Emavusertib

关注并星标CPHI制药在线 IRAK是指在前炎症细胞因子白细胞介素-1（IL-1）诱导下能和白细胞介素-1受体（IL-1R）相结合的一类丝/苏氨酸激酶，家族成员包括IRAK1、IRAK2、IRAK4和IRAKM。其中IRAK1、IRAK4在TLR介导的信号通路中起正向调节作用，IRAK2、IRAKM在TLR介导的信号通路中起负向调节作用。 关于IRAK4 IRAK4，全称白细胞介素1受体相关激酶4，是TLR/IL-1R介导的炎症信号转导通路下游的关键因子。TLRs /IL-1R与配体结合以后，募集MyD88分子，MyD88通过其N末端的死亡结构域进一步募集IRAK4， IRAK4通过自身磷酸化反应，发挥激酶活性，激活其底物IRAK1， IRAK1 随即磷酸化，进而活化下游丝氨酸/苏氨酸激酶TAK1，激活NF-κB及MAPK信号通路，随后产生促炎细胞因子、趋化因子和破坏性酶，最终导致产生炎症反应，介导先天性免疫。 此外，研究还发现 IRAK4过表达可以增强LPS诱导的NADPH氧化酶活性，诱导下游的p38 MAPK 的信号转导（p38 MAPK通路是在转录和翻译阶段促炎细胞因子生物合成的关键调节因子）。 IRAK4靶向药进展 IRAK4被认为是炎症性疾病和自身免疫性疾病药物开发的潜力靶点，目前已有多款靶向药进入临床试验阶段，详见下表。在研IRAK4靶向药药物类型多样，除了小分子化药（如TQH3821、MY004567、BAY1834845等），还包括PROTAC降解剂（如GS-6791、BGB-45035等）。 研发进度上，在研IRAK4靶向药最快进入2期临床。其中KT-474 是一种潜在首 创IRAK4降解剂，被开发用于治疗TLR/IL-1R驱动的免疫炎症性疾病，如特应性皮炎、化脓性汗腺炎、类风湿性关节炎等。与靶向单一细胞因子的单克隆抗体相比，KT-474旨在更广泛地阻断TLR/IL-1R介导的炎症，通过消除 IRAK4的激酶和支架功能来实现通路抑制。 2020年7月，赛诺菲与Kymera Therapeutics达成多项目战略合作，联合开发和商业化IRAK4靶向蛋白降解疗法。2023年11月，Kymera Therapeutics宣布KT-474的1期临床试验取得积极结果：KT-474对缓解化脓性汗腺炎(HS)和特应性皮炎(AD)患者的疾病负担和症状产生了积极的作用，且在中度至重度疾病患者中观察到了全身抗炎作用。 MY004567是国内首家申报临床的IRAK4抑制剂，临床前研究显示其与同靶点临床在研药物相比，药代行为更好、药效更优。目前，MY004567针对类风湿关节炎的2期临床试验正在进行中。 BGB-45035等处于1期临床，它是百济神州基于其CDAC平台上研发的一款靶向IRAK4的蛋白降解剂。公开资料显示，BGB-45035有潜力诱导更深、更快的IRAK4降解，并比其他同类药物具有更强的细胞因子抑制作用。2024年6月，评估BGB-45035在健康受试者中单次和多次递增剂量的安全性、耐受性、药代动力学和药效学以及食物效应的1期随机研究启动。2024年8月，BGB-45035在国内获批临床，治疗中重度特应性皮炎。 然而，IRAK4靶向药的开发并不顺利。拜耳在公布2024年Q1业绩时透露终止Zaberdosertib治疗特应性皮炎的2期临床（Damask研究）。BAY1834845是一款靶向IRAK4的小分子抑制剂。在健康男性受试者中进行的1期研究结果显示：BAY1834845可以显著抑制咪喹莫特乳膏诱导的皮肤炎症反应，也可以显著降低血清IL-6和TNF-α水平，并抑制C反应蛋白、降钙素原和IL-8对脂多糖诱导的炎症反应的应答。 从布局企业来看，除了国内药企，多家大型跨国药企（MNC），尤其是拜耳和吉利德也看好IRAK4靶点的潜力。其中吉利德除了自主开发，还从外部引进。2023年3月，吉利德行使选择权，获得NX-0479（GS-6791）的独家许可。NX-0479是一种有效、选择性口服IRAK4降解剂，靶向IRAK4蛋白激酶的支架和激酶功能，以阻断toll样受体(TLR)和促炎IL1细胞因子受体家族(IL1Rs)下游的炎症反应。与激酶抑制剂相比，GS-6791对IRAK4的降解对TLR/IL1Rs信号的抑制更持久、更深。 上述IRAK4靶向药被开发用于治疗自身免疫性疾病，但IRAK4靶向药还有望用于治疗肿瘤，如Curis公司的Emavusertib（CA-4948）被开发用于治疗急性髓细胞性白血病（AML）和骨髓增生异常综合征（MDS）。 总结 整体来看，IRAK4靶点治疗自身免疫性疾病的潜力已得到初步临床试验验证，不过未来还有很长的路要走。国内外药企积极开发IRAK4靶向药，且研发方向已开始出现新方向，不再局限于小分子化药，已开始研发IRAK4靶向PROTAC降解剂。期待在药企的不懈努力下，IRAK4靶点可以早日突破重围。 END 【智药研习社直播预告】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

EC Grants ODD to emavusertib in PCNSL Management to host conference call and webcast today at 8:30 a.m. ET LEXINGTON, Mass., Aug. 1, 2024 /PRNewswire/ -- Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of emavusertib (CA-4948), an orally available, small molecule IRAK4 inhibitor, today reported its financial and operating results for the second quarter ended June 30, 2024. Operational Highlights TakeAim Lymphoma In July 2024, emavusertib was granted Orphan Drug Designation (ODD) by the European Commission (EC) for the treatment of patients with primary central nervous system lymphoma (PCNSL). To qualify for ODD in the European Union, among several requirements, emavusertib must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating and the prevalence of the condition must be fewer than 5 in 10,000 across the EU. "We are extremely pleased that emavusertib has been granted ODD in the EU for the treatment of PCNSL. The designation is significant for the development of emavusertib in the EU and shows the high unmet need for this patient population," said Jonathan Zung, Chief Development Officer. In addition to the EC ODD designation, Curis continues to progress the clinical development of emavusertib and expects to have initial data for 15-20 patients with R/R PCNSL by late 2024. "We are pleased with our progress in the TakeAim Lymphoma study and look forward to providing updated data at the ASH conference in December. As we continue the expansion of clinical sites in our PCNSL study, we have initiated discussions with health authorities to align on a registrational development path for emavusertib in PCNSL. We are excited to take this next step in advancing a novel treatment for patients with PCNSL," said James Dentzer, President and Chief Executive Officer. TakeAim Leukemia In May 2024, Curis released data for 25 new patients in the Relapsed/Refractory (R/R) FLT3 mutation (FLT3m) and U2AF1/SF3B1 Splicing Factor mutation (SFm) cohorts who had received fewer than 3 lines of prior therapy and were treated with emavusertib as monotherapy at the Recommended Phase 2 Dose (RP2D) of 300 mg BID. 12 R/R AML patients with FLT3m were treated with emavusertib. Preliminary data show 6 objective responses in 11 response-evaluable patients: 3 complete remission (CR), 1 CR with partial hematologic recovery (CRh) and 2 morphologic leukemia-free state (MLFS) with on-treatment duration range of 46-324 days. 4 patients were ongoing at the data-cutoff, including 1 CRh and 1 MLFS. 20 R/R AML patients with SFm were treated with emavusertib. Preliminary data show 4 of 18 response-evaluable patients in this population have achieved objective response (CR/CRh/MLFS). 8 of 20 patients were ongoing at the data-cutoff, including 1 MLFS. 2 patients were not response-evaluable. Upcoming Presentations On September 26, 2024, Curis will be hosting the 3rd Annual Symposium on IRAK-4 in cancer. The symposium will be hosted by Dr. Eric S. Winer and Dr. Grzegorz S. Nowakowski and will focus on IRAK-4 and the promise of IRAK-4 inhibition in both hematologic malignancies and solid tumors. Upcoming Milestones TakeAim Lymphoma – updated clinical data from the on-going combination study of emavusertib with ibrutinib in patients with R/R PCNSL in late 2024. TakeAim Leukemia – updated clinical data from the on-going monotherapy study of emavusertib in patients with R/R AML with a FLT3 or SFm in late 2024. Initial safety data from the frontline triplet combination study of emavusertib with azacitidine and venetoclax in patients with AML in late 2024. Second Quarter 2024 Financial Results For the second quarter of 2024, Curis reported a net loss of $11.8 million or $2.03 per share on both a basic and diluted basis as compared to $12.0 million or $2.47 per share on both a basic and diluted basis, for the same period in 2023. Curis reported a net loss of $23.7 million or $4.08 per share on both a basic and diluted basis, for the six months ended June 30, 2024 as compared to a net loss of $23.5 million or $4.87 per share on both a basic and diluted basis for the same period in 2023. Revenues for the second quarter of 2024 were $2.5 million as compared to $2.2 million for the same period in 2023. Revenues were $4.6 million for the six months ended June 30, 2024 as compared to $4.5 million for the same period in 2023. Revenues consist of royalty revenues from Genentech/Roche's sales of Erivedge®. Research and development expenses were $10.3 million for the second quarter of 2024, as compared to $10.0 million for the same period in 2023. The increase was primarily attributable to higher employee related costs, partially offset by a decrease in consulting costs. Research and development expenses were $19.9 million for the six months ended June 30, 2024, as compared to $19.2 million for the same period in 2023. General and administrative expenses were $4.8 million for the second quarter of 2024, as compared to $4.2 million for the same period in 2023. The increase was primarily attributable to higher employee related costs. General and administrative expenses were $9.7 million for the six months ended June 30, 2024, as compared to $9.0 million for the same period in 2023. Other income was $0.7 million for the second quarter of 2024, as compared to $0.2 million for the same period in 2023. The increase was primarily attributable to a decrease in the non-cash expense related to the sale of future royalties. Other income, net was $1.3 million for the six months ended June 30, 2024 compared to $0.2 million for the same period in 2023. Curis's cash, cash equivalents and investments totaled $28.4 million as of June 30, 2024, and the Company had approximately 5.9 million shares of common stock outstanding. Curis expects its existing cash, cash equivalents and investments will enable its planned operations into the first quarter of 2025. Conference Call and Webcast Information Curis management will host a conference call and webcast today, August 1, 2024, at 8:30 a.m. ET, to discuss the business update and these financial results. To access the live conference call, please dial 800-836-8184 from the United States or 1-646-357-8785 from other locations, to access the webcast login to shortly before 8:30 a.m. ET. The webcast can also be accessed via the Curis website in the 'Investors' section. About Curis, Inc. Curis is a biotechnology company focused on the development of emavusertib, an orally available, small molecule IRAK4 inhibitor. Emavusertib is currently undergoing testing in the Phase 1/2 TakeAim Lymphoma study (CA-4948-101) in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL) in combination with the BTK inhibitor ibrutinib, as a monotherapy in the Phase 1/2 TakeAim Leukemia study (CA-4948-102) in patients with relapsed/refractory acute myeloid leukemia (AML) and relapsed/refractory high risk myelodysplastic syndrome (hrMDS) with either a FLT3 mutation or a splicing factor mutation (U2AF1 or SF3B2), and as a frontline combination therapy with azacitidine and venetoclax in patents with AML (CA-4948-104). Emavusertib has received Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of AML and MDS and from the European Commission for the treatment of PCNSL. Curis, through its 2015 collaboration with Aurigene, has the exclusive license to emavusertib (CA-4948). Curis licensed its rights to Erivedge® to Genentech, a member of the Roche Group, under which they are commercializing Erivedge® for the treatment of advanced basal cell carcinoma. For more information, visit Curis's website at . Cautionary Note Regarding Forward-Looking Statements: This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, including, without limitation, any statements with respect to Curis's plans, strategies and objectives, cash runway, clinical development timelines and commercialization plans, anticipated results or the therapeutic potential of emavusertib, any statements regarding the initiation, progression, expansion, use, safety, efficacy, dosage and potential benefits of emavusertib in clinical trials as a monotherapy and/or as a combination therapy, its plans and timelines to provide preliminary, interim and/or additional data from its ongoing or planned clinical trials, its ability to further patient enrollment in its TakeAim Lymphoma and TakeAim Leukemia studies and enroll patients in its AML triplet study, any statements concerning Curis's interactions with the FDA and/or health authorities on the potential development path for emavusertib in PCNSL or the potential benefits of having received orphan drug designation from the EC for emavusertib in PCNSL, statements with respect to mutations or potential biomarkers, and statements of assumptions underlying any of the foregoing. Forward-looking statements may contain the words "believes," "expects," "anticipates," "plans," "intends," "seeks," "estimates," "assumes," "predicts," "projects," "targets," "will," "may," "would," "could," "should," "continue," "potential," "focus," "strategy," "mission," or similar expressions. These forward-looking statements are not guarantees of future performance and involve risks, uncertainties, assumptions and other important factors that may cause actual results to be materially different from those indicated by such forward-looking statements. Curis may experience adverse results, delays and/or failures in its drug development programs and may not be able to successfully advance the development of its drug candidates in the time frames it projects, if at all. Curis's drug candidates may cause unexpected toxicities, fail to demonstrate sufficient safety and efficacy in clinical studies and/or may never achieve the requisite regulatory approvals needed for commercialization. Favorable results seen in preclinical studies and early clinical trials of Curis's drug candidates may not be replicated in later trials. Curis is dependent on the success of emavusertib and any delays in the development of emavusertib could have a material adverse effect on its business. There can be no guarantee that the collaboration agreement with Aurigene will continue for its full term, or the CRADA with NCI, that Curis or its collaborators will each maintain the financial and other resources necessary to continue financing its portion of the research, development and commercialization costs, or that the parties will successfully discover, develop or commercialize drug candidates under the collaboration. Regulatory authorities may determine to delay or restrict Genentech's and/or Roche's ability to continue to commercialize Erivedge in basal cell carcinoma. Competing drugs may be developed that are superior to Erivedge. In connection with its agreement with Oberland Capital, Curis faces risks relating to the transfer and encumbrance of certain royalty and royalty-related payments on commercial sales of Erivedge, including the risk that, in the event of a default by Curis or its wholly-owned subsidiary, Curis could lose all retained rights to future royalty and royalty-related payments, Curis could be required to repurchase such future royalty and royalty-related payments at a price that is a multiple of the payments it has received, and its ability to enter into future arrangements may be inhibited, all of which could have a material adverse effect on its business, financial condition and stock price. Curis will require substantial additional capital to fund its business. Based on its available cash resources, it does not have sufficient cash on hand to support current operations within the next 12 months from the date of this press release. If it is not able to obtain sufficient funding, it will be forced to delay, reduce in scope or eliminate its development of emavusertib, including related clinical trials and operating expenses, potentially delaying the time to market for, or preventing the marketing of, emavusertib, which could adversely affect its business prospects and its ability to continue operations, and would have a negative impact on its financial condition and its ability to pursue its business strategies. Curis faces substantial competition. Curis and its collaborators face the risk of potential adverse decisions made by the FDA and other regulatory authorities, investigational review boards, and publication review bodies. Curis may not obtain or maintain necessary patent protection and could become involved in expensive and time-consuming patent litigation and interference proceedings. Unstable market and economic conditions, natural disasters, public health crises, political crises and other events outside of Curis's control could significantly disrupt its operations or the operations of third parties on which Curis depends and could adversely impact Curis's operating results and its ability to raise capital. Other important factors that may cause or contribute to actual results being materially different from those indicated by forward-looking statements include the factors set forth under the captions "Risk Factor Summary" and "Risk Factors" in our most recent Form 10-K and Form 10-Q, and the factors that are discussed in other filings that we periodically make with the Securities and Exchange Commission. In addition, any forward-looking statements represent the views of Curis only as of today and should not be relied upon as representing Curis's views as of any subsequent date. Curis disclaims any intention or obligation to update any of the forward-looking statements after the date of this press release whether as a result of new information, future events or otherwise, except as may be required by law. SOURCE Curis, Inc.