ABCD2

A new scientific statement discusses rapid evaluation for transient ischemic attack (TIA) due to high risk of future stroke. Stroke symptoms that disappear in under an hour, known as a transient ischemic attack (TIA), need emergency assessment to help prevent a full-blown stroke, according to a new American Heart Association scientific statement published today in the Association's journal Stroke. The statement offers a standardized approach to evaluating people with suspected TIA, with guidance specifically for hospitals in rural areas that may not have access to advanced imaging or an on-site neurologist. TIA is a temporary blockage of blood flow to the brain. Each year, about 240,000 people in the U.S. experience a TIA, although this estimate may represent underreporting of TIA because symptoms tend to go away within an hour. While the TIA itself doesn't cause permanent damage, nearly 1 in 5 of those who have a TIA will have a full-blown stroke within three months after the TIA, almost half of which will happen within two days. For this reason, a TIA is more accurately described as a warning stroke rather than a "mini-stroke," as it's often called. TIA symptoms are the same as stroke symptoms, only temporary. They begin suddenly and may have any or all of these characteristics: The F.A.S.T. acronym for stroke symptoms can be used to identify a TIA: F Face drooping or numbness; A Arm weakness; S Speech difficulty; T Time to call 9-1-1, even if the symptoms go away. "Confidently diagnosing a TIA is difficult since most patients are back to normal function by the time they arrive at the emergency room," said Hardik P. Amin, M.D., chair of the scientific statement writing committee and associate professor of neurology and medical stroke director at Yale New Haven Hospital, St. Raphael Campus in New Haven, Connecticut. "There also is variability across the country in the workup that TIA patients may receive. This may be due to geographic factors, limited resources at health care centers or varying levels of comfort and experience among medical professionals." For example, Amin said, "Someone with a TIA who goes to an emergency room with limited resources may not get the same evaluation that they would at a certified stroke center. This statement was written with those emergency room physicians or internists in mind -- professionals in resource-limited areas who may not have immediate access to a vascular neurologist and must make challenging evaluation and treatment decisions." The statement also includes guidance to help health care professionals tell the difference between a TIA and a "TIA mimic" -- a condition that shares some signs with TIA but is due to other medical conditions such as low blood sugar, a seizure or a migraine. Symptoms of a TIA mimic tend to spread to other parts of the body and build in intensity over time. Who is at risk for a TIA? People with cardiovascular risk factors, such as high blood pressure, diabetes, obesity, high cholesterol and smoking, are at high risk for stroke and TIA. Other conditions that increase risk of a TIA include peripheral artery disease, atrial fibrillation, obstructive sleep apnea and coronary artery disease. In addition, a person who has had a prior stroke is at high risk for TIA. Which tests come first once in the emergency room? After assessing for symptoms and medical history, imaging of the blood vessels in the head and neck is an important first assessment. A non-contrast head CT should be done initially in the emergency department to rule out intracerebral hemorrhage and TIA mimics. CT angiography may be done as well to look for signs of narrowing in the arteries leading to the brain. Nearly half of people with TIA symptoms have narrowing of the large arteries that lead to the brain. A magnetic resonance imaging (MRI) scan is the preferred way to rule out brain injury (i.e., a stroke), ideally done within 24 hours of when symptoms began. About 40% of patients presenting in the ER with TIA symptoms will actually be diagnosed with a stroke based on MRI results. Some emergency rooms may not have access to an MRI scanner, and they may admit the patient to the hospital for MRI or transfer them to a center with rapid access to one. Blood work should be completed in the emergency department to rule out other conditions that may cause TIA-like symptoms, such as low blood sugar or infection, and to check for cardiovascular risk factors like diabetes and high cholesterol. Once TIA is diagnosed, a cardiac work-up is advised due to the potential for heart-related factors to cause a TIA. Ideally, this assessment is done in the emergency department, however, it could be coordinated as a follow-up visit with the appropriate specialist, preferably within a week of having a TIA. An electrocardiogram to assess heart rhythm is suggested to screen for atrial fibrillation, which is detected in up to 7% of people with a stroke or TIA. The American Heart Association recommends that long-term heart monitoring within six months of a TIA is reasonable if the initial evaluation suggests a heart rhythm-related issue as the cause of a TIA or stroke. Early neurology consultation, either in-person or via telemedicine, is associated with lower death rates after a TIA. If consultation isn't possible during the emergency visit, the statement suggests following up with a neurologist ideally within 48 hours but not longer than one week after a TIA, given the high risk of stroke in the days after a TIA. The statement cites research that about 43% of people who had an ischemic stroke (caused by a blood clot) had a TIA within the week before their stroke. Assessing stroke risk after TIA A rapid way to assess a patient's risk of future stroke after TIA is the 7-point ABCD2 score, which stratifies patients into low, medium and high risk based on Age, Blood pressure, Clinical features (symptoms), Duration of symptoms (less than or greater than 60 minutes) and Diabetes. A score of 0-3 indicates low risk, 4-5 is moderate risk and 6-7 is high risk. Patients with moderate to high ABCD2 scores may be considered for hospitalization. Collaboration among emergency room professionals, neurologists and primary care professionals is critical to ensure the patient receives a comprehensive evaluation and a well-communicated outpatient plan for future stroke prevention at discharge. "Incorporating these steps for people with suspected TIA may help identify which patients would benefit from hospital admission, versus those who might be safely discharged from the emergency room with close follow-up," Amin said. "This guidance empowers physicians at both rural and urban academic settings with information to help reduce the risk of future stroke." This scientific statement was prepared by the volunteer writing group on behalf of the American Heart Association's Emergency Neurovascular Care Committee of the Stroke Council and the Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists, and it is endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS). American Heart Association scientific statements promote greater awareness about cardiovascular diseases and stroke issues and help facilitate informed health care decisions. Scientific statements outline what is currently known about a topic and what areas need additional research. While scientific statements inform the development of guidelines, they do not make treatment recommendations. American Heart Association guidelines provide the Association's official clinical practice recommendations. Co-authors are Vice Chair Tracy E. Madsen, M.D., Ph.D.; Dawn M. Bravata, M.D.; Charles R. Wira, M.D.; S. Claiborne Johnston, M.D., Ph.D.; Susan Ashcraft, D.N.P.; Tamika Marquitta Burrus, M.D.; Peter David Panagos, M.D.; Max Wintermark, M.D., M.A.S.; and

▎药明康德内容团队编辑近期，又有多种创新药物取得了早期进展，其中包括双G蛋白偶联受体激动剂、肿瘤浸润淋巴细胞（TIL）疗法、质粒DNA（pDNA）皮肤癌疫苗等新颖的疗法类型，值得关注。在今天这篇文章里，药明康德内容团队将结合公开资料，与读者分享过去一周中部分创新药物的早期临床进展。ART27.13：启动1b期第4个队列的招募开发机构：Artelo Biosciences疗法类型：双G蛋白偶联受体激动剂适应症：癌症相关厌食症和体重减轻Artelo Biosciences宣布，在研疗法ART27.13的癌症食欲恢复研究（CAReS）已完成前3个队列的入组，并将启动第4个队列的入组，从而完成该1b期临床试验的第一阶段。ART27.13是一种被认为是针对大麻素受体CB1和CB2的外周选择性双G蛋白偶联受体激动剂，具有增加患者食欲和食物摄入量的潜力。ART27.13最初由阿斯利康公司开发，目前已在5个1期临床研究（共包括200多名受试者）中进行探索，结果显示，健康受试者的体重在统计学上显著增加，且呈剂量依赖性。更重要的是，这种体重的变化与体液潴留无关，药物的分布可以在影响全身代谢的同时将中枢神经系统介导的毒性降至最低。癌症厌食症和恶病质综合征（CACS）影响了超过60%的晚期癌症患者。目前，尚无FDA、MHRA或EMA批准的CACS疗法，且2020 ASCO指南不建议将特定的药物干预作为护理标准。Artelo Biosciences正在推进ART27.13作为患有厌食症和体重减轻的癌症患者的支持性护理疗法，有望填补这一空白领域。MDK-703：首个临床试验开始给药开发机构：Medikine疗法类型：IL-7类似物适应症：实体瘤Medikine宣布，其开发的半衰期延长的白细胞介素7（IL-7）类似物MDK-703将在健康志愿者中进行研究，用于评估以安慰剂为对照，肌肉注射剂量递增的MDK-703单药的安全性、耐受性、药代动力学和药效学。目前，该临床试验已开始给药，预计将在2022年第四季度获得最初的试验结果。在1期临床试验完成后，Medikine将探索MDK-703在实体肿瘤中的效果。IL-7是一种对T细胞的发育和维持至关重要的细胞因子，包括增强记忆T细胞的生成、功能和存活。在肿瘤治疗中，单独使用IL-7或与其它免疫疗法结合使用均能提高药物临床响应的速度、深度和持久性。MDK-703是一种免疫球蛋白Fc片段-肽融合蛋白，含有使用Medikine平台技术发现的IL-7 PEPTIKINE（细胞因子的肽模拟物）。MDK-703比其模拟的IL-7细胞因子小得多，在结构上与天然的细胞因子无关。因此，除了具有IL-7的抗肿瘤特性外，MDK-703还具有免疫原性低，易于结合靶点和其他药理学特征的特点。此外，MDK-703不会产生中和天然IL-7的抗药物抗体（ADA），这是之前在IL-7制剂应用于人体试验中时经常会观察到的问题。ITI-3000：完成首例患者给药开发机构：Immunomic Therapeutics疗法类型：pDNA疫苗适应症：默克尔细胞癌（MCC）Immunomic Therapeutics宣布，其质粒DNA（pDNA）疫苗ITI-3000已开启针对MCC的1期临床试验并完成了首例患者给药。这项单中心研究正在华盛顿大学医学院和华盛顿州西雅图的弗雷德哈钦森癌症中心进行，旨在评估ITI-3000在已接受过手术的MCC患者中的安全性、耐受性和免疫原性。MCC是一种罕见的具有侵袭性的皮肤癌，通常由默克尔细胞多瘤病毒（MCPyV）引起。ITI-3000借助了该公司的研究通用细胞内靶向表达（UNITE）平台，将MCPyV大T抗原（LT）突变序列融合到了编码LAMP-1蛋白的基因序列中。这种溶酶体靶向技术已被证明能够增强抗原呈递并平衡免疫反应，尤其是ITI-3000激活的体内抗原特异性CD4+T细胞。POLB 001：开启临床试验开发机构：Poolbeg Pharma疗法类型：小分子免疫调节剂适应症：严重流感 Poolbeg Pharma宣布，已获得伦理和主管当局的批准，开始其开发的小分子免疫调节剂POLB 001的人体临床试验，旨在解决严重流感治疗领域中未被满足的需求。该临床试验活动将于2022年7月22日正式开始，旨在评估POLB 001在抑制脂多糖（LPS）引起的严重免疫反应方面的疗效。POLB 001是一种p38 MAPK抑制剂，可以选择性地抑制病毒感染（如流感）中过度的炎症反应，同时保持必要的免疫功能以对抗感染。这与其他类固醇类的免疫调节方法形成鲜明对比，其他类固醇类药物会同时影响有益的和破坏性的免疫反应。VK0214：重启临床试验开发机构：Viking Therapeutics疗法类型：小分子甲状腺激素β受体（TRβ）激动剂适应症：X连锁肾上腺脑白质营养不良（X-ALD）  Viking Therapeutics宣布，在提交了其开发的小分子TRβ激动剂VK0214未显示出遗传毒性的证据后，FDA批准其重启临床试验，预计将在未来几周内恢复入组。该临床试验是一项针对患有肾上腺脊髓神经病（AMN）成年男性患者的多中心、随机、双盲、安慰剂对照研究，旨在评估VK0214的安全性和耐受性。X-ALD是一种罕见的致命代谢性疾病，由ABCD1基因突变引起，这种突变会导致肾上腺脑白质营养不良蛋白（ALDP）功能障碍。ALDP是一种重要的过氧化物酶转运体，当其功能发生障碍会阻止患者有效代谢某些脂肪酸，而这些脂肪酸的累积会导致大脑和神经细胞周围的保护屏障破裂（即脱髓鞘），进而引发认知障碍、运动能力下降，甚至死亡。AMN是X-ALD最常见的形式。目前，X-ALD尚无获批的治疗方法。VK0214是一种新型的口服小分子TRβ激动剂，已被FDA授予治疗X-ALD的孤儿药资格。临床前研究表明，TRβ可以调节ABCD2相关基因的表达，ABCD2能够编码一种称为肾上腺脑白质营养不良相关蛋白（ADLRP）的代偿转运体，通过增加ABCD2表达可以使特定脂肪酸水平恢复正常。OBX-115：IND申请获FDA批准开发机构：MD安德森癌症中心和Obsidian Therapeutics疗法类型：TIL疗法适应症：黑色素瘤 MD安德森癌症中心和Obsidian Therapeutics共同宣布FDA批准了OBX-115的IND申请，可开启1期临床试验。这项单臂、开放标签的1期研究将评估OBX-115单药治疗复发性的或此前接受过抗PD-1抗体疗法无效的转移性黑色素瘤成人患者的安全性和初步疗效。OBX-115是一种新型的经过工程改造的TIL疗法，附着了经过调节的膜结合IL-15，使治疗过程无需再伴随IL-2这种毒性较强的治疗。临床前数据表明，与未经工程改造的TIL相比，OBX-115的持久性和有效性均得到了改善，有潜力改善患有不同类型实体瘤的患者的临床结局。BLB-201：完成首例患者给药开发机构：Blue Lake Biotechnology疗法类型：呼吸道合胞病毒（RSV）疫苗适应症：预防老年人（>60岁）和儿科人群（<2年）的RSV相关急性疾病Blue Lake Biotechnology宣布完成了其鼻内给药的RSV疫苗BLB-201在1期临床试验中的首次给药。RSV是一种常见的高传染性呼吸道病毒，也是引起急性呼吸道疾病的主要原因之一，每年感染全球超过6400万人。尽管对于大多数人来说，RSV引起的症状类似于普通感冒，但对于婴儿、免疫功能低下者、患有慢性心脏疾病或肺部疾病者以及老年人来说，RSV可能会导致严重的疾病，甚至危及生命。此外，RSV会重复感染。目前，尚无针对RSV的预防性疫苗或抗病毒治疗获批。BLB-201是一种RSV候选疫苗，已获得FDA的快速通道资格，用于预防老年人（>60岁）和儿科人群（<2年）的RSV相关急性疾病。BLB-201的主要活性成分是表达RSV F蛋白的PIV5减毒株，并使用专有的PIV5载体，可以通过鼻腔给药诱导体液免疫和细胞免疫。这种给药方式可以提高儿科患者及对针头害怕的患者的接受度。临床前研究结果显示，BLB-201在各类动物模型中均能对RSV引起的感染具有保护作用。期待这些疗法在未来取得积极成果，早日为更多患者带来更多希望！参考资料：[1] Artelo Biosciences Completes Enrollment of the First Three Cohorts in its CAReS Study Evaluating ART27.13 for the Treatment of Cancer-Related Anorexia and Weight Loss. Retrieved July 19, 2022，from https://ir.artelobio.com/news-events/press-releases/detail/88/artelo-biosciences-completes-enrollment-of-the-first-three[2] Medikine Initiates First Clinical Trial of its Lead Program, an Interleukin-7 Mimetic, Under Management Team with Expertise in Next-Generation Cytokine Drug Discovery and Development. Retrieived July 19, 2022, from https://www.medikine.com/press-releases/medikine-initiates-first-clinical-trial-of-its-lead-program-an-interleukin-7-mimetic[3] Immunomic Therapeutics Announces First Patient Dosed in Phase I Clinical Trial of ITI-3000 pDNA Vaccine for the Treatment of Merkel Cell Carcinoma. Retrieived July 20, 2022, from https://www.immunomix.com/immunomic-therapeutics-announces-first-patient-dosed-in-phase-i-clinical-trial-of-iti-3000-pdna-vaccine-for-the-treatment-of-merkel-cell-carcinoma/[4] Major milestone reached as POLB 001 human challenge clinical trial ready to commence. Retrieived July 20, 2022, from https://polaris.brighterir.com/public/poolbeg_pharma/news/rns_widget_investors/story/xl85g9w[5] Viking Therapeutics Announces FDA Has Lifted Clinical Hold on Phase 1b Trial of VK0214 in Patients with X-ALD. Retrieived July 19, 2022, from http://ir.vikingtherapeutics.com/2022-07-19-Viking-Therapeutics-Announces-FDA-Has-Lifted-Clinical-Hold-on-Phase-1b-Trial-of-VK0214-in-Patients-with-X-ALD[6] MD Anderson and Obsidian Therapeutics announce FDA Clearance of IND application for novel TIL therapy OBX-115. Retrieived July 21, 2022, from https://obsidiantx.com/news-releases/md-anderson-and-obsidian-therapeutics-announce-fda-clearance-of-ind-application-for-novel-til-therapy-obx-115/[7] Blue Lake Biotechnology Announces First Participant Dosed in a Phase 1 Clinical Trial of Its BLB-201 Intranasal RSV Vaccine. Retrieived July 21, 2022, from https://www.biospace.com/article/releases/blue-lake-biotechnology-announces-first-participant-dosed-in-a-phase-1-clinical-trial-of-its-blb-201-intranasal-rsv-vaccine/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

Study Enrollment and Dosing to Resume SAN DIEGO, July 19, 2022 /PRNewswire/ -- Viking Therapeutics, Inc. (Viking) (NASDAQ: VKTX), a clinical-stage biopharmaceutical company focused on the development of novel therapies for metabolic and endocrine disorders, today announced that the FDA has lifted the clinical hold placed on the clinical trial of VK0214 in patients with X-linked adrenoleukodystrophy (X-ALD). As a result, the company expects to resume study enrollment in the coming weeks. The FDA lifted the clinical hold following its review of results from an in vivo genotoxicity study that it had requested due to the study being conducted with multiple doses in patients. Viking had planned to conduct this study prior to Phase 2 but accelerated its execution based on FDA's request. The study was completed and the results submitted to the Agency in the second quarter. The results showed no evidence of genotoxicity following exposure to VK0214. The company does not believe that the long-term development timeline for VK0214 has been significantly impacted by the temporary clinical hold. "We look forward to resuming study activities and working to complete patient enrollment as quickly as possible," said Brian Lian, Ph.D., chief executive officer of Viking Therapeutics. "We are confident in the overall safety and potential efficacy profile of VK0214 to date, and are eager to continue its advancement as a potential disease modifying treatment for patients with X-ALD." The Phase 1b study of VK0214 is designed to enroll patients with the adrenomyeloneuropathy (AMN) form of X-ALD. AMN is the most common form of X-ALD, affecting approximately 50% of patients. The trial is a multi-center, randomized, double-blind, placebo-controlled study in adult male patients with AMN. The primary objectives of the study are to evaluate the safety and tolerability of VK0214 administered once-daily over a 28-day dosing period. The study also includes an exploratory assessment of the impact of VK0214 on plasma levels of very long chain fatty acids (VLCFAs), as well as an evaluation of the pharmacokinetics of VK0214 in these patients. VK0214 is a novel, orally available small molecule thyroid hormone beta receptor (TRβ) agonist that has been granted orphan drug designation by the FDA for the treatment of X-ALD. Results from a successful Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects showed that VK0214 demonstrated encouraging safety and tolerability, as well as predictable pharmacokinetics. In addition, subjects who received VK0214 experienced reductions in low-density lipoprotein cholesterol (LDL-C), triglycerides, and apolipoprotein B following 14 days of treatment. About X-ALD X-ALD is a rare and often fatal metabolic disorder characterized by a breakdown in the protective barriers surrounding brain and nerve cells; a process known as demyelination. The disease, for which there is no approved treatment, is caused by mutations in the gene for a peroxisomal transporter of VLCFAs, known as ABCD1. These mutations lead to dysfunction of the adrenoleukodystrophy protein (ALDP), an important peroxisomal transporter, which prevents patients from efficiently metabolizing VLCFAs. The resulting accumulation of VLCFAs, which is believed to contribute to the onset and progression of the disease, can trigger demyelination of nerve cells, resulting in cognitive impairment, motor skill deterioration, and even death. X-ALD is estimated to occur in approximately 1 in 17,000 births. The thyroid beta receptor is known to regulate expression of a related gene called ABCD2, which encodes a compensatory transporter called the adrenoleukodystrophy related protein (ADLRP). Research in various preclinical disease models has shown that increasing ABCD2 expression can result in normalization of VLCFA levels. About Viking Therapeutics, Inc. Viking Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel first-in-class or best-in-class therapies for the treatment of metabolic and endocrine disorders. Viking's research and development activities leverage its expertise in metabolism to develop innovative therapeutics designed to improve patients' lives. The company's clinical programs include VK2809, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the treatment of lipid and metabolic disorders, which is currently being evaluated in a Phase 2b study for the treatment of biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis. In a Phase 2a trial for the treatment of non-alcoholic fatty liver disease (NAFLD) and elevated LDL-C, patients who received VK2809 demonstrated statistically significant reductions in LDL-C and liver fat content compared with patients who received placebo. The company is also developing VK2735, a novel dual agonist of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders. VK2735 is currently being evaluated in a Phase 1 clinical trial. The company's third clinical compound is VK0214, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the potential treatment of X-linked adrenoleukodystrophy (X-ALD). VK0214 is currently being evaluated in a Phase 1b clinical trial in patients with the adrenomyeloneuropathy (AMN) form of X-ALD. The company holds exclusive worldwide rights to a portfolio of five therapeutic programs, including VK2809 and VK0214, which are based on small molecules licensed from Ligand Pharmaceuticals Incorporated. For more information about Viking Therapeutics, please visit . Follow Viking on Twitter @Viking_VKTX. Forward-Looking Statements This press release contains forward-looking statements regarding Viking Therapeutics, Inc., under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, including statements about Viking's expectations regarding its clinical and preclinical development programs. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: risks associated with the success, cost and timing of Viking's product candidate development activities and clinical trials, including those for VK2809, VK2735, VK0214, and the company's other incretin receptor agonists; risks that prior clinical and preclinical results may not be replicated; risks regarding regulatory requirements; and other risks that are described in Viking's most recent periodic reports filed with the Securities and Exchange Commission, including Viking's Annual Report on Form 10-K for the year ended December 31, 2021, and subsequent Quarterly Reports on Form 10-Q, including the risk factors set forth in those filings. These forward-looking statements speak only as of the date hereof. Viking disclaims any obligation to update these forward-looking statements except as required by law. SOURCE Viking Therapeutics, Inc.