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 (¿) globin genes via acetylation of histones and opening ¿-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.
