Phase 1/2 Clinical Trial of HQK-1001, An Oral Fetal Hemoglobin Stimulant, In Sickle Cell Anemia

Abstract 943

Definitive therapies to reduce the underlying pathology in sickle cell syndromes are still needed, particularly non-cytotoxic therapeutics which could be used either alone or in combination with hydroxyurea. Increased fetal hemoglobin (HbF) levels correlate with reduction in organ damage and improved patient survival. An oral, promoter-targeted fetal globin gene stimulant, HQK-1001, which also prolongs erythroid survival and proliferation, has demonstrated favorable pharmacokinetic (PK) and safety profiles in normal volunteers in a Phase 1 clinical trial. Accordingly, a randomized, blinded dose-ranging Phase 1/2 trial was performed in 24 adult patients with sickle cell disease (including HbSS or S/ß thalassemia). The study therapeutic was administered once daily for two 6-week cycles of daily therapy with a 2 week treatment break between the two cycles. Three dose levels (10, 20, 30 mg/kg/dose) were studied sequentially, with 4 placebo treated subjects. 21 patients were evaluable. Five patients received active drug at the lower two dose levels; 7 patients received active study drug at the 30 mg/kg dose level. HQK-1001 was well-tolerated with no significant drug-related adverse events. Increases in HbF levels were observed at all dose levels with the highest effects observed at 30 mg/kg, where 5 of 7 treated patients responded with a mean peak increase of 2.6% HbF (absolute 0.2 g/dl, p=0.04) above baseline. HbF increased both in patients who did, and who did not, take concomitant hydroxyurea. A mean peak increase in total hemoglobin of 1.3 g/dL (range 0.9 to 2.4) above baseline was also observed in these HQK-1001-treated patients. F-reticulocytes and F-cells increased by 20–33% and 6–18%, respectively, in the 5 responders at the 30 mg/kg dose level. LDH declined in 4 of 5 responding subjects receiving 30 mg/kg doses. Fetal globin mRNA increased by 4- to 9-fold over baseline throughout the study period in treated patients and was still increasing at the end of the dosing period, implying that HbF expression had not yet peaked. Other fetal globin inducing agents, such as hydroxyurea require 6–9 months of treatment for optimal effects on HbF to be achieved. Therefore, the findings of HbF induction and rises in total Hgb in 70% of subjects with short treatment duration in the current study indicate that longer trials of HQK-1001 are warranted to evaluate potential therapeutic effects on HbF expression and anemia more definitively in sickle cell disease.