Value Assessment Framework. Institute for Clinical and Economic Review (2020), 9 Barbui et al. NEJM Evidence. 2023; Gisslinger et al. Lancet. 2020; Kiadjian et al. Leukemia. 2022; Kiladjian et al. ASH. 2022. 10 Cerquozzi S, Tefferi A. Blast Transformation and Fibrotic Progression in Polycythemia Vera and Essential Thrombocythemia: A Literature Review of Incidence and Risk Factors. Blood Cancer J (2015) 5, e366; doi:10.1038/bcj.2015.95.

ROCTAVIAN is a One-Time, Single-Dose Treatment Available for Adults with Severe Hemophilia A to Control Bleeds ROCTAVIAN's Approval was Based on Durability, Efficacy and Safety Results from the Largest and Longest Phase 3 Study for a Gene Therapy for Hemophilia Majority of Patients Continued to Respond to ROCTAVIAN Treatment over 3 Years SAN RAFAEL, CA, USA I June 29, 2023 I BioMarin Pharmaceutical Inc. (Nasdaq: BMRN ), a global biotechnology company dedicated to transforming lives through genetic discovery, today announced that the United States Food and Drug Administration (FDA) approved ROCTAVIAN™ (valoctocogene roxaparvovec-rvox) gene therapy for the treatment of adults with severe hemophilia A (congenital factor VIII (FVIII) deficiency with FVIII activity < 1 IU/dL) without antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test. The one-time, single-dose infusion is the first approved gene therapy for severe hemophilia A in the U.S. ROCTAVIAN was first approved by the European Medicines Agency in August 2022. "Adults with severe hemophilia A face a lifelong burden, with frequent infusions and a high risk of health complications, including uncontrolled bleeding and irreversible joint damage," said Dr. Steven Pipe, professor of pediatrics and pathology at the University of Michigan and an investigator in the Phase 3 study.  "The approval of ROCTAVIAN, as the first gene therapy for severe hemophilia A, has the potential to transform the way we treat adults based on years of bleed control following a single, one-time infusion." Hemophilia A is a lifelong, genetic condition caused by a mutation in the gene responsible for producing a protein called FVIII, which is necessary for blood clotting. When severely deficient in amount, the condition puts people with hemophilia A at risk for painful and potentially life-threatening bleeds, which can occur spontaneously. With the current standard of care, individuals undergo lifelong preventative therapy, receiving infusions or injections at burdensome routine intervals to maintain enough clotting factor in the bloodstream to prevent bleeds. ROCTAVIAN is designed to replace the function of the mutated gene, allowing people with severe hemophilia A to produce their own FVIII and thereby limit bleeding episodes. "Today's approval of ROCTAVIAN builds on BioMarin's proven track record of advancing treatments that target the underlying cause of life-threatening genetic conditions, which has produced eight best- or first-in-class commercial therapies," said Jean-Jacques Bienaimé, chairman and chief executive officer of BioMarin. "We are proud to now offer adults with severe hemophilia A, a one-time, single-dose treatment option. We are especially grateful to the bleeding disorders community for its support of this program, and to all the patients and healthcare providers who participated in our clinical trials." ROCTAVIAN is manufactured at the company's facility in Novato, California. The BioMarin-owned site is one of the largest gene therapy manufacturing facilities of its kind and will allow the company to meet commercial demand throughout its product lifecycle. Largest Phase 3 Gene Therapy Study in Hemophilia to Report More Than Three Years of Data The FDA approval is based on data from the global Phase 3 GENEr8-1 study, the largest Phase 3 trial of any gene therapy in hemophilia. Of the 134 patients who received ROCTAVIAN in the study, 112 patients had baseline annualized bleeding rate (ABR) data prospectively collected during a period of at least six months on FVIII prophylaxis prior to receiving ROCTAVIAN. The remaining 22 patients had baseline ABR collected retrospectively. All patients were followed for at least 3 years. As reported in the FDA-approved labeling for ROCTAVIAN, the 112 patients in whom 6-month baseline ABR was collected prospectively experienced a mean ABR reduction of 52% after receiving ROCTAVIAN (2.6 bleeds/year) through end of follow-up (median of three years) compared to their baseline ABR while receiving routine FVIII prophylaxis (5.4 bleeds/year).  This result was based on an FDA analysis that imputed an ABR of 35 in 13 patients for the periods when these patients were on prophylaxis. These patients also reported a substantial reduction in the rate of spontaneous bleeds and joint bleeds following treatment with ROCTAVIAN (observed mean ABR of 0.5 bleeds/year for spontaneous bleeds and 0.6 bleeds/year for joint bleeds) compared to their baseline rate while receiving routine FVIII prophylaxis (observed mean ABR of 2.3 bleeds/year for spontaneous bleeds and 3.1 bleeds/year for joint bleeds). The majority of study participants continued to respond to treatment through year three and beyond, without supplemental use of regular prophylaxis. BioMarin will continue to monitor the long-term effects of treatment with an extension study that will follow all clinical trial participants for up to 15 years, as well as post-approval studies to follow those dosed in a real-world setting for 15 years or more. Data Presented at the International Society on Thrombosis and Haemostasis (ISTH) 2023 Congress Additionally, results from the three-year analysis of the Phase 3 GENEr8-1 study that were presented on Sunday at ISTH showed that study participants had an 82.9% reduction in treated bleeds overall compared with baseline. The study also found ROCTAVIAN led to a 96.8% reduction in FVIII usage overall compared with baseline. Ensuring Access: Hemophilia Treatment Centers (HTCs) and Outcomes-Based Warranty Program BioMarin will begin educating physicians and patients about ROCTAVIAN immediately to ensure the hemophilia community is aware of this new treatment option. As part of the development of ROCTAVIAN, BioMarin has worked with private and public payers in the U.S. in parallel to enable access, with the goal of ensuring that every eligible adult interested in ROCTAVIAN is able to receive treatment. A key component of the company's approach to access is the outcomes-based warranty, which will be offered to all U.S. insurers. The warranty will reimburse government and commercial payers up to 100% of wholesale acquisition cost in the event that a person does not respond to ROCTAVIAN. If an individual treated with ROCTAVIAN loses response at any time in the first four years after dosing, BioMarin will reimburse payers on a prorated basis for the cost of treatment. Most people with hemophilia receive care at HTCs. The company is working closely with the leading U.S. HTCs to ensure that the centers are prepared to administer ROCTAVIAN following today's approval. "Our teams have been working for many months to ensure that the people who are eligible for ROCTAVIAN have access to this first-in-class medicine," said Jeff Ajer, executive vice president and chief commercial officer of BioMarin. "We appreciate the close partnership with health insurers, hemophilia treatment centers and the hemophilia community to ensure the greatest access for people with severe hemophilia A." It is estimated that there are approximately 6,500 adults living with severe hemophilia A in the U.S. BioMarin expects approximately 2,500 of those adults to be eligible to receive ROCTAVIAN with this initial approval. Robust Ongoing Clinical Program BioMarin has multiple clinical studies underway in its comprehensive gene therapy program for the treatment of severe hemophilia A. In addition to the global Phase 1/2 and Phase 3 GENEr8-1 studies, the company is also conducting a single-arm, open-label study to evaluate the efficacy and safety of ROCTAVIAN at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with severe hemophilia A (Study 270-303). There is also an ongoing study with the 6e13 vg/kg dose of ROCTAVIAN in people with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) and a study with the 6e13 vg/kg dose of ROCTAVIAN in people with severe hemophilia A with active or prior FVIII inhibitors (Study 270-205). Safety Summary Safety results for 134 patients have been reported through three years, demonstrating that ROCTAVIAN was well-tolerated. The Prescribing Information includes Warnings and Precautions for infusion-related reactions, hepatotoxicity, thromboembolic events and theoretical risk of hepatocellular carcinoma. Patients with detectable pre-existing antibodies to AAV5, active infections, history of thrombosis, immunosuppressive disorders and liver dysfunction were excluded. All patients had a median follow-up of 162 weeks (range: 66 to 255 weeks). The most common adverse reactions (≥ 5%) to ROCTAVIAN were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. ROCTAVIAN is contraindicated for patients with active infections, either acute or uncontrolled chronic, known significant hepatic fibrosis (stage 3 or 4), or cirrhosis and a known hypersensitivity to mannitol. The most common laboratory abnormalities were alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CPK), factor VIII activity levels, gamma-glutamyl transferase (GGT) and bilirubin > upper levels of normal (ULN). The majority of patients in the clinical trial required corticosteroids for ALT elevation (median duration of corticosteroid use was 35 weeks). See additional safety information in the Prescribing Information and Important Safety Information below. Patient Support for Accessing ROCTAVIAN To reach a BioMarin RareConnections ® case manager, please call 1-833-ROCTAVIAN (1-833-762-8284), or email This email address is being protected from spambots. You need JavaScript enabled to view it. // . For more information about ROCTAVIAN, please visit BioMarin.com or contact BioMarin Medical Information at This email address is being protected from spambots. You need JavaScript enabled to view it. // . About Hemophilia A Hemophilia A, also called FVIII deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective FVIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a new mutation that was not inherited. Approximately 1 in 10,000 people have hemophilia A. People living with hemophilia A lack sufficient functioning FVIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A (FVIII levels <1%) often experience painful, spontaneous bleeds into their muscles or joints. Individuals with the most severe form of hemophilia A make up approximately 50% of the hemophilia A population. People with hemophilia A with moderate (FVIII levels 1-5%) or mild (FVIII levels 5-40%) disease show a much-reduced propensity to bleed. Individuals with severe hemophilia A are treated with a prophylactic regimen of intravenous FVIII infusions administered 2-3 times per week (100-150 infusions per year) or a bispecific monoclonal antibody that mimics the activity of FVIII administered 1-4 times per month (12-48 injections or shots per year). Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life. About ROCTAVIAN ROCTAVIAN is an adeno-associated virus vector–based gene therapy indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without antibodies to adeno–associated virus serotype 5 (AAV5) detected by an FDA–approved test. The one-time infusion works by delivering a functional gene that is designed to enable the body to produce FVIII on its own, reducing the need for ongoing prophylaxis. The European Commission (EC) granted conditional marketing authorization to ROCTAVIAN on August 24, 2022. Important Safety Information Contraindications: Patients with active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B) . Patients with known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent), or cirrhosis, and patients with known hypersensitivity to mannitol. Infusion-related reactions including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during and for at least 3 hours after ROCTAVIAN administration. Administer ROCTAVIAN in a setting where personnel and equipment are immediately available to treat infusion-related reactions.  Discontinue infusion for anaphylaxis. Hepatotoxicity : The safety and effectiveness of ROCTAVIAN in patients with hepatic impairment has not been established.  Perform liver health assessments prior to administration. The majority of patients treated with ROCTAVIAN experienced ALT elevations and required corticosteroids for ALT elevation.  Assess patient's ability to receive corticosteroids and/or other immunosuppressive therapy that may be required for an extended period. Live vaccines should not be administered to patients while on immunosuppressive therapy. Monitor ALT weekly for at least 26 weeks and as clinically indicated, during corticosteroid therapy and institute corticosteroid treatment in response to ALT elevations as required.   Continue to monitor ALT until it returns to baseline. Monitor factor VIII activity levels since ALT elevation may be accompanied by a decrease in factor VIII activity.  One case of autoimmune hepatitis was reported during third year follow-up in a patient with history of hepatitis C and steatohepatitis. It is recommended that patients abstain from consuming alcohol for at least 1 year after administration and thereafter limit alcohol use. Concomitant medications may cause hepatotoxicity, decrease factor VIII activity, or change plasma corticosteroid levels which may impact liver enzyme elevation and/or factor VIII activity or decrease the efficacy of the corticosteroid regimen or increase their side effects.  Closely monitor concomitant medication use including herbal products and nutritional supplements and consider alternative medications in case of potential drug interactions. Thromboembolic events : Factor VIII activity above ULN has been reported following ROCTAVIAN infusion. Thromboembolic events may occur in the setting of elevated factor VIII activity above ULN.  Evaluate patients for risk of thrombosis including general cardiovascular risk factors before and after administration of ROCTAVIAN. Advise patients on their individual risk of thrombosis in relation to their factor VIII activity levels above ULN and consider prophylactic anticoagulation. Advise patients to seek immediate medical attention for signs or symptoms indicative of a thrombotic event. Factor VIII inhibitors and Monitoring for inhibitors . The safety and effectiveness of ROCTAVIAN in patients with prior or active factor VIII inhibitors have not been established.  Patients with active factor VIII inhibitors should not take ROCTAVIAN.  Following administration, monitor patients for factor VIII inhibitors (neutralizing antibodies to factor VIII). Test for factor VIII inhibitors especially if bleeding is not controlled, or plasma factor VIII activity levels decrease. Monitor Factor VIII using the same schedule for ALT monitoring.  It may take several weeks after ROCTAVIAN infusion before ROCTAVIAN-derived factor VIII activity rises to a level sufficient for prevention of spontaneous bleeding episodes. Exogenous factor VIII or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds.  Consider more frequent monitoring in patients with factor VIII activity levels ≤ 5 IU/dL and evidence of bleeding, taking into account the stability of factor VIII levels since the previous measurement. Factor VIII activity produced by ROCTAVIAN in human plasma is higher if measured with one-stage clotting assays compared to chromogenic substrate assays.  When switching from hemostatic products prior to ROCTAVIAN treatment, physicians should refer to the relevant prescribing information to avoid the potential for factor VIII activity assay interference during the transition period. Malignancy : The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development.  ROCTAVIAN can also insert into the DNA of other human body cells.  Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following ROCTAVIAN administration. In the event that any malignancy occurs after treatment with ROCTAVIAN, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100. Most Common Adverse Reactions: Most common adverse reactions (incidence ≥ 5%) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain.  Most common laboratory abnormalities (incidence ≥ 10%) were ALT, AST, LDH, CPK, factor VIII activity levels, GGT and bilirubin > ULN.  Patients also experienced adverse reactions from corticosteroid use. Isotretinoin, Efavirenz, and HIV Positive Patients .  Isotretinoin is not recommended in patients who are benefiting from ROCTAVIAN.  Efavirenz is not recommended in patients treated with ROCTAVIAN.   Clinical studies of ROCTAVIAN did not include sufficient numbers of patients with HIV to determine whether the efficacy and safety differs compared to patients without HIV infection. Females and Males of Reproductive Potential. ROCTAVIAN is not intended for administration in women. There are no data on the use of ROCTAVIAN in pregnant women or regarding lactation.  For 6 months after administration of ROCTAVIAN men of reproductive potential and their female partners must prevent or postpone pregnancy using an effective form of contraception, and men must not donate semen. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch . You may also report side effects to BioMarin at 1-866-906-6100. Please see the ROCTAVIAN full Prescribing Information for additional Important Safety Information. About BioMarin Founded in 1997, BioMarin is a global biotechnology company dedicated to transforming lives through genetic discovery. The company develops and commercializes targeted therapies that address the root cause of the genetic conditions. BioMarin's unparalleled research and development capabilities have resulted in eight transformational commercial therapies for patients with rare genetic disorders. The company's distinctive approach to drug discovery has produced a diverse pipeline of commercial, clinical, and pre-clinical candidates that address a significant unmet medical need, have well-understood biology, and provide an opportunity to be first-to-market or offer a substantial benefit over existing treatment options. For additional information, please visit BioMarin.com . SOURCE: BioMarin Pharmaceutical