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Etavopivat (FT-4202) is an orally administered, small-molecule allosteric activator of erythrocyte pyruvate kinase-R (PKR) in clinical development for the treatment of sickle cell disease and other hemoglobin disorders. This randomized, placebo-controlled, double-blind, first-in-human combination single-ascending dose and multiple-ascending dose phase 1 trial (NCT03815695) evaluated the safety and pharmacokinetics/pharmacodynamics of etavopivat in 90 healthy adult subjects. In 4 single-ascending dose cohorts, 8 participants were randomized 3:1 to a single oral dose of either etavopivat (n = 6) or placebo (n = 2). In four 14-day multiple-ascending dose cohorts, 12 participants were randomized 3:1 to 14 days of etavopivat (n = 9) or placebo (n = 3). In these studies, most treatment-emergent adverse events were of mild severity (grade 1) and none led to study discontinuation. Etavopivat exhibited a linear and time-independent pharmacokinetic profile (at doses ≤400 mg) and elicited the expected pharmacodynamic effects of PKR activation (decreased 2,3-diphosphoglycerate and increased adenosine triphosphate) and evidence of improved hemoglobin-oxygen affinity. In addition, pharmacodynamic responses were durable with effects continuing for 48 to 72 hours after the last dose, thereby supporting once-daily dosing. Food appeared to have no clinically meaningful effects on etavopivat exposure, thus facilitating administration with or without food. In conclusion, the evaluation of etavopivat in healthy subjects demonstrated proof of mechanism (PKR activation) without significant adverse events. This study also allowed for the selection of dose levels, projected to have an acceptable safety profile and provide therapeutic benefit, for evaluation in future trials in patients with sickle cell disease.

Etavopivat is a small molecule activator of erythrocyte pyruvate kinase (PKR), that increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers (HV) and patients (pts) with sickle cell disease (SCD) (Kalfa 2019, Brown 2020). Based on initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) data for HVs and pts with SCD, we performed multiple-dose studies in pts with SCD (NCT03815695): 2-wk multiple ascending dose (MD) cohorts to identify the once daily etavopivat dose that provides maximum PD activity with an acceptable safety profile and a 12-wk open label (OL) study to further characterize the safety and clinical activity at the maximum PD dose. These data are presented here. In the completed MD cohorts, 20 pts with SCD were randomized 8:2 to receive etavopivat (300 mg, then 600 mg) or placebo (PBO) once daily for 2 wks. In the ongoing OL cohort, up to 20 pts will receive etavopivat 400 mg once daily for 12 wks. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and peripheral blood laboratory parameters. PK/PD blood sampling was performed for up to 72 h after last dose and at end of study visit. RBC function studies were performed to assess membrane deformability (Lorrca ®). Enrollment in the MD cohorts (n=17 HbSS, n=2 HbSβ+thalassemia, n=1 HbSC) is complete and data unblinded (n=8: 300 mg etavopivat; n=8: 600 mg etavopivat; n=4: PBO). As of July 13, 2021, 11 pts (n=10 HbSS, 1 HbSC) have been treated in the OL cohort: median treatment duration was 12 (range 1-12) wks, 6 pts completed 12 wks of treatment. In MD pts, etavopivat demonstrated dose-proportional PK with overlapping PD responses (decreased 2,3-DPG and increased ATP), confirming prior results in HVs that etavopivat 400 mg once daily provides near maximal PD activity. Etavopivat was well tolerated in both MD and OL cohorts. AEs were reported in 1 of 4 (25%) MD PBO pts, most were grade (gr) ≤3, with 1 gr 4 blood creatine phosphokinase (CPK) increase. 13 of 16 (81%) etavopivat-treated MD pts reported AEs, most were gr 1/2 and commonly (>2 pts) included sickle cell pain (n=6 [38%]), headache (n=5 [31%]), and nausea (n=3 [19%]). One pt had a serious AE (SAE) of gr 3 vaso-occlusive crisis (VOC) after completion of etavopivat (considered unrelated). In the OL cohort, AEs were reported in 7 of 11 (64%) pts who received at least 1 wk of etavopivat. AEs reported in >1 pt were headache and VOC (n=2 [18%] each). Most AEs were gr 1/2; one pt had SAEs of gr 3 acute chest syndrome and VOC (unrelated), one pt had an SAE of gr 3 deep vein thrombosis (possibly related), and one pt had an AE of gr 4 transient blood CPK increase (unrelated). Hematologic and hemolytic parameters were significantly improved at end of treatment in both MD and OL cohorts (Table 1); 11 of 15 (73%) evaluable MD pts achieved a Hb increase ≥1g/dL over baseline (mean 1.1 g/dL, P1g/dL Hb increase over baseline (mean 1.39 g/dL). Reductions in ARC, indirect bilirubin and LDH were also observed. Of 9 pts on etavopivat for at least 4 wks, 8 (89%) reported an increase in Hb >1g/dL, and the highest mean Hb increase was 1.81 g/dL during active treatment. Etavopivat-treated RBCs from MD pts (n=14) demonstrated improved functional health, including point of sickling and deformability. The improved deformability persisted up to 1 wk after etavopivat treatment in 36% of pts. Similar results were observed in the initial OL pts. Data on additional treated pts will be presented. Etavopivat 400 mg once daily for up to 12 wks was well-tolerated, with a safety profile consistent with underlying SCD. Increases in Hb >1 g/dL were observed in 89% of pts and maintained throughout 12 wks of treatment in the majority (83%) of pts. Increased Hb and a significant reduction in ARC indicated that etavopivat enhanced survival of sickle RBCs and significantly improved the severe anemia associated with SCD. These longer-living sickle RBCs have improved membrane health that may further reduce the risk of VOCs and end-organ damage. These results support further evaluation of etavopivat in the ongoing Phase 2/3 Hibiscus Study in pts with SCD (NCT04624659). Figure 1 Figure 1. Disclosures Brown: Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Novo Nordisk: Consultancy; Forma Therapeutics: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Idowu: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics, Inc.: Research Funding; Ironwood: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalfa: Agios Pharmaceuticals, Inc.: Other: Steering Committee, Research Funding; FORMA Therapeutics, Inc: Research Funding. Geib: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Forsyth: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Schroeder: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Wu: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kelly: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Telen: GlycoMimetics, Inc.: Consultancy; Novartis, Inc.: Other: Data Safety Monitoring Board; Forma Therapeutics, Inc.: Consultancy, Research Funding; CSL Behring, Inc.: Research Funding; Doris Duke Charitable Foundation: Research Funding; National Institutes of Health: Research Funding.

While checkpoint inhibitor therapy has transformed treatment of multiple tumor types, many patients remain refractory. Tilsotolimod, a toll-like receptor 9 agonist, has been shown in preclinical models to activate plasmacytoid dendritic cells and increase T cell infiltration to the tumor microenvironment. Preliminary results of a phase 1/2 study suggested that intratumoral injection of tilsotolimod in combination with ipilimumab may revive an immune response in patients with immune checkpoint inhibitor-resistant metastatic melanoma. To further explore the role of tilsotolimod in modulating the tumor immune microenvironment, we conducted a Phase Ib monotherapy trial (ILLUMINATE-101). Adults with histologically or cytologically confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod in doses escalating from 8 mg to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Objectives of the dose evaluation portion included characterizing safety and pharmacokinetics, and evaluating alterations in the tumor microenvironment. Blood samples and tumor biopsies of injected and distal lesions were obtained at baseline and on treatment. Immune analyses included evaluation using Nanostring and/or flow cytometry of activation of the type 1 interferon (IFN) pathway, IFN gamma levels, activation of dendritic cell subsets, and changes in T cell status. As of November 7, 2018, 41 patients have been enrolled, including 38 patients into the dose evaluation portion and 3 patients into a melanoma expansion cohort. No dose-limiting toxicities or treatment-related adverse events have been observed. Within 24 hours, fresh tumor biopsies showed significant increases in IFN gamma levels, activation of the type 1 IFN pathway, induction of an antigen processing gene signature (a measure of the MHC class I antigen presentation pathway), and maturation of dendritic cells as measured by expression of HLA-DR (MHC class II), compared to pretreatment biopsies. Of 25 evaluable patients who received at least 1 dose of tilsotolimod and had at least 1 post-baseline disease assessment, 12 (48%) had a RECIST v1.1 disease assessment of stable disease. For patients with at least one disease assessment following documentation of stable disease (n=8), duration of stable disease ranged from 0.53 to 4.2+ months, with 3 patients ongoing. These results demonstrate that single agent tilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment. Citation Format: Hani M. Babiker, Vivek Subbiah, Orla Maguire, Shah Rahimian, Hans Minderman, Cara L. Haymaker, Chantale Bernatchez, Erkut Borazanci, James Geib, Srinivas K. Chunduru, Peter M. Anderson, Igor Puzanov, Adi Diab. Activation of innate and adaptive immunity using intratumoral tilsotolimod (IMO-2125) as monotherapy in patients with refractory solid tumors: a phase Ib study (ILLUMINATE-101) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4062.

e15150Background: Patients without palpable lesions who are candidates for intratumoral immunotherapy may need D/V IG agent delivery. Novel immuno-oncology (I-O) agents requiring ITI highlight the ...

Background: While checkpoint inhibitor (CPI) therapy has transformed metastatic melanoma (MM) treatment, many patients remain refractory. We reasoned that combining CPI with an agent that activates antigen presenting cells and improves T-cell priming may result in improved response. Our approach is to modulate the tumor microenvironment through image-guided intratumoral (i.t.) injection of the TLR9 agonist, IMO-2125, in combination with either ipilimumab (ipi) or pembrolizumab (pembro). We hypothesize that this will result in dendritic cell (DC) activation and induction of tumor-specific CD8+T-cells which will synergize with ipilimumab or pembrolizumab to overcome immune-escape. Based on this rationale we initiated a phase I/II clinical trial. Study Design/Methods: Adults with refractory MM that have had prior PD-1 blockade therapy (with or without a BRAF inhibitor) are eligible. IMO-2125, in doses escalating from 4mg to 32mg, is given i.t. weeks 1, 2, 3, 5, 8, and 11 along with standard doses of ipilimumab or pembrolizumab. Primary endpoints are safety, tumor response, and PK. Multiple biopsies are obtained in both the injected and distant tumor pre- and on-treatment. Immune analyses include DC subsets and their activation status as well as T cell activation, function and proliferation. T-cell repertoire diversity is evaluated by high-throughput CDR3 sequencing and changes in gene expression signatures are assessed by nanoString. Changes in circulating cytokines are also being assessed during therapy. Results: Enrollment is proceeding on both the IMO-ipilimumab and IMO-pembrolizumab dose-escalation arms of the trial. Safety is acceptable with no DLT recorded to date. Durable clinical responses (including 1 CR) have been observed with IMO-ipilimumab in patients who were refractory to PD-1 inhibitor. Fresh tumor biopsies show maturation (upregulation of HLA-DR) of the myeloid DC1 subset (CD1c+CD303-), upregulation of PD-L1 by malignant cells, as well as an IFNα response gene signature in the IMO-2125 injected tumor lesion 24 hrs post-treatment compared to pre-treatment biopsy. On-treatment biopsy results show a higher expression of CD56+ and Ki67+ effector CD8+ T-cells in responding patients. Initial CDR3 sequencing demonstrates increased diversity in the injected lesions of all patients assessed and expansion of top clones present in the distant lesion in a responding patient. Plasma analysis showed an increase in IFNγ levels in the plasma of responding patients. Conclusions: These results demonstrate that IMO-2125 with a checkpoint inhibitor is a viable strategy to revive the immune response in tumors that are refractory to PD-1 inhibitors. Further clinical evaluation of both the IMO-ipilimumab and IMO-pembrolizumab combination is planned in a Phase 2 expansion of the current trial. Citation Format: Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Rodabe Amaria, Sapna Patel, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem Overwjik, Chantale Bernatchez, Adi Diab. Translational evidence of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5652. doi:10.1158/1538-7445.AM2017-5652

Ribonuclease L (RNase L), the 2′,5′-oligoadenylate-dependent ribonuclease, is one of the cellular antiviral systems with enhanced activity in the presence of interferon. A reaction scheme has been developed to model the sequence of steps necessary for the activation of RNase L (Cole, J. L., Carroll, S. S., Blue, E. S., Viscount, T., and Kuo, L. C. (1997)J. Biol. Chem. 272, 19187–19192). The model comprises three sequential binding steps: the binding of activator to enzyme monomer, the subsequent dimerization of the activated monomer to form the active enzyme dimer, followed by the binding of substrate prior to catalysis. The model is used to evaluate the activation of RNase L by several synthetic analogs of the native activator. The 5′-phosphate of the activator has been determined to be an important structural determinant for the efficient activation of RNase L, and its loss caused a loss of activator affinity of 2–3 orders of magnitude. The length of activator is not an important determinant of activator potency for the activator analogs examined. The specific activity of the enzyme under conditions of saturation of activator binding and complete dimerization of the activated monomers varies only by about a factor of 3 for the activators examined, indicating that once dimerized in the presence of any of these activators, the enzyme exhibits a similar catalytic activity.

Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV.Patients with HCV infection and thrombocytopenia (platelet count75,000/μL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy.More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/μL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2.Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

RNase L, the 2',5' oligoadenylate-dependent ribonuclease, is one of the enzyme systems important in the cellular response to interferon. When activated in the presence of 2',5'-linked oligoadenylates, RNase L can catalyze the cleavage of synthetic oligoribonucleotides that contain dyad sequences of the forms UU, UA, AU, AA, and UG, but it cannot catalyze the cleavage of an oligoribonucleotide containing only cytosines. The primary site of the cleavage reaction with the substrate C11UUC7 has been defined to be 3' of the UU dyad by labeling either the 5' or the 3' end of the oligoribonucleotide and by examining the reaction products on polyacrylamide sequencing gels. Reaction time courses have been used to determine the kinetic parameters of the cleavage reactions. The effect of the overall length of the oligomeric substrate as well as the sequence of the bases around the position of the cleavage site on the kinetics of the cleavage reaction has been examined. The efficiency with which activated RNase L catalyzes the cleavage of the substrate C11UUC7 is 1.9 x 10(7) m-1 s-1. Because the cleavage of the synthetic oligoribonucleotide can be used to monitor the steady-state kinetics of catalysis by activated RNase L, this method offers an advantage over previous methods of assay for RNase L activity.

6-Chloro-(4S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl)-ethynyl)quinazol in- 2(1H)-one (L-738,372) is representative of a novel structural class of nonnucleoside inhibitors of human immunodeficiency virus, strain 1 (HIV-1), reverse transcriptase (RT), the quinazolinones. L-738,372 is a reversible inhibitor of HIV-1 RT and is noncompetitive against dTTP with a Ki of 140 nM with poly(rA).oligo(dT) as primer-template. Mixed noncompetitive inhibition by L-738,372 was observed against poly(rC).oligo(dG) as primer-template. This quinazolinone binds to RT at a site that overlaps the binding site of other nonnucleoside inhibitors as evidenced by the ability of L-738,372 to displace bound radiolabeled L-696,229, a member of the pyridinone class of inhibitors of HIV-1 RT, from complexes of RT and primer-template. Inhibition by L-738,372 shows slow binding characteristics in reactions with all of the primer-templates employed. Synergistic inhibition of RT activity was evident in combinations of L-738,372 and any of the nucleoside analogs, azidothymidine triphosphate, dideoxyinosine triphosphate, or dideoxycytosine triphosphate. The azidothymidine-resistant form of RT (D67N, K70R, T215Y, K219Q) is inhibited by L-738,372 with 2-3-fold more potency than is the wild-type RT. Comparison of inhibition by L-738,372 with inhibition by pyridinone inhibitors reveals differences in synergistic inhibition with nucleoside analogs and in the rates of binding of the inhibitors.

HIV-1 reverse transcriptase can catalyze the addition of either azidothymidine monophosphate (AZTMP) or thymidine monophosphate (dTMP) to a primer strand opposite template adenosine bases. The ratio of incorporation of AZTMP to dTMP as catalyzed by HIV-1 reverse transcriptase has been determined to be 0.4 using an RNA-DNA duplex substrate prepared from oligonucleotides with sequences taken from the HIV-1 genome sequence. Slight variations are found for the incorporation ratio of the two nucleotides on other substrates. Substrates containing more than one adenosine in the single-stranded part of the template allow for more chances to incorporate AZTMP and less full-length product. Variations in the intensity of bands on an autoradiograph of a DNA sequencing gel corresponding to different positions of incorporation of AZTMP suggest that not all template adenosine positions offer the same level of discrimination against incorporation of AZTMP. A reverse transcriptase containing a set of four mutations (D67N, K70R, T215Y, K219Q) known to cause resistance to AZT in cell culture assays has a ratio of incorporation that is 0.77 +/- 0.03 times the ratio for the wild-type reverse transcriptase opposite one specific template adenosine. In contrast, a hybrid mutant containing the same four mutations that cause resistance to AZT and an additional mutation, Y181C, which by itself causes resistance to the non-nucleoside inhibitor L-697,661 [Sardana et al. (1992), J. Biol. Chem. 267, 17526-17530], has a ratio of incorporation that is 1.34 +/- 0.01 times that of the wild-type, indicating that the hybrid mutant enzyme is more susceptible to inhibition by AZTTP than the wild-type reverse transcriptase.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and safety of intravenous (IV) ertapenem, 1 and 1.5 g once a day, for treatment of adults with complicated intra-abdominal infection were compared with those of IV ceftriaxone 2 g once a day plus IV metronidazole 500 mg every 8 h. After at least 3 days of IV therapy and satisfactory clinical response, patients could be switched to oral ciprofloxacin plus metronidazole. Fifty-nine patients were randomized to receive ertapenem 1 g and 51 to receive ertapenem 1.5 g; 55 patients were randomized to each comparator group. At the test of cure, 4-6 weeks post therapy, in the 1 g cohort, 84% (26/31) of patients treated with ertapenem and 85% (35/41) with comparator therapy had a favourable clinical and microbiological assessment. Success rates in the 1.5 g cohort were 83% (22/29) and 77% (24/31) in the ertapenem and comparator groups, respectively. Drug-related adverse events were generally similar in both treatment groups. Ertapenem 1 or 1.5 g once a day followed by optional oral therapy appeared similar to combined therapy with ceftriaxone plus metronidazole with the same optional oral switch for treatment of complicated intra-abdominal infections in adults. Although not compared directly in a randomized fashion, the efficacy and safety profiles of ertapenem 1 and 1.5 g appeared comparable. Ertapenem was generally well tolerated and had an overall safety profile similar to ceftriaxone plus metronidazole.

Abstract 2232 Introduction: Thrombocytopenia (TCP) is a common complication of cirrhosis in patients with hepatitis C virus (HCV) infections (Louie et al 2011); the presence of TCP impairs the ability to initiate peginterferon alpha (PEG) therapy and necessitates PEG dose reduction or discontinuation, thus reducing the potential for sustained virologic response (SVR). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic immune thrombocytopenia, increases platelet counts in patients with TCP due to HCV-related cirrhosis (McHutchison et al 2007). ENABLE 1 was a phase 3, multicenter, two-part study of eltrombopag for the treatment of HCV-associated TCP. Part 1 involved open-label, pre-antiviral treatment with eltrombopag. Patients achieving platelet counts ≥90,000/μL were randomized in Part 2 to receive eltrombopag or placebo in combination with antiviral therapy (PEG-2a plus ribavirin). Aim: To assess the safety and efficacy of eltrombopag during the open-label, pre-antiviral treatment phase (Part 1) of ENABLE 1 in patients with cirrhosis. Methods: Patients with chronic HCV and a baseline platelet count 200,000/μL. No thromboembolic events were observed during open-label treatment. Conclusions: Eltrombopag was generally well-tolerated and resulted in sustained increase in platelet counts during the open-label, pre-antiviral treatment phase. Platelet count increases were seen as early as 2 weeks following initiation of treatment. The vast majority of patients (97%) achieved platelet count increases to ≥90,000/μL, the threshold for initiating PEG-2a plus ribavirin therapy, and most did so within 4 weeks of initiating eltrombopag treatment. Disclosures: Dusheiko: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Off Label Use: Eltrombopag, inteferon and Ribavirin; eltrombopag is a thrombopoetin receptor agonist. Its efficacy and safety in raising platelet counts in hepatitis C positive patients (most with cirrhosis) and thrombocyotopaenia was studied in this protocol. Afdhal:Merck: Consultancy, Honoraria, Research Funding; Vertex: Consultancy, Honoraria, Research Funding; Idenix: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Springbank: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmasett: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding. Giannini:GlaxoSmithKline: Consultancy, Speakers Bureau; Hoffman-LaRoche: Consultancy, Speakers Bureau. Chen:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Geib:GlaxoSmithKline: Employment. Vasey:GlaxoSmithKline: Employment. Patwardhan:GlaxoSmithKline: Employment, company shares. Campbell:GlaxoSmithKline: Employment, Equity Ownership. Theodore:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.