Aerosolized Epigenetic Therapy for Metastatic Lung Cancer

雾化表观遗传疗法治疗转移性肺癌

• 批准号: 10760630
• 负责人: Steven A Belinsky
• 金额: $ 86.11万
• 依托单位: NOB HILL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760630
• 关键词: Acute leukemia; Aerosols; Air; Air Movements; Azacitidine; Brain; Breathing; Cancer Etiology; Cancer Model; Cancer Patient; Catabolism; Cells; Cessation of life; Characteristics; Chemicals; Chronic Obstructive Pulmonary Disease; Clinic; Clinical Research; Combination Drug Therapy; Cytidine Deaminase; Cytosine; Data; Deoxycytidine; Devices; Diagnosis; Disease; Documentation; Dose; Drug Kinetics; Dryness; Dysmyelopoietic Syndromes; Emulsions; Enzyme Inhibition; Epigenetic Process; Europe; Evaluation; FDA approved; Forced expiratory volume function; Formulation; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Half-Life; Hour; Human; Hypermethylation; Immune; Immunotherapy; Inhalation; Inhalation Toxicology; Inhalators; Injections; Investigational Drugs; Label; Legal patent; Liver; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Modeling; Nebulizer; Particle Size; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Powder dose form; Practice Guidelines; Progression-Free Survivals; Promoter Regions; Rattus; Regulatory Pathway; Relapse; Reporting; Research; Resistance; Rodent; Rodent Model; Safety; Signal Pathway; Small Business Innovation Research Grant; Solid Neoplasm; Stream; Technology; Testing; Therapeutic; Tissues; Toxicology; Tumor Burden; Work; absorption; aerosolized; aqueous; chemotherapy; epigenetic therapy; first-in-human; good laboratory practice; immune activation; improved; in vivo; innovation; manufacture; novel; nucleoside analog; phase III trial; pre-clinical; pressure; programs; promoter; pulmonary function; quality assurance; research clinical testing; response; safety study; scale up; standard of care; success; transcriptome; transcriptome sequencing; tumor; tumor heterogeneity

Project Summary Lung cancer (LC) with over 2 million cases/year worldwide also remains the leading cause of cancer- related death in the US and Europe. Treating LC remains challenging due to ~60% of patients presenting with Stage IV disease, the heterogeneity of tumors with respect to genetic and epigenetic mechanisms that alter gene expression, and treatment-related resistance. Combining chemotherapy with immunotherapy as the first treatment option for advanced LC has significantly improved response rates and survival; however, median duration for progression free survival (PFS) was still 8.8 versus 4.9 months for Stage IV LC patients receiving chemo/immune versus chemotherapy with 69% and 49% alive at one year, respectively. Second line drugs after relapse provide minimal benefit. Epigenetic deregulation involves cytosine methylation in the promoter region of hundreds of genes to impede transcription leading to loss of expression. Thus, a therapy that could reverse methylation and awaken these genes could produce durable and sustained tumor regression. The cytosine nucleoside analogs 5-azacytidine (5AZA) and 5-aza-2’-deoxycytidine (DAC) inhibit the enzyme responsible for cytosine methylation resulting in re-expression of genes silenced through cytosine promoter hypermethylation. These FDA approved drugs are serving as potent therapy for blood-borne cancers, myelodysplasia and acute leukemia. Epigenetic therapy for solid tumors including LC has been impacted by the poor stability in an aqueous solution of 5AZA and DAC and catabolism by cytidine deaminase in liver and GI. Lovelace Biomedical working with Bend Research/Lonza have overcome these barriers by developing a stable dry powder (DP) formulation of 5AZA (5AZA-DP). The novel dry powder nebulizer (DryNeb) developed by Nob Hill Therapeutics generates optimal aerosol particle sizes for local lung delivery-activity and optimal systemic absorption characteristics while facilitating patients’ “easy” tidal breathing inhalation with no forced pulmonary function maneuvers. In studies in which 5AZA-DP was delivered to tidally breathing rats, superior pharmacokinetics were achieved in the liver, and most impressively to the brain with a half-life of 4 hours when compared with injected aqueous solutions of 5AZA. Using a rat lung tumor model developed from instilling cells obtained from human lung tumors, tidally inhaled 5AZA-DP reduced tumor burden by 70–95% for the 4 different non-small cell lung tumors evaluated, far exceeding the 32% reduction seen with systemic injection of 5AZA. A proof-of-concept clinical study showed stable localized lung cancer in 3 of 8 Phase I patients treated with nebulized aqueous 5AZA. This Phase II SBIR through three specific aims builds on these exciting data by focusing on performing formulation scale up and stability optimization of 5AZA-DP, aerosol performance in the DryNeb, and GLP toxicology studies. Completion of these aims will support filing an investigational drug application (IND) to the FDA to allow evaluation of 5AZA-DP using DryNeb in a Phase I dose escalation safety study followed by a Phase IB study in LC patients who have relapsed on standard-of-care therapy.

项目概要 全球每年有超过 200 万例肺癌 (LC) 仍然是癌症的主要原因 - 美国和欧洲的相关死亡。治疗 LC 仍然具有挑战性，因为约 60% 的患者出现 IV 期疾病，肿瘤在遗传和表观遗传机制方面的异质性，改变 基因表达和治疗相关的耐药性。化疗联合免疫治疗为首 晚期 LC 的治疗选择显着提高了缓解率和生存率；然而，中位数 IV 期 LC 患者的无进展生存期 (PFS) 仍为 8.8 个月，而接受治疗的患者为 4.9 个月 化疗/免疫与化疗相比，一年存活率分别为 69% 和 49%。二线药物 复发后提供的益处微乎其微。表观遗传失调涉及启动子中的胞嘧啶甲基化 数百个基因的区域阻碍转录，导致表达丧失。因此，一种疗法可以 逆转甲基化并唤醒这些基因可以产生持久且持续的肿瘤消退。这 胞嘧啶核苷类似物 5-氮杂胞苷 (5AZA) 和 5-氮杂-2'-脱氧胞苷 (DAC) 抑制该酶 负责胞嘧啶甲基化，导致通过胞嘧啶启动子沉默的基因重新表达 超甲基化。这些 FDA 批准的药物可作为血源性癌症的有效治疗方法， 骨髓增生异常和急性白血病。包括 LC 在内的实体瘤的表观遗传学治疗受到以下因素的影响 5AZA 和 DAC 在水溶液中的稳定性较差，并且会被肝脏中的胞苷脱氨酶分解代谢， 地理标志。 Lovelace Biomedical 与 Bend Research/Lonza 合作，通过开发一种 5AZA (5AZA-DP) 的稳定干粉 (DP) 配方。开发出新型干粉雾化器（DryNeb） Nob Hill Therapeutics 生产的气雾剂颗粒大小适合局部肺部输送活性和最佳 全身吸收特性，同时促进患者“轻松”潮式呼吸吸入，无需用力 肺功能演习。在将 5AZA-DP 给予潮式呼吸大鼠的研究中， 药代动力学是在肝脏中实现的，最令人印象深刻的是在大脑中，半衰期为 4 小时 与注射的 5AZA 水溶液相比。使用通过滴注开发的大鼠肺肿瘤模型 从人肺肿瘤中获得的细胞，潮式吸入 5AZA-DP 可使肿瘤负荷在 4 天内减少 70-95% 对不同的非小细胞肺肿瘤进行评估，远远超过全身注射 32% 的减少 5AZA。一项概念验证临床研究显示，8 名接受 I 期治疗的患者中有 3 名患有稳定的局限性肺癌 雾化 5AZA 水溶液。第二阶段 SBIR 通过三个具体目标建立在这些令人兴奋的数据的基础上： 专注于 5AZA-DP 的配方放大和稳定性优化，气雾剂性能 DryNeb 和 GLP 毒理学研究。完成这些目标将支持提交研究药物 向 FDA 提交申请 (IND)，允许在 I 期剂量递增中使用 DryNeb 评估 5AZA-DP 的安全性 随后对接受标准护理治疗复发的 LC 患者进行 IB 期研究。