ALBERT

Description: 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.

Description: 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. Disclosures: Kutlar: HemaQuest Pharmaceuticals, Inc: Research Funding. Vichinsky:HemaQuest Pharmaceuticals, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Neumayr:Novartis : Honoraria, one time honoraium 10/09; NIH: Research Funding. Labotka:HemaQuest Pharmaceuticals, Inc: Research Funding. Keefer:HemaQuest Pharmaceuticals, Inc: Research Funding. Shen:HemaQuest Pharmaceuticals, Inc: Research Funding. Boosalis:HemaQuest Pharmaceuticals, Inc: Equity Ownership, Research Funding. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Bobbitt:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Patents & Royalties. Wallis:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Perrine:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Description: Incident stroke, both primary and recurrent are common in children with sickle cell anemia (SCA) in Jamaica with incidences of 7.8% by 14 years of age and 29/100 person-years respectively. Cerebral vasculopathy manifested by elevated transcranial doppler (TCD) velocity (〉170 cm/sec) is the major risk factor for both with a prevalence of 19.8% among Jamaican children with SCA. Chronic blood transfusion is the standard of care to reduce stroke risk and recurrence in children with SCA in high income countries, but in low-resource settings where blood availability, safety and local acceptance are limited, hydroxyurea (HU) is emerging as a viable alternative. However, the efficacy of HU for incident stroke prevention in children with newly diagnosed severe cerebrovascular disease without the use of transfusions in a low resource setting like Jamaica is unclear. The EXpanding Treatment for Existing Neurological Disease (EXTEND) trial (ClinicalTrials.gov NCT02556099) was designed to investigate the effects of open label HU on TCD velocities after 18 months of treatment, compared to the pre-treatment value. Secondary aims included the effects of HU on the incidence of neurological events including magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) changes, non-neurological events, hematological responses and toxicity. We enrolled 43 children with SCA, 2 to 17 years of age , between Nov 2014 and April 2016, stratified into 3 groups: Low Risk Group (LRG) - On Hydroxyurea with TCD ≥170 cm/sec, N=12; Medium Risk Group (MRG) - HU naive with TCD ≥170 cm/sec, N=21; and High Risk Group (HRG) - Previous Stroke, N=10. All children received HU initially at 20 mg/kg/day followed by two monthly dose escalation using weight and pre-defined laboratory criteria to maximum tolerated dose (MTD) and thereafter 3 monthly visits. The average HU dose at MTD (mean±1SD) was 25.3±0.4 mg/kg. TCD was performed every 6 months according to the Stroke Prevention in Sickle Cell Anemia (STOP) protocol. The average age at enrollment was 7.7±2.6 years, with MRG significantly younger than HRG (6.7±2.0 years vs 9.2±3.7 years; p

Description: Introduction Vaso-occlusive crises (VOC) remain the hallmark of Sickle Cell Disease (SCD) yet to date no agent has been approved to hasten the resolution of an acute painful event. MP4CO, a pegylated hemoglobin-based carbon monoxide (CO) carrier, has demonstrated potential in non-clinical studies for the prevention and reversal of red cell sickling and has exhibited anti-adhesive, anti-oxidant, anti-inflammatory and anti-apoptotic properties at circulating carboxyhemoglobin (CO-Hb) levels 〈 10% (Belcher: BLOOD, Aug 2013). These cellular protective effects are expected to limit the progression of vascular occlusion and mitigate the consequences of ischemic tissue damage and inflammation. The beneficial effects of MP4CO can be ascribed to 5 postulated mechanisms: 1) downregulation of ICAM-1, VCAM-1 and NF-κB 2) upregulation of Heme-Oxygenase-1 and Nrf2 leading to further increase in anti-inflammatory mediators, biliverdin and CO 3) delivery of oxygen to ischemic tissues 4) intravascular volume expansion and improved perfusion of ischemic tissue and 5) possible prevention and reversal of polymerization and sickling of red blood cells Methods We conducted a Phase 1b prospective, double-blind, comparator controlled, dose escalating, multi-center study designed to assess the safety profile of MP4CO in clinically stable adult sickle cell patients not experiencing painful crises at the time of testing. Patients with HbSS and S/β0 Thal genotypes, 18 years of age and older, meeting eligibility criteria were randomized to receive either MP4CO or normal saline (NS) in a sequential series of 6 escalating doses (Cohorts A-F). Each cohort included 4 patients; 3 patients per cohort received MP4CO (treated group) and 1 patient per cohort received NS (control group). Cohorts A through D received single dose IV infusions ranging from 15 mg/kg/dose (0.35 mL/kg infusion) to 172 mg/kg/dose (4 mL/kg infusion). Cohorts E-F, received fractionated doses of 172 mg/kg or 344 mg/kg (4-8mL/kg administered as two daily intravenous infusions of 2 mL/kg separated by 24 hours). Physical examination, vital signs, pulmonary artery pressure/TRJV, ECGs, pulse oximetry, venous blood co-oximetry, free plasma hemoglobin, pain assessments and laboratory measurements were conducted at defined intervals throughout the study. Safety variables were evaluated by an unblinded independent medical safety monitor from randomization through Day 28 for each cohort. Results Twenty-four patients were randomized. Eighteen subjects were exposed to MP4CO and 6 subjects received NS. Overall, 16/24 subjects (66.7%) reported mild to moderate adverse events (AEs) with 13/18 subjects (72%) from the MP4CO group and 3/6 subjects (50%) in the NS group. No serious adverse events (SAEs) were experienced and no deaths were reported. The most common AEs (reported by 〉2 subjects) included headaches (mostly mild and transient), dizziness, fatigue, and rash at the application site of the Holter electrodes No treatment-emergent abnormalities were noted throughout the study. Vital signs, ECG readings, standard laboratory values and pulmonary pressures remained within normal limits. The maximum increase in of CO-Hb level was only 2% which returned to pre-dosing levels within 8 hours after the completion of infusion. Mean increase in free plasma hemoglobin (an index of MP4CO dose) ranged from 0.2 to 0.35 g/dL in the two highest dosed cohorts with no significant change in total whole blood hemoglobin. There was no symptomatic or clinical evidence of renal dysfunction observed in either group based on serum creatinine and urinary albumin results. While two subjects had elevated levels of renal biomarkers, β2M and NAG at Hour 72, levels normalized at follow up visits. Both subjects had documented intercurrent illnesses during the trial and further testing of stored urine samples were within normal limits supporting the hypothesis that the β2M and NAG changes were reflective of a more generalized inflammatory state than of direct tubular injury. Conclusion MP4CO appears to be well tolerated at doses up to 344 mg/kg. Results of this Phase 1b safety study showed no obvious or concerning safety signals or clinical evidence of abnormal organ dysfunction/injury. Together with nonclinical evidence, this study supports the decision to proceed with further efficacy and safety evaluation of MP4CO in a larger phase 2 study for treatment of a painful VOC. Disclosures: Howard: Sangart: Membership on an entity’s Board of Directors or advisory committees. Galacteros:Sangart: Consultancy. Inati:Sangart: Consultancy. Reid:Sangart: Consultancy. Keipert:Sangart: Employment, Equity Ownership. Small:Sangart: Employment, Equity Ownership. Booth:Sangart: Employment, Equity Ownership.

Description: 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.