SLC6A8

A New York City drug developer led by well-known executives and backed by some of the top names in biotech investing is shutting down, a blow to a company that was prepping for a pivotal trial in colorectal cancer. Inspirna is “winding down” after “10 years as a fantastic biotech company,” CEO Oz Azam wrote in a LinkedIn post on Monday morning. The cell and gene therapy veteran joined Inspirna in 2023 after leading Empyrean Neuroscience and Tmunity Therapeutics. Inspirna’s team decided to close the company after a Phase 2 trial of its oral small molecule, called ompenaclid, “did not read out positively” in KRAS colorectal cancer, according to a source familiar with the decision, who agreed to speak on the condition of anonymity. Merck KGaA paid $45 million upfront last year for the ex-US rights to the SLC6A8 inhibitor and had the option to co-develop and co-promote it in the US. The companies were also working on follow-up SLC6A8 compounds. Merck KGaA will “not pursue further development of ompenaclid” and will not exercise its option in the US, a spokesperson for the drugmaker told Endpoints News via email. Azam did not immediately respond to an inquiry from Endpoints. Inspirna is at least the seventh biotech to shutter so far in 2025, following last week’s news about Lyndra Therapeutics . Inspirna was putting together a global pivotal study of ompenaclid for patients with certain forms of colorectal cancer, but the trial “requires additional funding and is dependent on further FDA feedback,” according to the company’s first-quarter presentation . Inspirna last disclosed a $50 million Series D in July 2022. Its backers included blue-chip investors like Vivo Capital, Sands Capital, Novo Holdings, and Sofinnova Partners. The financing was expected to keep the R&D engine humming until the second half of 2024, a spokesperson told Endpoints at the time of the Series D. Inspirna also had a small molecule called abequolixron in its pipeline. The LXR-beta selective agonist was being tested in Phase 1b/2 for certain forms of lung cancer. GSK discovered the asset and originally intended for it to treat cardiovascular disease before licensing it out to Inspirna. Inspirna was formed more than a decade ago as Rgenix from the Tavazoie Lab at The Rockefeller University. The biotech’s platform focused on microRNA, or miRNA, dysregulation, which is thought to contribute to the development of cancer and its progression. Dieter Weinand, a former CEO of Bayer’s pharma division, chaired Inspirna’s board.

Merck KGaA on Thursday reported its annual results for 2024, although investors eager for an update on a potential deal with SpringWorks Therapeutics were left frustrated. The German drugmaker simply reaffirmed that it is in advanced discussions about a possible acquisition of SpringWorks, although there is no certainty that an agreement will be signed. Rumours of a transaction between the parties first surfaced on February 10, with Merck confirming later the same day that talks were ongoing. A purchase of SpringWorks would give Merck the oral gamma secretase inhibitor Ogsiveo (nirogacestat), which is approved for desmoid tumours, as well as the MEK inhibitor mirdametinib, currently under review by the FDA for neurofibromatosis type 1-associated plexiform neurofibromas.The acquisition of SpringWorks would revitalise Merck's pipeline, following a number of recent setbacks, including the failure of a pair of Phase III studies for its lead oncology candidate xevinapant. While the company's healthcare segment posted 5% growth last year to €8.5 billion ($9.2 billion), driven by oncology — which was up 10.5% to €2 billion — it is heavily reliant on its 20-year-old drug Erbitux.Erbitux biosimilars on the horizonThe anti-EGFR monoclonal antibody generated sales in 2024 of €1.2 billion, up 13.3% over the prior year. Merck noted that growth for Erbitux was led by Latin America, particularly Mexico, as well as Europe and China, tempered by negative pricing effects in Japan.Asked on an analyst call about the growth potential of Erbitux, particularly in China, Peter Guenter — CEO of Merck's healthcare unit — noted that sales of the product are forecast to increase this year, with biosimilars not expected to launch before 2026. Guenter indicated that China, which accounts for about 25% of Erbitux revenue, is "an important growth driver, but actually the brand is very dynamic across the world."While Erbitux faces competition in China from Simcere Pharmaceutical's Enlituo, Guenter clarified that the product — approved last June — is not classified as a biosimilar, but rather a non-comparable biologic. "And that has, of course, relatively important implications in terms of, you know, lack of substitution," Guenter explained, as well as inclusion on the reimbursement drug list and volume-based procurement programme.Merck's other key drug, the multiple sclerosis (MS) therapy Mavenclad, achieved blockbuster status in 2024 for the first time, posting an 11.1% increase in revenue to €1.1 billion. Meanwhile, its older MS treatment Rebif declined 11.6% to €626 million in line with the wider interferon market.For the current year, the firm expects sales in its healthcare unit to be between €8.3 billion and €8.9 billion, representing organic growth of up to 5%.Pipeline questions continueMerck also disclosed Thursday that the oral TLR7/8 inhibitor enpatoran failed to meet the primary endpoint of the systemic lupus erythematosus cohort of the mid-stage WILLOW study. Despite what Guenter called "a near miss" in the trial, the company plans further development of the drug, given "promising responses" in patient subgroups and the totality of data, including positive results from the cutaneous lupus erythematosus arm of WILLOW.Guenter explained "the good news is that we see clear responses in predefined subpopulations. So we can really say that the drug clearly hits the target." These subgroups include patients with skin manifestations within the lupus cluster, those with a strong interferon gene signature and also those with high steroid use at baseline.Meanwhile, chief financial officer Helene von Roeder noted that Inspirna "informed [us] about negative top-line data" from an ongoing Phase II trial of ompenaclid in RAS-mutated advanced or metastatic colorectal cancer. The SLC6A8 inhibitor — also known as RGX-202 — was the focus of a licensing agreement between the parties last year. However, von Roeder indicated that the mid-stage failure means "we will not exercise the US option" on the drug, but will instead record an impairment charge of around €15 million in the current quarter.

关注并星标CPHI制药在线 近日，德国默克集团宣布，其备受瞩目的IAP抑制剂Xevinapant与放化疗联合治疗局部晚期头颈癌的三期临床试验惨遭终止。该决定是基于独立数据监测委员会进行的期中分析而做出的，此分析认为该研究不太可能达到主要终点，即延长患者无事件生存期。这一突如其来的消息犹如一颗重磅炸弹，让市场对默克公司的前景产生了严重质疑，股价应声暴跌8%！ 除此以外，考虑到数据的完整性，默克还决定停止xevinapant联合放疗对比安慰剂联合放疗用于接受过手术切除的局部晚期头颈癌患者的III期X-Ray Vision研究。 Xevinapant是一款first-in-class高效口服小分子细胞凋亡蛋白抑制因子（IAP）的抑制剂。2021年3月，德国默克宣布与Debiopharm公司达成一项全球性许可协议，以约9亿欧元获得该药在全球范围内的开发和推广权益。 彼时，Xevinapant被寄予厚望。在II期临床研究中，xevinapant加放化疗的患者五年生存率几乎是安慰剂的两倍（53% vs 28%）。2020年2月，它成为了首个获得FDA突破性疗法认定（Breakthrough Therapy Designation）的IAP抑制剂。结合目前的护理标准，用于先前未治疗的局部晚期头颈部鳞状细胞癌（LA SCCHN）。 Xevinapant及其II期临床研究结果简介 图片来源：参考来源1 IAP蛋白高度表达且与多种癌症相联，包括肺癌、头颈癌、乳腺癌、胃肠癌，以及黑色素瘤和多发性骨髓瘤等，并且和预后密切相关。因此，IAPs是抗肿瘤药物研发的重要方向。不过，目前并没有IAP类药物获批上市，Xevinapant是目前全球研发进展最快的IAP抑制剂产品之一，其通过抑制IAP，不但促进癌细胞的死亡，还可以增强抗肿瘤的免疫反应。 作为行业的领头羊，本次研究的终止对于默克来说，是一个很大的打击，直到2024年5月，默克的高管还在向分析师们保证，Xevinapant的三期试验“不太可能（unlikely）”失败。 除了本次终止的两项III期研究外，目前默克产品管线中已经没有列出针对Xevinapant开展的其他试验。 默克肿瘤产品管线 图片来源：默克公司官网 频繁出手扫货肿瘤创新药 去年以来，默克相继与国内和誉医药和恒瑞医药达成独家许可协议，分别引进一款CSF-1R抑制剂（Pimicotinib）和一款高选择性PARP1抑制剂（HRS-1167/M9466）。 Pimicotinib 由和誉医药自主研发，是一款全新的口服、高选择性、高活性CSF-1R小分子抑制剂，当前已在中国、美国、加拿大和欧洲同步开展全球多中心三期临床试验，该研究是腱鞘巨细胞瘤疾病领域首个在中国、美国、加拿大和欧洲同步开展的全球III期研究。  在去年11月的CTOS年会上，和誉医药还更新了Pimicotinib治疗TGCT患者的临床Ib期试验一年长期随访数据，ORR达到87.5%，展现出了药物的抗肿瘤活性和良好的安全性。 此外，NMPA已批准Pimicotinib用于慢性移植物抗宿主病、晚期胰腺癌的临床试验，和誉医药也仍在探索该药物在多种实体瘤中的临床潜力。 HRS-1167（M9466）是恒瑞医药研发的一款选择性、高活性、可口服的 PARP1 小分子抑制剂，属于第二代 PARP 抑制剂。与第一代PARP抑制剂相比，HRS-1167对PARP1的选择性更高、亲和力更强，且可诱导DNA捕获。 M9466用于晚期实体肿瘤的Ⅰ期研究入选了ASCO 2024年会的壁报展示环节，研究显示：M9466在伴HRR突变的晚期实体肿瘤患者中显示出了突出的抗肿瘤疗效，对晚期卵巢癌患者的缓解效果更佳。 再往前追溯，默克还曾于2022年9月斥资6500万美元首付款囊获Nerviano旗下PARP1抑制剂NMS-293的开发和商业化权益。两笔交易传达出的信号已十分明显，默克对于PARP1抑制剂是坚定看好而且势在必得。 此外，今年年初默克还引进了Inspirna开发的一款first in class的结直肠癌药物ompenaclid的专利权。ompenaclid是肌酸转运通道SLC6A8的一流口服抑制剂，目前正在开发用于RAS突变（RASm）二线（2L）晚期或转移性结直肠癌（mCRC）和SLC6a8靶向后续化合物。去年10月在欧洲肿瘤内科学会（ESMO）大会上报告的Ib/II期数据表明，Ompenaclid与标准二线疗法（FOLFIRI化疗和贝伐珠单抗）结合有可能改善疗效，同时不会增加其毒性负担。该药物总缓解率可达37%（41名接受治疗的患者中有11名病情得到了缓解），中位无进展生存期（PFS）为10.2个月，中位总生存期（OS)为19.1个月。 深耕“合成致死”领域 ATR，即共济失调毛细血管扩张突变（ATM）基因和Rad3相关激酶，激活后可通过多种信号调控细胞生物过程, 包括细胞周期阻滞、抑制复制起点、促进脱氧核苷酸合成、启动复制叉以及修复DNA双链断裂。 研究发现，ATM和ATR 激酶在癌细胞中被激活或上调，同时ATR是ATM突变的合成致死靶点，ATM缺失的肿瘤细胞对于ATR抑制剂更加敏感。二者间的选择性抑制为肿瘤治疗提供了新的思路，也为肿瘤研究提供了新的工具。 除了PARP1抑制剂，默克在“合成致死”领域还分别布局了一款ATR抑制剂(M1774)和ATM抑制剂(M4076)，其中M1774进展较快已经进入II期临床，M4076尚处于I期临床。 Tuvusertib(M1774)是默克开发的一款潜在的best-in-class ATR抑制剂。2024年美国临床肿瘤学会(ASCO)年会上发布的DDRiver 301 Part B数据表明，预测有效剂量的tuvusertib与PARP抑制剂尼拉帕利联合治疗具有能力，并且在PARP预处理过的卵巢癌中具有令人鼓舞的活性。这些发现补充了4月份在美国癌症研究协会(AACR)年会上首次提出的tuvusertib和lartesertib联合疗法的数据。默克正在三个II期研究中探索tuvusertib： 1.正在进行的Ib/II期DDRiver NSCLC 322研究(NCT05882734)联合cemiplimab治疗具有生物标志物分层的耐药晚期非小细胞肺癌(NSCLC)； 2.最近开展的2期DDRiver EOC 302研究(NCT06433219)将tuvusertib联合lartesertib或尼拉帕利用于生物标志物选择的parp耐药卵巢癌; 3.近期开展的JAVELIN DDRiver膀胱II期研究(NCT06424717)联合BAVENCIO®(avelumab)治疗ci耐药晚期尿路上皮癌。 ADC：新兴靶点打头阵 默克的ADC管线以靶向CEACAM5 M9140为首，CEACAM5作为一种细胞表面蛋白，在健康的成年人组织中表达较少，但在多种腺癌中却高度表达，特别是在结直肠癌中，高达90%的病例都有CEACAM5的表达。该药物的治疗窗宽，并且在血液循环中也稳定，该药与DDR抑制剂合用可产生协同作用。M9140中的细胞毒性有效负载是拓扑异构酶1 (TOP1) 抑制剂，可防止DNA修复。目前，M9140处于结直肠癌的Ⅰ期临床研究阶段。 在今年的ASCO大会上，M9140的Ⅰ期临床试验结果备受瞩目。该试验纳入了来自美国、欧盟和日本的40名晚期结直肠癌患者，他们在接受标准治疗后病情仍有所进展。在接受7个不同剂量的M9140治疗后，10%的患者出现了明确的治疗反应，而42.5%的患者病情保持稳定，其中6名患者的病情稳定期超过了100天。此外，15%的患者病情出现进展。初步数据显示，中位无进展生存期为6.7个月。截至数据统计时，仍有15名患者（占比37.5%）正在接受M9140的治疗。 参考来源:        1.Bourhis, J., Burtness, B., Licitra, L. F., Nutting, C., Schoenfeld, J. D., Omar, M., … Cohen, E. E. (2022). Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design. Future Oncology, 18(14), 1669– 2.James Waldron. Merck KGaA drops xevinapant with phase 3 head and neck cancer trial on course for failure. FierceBiotech. Jun 25, 2024. 3.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. 4.默克公司官网 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~