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Aims To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) Conclusions Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse clinical course and outcome, independently of other known prognostic factors such as age, aneurysm size, and initial clinical grade. METHODS In this post hoc analysis, patients with aSAH undergoing surgical clipping (n = 383) or endovascular coiling (n = 189) were pooled from the placebo arms of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS)–2 and CONSCIOUS-3 randomized, double-blind, placebo-controlled phase 3 studies, respectively. Patients without and with thick, diffuse SAH (≥ 4 mm thick and involving ≥ 3 basal cisterns) on admission CT scans were compared. Clot size was centrally adjudicated. All-cause mortality and vasospasm-related morbidity at 6 weeks and Glasgow Outcome Scale–Extended (GOSE) scores at 12 weeks after aSAH were assessed. The effect of the thick and diffuse cisternal aSAH on vasospasm-related morbidity and mortality, and on poor clinical outcome at 12 weeks, was evaluated using logistic regression models. RESULTS Overall, 294 patients (51.4%) had thick and diffuse aSAH. Compared to patients with less hemorrhage burden, these patients were older (median age 55 vs 50 years) and more often had World Federation of Neurosurgical Societies (WFNS) grade III–V SAH at admission (24.1% vs 16.5%). At 6 weeks, all-cause mortality and vasospasm-related morbidity occurred in 36.1% (95% CI 30.6%–41.8%) of patients with thick, diffuse SAH and in 14.7% (95% CI 10.8%–19.5%) of those without thick, diffuse SAH. Individual event rates were 7.5% versus 2.5% for all-cause death, 19.4% versus 6.8% for new cerebral infarct, 28.2% versus 9.4% for delayed ischemic neurological deficit, and 24.8% versus 10.8% for rescue therapy due to cerebral vasospasm, respectively. Poor clinical outcome (GOSE score ≥ 4) was observed in 32.7% (95% CI 27.3%–38.3%) and 16.2% (95% CI 12.1%–21.1%) of patients with and without thick, diffuse SAH, respectively. CONCLUSIONS In a large, centrally adjudicated population of patients with aSAH, WFNS grade at admission and thick, diffuse SAH independently predicted vasospasm-related morbidity and poor 12-week clinical outcome. Patients with thick, diffuse cisternal SAH may be an important cohort to target in future clinical trials of treatment for vasospasm.

Background Oral P2Y12 receptor antagonists exhibit delayed onset of platelet inhibition in patients with acute myocardial infarction (AMI). Selatogrel is a potent, highly selective, and reversible P2Y12 receptor antagonist with a rapid onset and short duration of action. Objectives This study sought to assess inhibition of platelet aggregation following subcutaneous administration of selatogrel in patients with AMI. Methods Patients with AMI were randomized to a single subcutaneous dose of selatogrel of 8 or 16 mg. The primary endpoint was response to treatment (P2Y12 reaction units Results Forty-seven patients received selatogrel 8 mg (n = 24) or 16 mg (n = 23) followed by ticagrelor (n = 43) or clopidogrel (n = 1). The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80% to 100%) and 96% (97.5% CI: 87% to 100%) with 8 and 16 mg, respectively (p values for responders >85% target; p = 0.142 and p = 0.009, respectively). Response rates were independent from type of AMI presentation, age, or sex. A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 91% [97.5% CI: 80% to 100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 96% [97.5% CI: 87% to 100%]). At 15 min, median P2Y12 reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2 to 175) for 16 mg. Selatogrel was well tolerated, without major bleeding complications. Conclusions Single-dose subcutaneous administration of selatogrel in patients with AMI was safe and induced a profound, rapid, and dose-related antiplatelet response. (A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Heart Attack; NCT03487445 , 2018-000765-36 [EudraCT])

Background Oral P2Y12 receptor antagonists exhibit a delayed onset of platelet inhibition in patients experiencing acute myocardial infarction (AMI). Selatogrel is a potent, reversible, and highly selective P2Y12 receptor antagonist with a rapid onset and offset of action when administered subcutaneously. Purpose To assess inhibition of platelet aggregation (IPA) after subcutaneous (s.c.) single-dose administration of selatogrel in patients with AMI receiving standard concomitant therapy. Methods Male and postmenopausal female adults (≤85 years) presenting with type 1 AMI (ST-elevation MI [STEMI] or non-STEMI [NSTEMI]) and onset of AMI symptoms >30 min to Results Forty-seven patients (median age 69 y; 72% male; 62% STEMI; 94% Killip class 1) received 8 mg (N=24) or 16 mg (N=23) selatogrel. Study-treatment concomitant medications included acetylsalicylic acid (98%), P2Y12 inhibitors (96%), heparins (94%), statins (94%), nitrates (68%) and morphine (38%). Oral ticagrelor (92%) with corresponding loading doses was only administered after selatogrel. The proportion of patients meeting the primary endpoint (responders) 30 min post-dose was 91% (95% CI: 72, 99) and 95% (95% CI: 77, 100) with 8 and 16 mg, respectively (p Conclusion Single-dose administration of s.c. selatogrel (8 mg and 16 mg) induced a rapid IPA response in patients with AMI at 30 min (as early as 15 min and maintained at 60 min post-dose) and was well-tolerated with no major bleeding events. Acknowledgement/Funding Fully funded by Idorsia Pharmaceuticals Ltd

Background In the setting of AMI, rapid platelet inhibition is desirable but the onset of pharmacodynamic (PD) effect of oral platelet P2Y12 inhibitors is delayed, sometimes for hours. Subcutaneous (s.c) administration of a rapidly-acting P2Y12 inhibitor would overcome many of the limitations of available therapies. Patients with stable CAD were investigated initially. Purpose To characterise the inhibition of platelet aggregation and pharmacokinetics (PK) of a single dose of selatogrel, a novel s.c P2Y12 inhibitor, in patients with stable CAD. Methods Patients with stable CAD receiving oral antiplatelet therapy (aspirin and/or oral P2Y12 inhibitor) were randomized to 1 of 8 groups based on treatment (selatogrel or matching placebo), dose (8 mg or 16 mg) and s.c injection site (thigh or abdomen). Venous blood samples were collected into PPACK anticoagulant tubes. Platelet reactivity was assessed by VerifyNow PRU (P2Y12 reaction units) test before and 15 min, 30 min and 1, 2, 4, 8 and 24 h after injection. Light-transmittance aggregometry (LTA; ADP 20 uM) was also performed. PK samples were collected up to 24 h post-dose. Adverse events occurring within 30 days were recorded. Responders were defined as having PRU Results 345 patients (mean age 65 y; 20% female; 31% diabetes) received selatogrel 8 mg (n=114), selatogrel 16 mg (n=115) or placebo (n=116). 97% were on background therapy with aspirin (or its derivative carbasalate) and 35% with oral P2Y12 inhibitor (clopidogrel 23%, prasugrel 4%, ticagrelor 8%). 89% of subjects were responders to selatogrel 8 mg, 90% to selatogrel 16 mg and 16% to placebo (P Conclusions Selatogrel has a rapid PD effect following s.c injection in patients with stable CAD, within 15 min in most patients. The consistent and high levels of P2Y12 inhibition with a single 8 mg or 16 mg dose are sustained for over 4 hours, following which platelet reactivity progressively recovers over 24 h. Selatogrel was well tolerated, with mostly mild, transient dyspnoea observed in Acknowledgement/Funding Fully funded by Idorsia Pharmaceuticals Ltd

Background and Purpose— Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH), although no effect on long-term functional outcome has been demonstrated. Thick clot on initial computed tomography is associated with an increased risk of vasospasm and delayed cerebral ischemia. In this post hoc analysis, we hypothesized that use of clazosentan in this subpopulation would provide stronger benefit. Methods— We analyzed SAH patients enrolled in the CONSCIOUS-2 and CONSCIOUS-3 studies (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) and compared the effects of clazosentan 5 mg/h, 15 mg/h, and placebo starting the day after aneurysm repair. The analysis was performed separately based on the presence or absence of thick (≥4 mm) and diffuse (≥3 cisterns) SAH on admission computed tomography. The primary composite end point was all-cause mortality and vasospasm-related morbidity at 6 weeks, and the main secondary end point was the extended Glasgow Outcome Scale at 3 months, adjusted for admission clinical grade. Results— Of 1718 randomized patients, 919 (53%) had thick and diffuse SAH. The primary composite end point in this group occurred in 36% of placebo-treated patients (n=294), 30% patients treated with clazosentan 5 mg/h (n=514; relative risk, 0.82; 95% CI, 0.67–0.99), and 19% patients treated with clazosentan 15 mg/h (n=111; relative risk, 0.54; 95% CI, 0.36–0.80). Despite this, death or poor functional outcome (Glasgow Outcome Scale ≤4) occurred in 33% of placebo-treated patients, 34% of patients treated with clazosentan 5 mg/h (relative risk 1.02; 95% CI, 0.84–1.23), and 35% of patients treated with clazosentan 15 mg/h (relative risk 1.14; 95% CI, 0.88–1.48). Conclusions— In an enriched population with thick and diffuse SAH, clazosentan at a dose of 5 and 15 mg/h was able to significantly reduce vasospasm-related morbidity in a dose-dependent manner. The absence of an effect on long-term functional status likely reflects the complexity and multiplicity of factors that contribute to poor outcome after SAH. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00558311; NCT00940095.

Background Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm. Methods The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis. Results The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0–61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively. Conclusions Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.

Background Antagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks. Methods A Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100–1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS). Results 579 participants were randomized in the Phase 2 trial (mean age 41.6–43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5–40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (−0.15 [95% CI −0.29, −0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (−0.02 [95% CI −0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile. Conclusions The Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies. Trial registration NCT01241214 and NCT01484119

The orally active dual OXProspective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18-64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated.From 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (-26.8 min and -19.5 min, respectively; both p 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo.Almorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder. CLINICALTRIALS.NCT00608985.

Objective: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake. Methods: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to

This subgroup analysis evaluated the effect of once-daily oral deferasirox on labile plasma iron (LPI) levels in patients from the prospective, 1-yr, multicentre ESCALATOR study. Mean baseline liver iron concentration and median serum ferritin levels were 28.6 +/- 10.3 mg Fe/g dry weight and 6334 ng/mL respectively, indicating high iron burden despite prior chelation therapy. Baseline LPI levels (0.98 +/- 0.82 micromol/L) decreased significantly to 0.12 +/- 0.16 micromol/L, 2 h after first deferasirox dose (P = 0.0006). Reductions from pre- to post-deferasirox administration were also observed at all other time points. Compared to baseline, there was a significant reduction in preadministration LPI that reached the normal range at week 4 and throughout the remainder of the study (Por = 0.02). Pharmacokinetic analysis demonstrated an inverse relationship between preadministration LPI levels and trough deferasirox plasma concentrations. Once-daily dosing with deferasiroxor =20 mg/kg/d provided sustained reduction in LPI levels in these heavily iron-overloaded patients, suggesting 24-h protection from LPI. Deferasirox may therefore reduce unregulated tissue iron loading and prevent further end-organ damage.

Background FTY720 is a novel immunomodulator that was developed to produce optimal graft protection with improved safety and tolerability. Phase II studies have demonstrated the efficacy of FTY720 up to the doses of 2.5 mg with full-dose cyclosporine (FDC). Methods This multicenter, double-blind, Phase IIb, randomized study evaluated the safety and efficacy of 5 mg FTY720 (n=87; Group 1) vs. 2.5 mg FTY720 (n=90; Group 2) vs. mycophenolate mofetil (MMF; n=94; Group 3) in de novo renal transplant patients receiving FDC and prednisone. Results The primary efficacy endpoint was the occurrence of treated biopsy-proven acute rejection, graft loss, death, or premature study discontinuation (composite endpoint) within 6 months. The primary endpoint was superior in Group 1 (24%) and statistically noninferior in Group 2 compared to Group 3 (24.1% vs. 29.2% vs. 39.4%; P=0.025 and 0.0039, respectively). FTY720 plus FDC was generally well tolerated, with a similar incidence of adverse events across all groups. FTY720 was associated with higher incidence of bradycardia (Group 1: 26.4%, P=0.0002 and Group 2: 15.6%, P=0.046, vs. Group 3: 6.4%), respiratory disorders (Group 1: 40.2%, not significant [P=NS] and Group 2: 34.4%, P=NS vs. Group 3: 28.7%). One macular edema occurred in Group 2. Lower creatinine clearances were observed with FTY720 versus MMF (Group 1: 52.4 ml/min, P=NS and Group 2: 51.7 ml/min, P=0.039 vs. Group 3: 62.5 ml/min). Conclusions Although FTY720 with FDC provided adequate protection from acute rejection the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients.

Objective This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients. Methods Totally 104 male and female patients were enrolled in a 50-week, exploratory, open-label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF-I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast-enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross-over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled. Results Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant ( P = 0·047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71% vs. 27%), hepatobiliary (41% vs. 8%) and respiratory (5% vs. 28%). Conclusion This first randomized study in unselected patients indicates that the 48-week treatment outcome of octreotide LAR as first-line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH-secreting macro-adenomas can be difficult, first-line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.

Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Background: Labile plasma iron (LPI) is a toxic, directly chelatable form of non-transferrin- bound iron that is produced continually in conditions of iron overload and, due to rapid uptake into hepatocytes, myocardium and endocrine tissues, leads to secondary expansion of the cellular iron pool. The sustained presence of an iron chelator in the plasma may help avoid accumulation of LPI, thereby minimizing iron-related morbidity and mortality. This analysis evaluates the effect of deferasirox on LPI levels in patients (pts) with transfusion-dependent anemias enrolled in the large-scale, prospective, 1-yr multicenter EPIC trial. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusion episodes or >100 mL/kg of RBCs) and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw). Deferasirox starting dose was determined based on blood transfusion frequency. Dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) were based on SF trends and safety markers. Blood samples to measure LPI and assess the deferasirox pharmacokinetic profile were taken pre-administration and 2 hrs post administration at baseline and wks 12, 28 and 52. Results: LPI data are available from 1602 pts (825 M, 777 F; mean 30.4±23.0 yrs). Underlying anemias were: β-thalassemia (n=1029), myelodysplastic syndromes (MDS; n=305), aplastic anemia (AA; n=104), sickle cell disease (SCD; n=79), rare anemias (mostly hemolytic in nature) (n=42), and other conditions associated with anemias requiring transfusion (n=43). Mean LPI, pre and post deferasirox administration, at baseline and wks 12, 28 and 52 are shown in Table 1. Table 1. Mean LPI, pre and post deferasirox administration, at baseline and after repeat doses Baseline Week 12 Week 28 Week 52 Pre Post Pre Post Pre Post Pre Post NOTE: Data are mean LPI±SD (μmol/L); normal levels are 0–0.40 μmol/L All pts 0.89 ±1.84 0.33 ±1.59 0.30 ±0.90 0.11 ±0.56 0.27 ±0.87 0.11 ±0.62 0.47 ±1.35 0.30 ±1.33 β-thalassemia 1.25 ±2.34 0.58 ±2.10 0.40 ±1.07 0.15 ±0.67 0.34 ±0.94 0.13 ±0.72 0.60 ±1.55 0.39 ±1.52 MDS 0.53 ±0.63 0.02 ±0.11 0.08 ±0.28 0.02 ±0.10 0.15 ±0.88 0.03 ±0.18 0.14 ±0.32 0.02 ±0.07 AA 0.23 ±0.34 0.01 ±0.02 0.08 ±0.20 0.01 ±0.04 0.06 ±0.20 0.01 ±0.03 0.04 ±0.10 0.03 ±0.10 SCD 0.11 ±0.54 0.04 ±0.29 0.09 ±0.42 0.06 ±0.31 0.11 ±0.28 0.14 ±0.46 0.10 ±0.21 0.07 ±0.19 Rare anemias 0.50 ±0.55 0.01 ±0.04 0.05 ±0.13 0.01 ±0.03 0.06 ±0.18 0.01 ±0.03 0.29 ±0.52 0.02 ±0.03 Overall mean deferasirox dose during the 1-yr treatment period was 22.4±6.0 mg/kg/day (β-thalassemia, MDS, AA, SCD and rare anemias: 24.3±5.5, 19.3±5.7, 17.8±4.7, 20.2±3.8 and 18.6±5.6 mg/kg/day, respectively). At each time point, peak LPI levels observed just before deferasirox dosing were decreased compared with baseline and were mostly within the normal range from week 12 onwards in each underlying anemia. A small rebound at 52 wks was seen in the thalassemia sub-group: this could be associated with decreased compliance or other reasons, to be investigated further. In all pts, mean steady-state plasma concentration (ie pre-administration value) of deferasirox at wks 12, 28 and 52 was 32.9, 35.9 and 39.4 μmol/L, respectively. At each time point this was approximately half of the concentration value observed at 2 hrs post administration (84.4, 89.3 and 97.0 μmol/L, respectively). Conclusions: The results from this 1-yr study confirm the ability of once-daily deferasirox to provide sustained reduction in toxic LPI levels across various transfusion-dependent anemias, supporting previous data in pts with β-thalassemia. This is likely due to trough levels of deferasirox being within the therapeutic range, thereby preventing LPI levels rebounding between doses. Deferasirox therapy may therefore reduce unregulated tissue iron loading and prevent further end-organ damage in these pts.

Background: Myocardial siderosis is a leading cause of cardiac morbidity in patients (pts) with β-thalassemia undergoing regular blood transfusion therapy. Myocardial and liver siderosis do not correlate in cross-sectional studies, hence the importance of monitoring both cardiac and liver iron in heavily transfused β-thalassemia pts. Iron chelation therapy has an important role in preventing the accumulation of cardiac iron. Deferasirox (Exjade®) is a once-daily, oral iron chelator with efficacy in removing cardiac iron in preclinical and small clinical studies. This subgroup analysis from the cardiac substudy of the EPIC trial, the largest prospective, multicenter clinical trial evaluating the effects of iron chelation therapy, assesses the longitudinal effect of deferasirox over 1 year in preventing myocardial siderosis (maintaining T2* values >20 ms) in non-cardiac iron overloaded pts with β-thalassemia and normal cardiac function. Methods: Pts with β-thalassemia (≥10 years) and with normal myocardial iron levels (magnetic resonance [MR] myocardial T2* of ≥20ms) were included in the prevention arm of the cardiac substudy. Other inclusion criteria were: serum ferritin (SF) >2500 ng/mL; MR (R2) liver iron concentration (LIC) >10 mg Fe/g dry weight (dw); left ventricular ejection fraction (LVEF) ≥56%; and a lifetime minimum of 50 previous packed red blood cell transfusions. Deferasirox was initiated at 30 mg/kg/day with subsequent dose adjustments of 5–10 mg/kg/day based on changes in SF, month-6 myocardial T2*, and safety parameters. Change from baseline in myocardial iron at 1 year was the primary endpoint. Changes in cardiac function, SF and LIC were also evaluated. Results: We enrolled 78 pts into the cardiac prevention arm (35 male and 43 female; mean age, 20.2±7.5 years). The geometric mean (± coefficient of variation) myocardial T2* was 32.0 ms ±25.6%. Mean baseline (±SD) LVEF was 67.7±4.7%, LIC 28.8±10.2 mg Fe/g dw, and median SF 4712 ng/mL. Transfusion requirements were 133.7 mL/kg in the year prior to enrollment. Previous chelation therapy had been received by 76 pts (deferoxamine [DFO], 69.2%; combination DFO/deferiprone, 28.2%). Mean deferasirox dose over 1 year was 27.6±6.0 mg/kg/day. After 12 months of therapy, the geometric mean myocardial T2* was 32.5 ms ±25.1% (ratio of geometric mean = 1.02; P=ns) and LVEF increased to 69.6% (P20 ms at baseline had a value below 20 ms at 12 mths. Median SF was significantly reduced from baseline at 12 months by 1048 ng/mL (P33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. No pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits. No pts died and no drug-related serious AEs were reported in this cohort. Conclusions: In β-thalassemia pts with normal myocardial iron levels at baseline, deferasirox treatment over 1 year maintained myocardial iron levels whilst significantly reducing body iron burden measured by SF and LIC. LVEF increased significantly. Deferasirox was well tolerated with a clinically manageable safety profile.

Background: The 1-year, prospective, multicenter EPIC trial, the largest ever conducted for an iron-chelating agent, evaluated the efficacy and safety of the once-daily, oral chelator deferasirox (Exjade®) in patients (pts) with transfusion-dependent anemias. 54% of 1744 pts had β-thalassemia major, providing one of the largest data sets assessing the use of deferasirox in this group. Data from this subgroup are presented. Methods: Pts (≥2 years old) with transfusional iron overload due to β-thalassemia and serum ferritin (SF) levels of ≥1000 ng/mL or 20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight, received an initial deferasirox dose of 10–30 mg/kg/day dependent on transfusion requirements. Protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 months based on SF trends and safety markers. The change at week 52 from baseline (BL) was the primary efficacy endpoint. Results: 937 pts with β-thalassemia major, 450 males and 487 females (mean age 18.4±10.8 years), were enrolled. Median BL SF was 3157 ng/mL (range 462–22320). In the year prior to enrollment, pts received a mean of 189.8 mL/kg of blood (range 0–1768). Most pts (n=625; 66.7%) had received deferoxamine (DFO); 234 (25.0%) DFO/deferiprone combination, 12 (1.3%) deferiprone alone and four (0.4%) other therapy; 66 (7.0%) were chelation naive. 798 pts (85%) started on ≤20 mg/kg/day and 139 (15%) on >20 mg/kg/day. 51% required a dose increase at a median of 24 weeks after treatment initiation (range 2–53). After 1 year, median SF significantly decreased from BL by 129 ng/mL (P=0.0007) at an average actual dose of 24.2±5.6 mg/kg/day. Pts receiving an average actual dose of ≥30 mg/kg/day achieved a significant reduction in SF at 1 year. Pts receiving an average actual dose of Table 1. Median change from BL in SF (ng/mL) by average actual dose received BL End of study Average actual dose categories Mean iron intake, mg/kg/day n Median SF n Median change from BL in SF P -value versus BL Only 9.5% of pts (n=89) discontinued therapy. Reasons for withdrawal were AEs (n=31, 3.3%), consent withdrawal (n=24, 2.6%), unsatisfactory therapeutic effect (n=12, 1.3%), lost to follow-up (n=5, 0.5%), death (n=4, 0.4%, three due to cardiac failure and one to septicemia following surgery, none treatment related by investigators’ assessment) and other (n=13, 1.4%). The most common investigator-assessed drug-related AEs were rash (n=115, 12.3%), diarrhea (n=76, 8.1%) and abdominal pain (n=50, 5.3%). The majority of AEs were mild-to-moderate (>95%). Thirty-seven pts (3.9%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Five (0.5%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in four pts. Conclusions: These data confirm that in heavily iron-loaded pts with β-thalassemia major, higher deferasirox doses are needed to achieve significant reductions in SF, while lower doses are able to maintain iron balance. The starting dose guided by the rate of iron intake from blood transfusions and current iron burden should be titrated individually and promptly (at 3 months) according to SF trends and safety markers. Deferasirox treatment in this subgroup was generally well tolerated (including doses ≥30 mg/kg/day) with a low discontinuation rate.

Background: Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. In registration trials, the starting dose was based on baseline liver iron concentration (LIC). The prospective multicenter EPIC trial, the largest ever conducted for an iron chelator, included patients (pts) with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. One-year results are presented. Methods: Pts (aged ≥2 yrs) had transfusion-dependent anemia and SF levels ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of RBCs) and R2 MRI-confirmed LIC of >2 mg Fe/g dry weight (dw). Deferasirox starting dose was 20 mg/kg/d for pts receiving 2–4 blood units/mth. An initial dose of 10 or 30mg/kg/d was considered for pts receiving less or more frequent blood transfusions, respectively. Protocol-specified dose adjustments of 5–10 mg/kg/d (range 0–40 mg/kg/d) were done every 3 months based on SF trends and safety markers. Primary efficacy endpoint was SF change from baseline (BL) at 1 year. Results: 1744 pts (901 M, 843 F; mean age 30.6±23.3 yrs) were enrolled; 33.1% (n=577) aged 20 mg/kg/d. 39% of pts had dose increases at a median of 24 weeks after treatment initiation (range 2–53). Overall, median SF was significantly decreased from BL by 264 ng/mL after 1 year (P Table 1. Median change from BL in SF (ng/mL) and mean iron intake (mg/kg/day) by average actual dose BL End of study Over the study Average actual dose categories N Median SF (ng/mL) N Median change from BL in SF (ng/mL) P -value vs BL N Mean iron intake (mg/kg/day) 1389 pts (79.6%) completed 1 year; reasons for discontinuation were adverse events (AEs; n=153; 8.8%), consent withdrawal (n=77; 4.4%), unsatisfactory therapeutic effect (n=20; 1.1%) and various other reasons (n=62; 3.6%); there were 31 (1.8%) drug related SAEs and 42 deaths, none assessed by investigators as treatment related. The most common drug-related (investigator-assessed) AEs were diarrhea (n=251; 14.4%), rash (n=174; 10.0%), nausea (n=135; 7.7%) and abdominal pain (n=97; 5.6%). 175 pts (10.0%) had serum creatinine value >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. 13 (0.7%) had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in 11 pts. Conclusions: This large study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated with a safety profile consistent with data from previous clinical trials.

Background: The prospective, 1-yr multicenter EPIC trial evaluated the efficacy and safety of once-daily oral deferasirox (Exjade®) in more than 1700 patients (pts) with transfusion-dependent anemias. Data were collected from each patient at enrollment, providing an insight into transfusion history, body iron burden, and the nature and success of previous chelation therapy in a large group of pts with iron overload previously treated with chelation therapy. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of RBCs) and MRI-assessed liver iron concentration (LIC) >2 mg Fe/g dry weight (dw). Baseline assessments included transfusion history, previous chelation therapy, SF levels and LIC (if carried out) in the previous yr. Results: 1744 pts (901 M, 843 F) were enrolled. Underlying anemias were: thalassemia major (TM; n=937), thalassemia intermedia (TI; n=84), myelodysplastic syndromes (MDS; n=341), aplastic anemia (AA; n=116), sickle cell disease (SCD; n=80), rare anemias (red cell aplasia and anemias mostly hemolytic in nature; n=43), Diamond-Blackfan anemia (DBA; n=14), and various other conditions associated with anemias requiring transfusion (n=129). Baseline characteristics for key underlying anemias are presented in Table 1. Median SF levels were >2500 ng/mL and mean LIC in the previous yr was >7 mg Fe/g dw in all groups (except DBA for SF levels). MDS pts had received the most transfusions in the previous yr, although they had also spent a smaller proportion of their lifetime, and less total time, receiving transfusions than any other cohort. Together with AA pts, the MDS cohort also contained the highest proportion of pts who were chelation-naive (68% and 48%). SCD pts were the least-transfused group in terms of amount of blood given, but had been receiving transfusions for more than 13 yrs. As expected, TM pts had spent the greatest proportion of their lifetime on transfusions and received the greatest volume of blood per kg in the previous yr. The group labeled by investigators as TI were relatively heavily transfused for this patient population. Table 1. Baseline characteristics for key underlying anemias | | All (n=1744) | TM (n=937) | TI (n=84) | MDS (n=341) | AA (n=116) | SCD (n=80) | Rare (n=43) | DBA (n=14) | |:-----------------------------------:| ------------ | ---------- | --------- | ----------- | ---------- | ---------- | ----------- | ---------- | | *Mean ± SD; **Median | | Age, yrs* | 30.6±23.3 | 18.4±10.8 | 19.2±14.4 | 67.9±11.4 | 33.3±17.1 | 23.9±13.2 | 39.5±22.7 | 17.3±13.2 | | Transfusions in last yr* | 17.8±12.5 | 17.5±8.8 | 13.5±7.1 | 24.3±17.7 | 12.5±13.0 | 10.7±8.2 | 21.0±18.7 | 19.0±18.7 | | Total transfused in last yr, mL/kg* | 159±136 | 190±139 | 155±87 | 116±123 | 116±179 | 84±57 | 153±142 | 185±148 | | Total yrs on transfusions* | 12.3±10.4 | 16.8±10.4 | 10.2±7.8 | 3.6±4.6 | 6.1±5.7 | 13.0±9.6 | 10.9±11.8 | 13.3±10.0 | | % of lifetime on transfusions* | 62.9±39.4 | 89.8±15.2 | 61.2±28.8 | 5.7±8.4 | 27.1±29.3 | 59.5±30.1 | 44.3±41.5 | 87.5±23.2 | | LIC in last yr, mg Fe/g dw* | 10.7±9.0 | 9.5±7.8 | 9.7±5.5 | 14.4±8.5 | 12.0±4.3 | 11.8±8.4 | – | 8.8±4.2 | | SF, ng/mL** | 3135 | 3157 | 3493 | 2730 | 3254 | 3163 | 3161 | 2289 | | Prior chelation, % | | | | | | | | | | DFO | 58.6 | 66.7 | 78.6 | 40.2 | 26.7 | 62.5 | 55.8 | 71.4 | | Deferiprone | 1.6 | 1.3 | – | 4.1 | – | 1.3 | 2.3 | – | | DFO/deferiprone | 16.7 | 25.0 | 4.8 | 7.0 | 5.2 | 12.5 | 11.6 | 14.3 | | Other | 0.3 | 0.4 | – | 0.3 | – | – | – | – | | None | 23.0 | 7.0 | 16.7 | 48.4 | 68.1 | 23.8 | 30.2 | 14.3 | Conclusions: Data from this study population show that, although most pts with thalassemia, SCD, DBA and rare anemias had received previous chelation therapy, LIC and SF levels were above levels associated with significant negative outcomes (>7 mg Fe/g dw and >2500 ng/mL, respectively), which suggests that previous chelation practices were sub-optimal. Many pts with MDS and AA were chelation-naive despite being heavily iron overloaded, highlighting that the risks of iron overload are still underestimated. These data highlight the need to carefully monitor iron levels in pts at risk of iron overload and initiate chelation therapy to avoid serious clinical sequelae.

Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis. Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5–2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr. Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was 4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by −6.6±9.9 mg Fe/g dw and −1257 ng/mL (P33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Two (1.8%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in these pts. Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.

Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF 20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, 33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values >33% and >ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Background: Steroid-resistant patients with Diamond-Blackfan anemia (DBA) require life-long transfusion therapy, which ultimately results in toxic iron overload. Efficacy and safety of a once-daily, oral iron chelator, deferasirox (Exjade®), in patients with DBA have been demonstrated in one trial in which patients were dosed based on liver iron concentration (LIC) at enrollment. More recently, patients with various transfusion dependant anemias have been enrolled as part of a large, prospective, multicenter trial, the EPIC study, to evaluate whether fixed starting doses of deferasirox, based on transfusion history and subsequent dose titration, can provide clinically acceptable chelation, as measured by serum ferritin (SF). Data for the DBA sub-group are presented. Methods: Fourteen patients with transfusion-dependent DBA and SF levels of ≥1000 ng/mL, or 20 transfusions or 100 mL/kg of blood) and a R2 MRI confirmed LIC >2 mg Fe/g dry weight, were enrolled. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of 3-month SF trends and safety markers. SF was assessed every 4 weeks; the primary efficacy endpoint was change in SF from baseline at 52 weeks. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters. Results: Male (n=7) and female (n=7) patients with DBA (mean age 17.3 years), had a median baseline SF of 2288.8 ng/mL, and received a mean of 185.0 mL/kg of blood in the year prior to enrollment. Most patients had received previous chelation therapy with deferoxamine (DFO; 71.4%); two patients (14.3%) had received combination DFO/deferiprone and two (14.3%) had received no prior chelation therapy. All patients completed 12 months of treatment with no discontinuation. At 12 months, a significant reduction in SF from baseline was observed in the total population at an average actual dose of 21.0±4.8 mg/kg/day (−789.5 ng/mL; 2288.8 ng/mL [baseline]; P=0.0121). A similar reduction was seen in patients receiving an average actual dose of deferasirox ≥20–80%). There were no clinically relevant changes in markers of renal function. Two (14.3%) patients had an increase in alanine aminotransferase (ALT) that exceeded >10xULN (upper limit of normal) on two consecutive visits; all had elevated ALT levels at baseline. Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent DBA patients with iron overload. Efficacy was demonstrated in patients receiving doses above and below 20 mg/kg/day, suggesting the need to individually titrate the dose according to the rate of iron intake from ongoing blood transfusions, as well as current iron burden and target SF levels. Deferasirox was well tolerated, with an AE profile similar to that observed in other patient groups.

Background: As iron overload can cause serious clinical sequelae in pediatric patients with β-thalassemia, it is important to assess the long-term efficacy and safety profile of any iron chelator used in children. The ESCALATOR study evaluated deferasirox (Exjade®) in β-thalassemia patients, during a 1-year core trial and an extension trial of at least 1 year’s duration. This analysis evaluates the efficacy and safety of deferasirox in a subgroup of pediatric patients enrolled in the ESCALATOR trial. Methods: β-thalassemia patients included in this analysis were aged 2– Results: In total, 166 pediatric patients entered, and 158 (95%) completed, the extension study; 149 (89.8%), 1 (0.6%) and 16 (9.6%) patients had received prior chelation with DFO, deferiprone and DFO/deferiprone combination, respectively. The median duration of exposure to deferasirox was 144 weeks (2.8 years). 101/166 patients (61%) had dose increases in the extension study; dose was increased above 30 mg/kg/day in most patients (n=75). Dose decreases due to AEs or abnormal lab values were required in only 4 (2%) patients. Three (2%) and 10 (6%) patients, respectively, had dose decreases and temporary treatment interruptions because target ferritin level (≤500 ng/mL ×2 consecutive occasions) had been achieved. At EOS, the final deferasirox dose exceeded 30 mg/kg/day in 114 patients (69%). Data for mean LIC and median SF at baseline, 1 year and end of study are presented in Table 1. Table 1. LIC and SF at baseline, 1 year following treatment initiation and end of study. Baseline 1 year End of study Overall change P -value LIC, mg Fe/g dw, mean ± SD 18.7±8.5 17.1±12.0 11.4±9.3 −7.9±8.7 Of eight discontinuations during the extension study, six patients were lost to follow-up, one was due to AEs and one patient died due to respiratory failure, considered by the investigator to be non-treatment related. Despite dose increases and longer exposure in the extension phase, there was no increase in drug-related AEs in the extension compared with the core phase. There were no significant changes in markers of liver or renal function during the extension phase. Mean left ventricular ejection fraction increased significantly from 65.3% at core baseline to 69.4% at study end (P Conclusions: Following a median of 2.8 years, adequate dose adjustments with deferasirox significantly reduced LIC and SF in heavily iron-overloaded children who were previously unsuccessfully chelated. Doses ≥30 mg/kg/day were achieved in 69% of patients in the extension phase and deferasirox was generally well tolerated, with no increase in drug-related AEs compared with the 1-year assessment, and a low discontinuation rate.