ALBERT

Description: New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.

Description: Background: Sickle cell disease (SCD) is a chronic, debilitating disorder caused by a mutation in beta globin, which leads to the production of sickle hemoglobin (HbS). Deoxygenated HbS polymerization results in red blood cell (RBC) sickling, which leads to anemia, hemolysis, vaso-occlusion, and organ damage. Voxelotor a first-in-class therapy in development for the treatment of SCD, stabilizes HbS in the oxygenated state and has been shown to reduce anemia and hemolysis. Hydroxyurea induces fetal hemoglobin (HbF) and is an FDA- and EMA-approved treatment for SCD. Because both voxelotor and hydroxyurea can affect anemia and hemolysis, and potentially have additive mechanisms of protection against HbS polymerization, the effects of concomitant hydroxyurea in the setting of voxelotor treatment were investigated. The objective of this analysis was to evaluate RBC parameters, such as hemoglobin (Hb), mean corpuscular volume (MCV), %HbF, absolute reticulocyte count (ARC), and red cell distribution width (RDW), as well as the absolute neutrophil count (ANC) to examine the potential impact of concomitant hydroxyurea use on the effects of voxelotor and on medication adherence during the treatment period. Serum erythropoietin (EPO) levels were also monitored to investigate the effects of increased Hb concentrations on oxygen delivery. Methods: The HOPE study is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo in participants aged 12 to 65 years with SCD. A per-protocol analysis was performed using available data for all participants at the interim data cutoff on October 31,2018. Concomitant hydroxyurea treatment was permitted per protocol if the dose was stable at enrollment and maintained, unless dose adjustments were required due to toxicities. Laboratory parameters were compared in participants with or without concomitant hydroxyurea use. Results: From the HOPE study, 274 participants with lab values for the specified parameters (Hb, MCV, %HbF, ARC, RDW, ANC, EPO) available through week 24 were analyzed. A total of 179 of 274 (65%) participants were receiving hydroxyurea at study enrollment, and they were evenly distributed across the 3 treatment arms. Baseline lab values documented the effects of current hydroxyurea treatment, with higher average Hb, MCV, and %HbF but slightly lower average ARC and ANC compared with those not receiving hydroxyurea. Voxelotor treatment led to significant dose-dependent Hb increases, regardless of concomitant hydroxyurea therapy (Table 1), but the average MCV, %HbF, ANC, and RDW were unchanged. A lower average ARC was noted, which was attributed to the increased Hb level, whereas EPO levels showed wide variability but no significant changes from baseline. Conclusions: The HOPE study demonstrated that voxelotor treatment increased Hb levels in study participants with SCD, irrespective of hydroxyurea use. Significant voxelotor-associated Hb increases were observed for participants on stable-dose hydroxyurea and were equivalent to those observed in participants not taking hydroxyurea. The lack of observed changes in MCV and ANC was consistent with stable hydroxyurea exposure throughout the treatment period, thus addressing questions about potential changes in hydroxyurea compliance during the study. The additive treatment effects on anemia and hemolysis by voxelotor suggest that combination therapy with hydroxyurea may be safe and effective for optimal disease modification. Disclosures Ware: Addmedica: Other: Research Drug Donation; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation. Brown:Novartis, Inc: Research Funding; Imara, Inc: Consultancy, Research Funding; Global Blood Therapeutics, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. de Montalembert:bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Novartis: Consultancy; Bioverativ: Consultancy; Global Blood Therapeutics: Employment, Equity Ownership; Imara: Consultancy. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Abboud:Novartis: Consultancy, Honoraria, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Research Funding; Amgen: Other: Travel support; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Sickle cell disease (SCD) is a genetic disorder in which deoxygenation results in polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell (RBC) deformation (sickling), hemolytic anemia, vaso-occlusion, inflammation, predisposition to infection, and chronic organ damage. Two distinct pathophysiologic mechanisms of SCD-severe anemia and vasculopathy-overlap to cause severe morbidity. Chronic anemia and recurrent cycles of ischemia-reperfusion injury, often manifesting as fatigue and/or pain (vaso-occlusive crisis [VOC]), accumulate over the lifespan, resulting in end-organ parenchymal damage. The severity of steady-state anemia predicts CNS injury (including stroke and neurocognitive impairment), renal disease, and cardiopulmonary dysfunction (pulmonary hypertension). Long-term complications contribute to decreased quality of life and are associated with early death. Voxelotor (GBT440) is an oral once-daily therapy that modulates Hb affinity for oxygen, thereby inhibiting HbS polymerization and the resultant sickling of RBCs, potentially interrupting the molecular pathogenesis of the disease. The Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization (HOPE) study (NCT03036813) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of voxelotor in patients with SCD aged 12 to 65 years. Methods: Part A of the HOPE study encompasses the first approximately 150 randomized patients, a group pre-specified in the protocol for analysis. Part A is a comparison of 2 doses of voxelotor (900 and 1500 mg/day) with placebo in patients treated for at least 12 weeks. The primary endpoint is an increase in Hb 〉1 g/dL from baseline (Hb responder). Secondary endpoints include SCD symptom assessment using a novel patient-reported outcome (PRO) measure, VOC during the treatment period, and change from baseline in measures of hemolysis (including % reticulocytes and unconjugated bilirubin). Eligible patients must have SCD (HbSS, HbSC, HbSβ0 thalassemia, or other variants), Hb ≥5.5 and ≤10.5 g/dL, and at least 1 VOC in the 12 months prior to study entry. Hydroxyurea is allowed if the dose has been stable for at least 90 days prior to study entry. Results: 154 patients with a median age of 28 years (range, 12-59), 42% male, have received treatment for a median of 21.9 weeks (voxelotor overall, range 1.7- 65.1) and 22.4 weeks (placebo, range 1.7-44.7). The majority have HbSS/HbSB0 genotype: 94% (900 mg), 92% (1500 mg), and 90% (placebo). Hydroxyurea use at study entry was 67% (900 mg), 62% (1500 mg), and 64% (placebo). Median Hb at study entry was 8.3 g/dL (900 mg; range, 6.3-10.8), 8.6 g/dL (1500 mg; range, 5.9-10.8), and 8.5 g/dL (placebo; range, 6.1-10.4). Data for Hb and measures of hemolysis at week 12 are available for 40 patients in the 900 and 1500 mg arms and 44 patients in the placebo arm. At week 12, the proportion of patients with a 〉1-g/dL increase in Hb from baseline was significantly larger for both voxelotor 900 mg and 1500 mg arms, compared with placebo (Table 1). Consistent with the improvements in Hb, treatment with voxelotor resulted in concordant and statistically significant improvement in measures of hemolysis (reticulocytes and indirect bilirubin) from baseline. Change from baseline in Hb at week 12 is shown in Table 2 and Figure 1. Treatment-related adverse events reported in 3 or more patients in any of the treatment arms were diarrhea (3 at 900 mg, 3 at 1500 mg, 1 on placebo), nausea (3 at 900 mg, 2 at 1500 mg, 3 on placebo), and vomiting (2 at 900 mg, 0 at 1500 mg, 3 on placebo). Data on additional endpoints will be provided at the time of the presentation. Conclusions: Data from Part A of the HOPE study demonstrate that treatment with voxelotor resulted in a dose-dependent increase in Hb with a large proportion of patients achieving Hb 〉1 g/dL improvement from baseline compared with placebo at 12 weeks. In addition, there was a dose-dependent decrease in hemolysis markers. Voxelotor was generally well tolerated at both doses. Hemolytic anemia of SCD has severe and life-threatening consequences and presents an unmet medical need. Voxelotor has potential to ameliorate complications of anemia associated with SCD. Disclosures Vichinsky: bluebird bio: Membership on an entity's Board of Directors or advisory committees; Protagonist: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Howard:Novartis: Speakers Bureau; Terumo: Speakers Bureau; Addmedica: Speakers Bureau; Global Blood Therapeutics: Consultancy. Ataga:Modus Therapeutics: Honoraria; Pfizer: Research Funding; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria. Brown:Global Blood Therapeutics: Consultancy, Research Funding. Hassab:Global Blood Therapeutics: Research Funding. Telfer:Pfizer: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria, Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo: Honoraria; ApoPharma Inc.: Membership on an entity's Board of Directors or advisory committees. Kanter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; Sancilio: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Global Blood Therapeutics: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Lehrer-Graiwer:Global Blood Therapeutics: Employment. Sherman:Global Blood Therapeutics: Employment. Tonda:Global Blood Therapeutics: Employment. Intondi:Global Blood Therapeutics: Employment. Yaron:Global Blood Therapeutics: Employment. Ware:Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Nova Laboratories: Consultancy; Biomedomics: Research Funding; Global Blood Therapeutics: Other: advisory board; Agios: Other: advisory board; Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Sickle hemoglobin (HbS) under conditions of deoxygenation polymerizes to cause sickling of red blood cells (RBCs) and other rheological abnormalities. Voxelotor has been previously shown in a preclinical model of sickle cell disease (SCD) to increase HbS affinity to oxygen, thus reducing its polymerization and sickling with subsequent increase in the half-life of RBCs. We hypothesized that given this mechanism of action, we would observe improvements in RBC physiology in patients receiving voxelotor. In the Phase 3 GBT HOPE trial, the use of voxelotor in patients with SCD caused a significant reduction in markers of hemolysis and anemia. Ektacytometry is considered the gold standard to study deformability of RBCs with membrane protein disorders. The deformability of RBCs can be assessed using a defined value of shear stress with an increasing osmotic gradient (osmoscan) as well as with a newer technology to subject these cells to gradual deoxygenation (oxygenscan). Both assays can be measured using the Laser Optical Rotational Red Cell Analyzer (LORRCA, RR Mechatronics, NL). In this pilot study, we analyzed samples from patients with SCD receiving voxelotor, before and 12 weeks after starting therapy to assess the benefits of voxelotor on RBC physiology. Methods: Our pilot study obtained whole blood from children ages 4-11 years with SCD, who were enrolled in the IRB approved GBT 440-007 clinical trial (NCT02850406; a study evaluating multiple doses of voxelotor at 1500 mg/day equivalent exposure to adults based on body weight) at Emory University/Children's Healthcare of Atlanta. All participants in this cohort continued their stable, optimal hydroxyurea dose during treatment with voxelotor. The below measurements were performed on the pre-dose and Week 12 visit samples. Deformability of RBCs was performed at a shear stress of 30 Pa and varying osmolality gradients (0-600 mOsm/Kg) for Osmoscan. Omin corresponds to the value of the hypotonic osmolality, where 50% of the cells hemolyze in an osmotic fragility assay and provides information on the initial surface area:volume ratio. Maximal deformability or Elongation Index (EImax) near isotonic osmolality informs us of the RBC cytoskeleton mechanics and Ohyper, the osmolality corresponding to 50% of the Elmax, provides information regarding the cytoplasmic viscosity. Oxygenscan was performed but under controlled deoxygenation using nitrogen. Point of Sickling (POS) is a point on the curve during deoxygenation when sickling begins, and EImin corresponds when sickle RBCs can least elongate. Oxygen dissociation curves were obtained using a HemOx Analyzer (TCS Scientific). Complete blood count parameters were determined on a clinical laboratory hematology analyzer (ADVIA, Siemens). Data was analyzed with Prism using a paired T-test. Results: Both pre-dose and Week 12 visit samples were available for 10 participants. Mean hemoglobin at baseline was 9.0 g/dL (7.6-10.0) and at 12 weeks, 10.3 g/dL (8.2-12.3). Six out of 10 participants had a hemoglobin response at Week 12 (defined as an increase in Hb from baseline by 〉1 g/dL), of which 5 had hemoglobin over 10 g/dL. Mean % change in percentage of reticulocytes was -17.0%. Significant improvement in EImax on osmoscan was noted at Week 12 (p=0.0147), suggesting RBCs were more deformable with improved cytoskeleton mechanics. In addition, oxygenscan curves shifted upwards towards normal with a significant increase in EImax (p=0.0347) and EImin (p=0.0079). These findings combined with a decrease in POS (p=0.0001) during deoxygenation suggests that at low oxygen tension, voxelotor treated RBCs were more deformable possibly from reduced HbS polymer inside these cells. Significant reductions in P50 (p=0.0011) and P20 (p=0.0001) with a left shift of the oxygen dissociation curve further demonstrates the effect of voxelotor on RBCs. Discussion: Voxelotor therapy in children with HbSS is associated with reductions in anemia and reticulocyte response, and recovery in RBC health as early as 12 weeks of treatment. Voxelotor's ability to inhibit HbS polymerization and RBC sickling is associated with specific modulation in red cell rheology at normoxic and deoxygenating conditions. Left shifted oxygen dissociation curves confirm voxelotor's ability to increase oxygen affinity. These findings suggest that voxelotor improves RBC deformability and anemia and delays the initiation of RBC sickling. Figure Disclosures Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Baratz:Prolong Pharmacuticals: Honoraria; Global Blood Therapeutics: Research Funding. Pochron:Global Blood Therapeutics: Employment, Equity Ownership. Dixon:Global Blood Therapeutics: Employment, Equity Ownership. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Brown:Pfizer: Research Funding; Novartis, Inc: Research Funding; Imara, Inc: Consultancy, Research Funding; Global Blood Therapeutics, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Archer:AstraZeneca: Research Funding; Prolong Pharmaceuticals: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding.

Description: Background: Sickle cell disease (SCD) is a genetic disorder caused by a mutated hemoglobin S (HbS) that polymerizes in the deoxygenated state and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion, and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis), and other clinical complications that are underrecognized, undertreated, and associated with early death. Voxelotor is an oral, once-daily therapy that modulates hemoglobin (Hb) affinity for oxygen, thereby inhibiting Hb polymerization. GBT440-007 is a phase 2a study designed to assess the safety, pharmacokinetics (PK), and efficacy of voxelotor in pediatric patients with SCD (HbSS or HbSβ0 thalassemia). Methods: This ongoing study is evaluating multiple doses of voxelotor at 2 dose levels, 900 mg/day and 1500 mg/day, for 24 weeks in adolescents aged 12 to 17 years. The primary objective is to assess the effect of voxelotor on anemia. Secondary objectives include the effects on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial doppler ultrasound (TCD), and safety. Results: Results for adolescents treated with 900 mg/day have been previously reported. As of June 18, 2018, partial data are available for 13 patients (9 females and 4 males). The median age was 14 years (range, 12-17 years) and median weight was 47 kg (range, 31-72 kg). All participants were on hydroxyurea (HU), and 46% had 2 or more painful crises (range, 2-15) in the year prior to enrollment. The median baseline TCD flow velocity was 112 cm/s (range, 92-177 cm/s), and all were less than 135 cm/s at baseline except for 1 with a baseline of 177 cm/s. Data for measures of hemolysis and TCD are available for 5 adolescents who received voxelotor for 12 weeks. The median increase in Hb was 1.0 g/dL at 12 weeks (Table). Median reductions in reticulocytes and indirect bilirubin were 29% and 18%, respectively (Table), consistent with previously reported results of voxelotor in adults with SCD. Preliminary data suggest linear PK up to 1500 mg, the highest dose evaluated. The adolescent with a baseline conditional TCD (177 cm/s of the bifurcation of the internal carotid artery) on background HU at the maximum tolerated dose (29 mg/kg) had a reduction in TCD flow velocity of 20 cm/s with a concordant increase in Hb of 1.7 g/dL at week 24 with voxelotor compared to baseline and a decrease in reticulocytes from 16.45% to 10.4% (Figure). TCD flow velocities in all other arterial segments showed an overall decline at week 24. All treatment-related adverse events were grade 1 or 2, and there were no treatment-related serious adverse events. Data for all adolescents treated with voxelotor 1500 mg/day for up to 24 weeks will be presented at the conference. Conclusions: Preliminary results indicate that voxelotor at 1500 mg/day was well tolerated. Data from 5 adolescents at 12 weeks show a marked improvement in Hb and reductions in clinical measures of hemolysis. Importantly, hematologic improvements are seen in adolescents already managed at the maximally tolerated dose of HU. Compared to previously reported data at 900 mg/day, this indicates a dose-dependent improvement in hemolytic anemia. One adolescent with conditional TCD, despite background HU, achieved normalized TCD flow velocity after voxelotor therapy. Overall, these results are consistent with in vivo inhibition of HbS polymerization by voxelotor and support the ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adolescents with SCD. Disclosures Brown: Global Blood Therapeutics: Consultancy, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Astra Zeneca: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Woods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees. Hsu:Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy. Piccone:Novartis: Consultancy. Fong:Global Blood Therapeutics: Employment. Dixon:Global Blood Therapeutics: Employment. Tonda:Global Blood Therapeutics: Employment. Washington:Global Blood Therapeutics: Employment. Lehrer-Graiwer:Global Blood Therapeutics: Employment.

Description: Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic anemia and hemolysis as well as episodic vaso-occlusive crises (VOC). These manifestations of SCD contribute to the cumulative organ damage that leads to disability, reduced quality of life, and accelerated mortality. In particular, VOCs and their associated episodic pain are a hallmark symptom of SCD and frequently require emergency medical attention. Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor in development for the treatment of SCD. It has demonstrated robust, rapid, and sustained improvements in patient Hb levels with numerically fewer VOCs compared with placebo, which suggests that viscosity was not increased with voxelotor treatment. The objective of this study was to further explore this observation by examining the association between absolute Hb achieved by voxelotor treatment and VOC incidence rate. In addition, to inform on the potential for symptom exacerbation after drug discontinuation, rates of VOCs after voxelotor discontinuation were analyzed. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients with SCD aged 12 to 65 years. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a 〉1.0 g/dL increase in Hb. Secondary endpoints included the annualized incidence rate of VOC. This abstract reports a post hoc analysis of VOC incidence in the per-protocol population stratified by Hb level at 24 weeks of treatment. In addition, VOCs in patients who discontinued voxelotor and completed a 28-day follow-up are reported here (data cutoff October 31, 2018). Results: The proportion of patients with ≥1 VOC was 67.0% (59/88) in the voxelotor 1500 mg group, 66.3% (61/92) in the voxelotor 900 mg group, and 69.2% (63/91) in the placebo group. Overall, the annualized adjusted incidence rate of VOCs (the number of crises per person-year) was 2.77 in the voxelotor 1500 mg group, 2.76 in the voxelotor 900 mg group, and 3.19 in the placebo group. When stratified by Hb level after 24 weeks of treatment, the incidence of VOCs was generally lower in patients who achieved higher absolute Hb levels on voxelotor treatment compared with placebo (Figure 1). Patients who discontinued voxelotor were also observed for 28 days post-treatment. At the time of data cutoff, 55 patients (n=21, voxelotor 1500 mg; n=17, voxelotor 900 mg; n=17, placebo) had discontinued treatment and had post-treatment follow-up. During the 28-day period after treatment discontinuation, 5 patients in the voxelotor 1500 mg group reported 6 VOCs; 3 patients in the voxelotor 900 mg group reported 3 VOCs; and 5 patients in the placebo group reported 8 VOCs. The estimated incidence rates of post-treatment VOCs were 4.63, 4.30, and 7.01 in the voxelotor 1500 mg, voxelotor 900 mg, and placebo groups, respectively. Conclusions: Patients who achieved the greatest absolute Hb level after 24 weeks of treatment with voxelotor had numerically fewer VOCs, suggesting that increasing Hb levels resulting from voxelotor treatment did not lead to a viscosity-related increase in risk of vaso-occlusion. Following drug discontinuation, there was a numerically lower incidence of VOCs in the voxelotor arms compared with placebo. Altogether, these results suggest that voxelotor treatment safely raises Hb without causing a viscosity-related increased risk of VOC and that treatment discontinuation did not increase risk for VOC. Disclosures Vichinsky: GBT: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Telfer:ApoPharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker activities, clinical trial activities; Terumo: Honoraria, Other: Speaker activity; Pfizer: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: clinical trial activity; Kyowa Kirin Limited: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial activities; Napp Pharma: Other: clinical trial involvement; Celgene: Other: clinical trial involvement; Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Ataga:Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic hemolysis and anemia as well as episodic vaso-occlusion. These manifestations of SCD contribute to the cumulative organ damage that leads to disability and accelerated mortality. Voxelotor is a first-in-class therapy in development for the treatment of SCD that has been shown to increase Hb levels and reduce markers of hemolysis, consistent with inhibition of sickle Hb polymerization. The objective of this analysis was to evaluate the association between Hb response and markers of hemolysis in voxelotor-treated patients. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients aged 12 to 65 years with SCD. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a 〉1.0 g/dL increase in Hb. Secondary endpoints include change in markers associated with hemolysis: absolute reticulocyte count and percentage of reticulocytes, indirect bilirubin level, and lactate dehydrogenase (LDH) level. The per-protocol population was defined as those who completed the week 24 visit of the assigned treatment regimen and who did not initiate hydroxyurea treatment between baseline and week 24. Pharmacokinetic/pharmacodynamic modeling was used to correlate voxelotor exposure with Hb response and measures of hemolysis. Results: A total of 229 patients (n=74, voxelotor 1500 mg; n=79, voxelotor 900 mg; n=76, placebo) were included in the per-protocol analysis. Among patients receiving voxelotor 1500 mg, all measures of hemolysis were consistently lower for those with changes in Hb of 〉1 g/dL compared with those with changes of ≤1 g/dL (Table 1). In the 900 mg group, percentage of reticulocytes, bilirubin, and LDH were lower for those with changes in Hb of 〉1 g/dL compared with those with changes of ≤1 g/dL; this pattern was not seen for absolute reticulocytes in this cohort. Generally, the degree of reduction in hemolysis markers was greater in the 1500 mg arm compared with the 900 mg arm. Linear relationships between voxelotor exposure and Hb and LDH response were observed. In addition, saturable relationships between reticulocytes and bilirubin were also observed. Conclusions: Among patients treated with voxelotor, those with Hb changes of 〉1.0 g/dL had the greatest reductions in the markers of hemolysis. In addition, patients with Hb changes of 〉1 g/dL and who received voxelotor 1500 mg had lower hemolytic markers than those who received voxelotor 900 mg, suggesting that exposure to a higher dose of voxelotor results in a greater decrease in hemolysis markers. Taken together, these results suggest that the mechanism by which voxelotor raises Hb is related to a reduction in hemolysis, which may modify the morbidity of SCD by improving hemolytic anemia. Disclosures Howard: Imara: Consultancy, Other: Travel grant; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Resonance Health: Other: Travel grant. Vichinsky:Global Blood Therapeutics: Consultancy; Agios: Research Funding; Pfizer: Research Funding. Knight-Madden:Global Blood Therapeutics: Research Funding; Nova Laboratories: Advisory Board on SCD 2017, Research Funding; Global Blood Therapeutics: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Addmedica: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; BlueBird Bio: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbott Nutrition: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbot International: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Pfizer: Other: Advisory Board on SCD 2017. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Gordeuk:Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Inctye: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Ironwood: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Pfizer: Research Funding.

Description: Background: Sickle cell disease (SCD) is a lifelong, inherited disorder characterized by mutations in the hemoglobin (Hb) subunit β gene that leads to the production of sickle hemoglobin (HbS). When HbS is deoxygenated, polymerization leads to red blood cell sickling and damage, resulting in hemolysis, chronic anemia, and episodic vaso-occlusive crises (VOCs). Patients with SCD are at an increased risk of developing long-term complications, including stroke, leg ulcers, and other end-organ damage. Lower Hb levels highly correlate with increased morbidity and early mortality in SCD. Voxelotor (Oxbryta®) is an oral, once-daily HbS polymerization inhibitor indicated for the treatment of SCD in adults and adolescent patients ≥12 years of age. The 24-week analysis of the HOPE trial demonstrated that treatment with voxelotor 1500 mg resulted in a significantly greater proportion of patients achieving a 〉1 g/dL Hb increase compared with placebo (51.1% vs 6.5%, P1 g/dL at 1 or more time points during the 72-week treatment period compared with 25% (95% CI, 16.2% to 33.8%) of those receiving placebo (P