A Phase 2 Clinical Study of HQK-1001 (2,2-dimethylbutyrate, sodium salt), a Fetal Hemoglobin Inducer, in Patients with Sickle Cell Disease
Authors: Kutlar Abdullah , Inati Adlette , Taher Ali T , El-Beshlawy Amal , Reid Marvin , Abboud Miguel R. , Smith Hedy , Ataga Kenneth I. , Buchanan George R. , Malik Punam , Koshy Nebu , Neumayr Lynne , Aiello Maria , Johnson Elsa , White J Michael , Ghalie Richard G. 
Published: October 2019

Abstract
Abstract 1066
Fetal hemoglobin (Hb F) induction (anti-switching therapy) is an effective therapeutic strategy in sickle cell disease (SCD), both for reducing acute complications such as painful episodes and acute chest syndrome, and decreasing hospitalizations and transfusion requirements. Long term use of the only approved anti-switching agent, hydroxyurea (HU) has also been shown to improve survival. Despite this, HU is still not widely prescribed, ∼30% of patients are non-responders, and there are concerns regarding long term use of this cytotoxic agent. There is, therefore, a clear need for alternative anti-switching agents with different mechanism(s) of action, that are not cytotoxic, and that could be used either alone, or in combination with HU to enhance Hb F response. HQK-1001, an orally bioavailable short-chain fatty acid, was shown to promote Hb F synthesis and prolong erythroid survival and proliferation in transgenic mice and non-human primate models. In a Phase 1/2, dose-escalation, placebo-controlled study in 24 patients with SCD, HQK-1001 given at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated, showed dose-proportional pharmacokinetics (PK), and resulted in dose-dependent increase in Hb F (A Kutlar et al, Blood 2010; 116: Abstract 943).
This randomized open-label Phase 2 study is being conducted to evaluate the safety, PK, and effect on Hb F of HQK-1001 administered at a higher dose and for a longer duration than previously studied. Patients with SCD age 12 years and greater were randomized to receive HQK-1001 at 30 or 40 mg/kg daily for 26 weeks. Enrollment at the 50 mg/kg dose level was opened after the Safety Monitoring Committee conducted a planned interim safety data review of the first 12 patients treated for 4 weeks. HQK-1001 is administered as 900 mg tablets, and daily oral iron supplementation is given to patients with plasma ferritin levels less than 700 ng/mL. A minimum of 14 patients stratified 1-to-1 by HU use at baseline will be enrolled at each dose level. Between 25 April 2011 and 5 August 2011, 39 patients have been enrolled and received HQK-1001 at 30 mg/kg (n = 14), 40 mg/kg (n = 14), and 50 mg/kg (n = 11). Patients were enrolled in North America (n = 18), Lebanon (n = 15) and Egypt (n = 6). Median age was 22 years (range, 12–47) and 7 (18%) were less than 18 years old. There were 20 (51%) males and 19 (49%) females. Patients had either Hb-SS (n = 34) or Hb-Sβ0 (n = 5), and 25 (64%) were on HU at baseline and continued HU while on study. Four patients have discontinued HQK-1001 per protocol following a transfusion to treat a SCD complication. One patient discontinued HQK-1001 due to pancreatitis. This patient was found to have a stone in the common bile duct and subsequently died postoperatively from multiorgan failure. The most common adverse events considered by the investigator as possibly drug-related were nausea in 10 patients (26%), abdominal/epigastric pain, vomiting, and headache in 5 (13%) each, and somnolence and dizziness in 3 (8%) each. Drug-related adverse events were graded as mild or moderate except for 1 case each of pancreatitis and gastritis graded as severe. No myelosuppression was observed. Assessment of HQK-1001 effect on Hb F and hemoglobin (Hb) is limited due to short follow-up. In 19 patients in which baseline and Week 4 data are available, the mean value at baseline for Hb was 8.9 g/dL (range, 7.4–11.4) and for Hb F was 1.11 g/dL (range, 0.15–3.33). Eight patients had data available both for Weeks 4 and 8. On Week 8, total Hb increased from baseline by a mean of 0.3 g/dL (range, −0.7 to 1.2) and Hb F increased by a mean of 0.14 g/dL (range, −0.19 to 0.42). The figure reports individual changes in Hb F from baseline to Weeks 4 (dark bars) and Week 8 (light bars), with “X” denoting the 4 patients on HU, and shows an increase in Hb F in 7 of 8 patients for that period.
Enrollment is expected to be completed in August 2011 and updated results will be available at the meeting. In conclusion, the safety profile of HQK-1001 is consistent with results reported in prior studies and shows no overlapping toxicity with HU. Hb F is apparently increased in 7 of 8 patients with data available at Week 8, and this increase is seen both in patients receiving HU or not. Longer follow-up is needed to fully assess the safety of HQK-1001 and the extent of its effect on Hb F, total Hb, and SCD-related events.

Disclosures:
Aiello: HemaQuest Pharmaceuticals: Employment. Johnson:HemaQuest Pharmaceuticals: Employment. White:HemaQuest Pharmaceuticals: Consultancy. Ghalie:HemaQuest Pharmaceuticals: Employment.