L-lactate dehydrogenase

此外，研究团队开发了一个交互式门户网站（http://cancerdiversity.asia/LICOB/）以实现类器官数据的分析和探索，使肝癌类器官生物样本库（LICOB）所产生的药物蛋白质组数据 作为全球第六大常见癌症，原发性肝癌是第三大致死恶性肿瘤，其中肝细胞癌（HCC）约占 85%，其次是肝内胆管癌（ICC）和肝细胞胆管细胞混合癌（CHC）。大多数患者在确诊时已处于晚期，可用的治疗方法有限，治疗效果不佳。近年来，靶向和免疫治疗的应用使得肝癌患者生存率得到提高。但是，已获批的肝癌靶向药物多为多激酶抑制剂，包括一线治疗药物索拉非尼和仑伐替尼，二线治疗药物瑞格非尼和卡博替尼，受限于肿瘤异质性及生物标志物的缺乏，肝细胞癌患者对治疗应答率较低，且很难通过基因组学预测患者的药物敏感性，使得适用患者选择成为一项重大挑战。 复旦大学附属中山医院樊嘉院士、高强教授团队联合中科院药物研究所周虎团队、中科院分子细胞科学卓越创新中心高大明团队开展了一系列中国人肝癌的蛋白质基因组学研究，相关成果发表于 Cell、Cancer Cell 和 National Science Review。不同于以往基于突变或转录组学的肝癌分子分型的特征不明，蛋白基因组分型将肝细胞肝癌分为代谢驱动型、微环境失调型和增殖驱动型，胆管细胞癌分为炎症型、间质型、代谢型、和分化型 ，这些分子分型与代谢紊乱、异常信号通路激活、基因组不稳定、肿瘤微环境、以及患者预后密切相关。除了肝癌组织，团队还揭示了癌旁正常邻近组织的蛋白组异质性，与肝癌预后和术后复发转移息息相关。研究揭示了不同分子分型的预后差异并鉴定了不同分型肝癌的分子靶标，为肝癌精准分子分型和个性化治疗提供了新策略。为了进一步实现肝癌精准用药疗效预测，建立能够复刻肿瘤分子分型特征的临床前模型以及获取相应的药物组学信息，是当前肝癌转化医学和药物开发的前沿难题之一。 近日，复旦大学高强教授课题组联合中国科学院脑科学智能技术卓越创新中心孙怡迪课题组、中国科学院上海药物研究所周虎课题组，在 Science 子刊 Science Translational Medicine 上发表了题为：Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology 的研究论文。 该研究对65个肝癌患者来源类器官（PDO）模型进行了全面的药物蛋白基因组学分析，基于蛋白质组学的特征建模重现了肝癌组织的蛋白基因组学分子分型，实现药物反应的高精准预测并评估了潜在的药物联合治疗方案，为临床患者选择和药物联合治疗提供指导。 在这项研究中，研究团队使用手术切除的组织建立了65个患者来源的肝癌类器官生物样本库（LICOB），包括三种主要类型的原发性肝癌即HCC、ICC和CHC，以及一种罕见的肝母细胞瘤。通过基因组（体细胞突变和拷贝数变异）、表观基因组（DNA甲基化）、转录组和蛋白质组在内的多组学分析证明，LICOB保留了不同肝癌类型的组织学和分子特征以及肿瘤内异质性。根据多组学分子分型，LICOB 被分为4个亚型，即L-ICC（ICC主导型）、L-PL（增殖主导型）、L-LM（脂质代谢途径主导型）和L-DM（ 药物代谢途径主导），后三类的特征与之前报道的基于 HCC 组织的蛋白组学分型结果相似，并且与患者预后相关。相比之下，肝癌细胞系模型主要表现出增殖特征，提示肝癌类器官是重现肝癌分子亚型多样性的有力模型。 为了探索肝癌类器官生物样本库（LICOB）是否可以作为发现肝癌新治疗靶点的研究平台，研究者探索了四种LICOB亚型蛋白表达特征，发现戊糖磷酸途径中的限速酶葡萄糖-6-磷酸脱氢酶（G6PD），在L-DM亚型中显著升高，并且与MYC扩增和NRF2表达上调有关。进一步敲低G6PD或者应用G6PD抑制剂能够减少NADPH和GSH等代谢物的生成导致氧化还原稳态失调进而抑制L-DM亚型类器官的生长，表明MYC扩增可能通过NRF2激活G6PD的转录，进而增强戊糖磷酸途径来支持细胞生长和抗氧化防御，以增强氧化应激下的肿瘤细胞的存活和进展。这些结果明确了靶向G6PD的临床治疗价值，肯定了类器官模型整合多组学数据驱动肝癌治疗靶标发现的可行性。 为了进一步实现肝癌类器官生物样本库（LICOB）对药物预测的价值，研究者开发了一个利用多组学数据预测药物反应的模型，其预测的耐药性或敏感性特征与药物作用机制密切相关。研究团队发现Tivantinib（一种选择性c-MET抑制剂）的药物响应与MET激活所需基因的上调有关，而不是与MET本身的表达相关，这与之前的临床研究一致 。此外，LICOB数据还可以成功预测一些研究的耐药机制，例如，仑伐替尼（一种治疗不可切除肝细胞癌的一线药物）耐药与EGFR酪氨酸激酶抑制剂耐药途径相关蛋白的高表达水平呈正相关，与相关基因的DNA甲基化呈负相关，进一步支持LICOB作为研究耐药机制的有力模型。这些结果表明基于LICOB的预测结果与临床信息和潜在药物响应机制之间具有良好的相关性，因此LICOB类器官是预测药物反应的可靠模型。 药物联合治疗可以有效克服单一药物的局限性和耐药性，获得更持久有效的疗效，在临床前模型中准确评估潜在的联合用药组合至关重要。研究者开发了一种基于弹性网络的机器学习算法，使用LICOB的多组学数据集来预测有效的药物组合，发现仑伐替尼与mTOR抑制剂替西罗莫司联合的协同治疗效果，在体外类器官模型、类器官移植瘤模型（PDOX）和患者来源移植瘤（PDX）模型中均得到验证。与单独使用两种药物相比，仑伐替尼和替西罗莫司联合用药治疗表现出明显更强的抑制肿瘤生长的作用，这表明由LICOB的药物蛋白质组学数据预测的药物组合方案有望实现良好的临床转化。 此外，研究团队开发了一个交互式门户网站（http://cancerdiversity.asia/LICOB/）以实现类器官数据的分析和探索，使肝癌类器官生物样本库（LICOB）所产生的药物蛋白质组数据充分服务于生物医学、转化研究和临床探索，有助于推动功能性精准医学的临床转化。

Biomedical engineers have developed an entirely new approach to building point-of-care diagnostic devices that only use gravity to transport, mix and otherwise manipulate the liquid droplets involved. The demonstration requires only commercially available materials and very little power to read results, making it a potentially attractive option for applications in low-resource settings. Biomedical engineers at Duke University have developed an entirely new approach to building point-of-care diagnostic devices that only use gravity to transport, mix and otherwise manipulate the liquid droplets involved. The demonstration requires only commercially available materials and very little power to read results, making it a potentially attractive option for applications in low-resource settings. "The elegance in this approach is all in its simplicity -- you can use whatever tools you happen to have to make it work," said Hamed Vahabi, a former postdoctoral researcher at Duke, who is now a lead analysis engineer at GE Hitachi. "You could theoretically even just use a handsaw and cut the channels needed for the test into a piece of wood." The study conducted in the laboratory of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke, appears online July 11 in the journal Device. There is no shortage of need for simple, easy-to-use, point-of-care devices. Many demonstrations and commercial devices seek to make diagnoses or measure important biomarkers using only a few drops of liquid with as little power and expertise required as possible. Their goal is to improve health care for the billions of people living in low-resource settings far from traditional hospitals and trained clinicians. All of these tests have the same basic requirements; they must move, mix and measure small droplets containing biological samples and the active ingredients that make measuring specific biomarkers possible. More expensive examples use tiny electrical pumps to drive these reactions. Others use the physics of liquids within microchannels (microfluidics) that create a sort of suction effect. This is the first demonstration that only uses gravity. Each approach offers uniquely useful abilities as well as drawbacks. "Most microfluidic devices need more than just capillary forces to operate," Chilkoti said. "This approach is much simpler and also allows very complex fluid paths to be deigned and operated, which is not easy or cheap to do with microfluidics." The new gravity-driven approach relies on a set of nine commercially available surface coatings that can tweak the wettability and slipperiness at any given point on the device. That is, they can adjust how much droplets flatten down into pancakes or remain spherical while making it easier or harder for them to slide down an incline. Used together in clever combinations, these surface coatings can create all the microfluidic elements needed in a point-of-care test. For example, if a given location is extremely slippery and a droplet is placed at an intersection where one side pulls liquid flat and the other pushes it into a ball, it will act like a pump and accelerate the droplet toward the former. "We came up with many different elements to control the motion, interaction, timing and sequence of multiple droplets in the device," Vahabi said. "All of these phenomena are well-known in the field, but nobody thought of using them to control the motion of droplets in a systematic way before." By combining these elements, the researchers created a prototype test to measure the levels of lactate dehydrogenase (LDH) in a sample of human serum. They carved channels within the test platform to create specific pathways for droplets to travel, each coated with a substance that stops the droplets from sticking along their journey. They also primed specific locations with dried reagents needed for the test, which are soaked up by droplets of simple buffer solution as they travel through. The whole maze-like test is then capped with a lid containing a couple of holes where the sample and buffer solution are dripped in. Once loaded, the test is placed inside a box-like device with a handle that turns the test 90 degrees to allow gravity to do its work. This device is also equipped with a simple LED and light detector that can quickly and easily detect the amount of blue, red, or green in the test results. This means that the researchers can tag three different biomarkers with different colors for various tests to measure. In the case of this prototype LDH test, the biomarker is tagged with a blue molecule. A simple microcontroller measures how deep of a blue hue the test results become and how quickly it changes color -- which indicates the amount and concentration of LDH in the sample -- to generate results. "We could eventually also use a smart phone down the line to measure results, but that's not something we explored in this specific paper," said Jason Liu, a PhD candidate in the Chilkoti lab. The demonstration provides a new approach for consideration when engineering inexpensive, low-power, point-of-care diagnostic devices. While the group plans to continue developing their idea, they also hope others will take notice and work on similar tests. "While a well-designed microfluidic system can be fully automated and easy-to-use by passive means, the timing of discrete steps is usually programmed into the design of the device itself, making modifications to protocol more difficult," added David Kinnamon, a PhD candidate in the Chilkoti group. "In this work, the user retains more control of the timing of steps while only modestly sacrificing ease-of-operation. Again, this is an advantage for more complex protocols." This work was supported by the National Institutes of Health (R01AI159992).

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