亚盛医药（6855.HK）今日宣布，公司在研1类新药IAP抑制剂APG-1387日前获得国家药品监督管理局药物审评中心（CDE）批准，将在中国开展其联合化疗（白蛋白紫杉醇及吉西他滨方案）在晚期胰腺癌患者中的Ib/II期临床研究。
该研究是一项多中心、开放性的Ib期剂量探索研究以及II期疗效探索研究，旨在评价APG-1387联合白蛋白紫杉醇及吉西他滨治疗晚期胰腺癌的安全性、PK特征及初步的疗效。
APG-1387
APG-1387为亚盛医药在研的新一代凋亡蛋白抑制因子 (IAP) 高效特异性抑制剂，主要通过模拟内源性 SMAC 分子降解 IAPs 来诱导和加速细胞凋亡的进程。在一系列体内外研究中，APG-1387单用以及与化疗药物或靶向治疗联用，能够有效抑制不同的异种移植瘤模型的肿瘤细胞生长，这为APG-1387在临床进一步开展抗肿瘤疗效的探索提供了有力的数据支持。APG-1387是中国首个进入临床阶段的IAP抑制剂。
APG-1387目前在中国和澳大利亚都完成了针对晚期实体瘤的I期研究，临床显示耐受性良好。APG-1387在美国正在进行的I期临床研究初期数据发表于2019年美国临床肿瘤学会（ASCO）年会。该研究发现，APG-1387 单药对于既往多线治疗失败的晚期胰腺癌患者，显示出了一定的抗肿瘤活性，10例单药治疗的晚期胰腺癌患者中，有4例获得疾病稳定（SD），其中1例45mg组SD超过9个治疗周期。总体上，APG-1387耐受性良好，不良事件可控。
胰 腺 癌
胰腺癌是一种恶性程度很高的消化系统肿瘤。由于预后较差，其发病率约等于死亡率1，已取代肝癌成为新一代的“癌中之王”。胰腺癌在中国是第九大肿瘤类型，其发病率逐年提升。由于胰腺解剖部位特殊，胰腺癌早期症状不明显。大多数患者在诊断时，疾病已处于进展期或者已出现转移，不能手术。转移性胰腺癌的中位生存期仅为4-6 个月。2015年统计数据显示中国胰腺癌患者的5年生存率为7.2%，是中国生存率最低的肿瘤2。近年来肿瘤治疗进展迅速，靶向治疗及免疫治疗的问世让肺癌、乳腺癌甚至肝癌等恶性肿瘤的生存率大大提高。然而，胰腺癌的治疗方案及药物依旧有限，对于不可切除的局部进展期或合并远处转移的胰腺癌患者，化疗仍然是主要治疗选择，但治疗后中位生存期依旧无法超过一年。因此胰腺癌治疗效果的提高是临床迫切需要解决的问题。
“对于胰腺癌特别是晚期胰腺癌的有效治疗，是目前全球都尚未满足的、急需的临床需求。作为中国首个进入临床阶段的IAP抑制剂，APG-1387 此前的临床数据显示出对晚期胰腺癌患者的较大潜力。我们将积极推进APG-1387在中国的Ib/II期临床试验开展，为胰腺癌患者提供新的治疗可能性。”
亚盛医药首席医学官翟一帆博士
关于APG-1387
APG-1387是亚盛医药设计开发的新型小分子细胞凋亡蛋白抑制因子（IAP）抑制剂。公司正在全球范围内开发APG-1387，目前已在中国和澳大利亚完成针对实体瘤的临床I期剂量爬坡试验，正在美国开展与帕博利珠单抗联合治疗的Ib/II期临床试验。同时正在中国进行用于治疗乙型肝炎的Ib期临床试验。
关于亚盛医药
亚盛医药（6855.HK）是一家立足中国、面向全球的处于临床阶段的原创新药研发企业，致力于在肿瘤、乙肝及与衰老相关的疾病等治疗领域开发创新药物。公司拥有自主研发的蛋白-蛋白相互作用靶向药物设计平台。2019年10月28日，亚盛医药在香港联交所主板成功上市。
亚盛医药研发产品管线主要专注细胞凋亡路径关键蛋白的抑制剂，通过抑制BCL-2、IAP 或 MDM2-p53 等，重启肿瘤细胞的凋亡程序；第二代和第三代的针对癌症治疗中出现的激酶突变体的抑制剂等。公司现有8个1类新药已进入到临床开发阶段，正在中国、美国及澳大利亚开展28项I/II期临床试验。
参考文献
1. PrabhuBray F,Ferlay J,SoerjomataramI, et al (2018) Global cancer statistics 2018: GLOBOCAN estimates ofincidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin;68(6):394-424
2. HongmeiZeng, Wanqing Chen, Rongshou Zheng, et al (2018) Changing cancer survival inChina during 2003–15: a pooled analysis of 17 population-based cancerregistries. Lancet Glob Health; 6: e555–67
Ascentage Pharma Announces Approval for the Phase Ib/II Clinical Trial of APG-1387 in Combination with Chemotherapy for the Treatment of Advanced Pancreatic Cancer in China
Ascentage Pharma (6855.HK), a globally-focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced that the company has received approval from Center of Drug Evaluation (CDE), China NMPA, for the Phase Ib/II clinical trial of APG-1387, Ascentage Pharma’s novel inhibitor of apoptosis proteins (IAP) inhibitor, in combination with chemotherapy (nab-paclitaxel plus gemcitabine) for the treatment of advanced pancreatic cancer.
This multi-center, open-label clinical trial is comprised of a Phase Ib dose-escalation study and a Phase II efficacy study, and it is designed to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of APG-1387 in combination with the nab-paclitaxel plus gemcitabine doublet chemotherapy in advanced pancreatic cancer.
APG-1387 is a novel, small molecule IAP inhibitor that induces apoptosis by mimicking the dimeric form of the SMAC protein. In a range of in vivo and in vitro studies in multiple xenograft tumor models, APG-1387, either as a monotherapy or in combination with targeted agents or chemotherapies, demonstrated its ability to effectively inhibit the growth of tumor cells, which provided supporting evidence to the further clinical investigation of APG-1387. APG-1387 is the first IAP inhibitor to enter clinical trials in China.
APG-1387 has completed Phase I clinical trials in advanced solid tumors in China and Australia, and it was shown to be well-tolerated. The preliminary result from the ongoing Phase I trial of APG-1387 in the U.S. was presented at the 2019 Annual Meeting of American Society of Oncology (ASCO). The data demonstrated APG-1387’s promising anti-tumor activity in advanced pancreatic cancer patients who had failed multiple prior lines of treatments. Among 10 advanced pancreatic cancer patients treated with APG-1387 monotherapy, 4 patients achieved SD (stable disease), including one patient at 45 mg who has been treated for over 9 cycles with confirmed SD. Overall, APG-1387 was well-tolerated with manageable adverse events.
Pancreatic cancer is a highly aggressive form of gastrointestinal cancer. With a poor prognosis and an incidence rate at par with its mortality rate 1, pancreatic cancer has overtaken liver cancer as the deadliest type of all malignancies. Pancreatic cancer is ranked the ninth largest cancer type in China, with a rising incidence rate year after year. Due to the unique anatomical characteristics of the pancreas, the symptoms of early-stage pancreatic cancer are relatively silent. As a result, pancreatic cancer patients are commonly diagnosed at advanced stages or when they have developed metastasis, disqualifying them for surgery. The current median survival of patients with mPC (metastatic pancreatic cancer) is four to six months, and the 2015 statistics shows a five-year survival rate of just 7.2%, making pancreatic cancer the malignancy with the lowest survival rate in China 2.
In recent years, the rapid advancement in cancer therapies, particularly the introduction of targeted therapies and immunotherapies, has significantly improved the survival of many malignancies, including lung cancer, breast cancer, and liver cancer. However, the treatment standard for pancreatic cancer remains unchanged with very limited options. For patients with unresectable locally advanced or remotely metastasized pancreatic cancer, chemotherapy is still the primary treatment, although it only delivers a median post-treatment survival for shorter than one year. That being the case, there is urgent need to improve the clinical outcomes of pancreatic cancer treatment.
“For pancreatic cancer, in particular those cases that have progressed to advanced stage, there remains an urgent clinical need for more effective treatment options globally. As the first IAP inhibitor to enter clinical trials in China, early clinical data of APG-1387 has demonstrated its great potential for the treatment of advanced pancreatic cancer,” said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. “We will start this Phase Ib/II trial of APG-1387 in China as early as possible, with the hope to bring new treatment options to pancreatic cancer patients.”
About APG-1387
APG-1387 is a novel small molecule IAP inhibitor (Inhibitor of Apoptosis Protein), which was discovered and is being developed by Ascentage Pharma. Ascentage is developing APG-1387 globally, and has completed dose escalation Phase I trials in solid tumors in China and Australia, and a Phase Ib/II clinical trial of APG-1387 and pembrolizumab combination is currently ongoing in the U.S. In addition, APG-1387 is also being investigated in a Phase Ib trial for the treatment of patients with Chronic Hepatitis B in China.
About Ascentage Pharma
Ascentage Pharma (6855.HK) is a globally-focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases. The company focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited.
Ascentage Pharma has built a pipeline of eight clinical drug candidates, including a novel, highly potent Bcl-2/Bcl-xL inhibitor, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors. The company has been conducting 28 Phase I/II clinical trials to evaluate the eight drug candidates in the United States, Australia, and China, developing the potential therapies as a single agent or in combination.
References:
1. PrabhuBray F,Ferlay J,SoerjomataramI, et al (2018) Global cancer statistics 2018: GLOBOCAN estimates ofincidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin;68(6):394-424
2. HongmeiZeng, Wanqing Chen, Rongshou Zheng, et al (2018) Changing cancer survival inChina during 2003–15: a pooled analysis of 17 population-based cancerregistries. Lancet Glob Health; 6: e555–67