Phase I study of panobinostat in adults with sickle cell disease: novel approach to recruitment and retention

摘要 尽管镰状细胞病(SCD)是美国的一种孤儿疾病，约有110,000人受到影响，但它构成了一种 主要的医疗经济问题，每年的住院费用高达10亿美元。系统性红斑狼疮患者 由于微血管闭塞、溶血性贫血和慢性血管闭塞引起的血管闭塞性疼痛发作。 由缺血-再灌注损伤引起的炎症状态，最终导致器官衰竭和寿命缩短 期望值。目前只有四种FDA批准的治疗SCD的疾病改良剂，包括羟基脲(HU) 1998年，Endari®(L-谷氨酰胺)于2017年问世，最近又推出了Adakevo®(Crizanlizumab)和Oxbryta®(Voxelotor) 2019年。HU主要通过逆转围产期从胎儿到成人的血红蛋白(Hb)表达而起作用； 增加红细胞(RBC)中胎儿血红蛋白(Hb-F)的含量具有很强的抗镰刀作用。 HU对存活和保护器官功能的长期有益影响被记录在多项研究中 中心对羟基脲的研究，基于17年的随访，以及对成人和儿童的许多其他研究 SCD；尽管有这些好处，HU在SCD中没有得到充分利用。而HU未得到充分利用的原因是 在NHLBI资助的一项实施研究中，八个中心进行了调查，临床经验表明患者 担心与HU相关的副作用、生育能力和致癌性，因此产生了未得到满足的需求 额外的疾病修正抗转换疗法。组蛋白脱乙酰酶抑制剂(HDACi)已被证明 在红系培养和小鼠SCD模型的临床前研究中诱导Hb F的表达，主要是通过 通过组蛋白乙酰化和开放γ-珠蛋白基因抑制胎儿(γ)珠蛋白基因的表观遗传沉默 染色质来激活转录。我们之前进行了一项由调查人员发起的PAN第一阶段试验- HDACi Panobinostat在成人SCD中的应用9名患者接受帕诺比斯特10 mg MWF治疗，3名患者接受治疗 不同给药计划的队列。该药耐受性良好，无毒副作用。微不足道 在10 mg的MWF持续治疗剂量下，Hb、F和F-细胞数显著增加。测试……的效果 Panobinostat，我们建议完成三个具体目标：1)完成I期试验并逐步升级 帕诺比妥剂量(18名患者，15 mg或20 mg MWF，间歇或连续治疗)。这个 主要目的是确定帕诺比妥在SCD患者中的安全性和耐受性。次要端点 将包括监测Hb、F和F细胞的变化。2)发起一种新的干预措施以支持学习坚持， 激励性访谈，已被证明在帮助个人克服障碍方面有效 在各种环境下坚持服药和治疗。3)确定预测潘诺比妥的生物标志物 治疗反应。NFkB、STAT、P53等非组蛋白乙酰化与炎症 将对标记物进行调查。此外，组蛋白乙酰化的全基因组生物标记物将通过 ChIPSeq和RNAseq差异表达基因。本研究将确定帕诺比妥在中国的安全性 SCD并将提供针对多个途径的概念验证，以扩大治疗选择。

ABSTRACT Although an orphan disease in the US with ~110,000 affected individuals, sickle cell disease (SCD) poses a major medical-economic problem, with hospitalization costs of >$1 billion annually. Patients with SCD suffer frequent vaso-occlusive pain episodes due to microvascular occlusion, hemolytic anemia, and a chronic inflammatory state precipitated by ischemia-reperfusion injury, culminating in organ failure and a shortened life expectancy. There are only four FDA-approved disease-modifying agents for SCD, including hydroxyurea (HU) in 1998, Endari® (l-glutamine) in 2017 and more recently Adakevo® (crizanlizumab) and Oxbryta® (voxelotor) in 2019. HU primarily acts by reversing the perinatal switch from fetal to adult hemoglobin (Hb) expression; increasing the fetal hemoglobin (Hb F) content in red blood cells (RBCs) exerts a potent anti-sickling effect. Long-term beneficial effects of HU on survival and preservation of organ function was documented in Multi- Center Study of Hydroxyurea, based on a 17-year follow-up, and many other studies in adults and children with SCD; despite these benefits, HU is underutilized in SCD. While the reasons for underutilization of HU are being investigated in eight Centers in an NHLBI-funded implementation study, clinical experience suggests patients have concerns about side effects, fertility, and carcinogenicity related to HU, thus creating an unmet need for additional disease-modifying anti-switching therapies. Histone deacetylase inhibitors (HDACi) have been shown to induce Hb F expression in erythroid cultures, and in preclinical studies in mouse models of SCD, primarily by inhibiting epigenetic silencing of the fetal (γ) globin genes via acetylation of histones and opening γ-globin genes chromatin to activate transcription. We previously conducted an investigator-initiated phase I trial of the pan- HDACi panobinostat in adults with SCD. Nine patients were treated with panobinostat 10 mg MWF, in three cohorts on different dosing schedules. The drug was well tolerated without toxicities or side effects. A slight increase in Hb F and F-cells was noted in the 10 mg MWF continuous treatment dose. To test the efficacy of panobinostat, we propose to complete three Specific Aims: 1) Complete a phase I trial with escalating panobinostat doses (18 total patients at 15 mg or 20 mg MWF on intermittent or continuous treatment). The primary end-point is to establish the safety and tolerability of panobinostat in SCD patients. Secondary endpoints will include monitoring changes in Hb F and F-cells. 2) Initiate a novel intervention to support study adherence, Motivational Interviewing, which has been shown to be effective in helping individuals overcome barriers to medication and treatment adherence in a variety of settings. 3) Define biomarkers predictive of panobinostat treatment response. The acetylation of non-histone proteins including NFkB, STAT, and p53 and inflammatory markers will be investigated. Furthermore, genome-wide biomarkers of histone acetylation will be discovered by ChIPSeq and differentially expressed genes by RNASeq. This study will establish the safety of panobinostat in SCD and will provide proof-of-concept for targeting multiple pathways to expand treatment options.