A Randomized, Open-Label, Multicenter, Dose Escalation Study of HQK-1001 (2,2-Dimethylbutyrate, Sodium Salt) in Sickle Cell Disease
Authors: Kutlar Abdullah , Reid Marvin , Taher Ali T , Inati Adlette , Abboud Miguel R. , El-Beshlawy Amal , Buchanan George R. , Smith Hedy , Ataga Kenneth I. , Koshy Nebu , Neumayr Lynne D , Malik Punam , Alvarez Ofelia A. , Ward Richard , White J Michael , Johnson Elsa , Ghalie Richard G. 
Published: October 2019

Abstract
Abstract 998
Fetal hemoglobin (Hb F) induction is an effective therapeutic strategy in SCD. Widespread use of hydroxyurea (HU), the only approved anti-switching agent, has been limited by patient concerns about tolerability, patient compliance, and long-term use of a cytotoxic agent. There is a need for alternative anti-switching agents that are not cytotoxic and with different mechanisms of action. HQK-1001, an orally bioavailable short-chain fatty acid, promotes Hb F synthesis and prolongs erythroid survival and proliferation in pre-clinical models. In an earlier placebo-controlled Phase I/II study in SCD, HQK-1001 at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated and resulted in dose-dependent increase in Hb F. This randomized, open-label, dose escalation study evaluated the safety, pharmacodynamics (PD) and pharmacokinetics (PK) of HQK-1001 given at higher doses and for longer duration (NCT01322269).
Patients with SCD ≥ 12 years of age were randomized to receive HQK-1001 at 30, 40, or 50 mg/kg daily for 26 weeks. Enrollment at 50 mg/kg was opened after an interim review of safety data at the 2 lower doses. Patients were stratified by HU at enrollment, and those on HU had to be on a stable dose for ≥ 6 months. HQK-1001 was discontinued if the patient was transfused. Oral iron was given daily if baseline plasma ferritin was < 700 ng/mL. Week 4 PK was evaluated in 4 patients at each dose. Pre-dose plasma concentrations were measured at each 4-weekly visits in all patients to verify compliance with dosing. Between April and September 2011, 52 patients were randomized to HQK-1001 at 30 mg/kg (n = 15), 40 mg/kg (n = 18), and 50 mg/kg (n = 19). There were 28 males and 24 females with a median age of 21 years (range, 12–46). The phenotype was Hb S-S in 45 and Hb S-β-thal-0 in 7, and 31 patients (60%) were on HU.
The median duration on study drug was 114 days (range, 8–192), with 27 patients (52%) having discontinued HQK-1001 prior to completing the planned 26 weeks of dosing, 12 due to a transfusion and 15 for other reasons including withdrawal of consent and adverse events (AEs). The most common drug-related AEs, nausea (44%), vomiting (29%), somnolence (25%), headache (17%) and upper abdominal pain (17%), were usually graded as mild or moderate. Oral iron may have exacerbated upper gastrointestinal (GI) AEs. Dose limiting toxicities identified at 40 and 50 mg/kg doses consisted of gastritis (n = 3), somnolence (n = 2), pancreatitis (n = 1) and increased AST (n = 1). The maximum tolerated dose was established as 30 mg/kg/day and the protocol was amended to dose all patients at 30 mg/kg/day and discontinue oral iron. To further improve GI tolerability, the protocol was then amended to switch all patients to 15 mg/kg twice a day. No new drug-related severe toxicities were reported after stopping oral iron and dosing all patients at 30 mg/kg/day.
Peak plasma concentrations were dose proportional. Average half-lives ranged from 9.8 to 11.7 hours and were dose independent. Plasma concentrations at 30 mg/kg were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Plasma concentrations were < 99% of the lower limit of confidence intervals in 16% of pre-dose samples collected at the scheduled times, suggesting non-compliance with HQK-1001 dosing in some patients.
Of the 21 patients receiving HQK-1001 alone, Hb F increased in 18 patients (86%), with a mean increase of 2% (range, −2% to +10%), total Hb increased by a mean of 0.5 g/dL (range, −0.7 to 2.4 g/dL), and reticulocytes increased by a mean of 4.1% (range, to −4% to +15%). In 31 patients receiving HQK-1001 + HU, Hb F increased in 25 patients (80%), with a mean increase of 2.7% (range, −3% to + 10%), total Hb increased by a mean of 0.75 g/dL (range, −1.2 to + 1.8 g/dL), and reticulocytes increased by a mean of 1.4% (range, −6% to +15%). Covariate analysis showed significant correlation between change in Hb F at peak value and baseline ferritin (positive correlation, p = 0.008) and TIBC (negative correlation, p < 0.0001).
This study demonstrated that HQK-1001 is well tolerated at 30 mg/kg/day. Plasma concentrations at this dose were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Hb F increased in most patients, both in HU and non-HU groups. HQK-1001 also increased erythropoiesis. Based on these positive results, a placebo-controlled Phase 2 study was launched to evaluate the PD, efficacy and safety of HQK-1001 at 15 mg/kg BID in SCD patients not currently treated with HU.

Disclosures:
Kutlar: HemaQuest Pharmaceuticals, Inc.: Research Funding. Reid:Haemaquest: Honoraria. Taher:Novartis: Research Funding, Speakers Bureau. Abboud:Novartis: Speakers Bureau; Pfizer: Research Funding; Sangart: Membership on an entity's Board of Directors or advisory committees. Buchanan:HemaQuest Pharmacuetical, Inc.: Research Funding. Ataga:HemaQuest Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:HemaQuest: Consultancy. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Ghalie:HemaQuest Pharmaceuticals: Employment, Equity Ownership.