Arog Pharmaceuticals, Inc.

Ruxolitinib extinguished arrhythmias in three different types of mouse models, including one condition that's often resistant to treatment. Biotechs have been investigating the therapeutic potential of drugs called calcium/calmodulin-dependent protein kinase II inhibitors, or CaMKII inhibitors, for at least a decade. But while the drugs have shown some promise in preclinical and early-stage clinical trials, questions remain about whether they have deleterious off-target effects on the brain. Now, the results of a new study published June 21 in Science Translational Medicine by researchers from the University of Chicago and Johns Hopkins University may begin to put some of those concerns to rest. They also suggest that the cancer drug ruxolitinib, a JAK1/2 inhibitor commercialized by Novartis as Jakavi, could be a viable treatment against atrial fibrillation and a dangerous pediatric cardiac arrhythmia called catecholaminergic polymorphic ventricular tachycardia (CPVT). “Our study was able to show for the first time that you can actually block the ‘bad’ CaMKII in the heart and completely spare the brain version of CaMKII with a small molecule, so you get the benefits without the side effects,” first author Oscar Reyes Gaido, an M.D.-Ph.D. student in the Johns Hopkins lab of Mark Anderson, M.D., Ph.D., told Fierce Biotech Research in an interview. “And we found that ruxolitinib behaves that way—it doesn’t cross into the brain very well, so this could be a really good repurposing candidate.” While CaMKII, an enzyme, has some functions in the heart, experiments in animals have shown that it isn’t essential, Reyes Gaido and his team noted in their paper. On top of that, there’s increasingly abundant evidence that excessive CaMKII activity contributes to heart disease and arrhythmias, as the team explained in a January 2023 review article. There have been but a handful of attempts to develop a CaMKII inhibitor for heart disease, and so far, such drugs have failed to translate from preclinical models to humans. Scientists are only just learning how many different conditions may be precipitated by excess CaMKII activity, so it makes sense that innovation on the front hasn’t yet picked up. But there’s another reason for stifled progress, too: There are four different isoforms, or types, of CaMKII found throughout the body. Hitting the wrong one—or all of them—could cause serious harm. “They basically look identical, so it’s really challenging to inhibit one version without inhibiting all four,” Reyes Gaido explained. “That’s kept a lot of people from even trying.” Given the inherent difficulty of developing a new CaMKII inhibitor, the Anderson lab wondered whether any drugs already approved by the U.S. FDA might have activity against the molecule. Their proven safety profile would mean the toxicity hurdle had already been surmounted, and they could potentially be fast-tracked to clinical trials. “If we start with only molecules that are safe for humans, then you’ve completely eliminated that one deal breaker that all these other molecules have fallen to,” Reyes Gaido said. But first, the researchers would need a better way to visualize the effects of the drugs on the enzyme’s activity. To that end, Reyes Gaido developed what’s known as a reporter molecule that could enable the researchers to monitor CaMKII levels in cells. Using a jellyfish-derived protein called green fluorescent protein—one that emits green light, just as it sounds—he created CaMKII Activity Reporter, or CaMKAR. The reporter molecule is injected into the tissue being studied, where it glows bright green whenever CaMKII is activated. The team’s experiments showed CaMKAR to be far more sensitive to CaMKII levels than other biosensors used by the industry. It could detect CaMKII activity directly, rather than relying on proxy signals. That would be vital for figuring out which drugs were truly efficacious against CaMKII itself and weren’t instead targeting similar molecules, a problem that might explain why earlier inhibitors that seemed promising in preclinical studies failed to pan out in clinical trials. It would also lower the cost of high-throughput screening, as the researchers could draw conclusions from a smaller number of cells. Using CaMKAR, the researchers analyzed how 4,475 different FDA-approved drugs affected CaMKII levels in human heart cells. They found five: baricitinib, a JAK1/2 inhibitor commercialized by Lilly for rheumatoid arthritis as Olumiant; the CK2 inhibitor silmitasertib, from Senhwa Biosciences, which has orphan-drug status for biliary tract cancer; crenolanib, a tyrosine kinase inhibitor by Arog Pharmaceuticals that was fast-tracked by the FDA in 2017 for acute myeloid leukemia; Lilly’s breast cancer drug abemaciclib, trade name Verzenio; and ruxolitinib. Out of the five hits, ruxolitinib was the most potent CaMKII inhibitor. To see whether it had efficacy in the context of arrhythmia, the team first looked at whether it could hinder the enzyme in cells with a genetic mutation that caused CPVT. Seeing positive results, they moved to testing the drug in a mouse model of the same condition. Ten minutes after injecting the mice with ruxolitinib, CaMKII levels plunged and the arrhythmia was extinguished. “It was surprising how well this drug worked,” Reyes Gaido said. “We could see CaMKII activity go to basically zero in 10 minutes, which was quite striking.” The researchers saw similar results in two mouse models of acquired afib. Hyperglycemic mice with different forms of arrhythmia were given the same dose of ruxolitinib as the CPVT models. Ten minutes later, the arrhythmia could no longer be induced in one model and its frequency had fallen from 95% to 33% of heartbeats in the other. But did the benefits come at the cost of cognition? To find out, the researchers ran mice through various types of learning and memory tests after giving them a single dose of ruxolitinib. They also ran longer studies where mice received daily doses of the drug before being trained on how to get through a maze, which would show any impacts on long-term spatial memory formation. The treated mice performed just as well as the control animals. One concern going forward is that while ruxolitinib may not damage the brain, it does have known side effects including thrombocytopenia, a condition where blood platelets are too low. But for patients with conditions like CPVT—where as many as 30% of patients are resistant to treatment, and a full 31% die before reaching age 30—the benefits may outweigh the downsides. Editor's note: This story has been updated to clarify a comment from Oscar Reyes Gaido. 

精彩内容近日，东阳光药业启动一项III期临床，以评估苯磺酸克立福替尼片治疗FLT3-ITD突变的复发/难治急性髓系白血病(AML)患者的疗效和安全性。克立福替尼属于新一代、高特异性的FLT3抑制剂，国内同靶点获批药物主要有吉瑞替尼，该产品于2021年2月获批进口，2021年在中国城市实体药店终端的销售额超过5000万元。来源：中国药物临床试验登记与信息公示平台克立福替尼(HEC73543)是一款新一代、高特异性的FMS样酪氨酸激酶3(FLT3)抑制剂。FLT3通过与配体结合被激活，进而通过PI3K、RAS和STAT5等多种信号通路促进细胞存活、增殖和分化。东阳光药业最新启动的是一项随机、开放、挽救性化疗对照、多中心III期临床试验，旨在评估苯磺酸克立福替尼片治疗FLT3-ITD突变的复发/难治AML患者的疗效和安全性。东阳光药克立福替尼临床开展情况来源：米内网新版数据库急性髓系白血病(AML)是成年人最常见的白血病类型，而FLT3基因突变是AML患者最常见的基因改变和预后不良因素。国内已上市靶向FLT3的药物中，索拉非尼、舒尼替尼等属于第一代FLT3抑制剂，是非特异性的多靶点TKI抑制剂，单药治疗AML时疗效并不显著；吉瑞替尼则属于第二代FLT3抑制剂，具有更高的选择性和更强的抑制活性。2021年2月，安斯泰来的富马酸吉瑞替尼片获得附条件批准上市，成为国内首个获批用以治疗FLT3突变的AML靶向疗法。该产品于2020年11月被列入第三批临床急需境外新药名单，顺利获批后将进一步满足国内AML患者的临床治疗需求。近年来中国城市实体药店终端吉瑞替尼销售情况（单位：万元）来源：米内网中国城市实体药店终端竞争格局米内网数据显示，富马酸吉瑞替尼片2021年在中国城市实体药店终端的销售额超过5000万元，预测2022年将突破7000万元，同比增长约36%。部分在国内开展临床的靶向FLT3的药物来源：米内网中国药品临床试验公示库国内同靶点在研药物中，以多靶点的小分子抑制剂居多。从研发进展看，广东东阳光药业的克立福替尼、石药的SKLB1028、新基的Fedratinib、Arog/济莱安的Crenolanib、科文斯的AC220等多款新药均步入III期临床。资料来源：米内网数据库注：米内网中国城市实体药店终端竞争格局数据库是覆盖全国297个地市及以上城市实体药店（不含县乡村实体药店），对全品类进行连续监测的放大版城市实体药店数据库。上述销售额以产品在终端的平均零售价计算。数据统计截至10月24日，如有疏漏，欢迎指正！本文为原创稿件，转载请注明来源和作者，否则将追究侵权责任。投稿及报料请发邮件到872470254@qq.com稿件要求详询米内微信首页菜单栏商务及内容合作可联系QQ：412539092【分享、点赞、在看】点一点不失联哦

Dublin, Aug. 05, 2021 (GLOBE NEWSWIRE) -- The "Acute Myeloid Leukemia (AML)- Market Insight, Epidemiology and Market Forecast - 2030" report has been added to ResearchAndMarkets.com's offering. The total number of incident cases of Acute Myeloid Leukemia (AML) associated in 7MM countries was 41,715 in 2020. The Acute Myeloid Leukemia (AML) market report provides current treatment practices, emerging drugs, and their market share of the individual therapies, current and forecasted Acute Myeloid Leukemia (AML) symptoms market size from 2018 to 2030 segmented by seven major markets. The report also covers current Acute Myeloid Leukemia (AML) symptoms treatment practice/algorithm, market drivers, market barriers, and unmet medical needs to curate the best opportunities. It assesses the underlying potential of the market.Acute Myeloid Leukemia (AML) Drug ChaptersThe Acute Myeloid Leukemia (AML) report's drug chapter segment encloses the detailed analysis of Acute Myeloid Leukemia (AML) early-stage (Phase- I, II, and III) pipeline drugs. It also helps understand the Acute Myeloid Leukemia (AML) clinical trial details, expressive pharmacological action, agreements and collaborations, approval and patent details, advantages and disadvantages of each included drug, and the latest news and press releases.Acute Myeloid Leukemia (AML) Emerging DrugDevimistat (CPI-613): Rafael Pharmaceuticals Inc.Rafael Pharmaceutical's first-in-class clinical lead compound, CPI-613 (devimistat), targets enzymes involved in cancer cell energy metabolism and is located in the mitochondria of cancer cells. CPI-613 is being evaluated in multiple Phase I, I/II, II, and III clinical studies as a single agent and combined with standard drug therapies in patients diagnosed with advanced solid tumors or blood cancers. Enrolment is currently underway in a Phase III clinical trial in r/r AML.Crenolanib: Arog PharmaceuticalsCrenolanib besylate is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including AML, gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzimidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3 (FMS-like Tyrosine Kinase 3), PDGFR (Platelet-Derived Growth Factor Receptor), and PDGFR. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the 'DFG in' conformation motif.Acute Myeloid Leukemia (AML) Market OutlookThe report's Acute Myeloid Leukemia (AML) market outlook helps build a detailed comprehension of the historic, current, and forecasted Acute Myeloid Leukemia (AML) market trends by analyzing the impact of current therapies on the market, unmet needs, drivers and barriers, and demand for better technology.This segment gives a thorough detail of Acute Myeloid Leukemia (AML) market trend of each marketed drug and early-stage pipeline therapy by evaluating their impact based on the annual cost of therapy, inclusion and exclusion criteria's, mechanism of action, compliance rate, growing need of the market, increasing patient pool, covered patient segment, expected launch year, competition with other therapies, brand value, their impact on the market and view of the key opinion leaders. The calculated market data are presented with relevant tables and graphs to clearly view the market at first sight. Key Topics Covered: 1 Key Insights 2 Report Introduction 3 Acute Myeloid Leukemia (AML) Market Overview at a Glance 4 Executive Summary of Acute Myeloid Leukemia (AML) 5 Disease Background and Overview 6 Epidemiology and Patient Population 7 Organizations contributing towards Acute Myeloid Leukemia (AML) 8 Case Reports 9 Patient Journey 10 Marketed Therapies 11 Emerging Therapies 12 Other Promising Therapies 13 Acute Myeloid Leukemia (AML): Seven Major Market Analysis For more information about this report visit