A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

Abstract

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

Trial registration: ClinicalTrials.gov NCT01186419.

Figures

Figure 1

Creatinine measures by dose group. The mean creatinine values at each of the study visits shown are represented by mean ± SD. ○ represents the low-dose cohort; and ▵, the high-dose cohort. No significant difference between groups was noted at any time during the study, and the week 24 and study week 28 values did not differ from baseline. Most patients remained on drug for the week 28 measures, in the extension phase of the study. “Week 0” indicates baseline values before administration of FBS0701. Details of creatinine by patient and by treatment group are presented in supplemental Figure 1.

Figure 2

LIC assessed by FerriScan (R2) MRI. For each dose cohort, mean ± SD of the LIC values are shown. ○ represents the low-dose cohort; and ▵, the high-dose cohort. At week 24 MRI assessment, the difference between dose cohorts was significant (P < .03).

Figure 3

Distribution of LIC changes compared with baseline in the 29 mg/kg per day dose cohort, assessed at week 24. Histogram depiction of the number of patients in the high-dose cohort who achieved specified change in LIC compared with baseline. A statistical analysis is presented in supplemental Figure 2.