Kura Oncology, Inc.

关注并星标CPHI制药在线 11月15日，Syndax Pharmaceuticals的Revumenib获FDA批准，用于治疗赖氨酸甲基转移酶2A基因（KMT2A）易位的复发或难治性（R/R）急性白血病成人和1岁以上儿童患者，商品名为Revuforj。 急性白血病是起源于造血干细胞的恶性克隆疾病，源于造血细胞基因改变，这种改变导致造血过程中分化受阻和细胞无限增殖。约10%的儿童和成人急性白血病患者发生KMT2A基因重排（KMT2Ar），这类患者预后极差且复发率高。 研究发现，KMT2A基因重排会导致同源（HOX）基因及其DNA结合辅助因子MEIS1表达异常。这种基因表达方式通常出现在干细胞中，会导致造血分化阻滞和白血病转化。据悉，超50%的KMT2Ar急性白血病患者在接受传统一线治疗后会复发，中位总生存期（OS）不到一年。在接受三线或后续治疗时，仅5%的患者可达到完全缓解，中位OS不足三个月。 Revumenib是一种口服、强效、小分子Menin-KMT2A相互作用抑制剂，能够阻断Menin与KMT2A的相互作用，在一项针对经过多次治疗失败的KMT2A重排急性白血病患者的1期研究中显示出良好的疗效和安全性。 作为首款获批的Menin抑制剂，Revumenib获FDA批准是基于I/II期临床AUGMENT-101的积极结果。该研究是一项开放标签、剂量递增和扩展研究，数据显示：在104例可评估疗效的伴KMT2A易位R/R急性白血病患者中，实现完全缓解及部分血液学恢复（CR+CRh）的患者比例为21%（22/104），实现CR+CRh的中位持续时间为6.4个月，达到CR或CRh的中位时间为1.9个月。23%（24/104）的患者在接受Revumenib治疗后进行了造血干细胞移植（HSCT）。 安全性方面，基于对135名携带KMT2A易位的R/R急性白血病患者的数据分析显示：最常见的不良反应（≥20%）包括实验室检测异常。10%和12%的患者因不良反应降低治疗剂量和永久停药。 Menin抑制剂研究进展 对于由KMT2Ar驱动的白血病，Menin是一个关键的致癌辅助因子。Menin由MEN1基因编码，主要存在于细胞核中，作为一种支架蛋白，在细胞生长调节、细胞周期控制、基因组稳定性、骨发育和造血等生物学途径中起着多种关键作用。在细胞核中，Menin与不同的结合伙伴在功能上串扰，以调节基因转录，并与多种信号通路相互作用。在临床前模型中，破坏 Menin-KMT2A 的相互作用可逆转这种异常基因表达，导致造血分化和抗白血病效应。此外，NPM1突变的急性白血病对Menin-KMT2A 相互作用也有依赖性。 Menin抑制剂被认为是白血病治疗的潜在利器。而且，临床前研究表明，Menin抑制剂与去甲基化药物、venetoclax和FLT3抑制剂联合使用具有协同作用。除了已获批的Revumenib，全球还有多款在研新药，如Kura Oncology的Ziftomenib、强生的Bleximenib（JNJ-75276617）、烨辉医药的BN104、住友制药的DSP-5336、第一三共的DS-1594、和黄医药的HMPL-506、Biomea的BMF-219。 Ziftomenib是一款口服、选择性Menin抑制剂，已在Menin依赖型急性髓性白血病（AML）模型中证实具有临床前活性，此前被FDA授予治疗AML的孤儿药资格。2024年4月，Ziftomenib被FDA授予突破性疗法认定，用于治疗携带NPM1基因突变的复发/难治性急性髓系白血病（AML）。 已公布的1期临床试验KOMET-007结果显示：对于新确诊NPM1突变和KMT2A重排AML患者，Ziftomenib联合标准治疗的完全缓解（CR）率达100%；对于未接受过Menin抑制剂治疗的难治/复发（R/R）性AML患者，Ziftomenib联合标准治疗的完全缓解或完全缓解伴部分血液学恢复（CRh）率为56%。 Bleximenib是一款强效、选择性Menin-KMT2A相互作用抑制剂，临床前研究表明其与Menin具有独特的结合模式，不同于其他的同类产品。目前，该药正处于1/2期临床研究阶段，单药或联合与其他靶向疗法治疗急性白血病。 Blood杂志上公布的Bleximenib单药治疗KMT2A或NPM1变异的复发/难治性急性白血病成人患者的首次人体1期研究结果显示：Bleximenib单药疗法表现出可接受的安全性，以及令人鼓舞的抗白血病活性。 2024 EHA上公布的Bleximenib联合venetoclax和阿扎胞苷治疗伴有KMT2A重排或NPM1突变的复发/难治性AML的1b期研究结果显示：在Bleximenib BID剂量水平为50mg的疗效数据集中，ORR为86%，CR/CRh/CRi率为48%，CR/CRh率为24%。对于先前有VEN暴露的患者，ORR为82%，cCR为36%，CR/CRh为18%。疗效数据集中至首次反应的中位时间为23天，至cCR的中位时间为52天。 安全性方面。87%的患者至少经历一次TRAE，其中恶心、呕吐和血小板减少最为常见。60%的患者观察到≥3级TRAE，22%的患者观察到单独归因于JNJ-75276617的TRAEs。 BN104是烨辉医药自主设计发现的新型、高选择性、口服Menin抑制剂，曾被FDA授予治疗AML的孤儿药资格，以及治疗复发/难治急性白血病的快速通道资格。与其他临床阶段的Menin抑制剂相比，BN104再临床前研究中展现出更优异的疗效和明显更大的安全窗口。在急性髓系白血病移植瘤的临床前动物模型中，BN104表现出高效的抗癌活性。 DSP-5336是住友制药开发的一款Menin-KMT2A相互作用抑制剂，曾被FDA授予治疗AML的孤儿药资格。2024年7月，DSP-5336被FDA授予快速通道资格，用于治疗具有KMT2A重排或NPM1突变的复发或难治性AML患者。 2024 ASH大会上公布的DSP-5336治疗复发或难治性急性白血病的1/2期首次人体临床研究数据显示：1期部分，DSP-5336剂量从40mg BID增加到300mg BID，未观察到剂量限制性毒性（DLT）。在22例KMT2Ar患者中，据ELN 2017（CR+CRi+MLFS）评估的ORR为59.1% ，其中22.7%的患者达到CR或CRh。其中在13例NPM1m突变AML患者中，ORR为53.8%，23.1%患者达到CR+CRh。 DS-1594是第一三共开发的选择性小分子Menin抑制剂。临床前研究显示，DS-1594表现出对AML和ALL细胞的选择性生长抑制，其中在AML模型中显示出稳健和持久的抗肿瘤活性，且表现出可接受的安全性。 HMPL-506是一种新型、高选择性、口服小分子Menin抑制剂。2024 AACR年会上公布的初步临床前数据显示：该药在KMT2A重排和NPM1突变的白血病细胞系模型中展示出较强的抑制活性，在体外和体内试验中与阿扎胞苷、维奈克拉或吉瑞替尼联用在KMT2A重排的白血病中均起到协同抗肿瘤作用。此外，该药还表现出良好的药代动力学特征、高选择性和低心脏毒性风险。 BMF-219是Biomea开发的一款潜在首创不可逆共价Menin抑制剂，具备从根源上治疗糖尿病的潜力，其可恢复、保护和强化胰岛β细胞功能，从而改善糖尿病患者的血糖控制。除治疗糖尿病，BMF-219还被开发用于治疗血液瘤和实体瘤，但其实目前唯一一款被开发治疗糖尿病的Menin抑制剂。然而，FDA根据COVALENT-111研究报告的数据认为BMF-219存在肝毒性风险，要求Biomea完全暂停BMF-219治疗2型糖尿病和1型糖尿病的COVALENT-111研究和COVALENT-112研究。 总 结 Menin抑制剂是治疗KMT2A重组或NPM1突变急性白血病的潜在靶向疗法。Revumenib的获批不仅验证了这一点，还增强了Menin布局企业的信心。整体来看，目前Menin抑制剂竞争并不激烈，在研数目较少，且大多处于1期临床或2期临床。未来Menin抑制剂市场如何，还有待临床试验及监管部门的检验。除了治疗白血病，Menin抑制剂还有望用于治疗糖尿病，但Menin抑制剂在糖尿病领域的进展并不顺利，Biomea的BMF-219因存在肝毒性风险，已被FDA要求暂停临床试验。 END 【智药研习社近期课程】 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~

The annual meeting of the American Society of Clinical Oncology drew more than 30,000 attendees to San Diego, and more who participated in the conference virtually, all of them looking to see and hear the latest developments in blood cancers and hematological disorders. Multiple myeloma is always a big topic of discussion at the annual ASH meeting, and developments this year include clinical data supporting the use of certain therapies in even earlier lines of treatment. On the cell therapy front, there is an ongoing effort to improve the manufacturability of these treatments. Data were presented demonstrating shorter “vein-to-vein times,” the time from when cells are harvested to when therapeutic cells are infused into the patient. And in sickle cell disease, encouraging early data were presented showing promise for a gene-editing therapy that could offer patients a one-time treatment. We couldn’t catch everything at what is one of the biggest medical meetings of the year. Here’s a recap of some highlights from the ASH 2024 meeting: Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech Movement in Multiple Myeloma —GSK reported Phase 3 data that support bringing the multiple myeloma drug Blenrep back to the market. The latest results show a Blenrep drug regimen, as a second-line of treatment, helped patients live longer compared against a drug regimen that includes the blockbuster Johnson & Johnson drug Darzalex. These results at ASH follow a Phase 3 data readout earlier this year showing Blenrep beat a drug combination that includes the Bristol Myers Squibb cancer drug Pomalyst. Blenrep won accelerated approval in 2020. GSK withdrew Blenrep from the market after it failed a confirmatory Phase 3 study. But that test evaluated the drug as a monotherapy and as a fifth line of treatment. The Phase 3 studies that are part of regulatory submissions currently under review tested the drug in combination with other multiple myeloma therapies and as an earlier line of treatment. GSK’s plans for the drug include a study underway that could support expanding the drug’s use to first-line multiple myeloma treatment, where its competition will include Darzalex. —Speaking of Darzalex, Johnson & Johnson reported data for an injectable formulation of the drug, Darzalex Faspro, as a treatment for smoldering multiple myeloma, which is an asymptomatic precursor to this type of blood cancer. In smoldering multiple myeloma, patients have high levels of abnormal plasma cells and elevated levels of monoclonal protein in the blood. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions In a Phase 3 test that enrolled 390 participants, J&J’s Darzalex Faspro significantly delayed high-risk smoldering multiple myeloma from progressing to active disease. The drug also extended overall survival compared to active monitoring, which is the current standard of care. Darzalex Faspro currently has nine approvals in multiple myeloma. Last month, the company submitted applications in the U.S. and Europe seeking to add smoldering multiple myeloma to the product’s list of approved indications. —Arcellx’s BCMA-targeting cell therapy, anito-cel, posted Phase 2 results in multiple myeloma that analysts say are comparable to Carvykti from partners Legend Biotech and Johnson & Johnson. It’s the safety results that reinforce their view of the Arcellx cell therapy as potentially best in class. Carvykti’s trials showed some cases of delayed neurological toxicities, including parkinsonism, a movement disorder. Arcellx is engineered to offer better safety and the results so far show no signs of parkinsonism. Analysts say Arcellx also has advantages through its partnership with Gilead Sciences, which has a global cell therapy manufacturing infrastructure and experience commercializing such products. —J&J and Legend added to the body of evidence showing that Carvykti is helping multiple myeloma patients live longer compared to standard therapies. The Phase 3 study, which tested the cell therapy in patients who had received one to three prior lines of therapy, showed that after a median 33.6 months of follow-up, Carvykti led to significantly increased rates of rates of minimal residual disease negativity, a marker of survival outcomes for multiple myeloma patients. A Look at Leukemia & Lymphoma Drugs —Kura Oncology reported more detailed data for ziftomenib, a drug candidate now partnered with Kyowa Kirin. The small molecule menin inhibitor is being developed to treat leukemias driven by certain genetic mutations. Results from the Phase 1 dose-escalation study showed a 100% complete response rate in those with NPM1 mutations. In patients whose disease harbored KMT2A mutations, the complete response rate was 83%. The companies said the drug was safe and well tolerated in combination with standard of care therapies. Last month, Kyowa Kirin paid $330 million to begin the alliance on ziftomenib. If the drug reaches the market, it will compete against Revuforj, a Syndax Pharmaceuticals menin inhibitor that won FDA approval in November. —Eli Lilly drug Jaypirca landed accelerated FDA approval last year as a treatment for advanced cases of mantle cell lymphoma following at least two prior lines of therapy. At the ASH conference, Lilly reported Phase 3 data that could support full approval for the drug, a small molecule inhibitor of a protein called BTK. Results show Jaypirca reduced the risk of disease progression or death by 46% compared to standard treatments. Treatment with the Lilly drug also prolonged the time to the next treatment or death by a median 23.9 months. Lilly said the safety profile of Jaypirca in Phase 3 was consistent with the Phase 1/2 test used to support the drug’s accelerated approval. —In a pre-planned analysis of a Phase 2 clinical trial in diffuse large B-cell lymphoma, Merck’s experimental drug zilovertamab vedotin led to a 97.2% complete response rate. What kept the study from achieving the 100% mark was discontinuation of two participants by physician decision, one patient each in the middle- and high-dose cohorts. All participants in the low-dose group showed a complete response. Based on the clinical trial results for the drug candidate, an antibody drug conjugate (ADC), Merck has selected the low dose to advance to Phase 3 testing. The results so far are encouraging for this therapy and others developed to seek out ROR1, a novel target currently unaddressed by any approved drugs. Other companies developing ROR1-targeting ADCs include Ipsen, which licensed its candidate from Sutro Biopharma earlier this year, and CStone Pharmaceuticals. Sickle Cell Disease Developments —Last month, Beam Therapeutics teased encouraging early clinical results for six patients dosed with BEAM-101, a gene-editing therapy for sickle cell disease. Updated data at ASH put some figures to the results as of an Oct. 28 data cutoff. Results showed these patients achieved fetal hemoglobin levels exceeding 60% and a reduction in sickle-shaped hemoglobin below 40% at month 1. Those levels were sustained to the last time point available, indicating that the effects of the one-time treatment are durable so far. The therapy’s safety profile was consistent with that of busulfan, the conditioning therapy that is used to prepare a patient to receive BEAM-101. As previously reported, there was one fatality from respiratory failure, which investigators attributed to busulfan. In all six patients dosed, there have been no serious adverse events attributed to BEAM 101. —Novo Nordisk presented Phase 2 data for etavopivat showing the once-daily oral drug led to a reduction in vaso-occlusive crises, a complication of sickle cell disease. The one-year, proof-of-concept study also showed an increase in hemoglobin levels. With these results, Novo Nordisk said it has selected the dose to test in a Phase 3 clinical trial. Etavopivat came to Novo Nordisk from the $1.1 billion acquisition of Forma Therapeutics in 2022. Catching Up on Cell Therapies —The cancer target GPRC5D is currently addressed by only one FDA-approved drug, the Johnson & Johnson bispecific antibody Talvey, a treatment for multiple myeloma. Bristol Myers Squibb aims to be the first to drug GPRC5D with a cell therapy. At the ASH meeting, BMS presented Phase 1 data showing its candidate, arlocabtagene autoleucel (arlo-cel), led to durable responses that deepened over time. Bristol says these results support arlo-cel as a potential first-in-class treatment for relapsed or refractory multiple myeloma in heavily pretreated patients. A Phase 2 test of the cell therapy is ongoing. —Galapagos’s non-Hodgkin lymphoma cell therapy candidate GLPG5101 posted additional Phase 1/2 results showing encouraging efficacy and safety. The company also pointed out that the vein-to-vein time was a median seven days. By comparison, the multi-step manufacturing process for currently available cell therapies can take a month or more. Galapagos’s process leverages Cocoon, a point-of-care manufacturing system from contract manufacturing giant Lonza. —Orca Bio posted data for Orca-T, an allogeneic T-cell immunotherapy in testing as a treatment for three types of blood cancer: acute myeloid leukemia, acute lymphoblastic leukemia, and high-risk myelodysplastic syndrome. Results from a three-year follow-up analysis from Phase 1b showed an overall survival rate of 86% for the study drug compared to 67% in a non-randomized historical group that received an allogeneic stem cell transplant. Orca-T is comprised of highly purified immune cells from donors. In the Phase 1b test, Orca Bio said this allogeneic therapy was manufactured reliably with vein-to-vein time of 72 hours or less across the U.S. An ongoing Phase 3 test comparing Orca-T to conventional allogeneic stem cell transplants is expected to report preliminary data in the first half of 2025. A Recap in Rare Blood Disease —Sanofi revealed details of its Phase 3 test of rilzabrutinib in persistent or chronic immune thrombocytopenia, a rare immune disorder leading to low platelet levels. Results show the small molecule BTK inhibitor led to platelet response in 65% of patients in the study drug arm compared to 33% of those who received a placebo. Furthermore, a durable platelet response was observed in 23% of patients who received rilzabrutinib versus zero in the placebo group. The drug, which came from the $3.7 billion acquisition of Principia Biopharma in 2020, is currently under regulatory review in the U.S. and Europe. —Standard of care for the rare blood disorder paroxysmal nocturnal hemoglobinuria (PNH) includes two blockbuster AstraZeneca drugs, Soliris and Ultomiris, though Apellis Pharmaceuticals and Novartis are trying to take market share with their FDA-approved therapies. Regeneron Pharmaceuticals aims to compete with those complement inhibitors with a drug combination: the approved antibody pozelimab (brand name Veopoz) and the experimental RNA-interference therapy cemdisiran. A Phase 3 test is underway testing the combination against Soliris. At ASH, Regeneron reported data from an exploratory cohort testing the two drugs against Ultomiris. Results showed the Regeneron drug combo helped patients achieve and maintain greater control over their disease compared to Ultomiris. Public domain image by Flickr user SciTechTrend

SAN DIEGO — As Kura Oncology awaits key pivotal data in relapsed or refractory acute myeloid leukemia, the company is going all in on combinations in the frontline setting. On Monday, Kura and its partner Kyowa Kirin announced positive early responses from a Phase 1 trial of their oral menin inhibitor ziftomenib and said the data support the decision to start a Phase 3 trial evaluating first-line ziftomenib in combination with current standards of care. If the drug wins approval, CEO Troy Wilson said it could potentially reach $3 billion in peak US sales, a majority of which would likely come from the first-line setting. “One of the advantages of ziftomenib relative to the other drugs is its safety and tolerability in combinations is quite good,” Wilson said. “That’s why you see us moving so aggressively.” The data were presented at this year’s American Society of Hematology annual meeting. The partners said they didn’t observe any dose-limiting toxicities in the Phase 1a dose escalation portion of the KOMET-007 trial, nor any evidence of additive myelosuppression (a decrease in bone marrow activity) or ziftomenib-related QTc prolongation (a type of irregular heart rhythm). The latter condition is in the warning label for Syndax Pharmaceuticals’ recently approved rival menin inhibitor Revuforj. “These updated data overall continue to support ziftomenib’s best-in-class potential within the menin class,” Leerink analysts said in a note to investors on Monday. Mizuho analysts said the data are promising, but noted that it’s “still early days.” Kura also reported early signs of efficacy. Among 46 evaluable patients who received first-line ziftomenib alongside the chemotherapy regimen cytarabine and daunorubicin, 91% achieved a complete remission, Kura said. That includes all patients with a form of AML caused by a common mutation in the NPM1 gene and 83% of patients with a different genetic alteration called KMT2A rearrangement. While KMT2A is a less common genetic alteration, those patients tend to have worse prognoses. In relapsed or refractory AML patients who received ziftomenib in combination with the standard-of-care regimen venetoclax and azacitidine, 68% of NPM1 patients responded to treatment, as well as 30% of KMT2A patients. The Phase 1b expansion portion of the KOMET-007 study is currently enrolling at a 600 mg dose in all cohorts. “It’ll be interesting, for example, to take this data set and then look another six months on or another 12 months on,” Wilson said. “That will help educate us, and it will also help us to de-risk the Phase 3s.” In mid-2025, Wilson expects to launch the Phase 3 KOMET-017 trial, which will evaluate ziftomenib in newly diagnosed patients in combination with venetoclax and azacitidine as well as with cytarabine and daunorubicin. In early 2025, the partners also plan to read out pivotal results for ziftomenib as a monotherapy in NPM1-mutated AML. Syndax recently announced that its own pivotal trial NPM1 patients met the primary endpoint, and the company is planning to file for US approval in the first half of next year.