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）在美国是一种孤儿病，约有110，000人受影响，但它仍是一种严重的疾病。 这是一个重大的医疗经济问题，每年的住院费用超过10亿美元。SCD患者遭受 由于微血管闭塞、溶血性贫血和慢性血管闭塞性疼痛， 缺血-再灌注损伤引起的炎症状态，最终导致器官衰竭和生命缩短 期待FDA批准的治疗SCD的疾病缓解剂只有四种，包括羟基脲（HU） 1998年，Endari®（l-谷氨酰胺）在2017年，最近Adakevo®（crizanlizumab）和Oxbryta®（voxelotor） 2019年HU主要通过逆转从胎儿到成人血红蛋白（Hb）表达的围产期转换起作用; 增加红细胞（RBC）中的胎儿血红蛋白（HbF）含量发挥有效的抗镰状化作用。 HU对生存和器官功能保护的长期有益作用记录在多项研究中。 基于17年随访的羟基脲中心研究，以及许多其他成人和儿童研究， SCD;尽管有这些好处，但HU在SCD中未得到充分利用。虽然人们正在研究HU利用不足的原因， 在NHLBI资助的实施研究中，在八个中心进行了调查，临床经验表明， 担心与HU相关的副作用、生育力和致癌性，因此产生了未满足的需求， 额外的疾病缓解抗转换疗法。组蛋白去乙酰化酶抑制剂（HDACi）已被证明 在红系培养物和SCD小鼠模型的临床前研究中诱导Hb F表达，主要通过 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 染色质激活转录。我们之前进行了一项由制药商发起的泛- HDACi帕比司他在SCD成人中的应用。9名患者接受帕比司他10 mg MWF治疗，3名患者接受帕比司他10 mg MWF治疗。 不同给药方案的队列。该药物耐受性良好，无毒性或副作用。略有 在10 mg MWF连续治疗剂量下观察到Hb F和F细胞增加。为了测试 帕比司他，我们建议完成三个具体目标：1）完成I期试验， 帕比司他剂量（总共18名患者，15 mg或20 mg MWF，间歇或连续治疗）。的 主要终点是确定帕比司他在SCD患者中的安全性和耐受性。次要终点 将包括监测Hb F和F细胞的变化。2)启动新的干预措施以支持研究依从性， 动机面试，已被证明是有效的，在帮助个人克服障碍， 药物和治疗依从性在各种设置。3)定义预测帕比司他的生物标志物 治疗反应。包括NF κ B、STAT和p53在内的非组蛋白蛋白的乙酰化和炎性细胞因子的表达。 标记将被调查。此外，组蛋白乙酰化的全基因组生物标志物将被发现， ChIPSeq和RNASeq差异表达基因。本研究将确定帕比司他在以下患者中的安全性： SCD将为靶向多种途径提供概念验证，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.