I-131-Apamistamab

日前，Actinium Pharmaceuticals的核心管线放射性同位素偶联药物（ARC）Iomab-B，针对AML的生物制品许可申请（BLA）被FDA拒绝。 在上市申请被拒之后，Actinium公司宣布将为Iomab-B寻找战略合作伙伴，暂时搁置了Iomab-B，并将重点转移到其他管线开发上。 新型抗体开发难度高、风险大，同时还伴有监管不确定性。Thermo Fisher聚焦抗体药，铸就全流程新范式，助力创新药开发。 备受关注的Iomab-B Iomab-B是CD45靶向药物中研发速度最快的项目，备受业内关注。 Iomab-B由CD45靶向单克隆抗体apamistamab与放射性同位素碘-131偶联而成。CD45是一种广泛表达于所有类型的血液癌细胞和免疫细胞(包括骨髓祖细胞)的抗原，Iomab-B通过apamistamab特异性靶向，实现碘-131精准递送，避免非靶向化疗和/或外部光束辐射对大多数健康组织的副作用，同时有效地杀死患者的癌症和骨髓细胞。 Iomab-B主要被开发作为一种诱导或处理疗法，旨在通过快速耗竭特异性表达CD45的血液癌细胞、免疫细胞和骨髓干细胞，以增加血液肿瘤患者接受骨髓移植（BMT）的机会。BMT能够提高血液肿瘤患者的生存率，但是大多数患者并未能够获得接受BMT的资格，因为BMT需要患者获得疾病缓解。 2023年2月，Actinium公司发布了Iomab-B针对急性髓细胞白血病（AML）的3期临床SIERRA研究的数据，数据显示：22%的患者持续6个月完全缓解（dCR），这种效果在统计学上被认为非常显著；那些达到6个月dCR的患者一年存活率为90%，两年存活率为60%。 延伸阅读：ARC药物临床大获全胜，但是？ 同时，Actinium报告，接受Iomab-B治疗的患者100%能够接受BMT；对照组仅有17%的患者能接受BMT，82%的患者未能够达到持久的完全缓解，没有资格接受BMT。 2023年年底，Actinium向FDA提交了Iomab-B的BLA。 被拒原因 事实上，Actinium对于Iomab-B的商业化推进十分有信心——从其2022年开始大肆扩招高管团队可以佐证。 但，出乎Actinium意料的是，FDA拒绝了Iomab-B用于AML的的BLA申请。 根据新闻稿，FDA肯定Iomab-B的主要终点具有统计学意义，但3期SIERRA试验不足以支持Iomab-B的BLA申请。 FDA建议Actinium进行额外的头对头随机临床试验，评估 lomab-B+Flu/TBI 与  环磷酰胺+Flu/TBI 预处理后的同种异体BMT，来证明Iomab-B的总体生存期获益。 该方案与SIERRA试验不同，SIERRA试验允许医生在对照组中选择挽救疗法和异质预处理方案。此外，拟议的研究方案不允许对照组交叉设计；然而在SIERRA试验中是允许的，同时由于交叉设计，对照组的OS被交叉混淆，而这个OS的次要终点在治疗意向(ITT)人群中没有达到。 在Actinium与FDA的讨论中，Actinium打算进一步讨论包括患者群体在内的额外临床试验的细节，FDA建议可能包括所有成年AML患者。 寻找“接盘侠” 在同一份新闻稿中，Actinium宣布将在美国寻找Iomab-B的战略合作伙伴，并将未来开发工作重点放在Actimab-A、Iomab-ACT和临床前项目上。 虽然不清楚具体原因，但是这表明了Actinium公司认同放弃了对Iomab-B，不过Actinium公司在Iomab-B的开发上投入了大量心血。 有可能是FDA对Iomab-B提出的头对头研究，也有可能是因为Iomab-B后续开发的资金缺口。根据Actinium发布的2024年第二季度财报，该公司的现金、现金等价物和限制性现金为8635.5万美元。 Actimab-A是一款CD33靶向的、基于锕-225的放射性同位素偶联药物（ARC），旨在与其他方案联合应用，开发一种AML骨干疗法。目前，Actimab-A正在进行2项1/2期研究，分别是Actimab-A+CLAG-M联用治疗AML，和Actimab-A+Venetoclax联用治疗AML。 Iomab-ACT与Iomab-B相似，但是由CD45单抗apamistamab与较低水平的非清髓性碘-131偶联而成，作为CAR-T等细胞或基因治疗前的预处理开发。目前处于临床开发阶段。 小结 最近，核药很火，多笔大额投资、并购和交易。 相较于传统的放射疗法，放射性偶联药物能够实现特异性给药，能够提高潜在疗效，并且降低治疗副作用，减少对健康细胞的伤害。 参考资料： 1.https://www.biospace.com/drug-development/actinium-to-farm-out-aml-radioactive-drug-after-fda-asks-for-another-trial 2.https://ir.actiniumpharma.com/press-releases/detail/486/actinium-provides-regulatory-update-on-planned-bla-filing

FDA determined that the Phase 3 SIERRA trial is not adequate to support a BLA filing for Iomab-B despite its statistically significant primary endpoint Additional head-to-head randomized clinical trial demonstrating overall survival benefit with Iomab-B is required by FDA to support a BLA filing Actinium to request a meeting with the FDA to further discuss specifics of additional trial Actinium will seek strategic partner for Iomab-B in the U.S. following completion of FDA interactions and focus development efforts on Actimab-A, Iomab-ACT and preclinical programs NEW YORK, Aug. 5, 2024 /PRNewswire/ -- Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of Antibody Radiation Conjugates ("ARCs") and other targeted radiotherapies, today announced a regulatory update on the Company's planned Biologics License Application ("BLA") filing for Iomab-B in patients with active relapsed or refractory acute myeloid leukemia ("r/r AML"). Iomab-B is an induction and conditioning targeted radiotherapy agent comprised of an anti-CD45 monoclonal antibody and Iodine-131 radioisotope payload. The Company announced that it has now concluded both its clinical and Chemistry, Manufacturing and Controls ("CMC") interactions with the FDA regarding the BLA pathway for Iomab-B. Despite the SIERRA trial meeting the primary endpoint of durable Complete Remission ("dCR") with statistical significance (p-value<0.0001) and other positive secondary endpoints including Event Free Survival ("EFS") and safety, the FDA has now determined that demonstrating an overall survival benefit in a randomized head-to-head trial is required for a BLA filing. The FDA has advised Actinium to conduct a study to evaluate allogeneic bone marrow transplant ("BMT") using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation ("Flu/TBI") versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI, a difference from the SIERRA trial, which had allowed physician's choice of salvage therapies and heterogenous conditioning regimens in the control arm. Additionally, the proposed new study will not allow patients to crossover from the control arm which was allowed in the SIERRA trial and confounded the overall survival analysis in the intent to treat ("ITT") patient population, as nearly 60% of patients crossed over from the control arm. The Phase 3 SIERRA trial enrolled 153 patients with r/r AML and compared outcomes of patients receiving Iomab-B and BMT to patients receiving physician's choice of care with salvage chemotherapy and standard allogeneic BMT in the control arm. In February 2023, Actinium announced that the SIERRA trial met the primary endpoint with statistical significance as 22% of patients (13/76) on the Iomab-B arm achieved dCR compared to 0% of patients (0/77) on the control arm resulting in a p-value of <0.0001. The SIERRA trial was conducted in accordance with guidance from the End of Phase 2 meeting with the FDA, which stated that positive results for dCR as the primary endpoint would be an acceptable endpoint to support an Iomab-B BLA filing. SIERRA did not meet the secondary endpoint of overall survival on an intent to treat basis analysis due to the high crossover rate with nearly 60% of control arm patients receiving Iomab-B followed by a BMT. Over the last several years, a majority of therapies for patients with AML have been approved based on achieving a positive overall survival endpoint. Actinium presented several additional analyses from the SIERRA study to the FDA including long-term follow-up that demonstrated a trend towards improved overall survival and evidence of survival benefit in patients with high-risk TP53 mutations to support Iomab-B's impact on overall survival. The SIERRA trial data were presented in 12 oral presentations at several leading bone marrow transplant, hematology and nuclear medicine conferences in both the U.S. and Europe, which Actinium believes demonstrates the high unmet medical need and scientific importance of Iomab-B's ability to provide improved access and outcomes for patients with active r/r AML to the transplant community. However, the FDA has now determined that the analyses from the SIERRA trial do not adequately support a BLA filing for Iomab-B and requires an additional clinical study. Actinium expects the safety and efficacy data from the SIERRA trial will provide supportive evidence for a future Iomab-B BLA filing . Key Outcomes and Implications of FDA Interactions Phase 3 SIERRA trial results are not adequate to support a BLA filing for Iomab-B in patients with active r/r AML FDA is requiring an additional randomized head-to-head trial to demonstrate an overall survival benefit evaluating allogeneic BMT using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation (Flu/TBI) to allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI Proposed additional clinical trial to evaluate Iomab-B plus Flu/TBI compared to a single regimen comprised of cyclophosphamide plus Flu/TBI which differs from the SIERRA trial that allowed physician's choice of salvage therapy and heterogenous conditioning regimens in the control arm The proposed additional clinical trial will not allow crossover, which was allowed in SIERRA, and confounded the overall survival analysis in the intent to treat (ITT) patient population as nearly 60% of patients crossed over from the control arm Actinium intends to further discuss the specifics of the additional clinical trial including the patient population, which the FDA has suggested could include all adult AML patients Upon conclusion of its interactions with the FDA, Actinium will seek a strategic partner for Iomab-B for the U.S. Dr. Avinash Desai, Actinium's Chief Medical Officer, said, "While this is not the outcome we expected, we will work with the FDA to further discuss specifics of the proposed randomized head-to-head clinical study to determine its strategic feasibility. The 12 oral presentations of the SIERRA results at prestigious bone marrow transplant, hematology and nuclear medicine medical conferences in the U.S. and EU are an attestation of the strong interest from the transplant community for better conditioning regimens due to the high unmet need. We are grateful to the patients, their families, as well as the study investigators and their staff who participated in the SIERRA trial. As a first of its kind study, SIERRA broadened the investigation of Iomab-B as a targeted induction and conditioning agent from a single center to twenty-four leading bone marrow transplant centers in North America, demonstrating its potential for the first time in a randomized, controlled study. Through the conduct of SIERRA, Actinium also built strong relationships with key thought leaders. This track record will provide a solid foundation to work with a partner on a subsequent Iomab-B trial, and we look forward to finalizing the path forward for Iomab-B in the U.S. with the FDA." Sandesh Seth, Actinium's Chairman and CEO, said, "We are disappointed that the positive results from the SIERRA trial are not deemed adequate by the FDA to support a BLA filing despite meeting the primary endpoint with statistical significance and producing positive efficacy and safety outcomes on several measures. SIERRA represented a first of its kind radiotherapeutic trial and demonstrated Actinium's ability to execute seamlessly across manufacturing, supply chain, clinical development, and operations. We intend to leverage these capabilities as we continue to advance our highly differentiated antibody radiation conjugate pipeline for cell & gene therapy conditioning, hematology therapeutics and solid tumor candidates. We are committed to establishing the best development path forward for Iomab-B in the U.S. and finding a partner, while keeping internal resources and strategic priorities in focus." About Actinium Pharmaceuticals, Inc. Actinium develops Antibody Radiation Conjugates ("ARCs") and other targeted radiotherapies intended to meaningfully improve outcomes for people who have failed existing oncology therapies. Iomab-B is an induction and conditioning agent prior to bone marrow transplant in patients with relapsed and refractory acute myeloid leukemia ("r/r AML"), which Actinium plans to advance with a potential strategic partner in the U.S. following completion of FDA interactions. The company continues to advance its development for product candidate Actimab-A, a therapeutic agent that has demonstrated potential activity in r/r AML patients. In addition, Actinium is engaged with the National Cancer Institute ("NCI") under the Cooperative Research and Development Agreement ("CRADA") for development of Actimab-A in AML and other myeloid malignancies. Iomab-ACT, Actinium's next generation conditioning candidate, is being developed with the goal of improving patient access and outcomes for potentially curative cell and gene therapies. In addition, the company's R&D efforts are primarily focused on advancing several preclinical programs for solid tumor indications. Actinium holds more than 235 patents and patent applications including several patents related to the manufacture of the isotope Ac-225 in a cyclotron. For more information, please visit: Forward-Looking Statements This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time. Investors: [email protected] SOURCE Actinium Pharmaceuticals, Inc.