PB-04 Induces HbF Expression in a Ph1b Trial in Sickle Cell Disease

Abstract Presentation Date: 6/9/2024 Presentation Start Time: 2:27:00 PM Background Fetal hemoglobin (HbF) is established as a potent modulator of severity in sickle cell disease (SCD); any increment has been shown to be beneficial. Hydroxyurea maintains HbF at high levels in children with SCD, with some decline at age 10 years. HU reduces widespread organ damage, and a HbF level > 8.6% corrects survival. Proportions of RBCs containing HbF (F-cells) and amount of HbF/cell are both considered important parameters for benefit, with >70% F-cells and 10 pg F/cell proposed as targets. As many adults do not tolerate optimal doses due to myelosuppression, additional therapies which can be used with HU are considered desirable. Benserazide (PB-04) was discovered in a high throughput screen to induce the fetal globin gene promoter, and to suppress or displace 4 repressors associated with HPFH, including Bcl-11A, KLF-1, LSD-1, and HDAC-3. In a Ph1b dose-ranging Study of PK, Safety, and preliminary efficacy (NCT04432631) which first enrolled beta thalassemia patients, active doses were identified which induced F-reticulocytes up to 14.8-fold, F-cells up to 7-fold, HbF/cell up to 11-fold, and HbF up to 14% >baseline. In a prior report, PB-04 treatment restored myelopoiesis which was profoundly suppressed by HU in sickle mice and reduced organ damage. Accordingly, 2 single daily doses were explored in 7 individual subjects with SCD, of whom 3 were taking HU at MTD. Methods Patients with HbSS or S-beta thalassemia were enrolled sequentially to receive either 3 or 5 mg/kg/dose to a maximum dose of 350 mg, once/day, 3 days/week (QOD) for 24 wks. Baseline chemistry and CBC laboratory values, medical history, QOL assessments, and assays of HbF, F-cells, F-reticulocytes, and mean HbF/cell by flow cytometry were obtained during screening, every 4 weeks during the treatment period, and at 4-8 weeks afterwards. PK studies were performed on day 1 and at/ after week 4. Sickling of F-cells, F-reticulocytes after 20 minutes of deoxygenation was assessed by ImageMaster for round or sickled cells, and whole blood adhesion to VCAM were performed every 3 months. Although not powered to detect statistical significance, signed rank non-parametric tests or t-tests were preliminarily performed to assess potential early trends. Results Seven individual subjects (ages 31-51 years, mean 37 years; 4 female) enrolled on 8 treatment courses. There were no drug-related SAEs. Significant increases in F-cells (from mean BL 48.9% to 62.9% (p = 0.03), F-reticulocytes (mean increase 20%, p < 0.001), and HbF (up to 13.8% above BL) were observed. In HU-treated subjects, F-cells increased from mean 63% to 80%. A dose-proportional increase was observed in 3 subjects who were taking HU at MTD. Addition of PB-04 to 2/2 subjects at 5 mg/kg increased HbF further to levels >30% and F-cells >80%, and to 13% HbF, 94.7% F-cells in the subject who received the 3 mg/kg dose. The mean proportion of RBCs with normal morphology after prolonged deoxygenation increased from BL 50.9% to 82% (p = 0.043). Whole blood adhesion to VCAM declined in 3 subjects. Responses are illustrated in Figure 1. Conclusions Preliminary investigation on a Ph1b safety study strongly suggests that PB-04 increases HbF expression assessed by F-cell proportions, amount of HbF/cell, and total HbF levels, has additive activity with HU, achieving targets for reducing disease severity. The findings support further investigation of this therapeutic and additional dosing regimens in larger numbers of patients with sickle cell disease. HbF Expression with PB-04 Baseline values are shown in blue; peak values with PB-04 are shown in yellow. Left panel: F-reticulocytes The top three subjects in the left panel were taking HU at MTD. Right panel: HbF/cell (MFI)

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