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 caused by polymerization of Hemoglobin S, resulting in red blood cell (RBC) sickling, RBC destruction, vaso-occlusive episodes and end-organ damage. No direct anti-polymerization, mechanism-based, preventive therapy is available. GBT440 is a novel small molecule hemoglobin modifier which increases hemoglobin oxygen affinity. In vitro and in vivo studies have shown it to be a potent and direct anti-sickling agent with high specificity for hemoglobin, and that 10-30% hemoglobin modification could be both safe (not compromising oxygen delivery) and effective (preventing HbS polymerization). We hypothesized that a potent antisickling hemoglobin modifier should rapidly interrupt RBC hemolysis, improve anemia and potentially become a safe and effective long-term disease-modifying therapy. We therefore explored safety, pharmacokinetics and pharmacodynamics and potential efficacy in healthy volunteers and SCD patients. Methods: This prospective, randomized, placebo-controlled, double blind, parallel group phase I/II study enrolled healthy volunteers (HV) ages 18-55, and homozygous HbSS SCD patients ages 18-60 with baseline Hb levels ³6 g/dL and ²10 g/dL and without vaso-occlusive crisis or transfusion within 30 days of screening. The study was conducted in two parts: part A tested single ascending doses and part B multiple ascending doses of study drug with 6:2 randomization (GBT440:placebo). Doses administered were: part A, HV cohorts 100mg to 2800 mg, SCD cohort 1000 mg; part B, HV cohorts 300 mg to 900 mg once daily for 15 days, SCD cohort 700 mg once daily for 28 days. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK) and pharmacodynamics (PD). Clinical indices of hemolysis were prespecified as endpoints and are described for the SCD multiple dose cohort (700 mg QD for 28 days). Descriptive statistics were used to analyze data. Results: As of July 24 2015, 64 healthy volunteers (HVs) and 16 SCD patients had been enrolled. 54 healthy volunteers had completed the study, 2 were discontinued due to mild-moderate nonserious adverse events (headache, rash) and 8 were in follow-up; 8 SCD patients had completed Part A of the study and 8 were in Part B follow-up. No SCD patients were discontinued; one part B subject had a dose reduction from 700 mg to 400 mg (due to abdominal discomfort). GBT440 was generally well-tolerated, most adverse events were mild, there were no deaths, and there was one serious adverse event (AE) of acute painful crisis in a placebo subject. There were no AEs related to tissue hypoxia. GBT440 showed dose proportional PK, a terminal half-life of 1.5-3 days, high partitioning into RBCs (RBC:Plasma 60-90:1), and a dose dependent increase in hemoglobin oxygen affinity in both HV and SCD patients. In the multiple dose SCD cohort, all patients were evaluable at 28 days (age range 21-52 years; 2 were on hydroxyurea; 3 males/5 females). GBT440-treated patients showed increased hemoglobin, hematocrit and erythrocyte counts with corresponding decreases in LDH, unconjugated bilirubin, reticulocytes and erythropoietin levels with trends evident as early as day 8 compared to no changes in the placebo group (Figure 1 and Table 1). Analysis of peripheral blood smears revealed a marked reduction in sickle cells with GBT440 treatment. Conclusions: Single, oral, daily dosing with GBT440 was well tolerated across a wide dose range and demonstrated dose proportional and predictable PK and PD. GBT440 demonstrated proof of mechanism with a dose-dependent increase in hemoglobin oxygen affinity without causing tissue hypoxia. GBT440 demonstrated proof of concept in SCD patients with rapid reduction in RBC hemolysis and improved oxygen delivery to tissues as evidenced by reduced erythropoietin level, and a marked reduction in circulating sickle cells. These results support further clinical investigation of GBT440 as a potential disease-modifying therapy for SCD. Table 1. Mean change to Day 28 (SEM) GBT440 PLA Hemoglogin (g/dL) 0.8 (0.2) -0.5 (0.4) % Sickle cells in peripheral blood (%) -83 (9) 19 (4) Erythrocyte count (1012/L) 0.5 (0.1) -0.1 (0.2) Reticulocyte count (%) -2.2 (1) 0.8 (1.6) LDH (% change from baseline) -12 (7) -9 (1) Unconjugated bilirubin (% change from baseline) -25 (10) -9.6 (16) Erythropoietin (U/L) -29 (16) 21 (33) GBT = GBT440 treated subject; PLA = placebo subject; SEM = standard error of the mean Figure 1. Figure 1. Disclosures Lehrer-Graiwer: Global Blood Therapeutics: Employment, Equity Ownership. Howard:Pfizer: Consultancy; Novartis: Consultancy, Other: Travel Grant; Aes-Rx: Consultancy. Layton:Agios: Consultancy; Novartis: Consultancy; Glaxo Smith Kline: Consultancy. Mant:Quintiles: Employment, Equity Ownership. Dufu:Global Blood Therapeutics: Employment, Equity Ownership. Hutchaleelaha:Global Blood Therapeutics: Employment, Equity Ownership. Koller:Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Patel:Global Blood Therapeutics: Employment, Equity Ownership. Ramos:Global Blood Therapeutics: Employment, Equity Ownership.

Description: Background: SCD is caused by a point mutation in the β-globin gene producing hemoglobin S (HbS) that polymerizes upon deoxygenation with subsequent formation of sickled red blood cells (RBCs). GBT440 is a novel, orally bioavailable small molecule that inhibits HbS polymerization by increasing the affinity of O2 to hemoglobin (Hb). Methods: The pharmacokinetics, mass balance, and metabolite profile of [14C]-GBT440 were evaluated in 7 healthy male subjects in this open-label study. In order to evaluate the disposition kinetics of GBT440 at steady-state concentrations, a loading/maintenance dose schema was employed. Each subject received an oral loading dose of 2000 mg GBT440 on Day 1 followed by oral maintenance doses of 400 mg once daily on Day 2 to Day 4. Once the target steady-state was achieved, a single [14C]-GBT440 400 mg dose (approximately 100 μCi) was administered orally on Day 5. Blood, plasma, urine and feces were collected serially up to 26 days postdose. Results: There were no serious adverse events or discontinuations due to adverse events for any of the healthy subjects participating in this study. GBT440 reached Cmax in plasma and whole blood with median time to maximum concentration (Tmax) values of 2.00 hours in plasma and whole blood and in 6.00 hours in RBCs. After reaching Cmax, GBT440 concentrations appeared to decline in a monophasic manner, with the terminal elimination phase for GBT440 in plasma, whole blood, and RBCs appearing to decline in a parallel manner, with geometric mean T1/2 values of 98.0 hours in plasma, 66.3 hours in whole blood, and 65.8 hours in RBCs. This study achieved 98.0% average recovery of total radioactivity in urine and feces over the course of the study. Most of the administered radioactivity (88.2%) was recovered by 144 hours postdose (Day 7). GBT440 was eliminated primarily in feces (62.6% of the total radioactive dose) with urinary excretion accounting for 35.4% of the total radioactive dose. In whole blood, the majority of the total radioactivity (TRA) was unchanged GBT440 (97.5%) while three metabolites accounted for the remaining TRA (2.5%). In plasma, unchanged GBT440 was the prominent circulating radioactive component, accounting for 48.8% of the TRA. Eleven circulating metabolites with corresponding radioactive peaks were identified. There was one major Phase II metabolite (GBT440 O-dealkylation-sulfation), accounting for 16.8% of the TRA. Two potential active metabolites were identified but only accounted for 2.5% of the dose in whole blood. GBT440 was eliminated predominately in feces. Unchanged GBT440 was the most abundant radioactive component, accounting for 33.3% of the administered dose. Four metabolites were identified, each accounting for 5.62%, 2.66%, 1.66% and less than 6% of the dose in the 0-216-hr human feces. Urine was a relatively minor excretion route for GBT440 in humans. An average of 34.3% of the dose was recovered in the urine samples. Unchanged GBT440 accounted for 0.08% of the administered dose and the rest were metabolites. GBT440 glucuronidation and reduction-glucuronidation products, which are Phase II metabolites, were the most abundant metabolites in urine, accounting for a combined 9.22% of dose. Because GBT440 does not undergo renal elimination, patients with renal disorders should not experience changes in pharmacokinetics of GBT440. Conclusions: Although GBT440 has high specific binding to hemoglobin, it was completely excreted from the body with a half-life of approximately three days in healthy subjects. Since the half-life of GBT440 was much shorter than RBC lifespan (~ 120 days), this supports the hypothesis that the binding between GBT440 to hemoglobin is a reversible process. Following an oral administration, approximately one-third of the dose was excreted as the unchanged drug into the feces (unabsorbed and/or via biliary excretion). Two-thirds of the administered dose was metabolized and excreted into urine and feces. The major metabolic pathway was via Phase I and Phase II metabolism. Because GBT440 was not excreted directly into the urine, the pharmacokinetics are unlikely to be affected in patients with renal disorders. Disclosures Rademacher: Global Blood Therapeutics: Employment, Equity Ownership. Hutchaleelaha:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer:Global Blood Therapeutics: Employment, Equity Ownership. Ramos:Global Blood Therapeutics: Employment, Equity Ownership.

Description: Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene leading to production of hemoglobin S (HbS) that polymerizes upon deoxygenation with subsequent formation of sickled red blood cells (RBCs). GBT440 modulates O2 affinity of hemoglobin (Hb) by binding to the N-terminal α chain of Hb via a reversible Schiff base. We previously demonstrated that GBT440 preventedsickling of RBCs from sickle cell patients, in vitro. Also, in a murine model of sickle cell disease (Townes SS mice), GBT440 prevented ex vivo sickling of RBCs and prolonged RBC half-life. Pharmacokinetic (PK) studies of GBT440 were conducted in mouse, rat, dog and monkey following IV and oral administration. Both blood and plasma samples were collected and assayed for GBT440 concentration using LCMS. Following IV and oral administrations, GBT440 quickly partitions into the RBC with a high blood/plasma ratio of ~70:1 which corresponded to a RBC/plasma ratio of ~150:1. Volume of distribution (Vss) was small in whole blood (0.041-0.171 L/kg) but much larger in plasma (1.44-8.45 L/kg) indicating that RBCs are a reservoir of GBT440. Systemic clearance (CLs) was low in both blood (0.016-0.113 mL/min/kg) and plasma (0.943-3.16 mL/min/kg) indicating that GBT440 was mostly bound to hemoglobin and only a small fraction of unbound GBT440 re-distributed into the plasma and was available for clearance. Terminal elimination half-life (t1/2) was similar between whole blood and plasma for each species and was long, ranging from 6.4 hours in mouse plasma to 93.5 hours in dog plasma. GBT440 was well absorbed and absolute oral bioavailability ranged from 33% to 70% in four species. A quantitative whole body autoradiography study to determine tissue distribution of GBT440 was conducted in male rats following an oral dose of 14C-GBT440 (10 mg/kg; 150 µCi/kg PO). The data showed that GBT440 is co-located in hematopoietic tissues as expected for a molecule whose target is hemoglobin, including blood, spleen, liver and bone marrow. A mass balance study of 14C-GBT440 (10 mg/kg; 150 µCi/kg PO) was conducted in rats to determine route of elimination of GBT440. The 14C-GBT440-derived radioactivity was well absorbed and rapidly excreted after oral administration. By 240 hours postdose, mean values of 79.0 ± 3.86 and 9.74 ± 3.02% of the administered radioactivity were excreted in feces and urine, respectively. The mean overall recovery of radioactivity was 92.4 ± 0.875%. Metabolism via both Phase I and Phase II pathways was the major route of elimination of GBT440. These data indicate that despite its high affinity binding toward Hb, GBT440 could be released from the hemoglobin complex and completely eliminated from the body. To further correlate PK to pharmacological activity (hemoglobin modification based on changes in the oxygen equilibrium curve), mice were given an oral dose of 30, 50 and 100 mg/kg and blood were collected at 4 and 6 hr postdose for hemoximetry analysis. Data showed good correlation between blood concentrations and changes in p50. Blood concentrations following 30, 50 and 100 mg/kg at 4 hr were 243, 446, and 806 µM, which resulted in changes in p50 of 11%, 25% and 55%, respectively, indicating that GBT440 elicits an ex vivo dose dependent increase in Hb-O2 affinity following increasing dosage to mice. Based on PK data from 4 animal species, PK profile of GBT440 in human was predicted using a simple allometric scaling technique. The predicted PK profile following an oral administration was highly concordant with actual data from healthy subjects for Cmax, AUC and T½, which suggested that the disposition kinetics of GBT440 in humans were consistent to that in animals. In summary, nonclinical PK studies support previous findings that GBT440 partitions to RBCs, binds specifically to Hb with a slow off rate, modulates Hb-O2 affinity, and is completely eliminated from the body. GBT440 is in clinical trials for the treatment of SCD. Disclosures Hutchaleelaha: Global Blood Therapeutics: Employment, Equity Ownership. Patel:Global Blood Therapeutics: Employment, Equity Ownership. Silva:Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Metcalf:Global Blood Therapeutics: Consultancy, Equity Ownership.

Description: Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene leading to production of hemoglobin S (HbS) that polymerizes under hypoxic conditions with subsequent formation of sickled red blood cells (RBCs). We have developed a novel small molecule, GTx011, which attains effective concentrations in blood upon oral dosing in multiple species. GTx011 increases the affinity of oxygen (O2) for HbS, delays in vitro HbS polymerization and prevents sickling of isolated RBCs under hypoxic conditions. We report here that GTx011 prevents in vitro sickling of RBCs in blood from sickle cell patients. Moreover, in a murine model of sickle cell disease (Townes SS mice), GTx011 prevents ex vivo sickling of RBCs and prolongs RBC half-life. We previously reported that GTx011 prevents sickling of isolated sickle cell RBCs (SSRBCs) subjected to a fixed hypoxic condition (pO2 of ~30 mm Hg) for 30 min. For a more physiologically relevant evaluation, we determined the anti-sickling activity of GTx011 in blood under variable hypoxic conditions over a shorter duration of time. Sickling of SSRBCs in blood was evaluated using a combination of hemoximetry and morphometric measurements. Whole blood from sickle cell patients was modified in vitro with GTx011 prior to hemoximetry. Conversely, blood from SS mice with GTx011 orally dosed acutely or chronically for 10-12 days was used for hemoximetry. SSRBCs were harvested during hemoximetry at various O2 tensions and immediately fixed in a deoxygenated solution of 2% glutaraldehyde/PBS prior to morphological quantitative analysis with CellVigene software or imaging flow cytometry (AMNIS ImageStreamX MkII). To evaluate the effect of GTx011 on RBC half-life in SS mice, N-hydroxysuccinimide biotin was injected into SS mice on day 5 of chronic dosing, producing a pulse-label. Flow cytometry was performed using fluorescently labeled streptavidin to determine the decay of biotinylation and RBC half-life. Reticulocyte counts were measured at different intervals during the dosing regimen by determining the percentage of blood cells that were Ter-119+, Thiazole-Orange+ and CD45- by flow cytometry. In a dose-dependent manner, GTx011 decreased the p50 value of human blood indicating an increase in Hb-O2 affinity. In parallel, GTx011 dose-dependently reduced the number of sickled SSRBCs under all hypoxic conditions (pO2 of 30% calculated Hb target occupancy. Taken together, these data suggest that GTx011 has the potential to be a beneficial therapeutic agent for the chronic treatment of SCD. Table SS mice RBC half life Reticulocytes Sickled RBCs Hemoximetry Chronic treatment, PO, BID, 10-12 days (Days) (%) (% at 10 mm Hg) p20 (mm Hg) p50 (mm Hg) Vehicle-treated 2.4 53 56 18 32 GBT440-treated (100mg/kg) 3.8 32 19 4.5 21 Disclosures Dufu: Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Zhou:Global Blood Therapeutics: Research Funding. Hutchaleelaha:Global Blood Therapeutics: Employment, Equity Ownership. Archer:Global Blood Therapeutics: Consultancy, Research Funding.

Description: Background Direct factor Xa inhibitors have demonstrated compelling anticoagulant efficacy and/or safety profiles across multiple diverse patient populations. A specific antidote to reverse anticoagulation during episodes of serious uncontrolled bleeding or before urgent/emergent surgery is lacking. Andexanet alfa (proposed INN)(AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct fXa inhibitors. It thus acts as a decoy to reverse fXa inhibitor-mediated anticoagulation in preclinical and early clinical studies. Methods This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of rivaroxaban (riva), as well as the pharmacokinetics and safety in healthy subjects. Reversal of riva anticoagulation will be studied with up to 6 different dose cohorts/ regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Riva is administered at an oral dose of 20 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last riva dose – the approximate time of maximum riva concentration (mean ± SD: 0.64 ± 0.22 mM, n=18). Pharmacodynamic and safety data are collected through Day 48 with pharmacokinetic data through Day 10. Results We report here available data from the first 2 AnXa dose cohorts (210 mg and 420 mg, n =18). Immediately after completion of the 210 mg and 420 mg doses, anti-fXa activity decreased dose-dependently by 20% and 53%, respectively, from the pre-AnXa level and returned to placebo levels by approximately 2 hours after treatment (Figure). In parallel, the plasma concentrations of unbound riva were decreased by 32% and 51%, respectively, relative to pre-AnXa values. In addition, riva-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time were also rapidly partially reversed by AnXa in a dose-dependent manner. At 2 minutes after AnXa administration, the molar ratio of AnXa to total plasma riva was 0.8 for the 210 mg dose (1.2 µM/1.6 µM, respectively) and 1.2 for the 420 mg dose (2.6 µM/2.1 µM, respectively). AnXa infusion was not associated with increases in prothrombin fragments F1+2, thrombin-antithrombin, or D-dimer (all values were within normal ranges). As expected, tissue factor pathway inhibitor activity decreased due to its binding to AnXa. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. Adverse events occurring in 1 or more AnXa or placebo recipients included infusion-related reactions (n = 3, all mild in severity) and post-procedural hematoma, headache, or postural dizziness (n = 2 each). Summary/Conclusions Results from this ongoing clinical trial demonstrate that AnXa is able to dose-dependently partially reverse the anticoagulant effects of rivaroxaban, as assessed by pharmacodynamic markers, in healthy subjects. These data are consistent with previously reported results with apixaban in that AnXa sequesters rivaroxaban and apixaban in a similar stoichiometric manner. Additional data with higher doses of AnXa will also be presented. AnXa is well-tolerated and a potentially promising, universal antidote for fXa inhibitors. Disclosures: Mark: Portola Pharmaceuticals: Consultancy. Off Label Use: The use of PRT064445 as an antidote for reversal of anticoagulation from direct and indirect fXa inhibitors is investigational. Vandana:Portola Pharmaceuticals: Consultancy. Michael:Portola Pharmaceuticals: Employment, Equity Ownership. Genmin:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Stanley:Portola Pharmaceuticals: Employment, Equity Ownership. Castillo:Portola Pharmaceuticals: Employment, Equity Ownership. Hutchaleelaha:Portola Pharmaceuticals: Consultancy. Karbarz:Portola Pharmaceuticals: Employment. Lin:Portola Pharmaceuticals: Employment. Barron:Portola Pharmaceuticals: Employment. Russell:Portola Pharmaceuticals: Employment. Levy:Portola Pharmaceuticals: Employment. Connolly:Portola Pharmaceuticals: Consultancy. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

Description: Abstract 2266 Betrixaban is a once daily oral Factor Xa inhibitor being investigated in a Phase 3 clinical trial to prevent venous thromboembolism in acute medically ill patients (APEX Study). Mass balance, metabolite profile and interaction with major CYP enzymes were evaluated in this study. Portola study 06–005 was an open-label, single-dose, mass-balance and metabolic profiling study using 14C-labeled betrixaban in 5 healthy male volunteers. Each subject received a single oral solution containing 40 mg of betrixaban labeled with 100 μCi of 14C. Blood samples were taken serially over a 168-hour interval. Urine samples and fecal samples were collected during the 7–14 day confinement period. Subjects were discharged from the unit when at least one of the following criteria were met: 90% of the radioactivity was recovered in urine and feces, daily excreted radioactivity was 1% or less of administered dose on two consecutive days, or subject reached 336 hours (14 days) post dose. The plasma concentration equivalents of total radioactivity increased rapidly following dosing with a mean peak of 31.69 ng eq/mL occurring at 3.5 hours post-dose. AUC and half-life could not be calculated as radioactivity in plasma could only be detected up to 6 hours post dose. Terminal elimination half life determined in other clinical pharmacology studies was 37 hours. Total radioactivity recovered from urine and feces was approximately 96% (range 92% to 99%), with the majority of 14C recovery in feces (82% to 89% of the dose). The 14C dose recovered in urine, composed of betrixaban and inactive metabolites, ranged from 6% to 13%. The metabolic profile of betrixaban was determined in plasma, urine and feces. Unchanged betrixaban was the predominant component found in human plasma and excreta, accounting for 85.3% of the dose excreted in urine and feces. The major biotransformation pathway for betrixaban was hydrolysis to form PRT062802 and PRT062803, a non-14C labeled metabolite (Figure 1). PRT062803 can be demethylated to form PRT062799 or hydroxylated to form PRT062982. PRT062982 is further conjugated with sulfate to form PRT063069. Both PRT062802 and PRT063069 were major circulating metabolites in human plasma with AUC of 34% and 24% that of betrixaban, respectively. PRT062802 was the only prominent metabolite detected in human urine and feces. In addition to hydrolysis metabolites, two CYP-mediated metabolites, O-desmethyl betrixaban (PRT058326) and N-desmethyl betrixaban (PRT054156), were observed in plasma at trace levels (AUC of each was 10 μM). PRT058326 and PRT054156 have an IC50 for fXa inhibition of approximately 5 nM compared to betrixaban Ki of 0.117 pM. Interaction of betrixaban with CYP enzymes was studied in vitro. CYP inhibition potential was evaluated in human liver microsomes with or without 30 minute pre-incubation of betrixaban. Selective probe substrates were used to monitor CYP activities, i.e. phenacetin for 1A2, tolbutamide for 2C9, S-mephenytoin for 2C19, dextromethorphan for 2D6, and testosterone and midazolam for 3A4. Betrixaban had IC50 〉 80 μM for CYP1A2, 2C9, 2D6 and 3A4 for both competitive and time-dependent inhibition. IC50 for 2C19 were 43 and 88 μM for competitive and time-dependent inhibition, respectively. The CYP inhibition IC50's are much higher than the betrixaban therapeutic concentration of 50 nM. CYP induction by betrixaban was also studied using cryopreserved human hepatocytes (n=3). Betrixaban at 1, 10 and 25 μM were incubated in hepatocyte preparation for 48 hours. The activities for CYP1A2, CYP2C9, CYP2C19, and CYP3A4 were determined by measuring the formation of metabolites of the probe substrates similar to those used in the CYP inhibition study. CYP2C19 activities were not quantifiable in all three donors; therefore, induction for this CYP isoform could not be assessed. Betrixaban did not induce the activities of CYP1A2, CYP2C9, and CYP3A4. These results demonstrated that betrixaban was mainly excreted as the unchanged drug most likely via biliary secretion. Renal excretion and metabolism were minor elimination pathways. Betrixaban is unlikely to have drug-drug interactions with CYP-substrate, inducer, or inhibitor drugs. Disclosures: Hutchaleelaha: Portola pharmaceuticals: Employment. Ye:Portola Pharmaceuticals: Employment. Song:Portola Pharmaceuticals: Employment. Lorenz:Portola Pharmaceuticals: Employment. Gretler:Portola Pharmaceuticals: Equity Ownership. Lambing:Portola Pharmaceuticals: Employment.