Cure JM线上青少年肌炎新药物研讨会主要内容

New Drugs for Juvenile Myositis Symposium

          青少年肌炎新药研讨会(会议主要内容)

Summary by Cure JM’s Chief Scientific Officer, Andrew Heaton, PhD.

 Cure JM’s首席科学官Andrew Heaton博士汇总

The Cure JM Foundation and the Cure JM Center of Excellence at Duke University co-hosted a virtual symposium, New Drugs for Juvenile Myositis, on October 17, 2020. The core mission of the foundation is to foster research that leads to better treatments and ultimately a cure for Juvenile Myositis (JM). As JM is a rare pediatric auto-immune disease it suffers from a paucity of drugs that have a specific label claim. To date, the treatment of JM has relied on the use of off-label drugs as part ofconsensus treatment protocols. The consensus treatment protocols are based on years of different treatments and concomitant research by the global pediatric rheumatology community. The diligent research into JM has helped uncover genetic markers that are linked to a JM predisposition and the definition and delineation of different disease phenotypes. The complexity of the drivers of JM has hindered the development of validated in vitro and in vivo models of the disease. The drugs used to treat JM are therefore largely based on the migration of drugs prescribed for other indications. As the JM research community uncovers more data on the underlying pathogenesis and etiology of the disease, the process of migrating drugs is being significantly improved.

Cure JM基金会和杜克大学治疗 Cure JM英才中心于2020年10月17日共同主办了一次线上青少年肌炎新药物研讨会。 该基金会的核心使命是促进更好的治疗方案的研究，并最终治愈青少年肌炎(JM)。 由于JM是一种罕见的儿科自身免疫性疾病，它缺乏针对性的特效药物。 迄今为止，JM的治疗依赖于使用其它JM标签外药物作为共识治疗方案的一部分。共识的治疗方案是基于全球儿科风湿病多年的不同治疗和相关的研究。 对JM的细致研究有助于发现与JM易感相关的遗传标记和不同疾病表型的定义和描述。 JM驱动因素的复杂性阻碍了该疾病的体外和体内验证模型的开发。 因此，用于治疗JM的药物在很大程度上是基于用于其他适应症的药物的迁移。 随着JM研究发现更多关于该疾病潜在发病机制和病因的数据，药物迁移的过程正在显著改善。

The symposium’s focus was on drugs that are either in clinical studies for JM, or there are increasingly compelling data sets to suggest their utility in treating JM. The symposium was structured to define: different druggable targets in JM, up to date examples of drugs in JM clinical trials, and drugs that may enter JM clinical trials within the next few years.

研讨会的重点是JM的临床研究中的药物，或者越来越有说服力的数据集来表明它们在治疗JM中有效的药物。 研讨会的结构是为了定义：JM中不同的可药物靶点，JM临床试验中药物的最新例子，以及可能在未来几年内进入JM临床试验的药物。

The initial focus of the symposium was a broad discussion on JM presented by Jeffrey Dvergsten, MD, of Duke University’s Children’s Health Center. Dr. Dvegsten’s elegant and detailed presentation set the scene for the symposium, detailing the current understanding of JM pathogenesis, the role of the innate and adaptive immune systems in pathogeneses, the rationale for the current consensus treatments and finally, the exciting future of new potential drug targets and the underlying science behind these new targets.

研讨会的最初焦点是杜克大学儿童健康中心的Jeffrey Dvergsten博士对JM的广泛讨论。Dvegsten博士简洁而详细的演讲为研讨会做了铺垫，详细介绍了目前对JM发病机制的理解、先天免疫系统和适应性免疫系统在病因中的作用、当前共识治疗的基本原理，以及新的潜在药物靶点的令人兴奋的未来以及这些新靶点背后的潜在基础科学。

One of the key drivers of JM is the interferon signal transduction. While Dr. Dvergsten’s presentation covered this aspect of the disease and its potential as a drug target for JM, the importance of the interferon signal mechanism was highlighted in a more detailed presentation by John O’Shea, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH). Dr. O’Shea, gave an elegant and detailed description of this highly complex signal transduction mechanism, detailing the number of different points on the pathway that are currently being targeted or are potential targets for future discovery programs.

干扰素信号转导是JM的关键驱动因素之一。Dvergsten博士的报告涵盖了该疾病的这一方面及其作为JM药物靶点的潜力，同时美国国立卫生研究院(NIH)关节炎、肌肉骨骼和皮肤病研究所（NIAMS）的John O'Shea博士更详细的介绍中强调了干扰素信号机制的重要性。O'Shea博士对这一高度复杂的信号转导机制进行了简洁而详细的描述，详细描述了路径上目前正在被靶向或是未来发现程序潜在目标的通路上的不同点的数量。

Following Dr. O’Shea, Hanna Kim, MD, MS, of NIAMS at the NIH, presented data on the JAK inhibitor, baractitinib, a class of drug that targets the interferon pathway. While Dr. Kim’s study was only on four patients, the data presented demonstrated considerable promise for JAK drugs in JM. Dr. Kim presented data on the four patients that had an early and sustained decrease in physician and patient global activity score and a notable improvement in strength and skin activity. Significantly, Dr. Kim reported that patients were able to decrease other immunosuppressive medications. The JM community is eagerly anticipating the next larger trial of baracitinb in JM patients.

继O'Shea博士之后，NIH NIAMS的Hanna Kim医学博士、医学硕士介绍了JAK抑制剂baractinib的数据，baractinib是一类针对干扰素途径的药物。虽然Kim博士的研究仅针对四名患者，但所提供的数据显示，JAK药物在JM的应用前景可观。Kim博士介绍了四名患者的数据，这些患者在早期和持续地降低了医生和病人的全球活动评分，力量和皮肤活动显著改善。值得注意的是，金博士报告说，患者能够减少其他免疫抑制药物。JM社区热切期待着在JM患者中进行下一个更大规模的baracitinb试验。

Another target within the interferon pathway is the SOCS1. This suppressor of cytokine signaling data was presented by Charlly Kao, PhD, of the Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP). Dr. Kao presented some encouraging early-stage data on kinase inhibitory region peptide mimetic. The initial work on this peptide mimetic came out of the University of Florida. Dr. Kao presented their detailed background data comprising significant resolution of skin lesions in an in vivo lupus-prone mouse model. Dr. Kao also presented further compelling data in a novel imiquinoid induced murine psoriasis model, as well as equine uveitis model. CHOP plans to take this exciting drug from animal models into the clinic.

干扰素途径中的另一个靶点是SOCS1。 这种抑制细胞因子信号的数据是由费城儿童医院应用基因组学中心(CHOP)的CharlyKao博士提供的。 Kao博士提出了一些令人鼓舞的早期数据激酶抑制区域肽模拟。 关于这一肽模拟的最初工作来自佛罗里达大学。 Kao博士介绍了他们的详细背景数据，包括在体内狼疮易发小鼠模型中皮肤病变的显著分辨率。 Kao博士还在一种新的咪唑啉诱导的小鼠银屑病模型以及马葡萄膜炎模型中提供了进一步的令人信服的数据。 CHOP计划将这种令人兴奋的药物从动物模型中带入临床。

The symposium shifted focus from interferon pathway targets to drug treatments. The first presentation was from Rodolfo Curiel, MD, FACP, FACR, of Medical Faculty Associates at The George Washington University. Dr. Curiel is studying the human fusion protein abatacept in Juvenile Dermatomyositis (JDM) patients. Dr. Curiel detailed the mechanism of action of abatacept, and the compelling data that has already been acquired on this drug in Adult Dermatomyositis (DM). The data in Adult DM included significant improvement in core set measures at three and six months, patient global activity, and extramuscular global activity. Dr. Curiel detailed the inclusion and exclusion criteria for the JDM clinical trial, highlighting that the trial requires only one more patient to enroll to finalize the study and allow for a full data analysis in JDM.

研讨会将焦点从干扰素途径转移到药物治疗上。第一份报告来自乔治华盛顿大学医学院联合会的Rodolfo Curiel（医学博士、美国内科医师学会会员、美国放射学学会会员）。Curiel博士正在研究青少年皮肌炎（JDM）患者的人类融合蛋白Abatacept。Curiel博士详细介绍了Abatacept的作用机制，以及在成人皮肌炎（DM）中已经获得的令人信服的数据。成年皮肌炎患者的数据包括三个月和六个月时核心集测量值，患者的整体活动和肌肉外的整体活动均显著改善。Curiel博士详细介绍了JDM临床试验的入选标准和排除标准，强调该试验只需要再登记一名患者即可完成研究，并允许在JDM中进行全面的数据分析。

Calcinosis is often associated with JDM and has been associated with worse physical function. Adam Schiffenbauer, MD, of the National Institute of Environmental Health Sciences at the NIH, presented data on a trial of sodium thiosulfate in JDM patients with calcinosis. Dr. Schiffenbauer detailed the issues around assessing and quantifying calcinosis, a requirement to quantify the effect of a drug targeting calcinosis. Further discussion compared and contrasted a number of drugs that have been used to treat calcinosis in JDM patients, setting the scene for the comparative advantage of the sodium thiosulfate trial. Dr. Schiffenbauer detailed the multiple mechanisms by which sodium thiosulfate could work and detailed the inclusion and exclusion criteria for the trial. Like the abatacept trial, the current trial has not completed enrollment, which is required to lock the data sets and complete the analyses to determine the efficacy of sodium thiosulfate in JDM patients with calcinosis.

钙质沉着症常与JDM相关，并与较差的身体功能有关。美国国立卫生研究院国家环境卫生科学研究所的Adam Schiffenbauer博士介绍了一项在JDM患者中应用硫代硫酸钠治疗钙质沉着症的试验数据。Schiffenbauer博士详细介绍了有关评估和量化钙质沉着的问题，这是一种量化针对钙质沉着的药物效果的要求。进一步的讨论比较和对比了许多已用于治疗JDM患者钙质沉着症的药物，为硫代硫酸钠试验的比较优势奠定了基础。Schiffenbauer博士详细阐述了硫代硫酸钠的多种作用机制，并详细说明了试验的纳入和排除标准。与abatacept试验一样，目前的试验还没有完成登记，这需要锁定数据集并完成分析，以确定硫代硫酸钠对JDM钙质沉着患者的疗效。

Corticosteroids are a class of drug that underpin many of the consensus treatment protocols for JDM. Eric Hoffman, PhD, Vice President of Research, ReveraGen, gave a finely detailed history on the steroid replacement he has been taking through clinical trials. The drug ReveraGen is developing, vamorolone, is a potential significant replacement for the standard of care steroids used to treat JDM. Dr. Hoffman detailed that standard of care steroids have two mechanisms of action: transactivation and transrepression. The former leads to an array of unwanted side effects and the latter to the efficacy of steroids. Vamorolone has been demonstrated to have significantly less transactivation while retaining similar levels of transrepression, which is ideal for a steroid replacement. Dr. Hoffman detailed the in vitro and in vivo work that supported the switching of the transactivation. Vamorolone is currently in a licensure trial for Duchenne’s Muscular Dystrophy and is expected to get approval later in 2021. The ReveraGen, Duke and Cure JM team are now looking at how to start a clinical trial of this exciting drug in a JDM cohort of patients.

皮质类固醇是一类药物，是许多JDM治疗方案的基础。Eric Hoffman博士，ReveraGen公司的副总裁，详细的介绍了他在临床试验中服用的类固醇替代品发展历史。ReveraGen公司正在开发的药物，vamorolone，是治疗JDM的标准护理类固醇的潜在重要替代品。Hoffman博士详细说明了护理标准类固醇有两种作用机制：反式激活和转抑制。前者会导致一系列不必要的副作用，而后者会导致类固醇的疗效。vamorolone已被证明具有明显较少的反式激活，同时保留类似水平的转抑制，这是类固醇替代品的理想选择。Hoffman博士详细介绍了支持反式激活转换的体外和体内工作。vamorolone目前正在进行杜氏肌营养不良症的许可试验，预计将在2021年晚些时候获得批准。Reveagen公司，Duke和Cure JM团队正在研究如何在JDM患者队列中开始这种激动人心的药物的临床试验。

The final presentation for the day was on a novel drug, lenabasum, which targets the endocannabinoid system. Quin Dinh, MD, Vice President, Head of Medical Affairs, Corbus Pharmaceuticals, gave an elegant, detailed discussion on the cannabinoid system, including validation of activating the CB2 receptor, that is expressed in activated immune cells. The discussion detailed the extensive use of well-engineered models including CB1 and CB2 knock-out mouse models. These models validated that CB2 modulates inflammation and fibrosis. Dr. Dinh detailed the exciting results to date in several studies in adults of lenabasum, including its significant reduction of skin disease in patients that were refractory to other immunosuppressive agents.

当天的最后一场报告是关于一种新型药物lenabasum，它的靶点是内源性大麻素系统。Corbus Pharmaceuticals公司副总裁兼医疗事务主管Quin Dinh博士就大麻素系统进行了简洁而详细的讨论，包括验证激活免疫细胞中表达的CB2受体。讨论详细说明了工程模型CB1和CB2敲除小鼠模型的广泛应用。这些模型证实了CB2调节炎症和纤维化。Dinh博士详细介绍了迄今为止在成人lenabasum的一些研究中取得的令人兴奋的结果，包括它显著减少了对其他免疫抑制剂无效的患者的皮肤病。

The symposium wrapped up with a thought-provoking talk by Kaveh Ardalan, MD, of Duke University’s Duke Children’s Health Center. Dr. Ardalan discussed looking beyond traditional biomarkers of success in a clinical trial. He emphasized treating the whole patient and underlined that the mental health of patients and their families are very valid determinants of the success of a clinical trial.

这次研讨会结束时，杜克大学儿童健康中心的医学博士Kaveh Ardalan发表了一篇发人深省的演讲。 Ardalan博士讨论了在临床试验中超越传统的成功生物标志物的问题。 他强调完整治疗病人，并强调病人及其家属的心理健康是临床试验成功的非常有效的决定因素。