A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis.

BACKGROUND: Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. METHODS: 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. RESULTS: Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. CONCLUSIONS: These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02689206 ; date registered: 02/11/2016.

Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial.

BACKGROUND: The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. METHODS: PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. FINDINGS: Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. INTERPRETATION: Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. FUNDING: GlaxoSmithKline.

Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.

Patients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment lasting ≤ 6 months. This interim analysis of the ongoing open-label EXTEND (Eltrombopag eXTENded Dosing) study evaluates the safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and nonsplenectomized patients achieved platelets ≥ 50 000/µL at least once (80% and 88%, respectively). Platelets ≥ 50 000/µL and 2 × baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks, respectively. Bleeding symptoms (World Health Organization Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45 of 69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range.

Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study.

Thrombopoietin receptor agonists, which raise platelet counts in patients with chronic immune thrombocytopenia, may be associated with increases in bone marrow (BM) reticulin. Patients with chronic immune thrombocytopenia participating in the Eltrombopag Extended Dosing (EXTEND) study underwent BM biopsies to identify clinically relevant BM fibrosis-related increases. Specimens were centrally reviewed by 2 hematopathologists. Two hundred thirty-two biopsy specimens were collected from 117 patients treated for ≤5.5 years. Moderate to marked reticulin fibrosis was found in 2 patients. After withdrawing from the study, the biopsy of 1 patient reverted to normal. There were no other pathologic changes identified among on-treatment specimens, and no pattern of abnormal reticulin deposition associated with eltrombopag treatment was evident.

Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial.

BACKGROUND AND OBJECTIVES: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis with a baseline hemoglobin of 8-11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly (n=270) or conventional epoetin (n=137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28-52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability. RESULTS: Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%). CONCLUSIONS: Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033.

Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies.

BACKGROUND: Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. OBJECTIVE: The aim of these studies was to assess the effect of food and antacids on the pharmacokinetic and safety profiles of eltrombopag. METHODS: Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrombopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication. RESULTS: In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC(0-infinity)) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36-0.46) and C(max) by 65% (GMR, 0.35; 90% CI, 0.30-0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87-1.03 for AUC(0-infinity) and 0.85-1.01 for C(max) across the 3 studied meals). Mean plasma AUC(0-infinity)) and C(max) values decreased by approximately 70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC(0-infinity)) and 0.24-0.38 for C(max)) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%-29.2%). CONCLUSIONS: Concomitant administration of eltrombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrombopag was generally well tolerated in these healthy volunteers.

Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study.

BACKGROUND: The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia. METHODS: PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037. FINDINGS: Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase. INTERPRETATION: Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults. FUNDING: GlaxoSmithKline.

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is characterized by the presence of ubiquitinated, intranuclear inclusions associated with molecular chaperones and 26S proteasome components, although the role of these inclusions in the pathogenesis of polyglutamine diseases remains unclear. The over-expression of molecular chaperones of the Hsp70 and Hsp40 families has been shown to modulate inclusion frequency and cellular toxicity. We developed a cell culture system which enables the quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. Using this approach, we demonstrate that Hsp70 and its co-chaperone Hsp40 not only increase expanded repeat AR solubility, but function to enhance the degradation of expanded repeat AR through the proteasome. Furthermore, our studies indicate that these molecular chaperones significantly decrease the half-life of an expanded repeat AR. Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases.