Birinapant

*仅供医学专业人士阅读参考 胰腺导管腺癌（PDAC）是癌症相关死亡的第四大原因，具有极高的恶性和侵袭性，其五年生存率不足12%。当前PDAC的治疗选择有限，以吉西他滨（GEM）作为一线化疗药物，但只有约23.8%的患者对其有临床反应，中位生存期仅为6.7到8.5个月。 这种不理想的化疗治疗效果，主要是由于PDAC中存在癌症干细胞（CSCs）。与正常干细胞相似，癌症干细胞不仅具有自我更新和分化能力，还拥有能够帮助细胞排出有害物质的药物转运蛋白，并在身边形成保护性生态位、DNA损伤能力修复增强，抵御化疗药物的影响。因此，探索PDAC维持干性和化疗耐药性的机制，对于优化治疗策略至关重要。 天津医科大学刘静、常安涛、黄崇标、郝继辉等人的最新研究于近日发表在《科学·进展》期刊上[1]。他们发现，蛋白质BICC1过度表达时，能够通过上调限速酶IDO1来促进色氨酸代谢，从而增强胰腺癌的干细胞特性和化疗耐药性。使用药理方法或饮食干预的方式抑制这条信号通路，可以增加BICC1高表达的胰腺癌细胞对吉西他滨的敏感性，延长小鼠生存期。 论文首页 BICC1是一种RNA结合蛋白，能在细胞质中调控多个mRNA的翻译。天津医科大学团队在之前的工作中发现，BICC1通过促进PDAC中的血管生成来促进肿瘤生长，在PDAC中的高表达与不良的临床特征和预后有关[2]。 此次，研究团队首先通过免疫组织化学（IHC）染色，分析了68例接受吉西他滨联合白蛋白紫杉醇（nab-paclitaxel）治疗的晚期PDAC患者的BICC1表达情况，结果显示BICC1低表达的患者对化疗反应更好。同样，在另一组包括65例接受根治性切除手术后吉西他滨辅助化疗的PDAC患者中，BICC1高表达的患者复发无病生存期更短。 这些结果支持了BICC1在预测化疗反应和患者预后中的潜在价值。 BICC1表达与患者化疗反应相关 通过构建几种BICC1过表达或BICC1沉默的PDAC细胞系，研究团队在体外实验和小鼠体内实验中验证表明，BICC1本身对PDAC细胞的存活和增殖影响甚微，但是会妨碍化疗药物的效果。BICC1过表达能够显著增强PDAC细胞对吉西他滨的耐药性，增加肿瘤体积和生长速度；而BICC1沉默则增强对吉西他滨的敏感性，导致诱导的凋亡细胞数量增加。 此外研究发现，除了吉西他滨，BICC1还会增强PDAC细胞对5-氟尿嘧啶和白蛋白紫杉醇的耐药性，并在一定程度上增加其对TNF-α和Birinapant（一种细胞死亡诱导剂）组合治疗的抗性。这些表明BICC1在PDAC中广泛影响了多种化疗药物效果。 接下来就是顺藤摸瓜，根据BICC1的作用机制找出相应的解决方案。 考虑到化疗耐药性和癌细胞干细胞表型之间的关联已得到充分证实，研究团队将重点放在探索BICC1是否调节PDAC的干细胞特性。 结果颇有收获。对100多例PDAC组织样本进行分析发现，BICC1能够帮助PDAC细胞维持癌症干细胞特征，上调与干性相关的基因，增强成球能力等干细胞特性。沉默BICC1会导致癌症干细胞的占比大幅降低。 BICC1促进PDAC干性，干细胞样PDAC细胞表达更多的BICC1 从机制上看，BICC1作为一种RNA结合蛋白，直接与色氨酸代谢限速酶的编码基因IDO1的mRNA结合，以增加其稳定性，从而增强IDO1的表达和促进色氨酸的代谢，提高色氨酸代谢产物水平。这些代谢物通过促进线粒体中进行的NAD+合成和氧化磷酸化（OXPHOS）过程，增强PDAC细胞的干性和化疗耐药性。 机制 既然已明确BICC1/IDO1/色氨酸通路的作用，研究团队尝试从已在临床应用或先前临床试验中验证过的药物里寻求新的治疗方案。 氟他胺是一种用于前列腺癌治疗的非甾体雄激素受体拮抗剂，在这里，研究团队利用大规模毒理基因组学数据库和蛋白质印迹分析技术发现，氟他胺可作为PDAC中BICC1的强效抑制剂。 异种移植瘤PDAC小鼠模型实验结果显示，氟他胺或Epacadostat（一种在III期临床试验中失败的IDO1抑制剂）治疗，或者低亮氨酸含量的饮食干预，与吉西他滨联合使用时对BICC1高表达的PDAC肿瘤具有明显的抑制作用，延长小鼠总生存期。 不结合化疗、只针对BICC1/IDO1/色氨酸通路进行治疗时影响微乎其微，且联合治疗对BICC1低表达的肿瘤效果无提升。 三种方法抑制BICC1/IDO1/色氨酸通路，可以增强PDAC对吉西他滨治疗的敏感性 总之，这项研究表明BICC1可作为预测PDAC化疗结果的潜在生物标志物，并提出了靶向BICC1/IDO1/色氨酸代谢途径的治疗策略，包括副作用较小的饮食干预，有望提高PDAC患者对化疗的敏感性、改善治疗效果。未来的研究应进一步探索BICC1在肿瘤微环境中的作用，开发针对BICC1的特异性抑制剂，以评估其临床应用潜力。 参考文献： [1]https://www-science-org.libproxy1.nus.edu.sg/doi/10.1126/sciadv.adj8650 [2]C. Huang, H. Li, Y. Xu, C. Xu, H. Sun, Z. Li, Y. Ge, H. Wang, T. Zhao, S. Gao, X. Wang, S. Yang, P. Sun, Z. Liu, J. Liu, A. Chang, J. Hao, BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis. Signal Transduct. Target. Ther. 8, 271 (2023). 本文作者丨张艾迪

STOCKHOLM, Feb. 15, 2024 /PRNewswire/ -- "The clinical efficacy of fostrox in combination with Lenvima continues to improve with median time to progression having increased to over 6 months" October – December Financial summary for the quarter Net turnover amounted to SEK 4.4 (2.3) million. The loss before interest, tax, depreciation and amortization (EBITDA) amounted to SEK -20.1 (-17.9) million. Basic and diluted earnings per share amounted to SEK -0.28 (-0.32) and SEK -0.28 (-0.32) respectively. Cash flow from operating activities amounted to SEK -4.6 (-24.7) million. Cash and cash equivalents at the end of the period amounted to SEK 169.5 (117.4) million. Significant events during the quarter In October, data from an investigator evaluation showed continued promising tumor control with fostrox + Lenvima in HCC. All patients in the phase 2a study had dosed at least two treatment cycles. In October, the Board of Directors announced that Anette Lindqvist is leaving her position as Board Member of Medivir AB due to personal reasons. In October the nomination committee was appointed ahead of the AGM in May 2024. The Nomination Committee consists of Karl Tobieson, appointed by Linc AB, Richard Torgerson, appointed by Nordea Investment Funds, Anders Hallberg, appointed by HealthInvest Partners and Uli Hacksell, Chairman of the Board, Medivir AB. The Q3 report and the subsequent webcast included in-depth interim data from the 18 patients in the phase 1b/2a study who had a minimum follow-up of 12 weeks. These data continued to demonstrate clear patient benefit for the fostrox + Lenvima combination. In November it was announced that the company's interactions with the FDA regarding fostrox's clinical development plan had intensified with a first Type D meeting with a positive response regarding critical elements of the design for the planned phase 2b study. Late November it was announced that the development of an updated formulation of fostrox, suitable for commercial manufacture, had been finalized. In December, Medivir's partner IGM Biosciences, communicated a strategic pipeline cost-saving prioritization that among other things affects IGM's DR-5-agonist, aplitabart, in combination with birinapant, which was licensed in from Medivir in 2021. In December it was announced that Medivir has signed an agreement with Lonza for the manufacture of fostrox drug substance for the planned phase 2b study. In December it was announced that the durable clinical benefit in the ongoing phase 1b/2a study continues to improve, as data become more mature. In December, a rights issue was carried out, through which the company received proceeds of approximately SEK 129 before deduction of costs attributable to the rights issue. January – December Financial summary for the period Net turnover amounted to SEK 7.6 (4.4) million. The loss before interest, tax, depreciation and amortization (EBITDA) amounted to SEK -88.7 (-84.8) million. Basic and diluted earnings per share amounted to SEK -1.48 (-1.59) and SEK -1.48 (-1.59) respectively. Cash flow from operating activities amounted to SEK -59.7 (-101.8) million. Cash and cash equivalents at the end of the period amounted to SEK 169.5 (117.4) million. Events after the end of the period In January, a directed issue to Hallberg Management AB was carried out amounting to approximately SEK 20 million before deduction of issuance costs. In January, positive data from the ongoing phase 1b/2a study in advanced liver cancer (HCC) showing further improved response and time to progression was presented at the ASCO GI Symposium in San Francisco. In January Tango Therapeutics announced that it has dosed the first patient with TNG348, a new USP1-inhibitor from the preclinical USP1 program inlicensed from Medivir in 2020 Conference call for investors, analysts and the media The Year-End Report January - December 2023 will be presented by Medivir's CEO, Jens Lindberg. Time: Thursday, February 15, 2024, at 14.00 (CET). To access the webcast and find information about the teleconference, please klick HERE! The conference call will also be streamed via a link on the website: . The presentation will be available on Medivir's website after completion of the conference. CEO's message Fostrox in combination with Lenvima continues to show improved efficacy for patients with advanced primary liver cancer (HCC). The data presented in January 2024 at the ASCO-GI congress in San Francisco showed a further increase in the proportion of patients who achieve a clinically relevant reduction of their liver tumor and that patients stay on treatment longer with interrupted tumor growth. These data attracted very strong interest, which makes us even more convinced of fostrox's future role in the treatment of HCC and creates the opportunity for a faster route to market. The unmet medical need in the treatment of advanced HCC is significant. Primary liver cancer is the third leading cause of cancer-related deaths. In today's treatment guidelines, an immunotherapy combination (Tecentriq®/Avastin®) is recommended as first-line treatment. However, when this combination has stopped working, there are no approved alternatives for second-line treatment. There is thus a large need for additional treatment options in second-line that attacks the tumor in different ways compared to what Tecentriq and Avastin does. Fostrox is an organ specific, so-called smart chemotherapy, that selectively kills cancer cells in the liver. Together with Lenvima, these two form a unique combination of complementary drugs that have shown promising interim results in an ongoing phase 1b/2a study, including a complete tumor response in one patient. All patients in the study have now had at least 18 weeks of follow-up. The more mature and in-depth data we see from the study, the more convincing the clinical benefit for patients has become. Data from this study was presented at the ASCO GI Congress on January 19, 2024. These results, evaluated by investigators and local radiologists, showed further improvement as the Overall Response Rate (ORR) had increased to 25% (RECIST 1.1), a notably higher percentage than the 5-10% shown in second-line HCC in previous studies. The update also showed continued good tolerability without any new unexpected side effects. At the time of this quarterly report over 40% of patients remain on treatment in the study, and the clinical efficacy keeps improving. The median time to progression has increased further to 6.3 months, compared to 5.1 months at ASCO GI, significantly better than previous studies in second-line HCC. The patient who has benefited the longest remains on treatment after 18 months with partial response and continued shrinking tumor. Our data was met with great interest at ASCO GI, where we had the opportunity to discuss with leading global experts what the fostrox + Lenvima combination could mean for these patients. The discussions confirmed the great need that exists in the second-line treatment of HCC, where patients are today without any approved treatment alternative. With these promising data, fostrox has the opportunity to become the first approved medicinal treatment in a market worth ~2.5 billion USD annually, through a so-called accelerated approval by the regulatory authorities. We have therefore put in a higher gear in 2023 to ensure maximum momentum in fostrox's development program based on this possibility of accelerated approval. In Q4 2023 the development of an updated, commercially adapted formulation of fostrox was completed. In parallel, we have initiated the process with the FDA for a so-called Type C meeting to discuss the final study design of the planned registrational phase 2b study. In conjunction with these measures, we can now also deepen our discussions with potential partners, in accordance with previously communicated plans. We can also note that several of the projects that Medivir has licensed out to collaboration partners is entering clinical stage. In January 2024, Tango Therapeutics initiated a phase 1/2 study and dosed the first patient with TNG348, a USP-1 inhibitor developed from the preclinical USP1 program that was in-licensed from Medivir in 2020. INFEX Therapeutics also intends to initiate phase 1 study in 2024 - with the preclinical program MBLI, previously in-licensed from Medivir. IGM Biosciences has completed the fifth dose escalation cohort in the company's phase 1 study in solid tumors with Medivir's clinical project birinapant in combination with its own DR5 agonist antibody IGM-8444, now called aplitabart. For Medivir, the clinical development of fostrox is clearly in focus. With the promising data showing further improved clinical efficacy compared to expected treatment results in second-line HCC, we are even more confident that fostrox can become an effective liver cancer drug that makes a real difference to patients. I would like to thank old and new shareholders for the trust in our rights issue and for the capital injection that benefited us in the directed share issue. I look forward to keeping you informed of Medivir's continued development. Jens Lindberg Chief Executive Officer For further information, please contact Magnus Christensen, CFO Phone: +46 (0)8 5468 3100 E-mail: [email protected] This report has not been subject to auditors' review. The information was submitted for publication at 08.30 CET on February 15, 2024 The following files are available for download: SOURCE Medivir