ALBERT

Description: Background: The value of understanding deferiprone's comparative pharmacokinetics (PK) in differing indications and human subpopulations derives from its potential versatility in treating, not only transfusional iron overload, but also conditions in which iron mishandling is localized. While some PK on deferiprone in patients with thalassemia has been published, little is known for patients without systemic iron overload, or for those requiring special consideration (e.g., children, patients with hepatic or renal impairment). Reporting of characteristics such as deferiprone's rapid absorption, extensive glucuronidation, and principally urinary excretion has been consistent, but some publications have followed false trails, and lack of IV data and the dearth of PK information in non-iron-overloaded patients have limited the overall picture. Availability of a comprehensive integration of deferiprone human PK would address misconceptions and help in predicting doses for patients with various indications currently being investigated, as well as in special populations. Objective: To provide data on the PK of deferiprone generated from currently unpublished studies, to enable dosing guidance for deferiprone use in conditions beyond adult patients with thalassemia. Methods: Data from PK studies, conducted as part of our development programme with deferiprone in thalassemia, sickle cell disease, and conditions without systemic iron overload, as well as in children and subjects with impaired renal function or impaired hepatic function are presented. Results: The absolute (oral vs IV) bioavailability of deferiprone was 72% (Studies were conducted with Ferriprox™ 500 mg tablets). Following an oral dose of 1,500 mg (20 mg/kg), the mean maximum serum deferiprone concentration (Cmax) in the fasting state in non-iron-loaded healthy subjects was 20 mcg/mL, and the mean total area under the concentration-time curve (AUC) was 53 mcg·h/mL. Cmax of deferiprone occurs approximately 1 hour after a single dose in fasted subjects, but may be delayed to 2 hours in the fed state. Food decreases the Cmax of Ferriprox tablets by about a third and the AUC by 10%. Steady state is achieved on the first day of dosing and cross-study comparisons indicate dose proportionality. Protein binding of deferiprone in human plasma is ≤20%. Metabolism is predominantly UGT 1A6-mediated conjugation to form a 3-O -glucuronide, which is rapidly cleared by renal excretion (Tmax 2-4 hours in fasting subjects) and lacks iron binding capability. There is no evidence of genetic polymorphism. Most of a dose of deferiprone is rapidly eliminated from plasma, with a t½ of about 2 hours, and is excreted primarily into the urine as the glucuronide. Dose adjustment is not necessary in patients with renal impairment, as confirmed by similar total body clearance to healthy controls. Subjects with mild or moderate hepatic impairment retain sufficient capacity for glucuronidation to also not require dose adjustment. The clearance of deferiprone in children is comparable to that in adults. The pharmacokinetics in patients with Friedreich Ataxia, PKAN and Parkinson's disease, conditions in which deferiprone is currently being evaluated by various investigators, is expected to be comparable to PK in healthy volunteers. Conclusions: Comparative IV and oral dosing of deferiprone reveals that it is extensively and rapidly absorbed from the gut. The PK of deferiprone in patients without systemic iron overload is predicted to be similar to the PK in healthy subjects. Studies in special populations demonstrate that dose adjustment in children or in patients with renal or moderate hepatic impairment is not necessary. Disclosures Spino: ApoPharma Inc.: Employment. Off Label Use: Deferiprone is approved for the treatment of iron overload in thalassemia syndromes. Connelly:ApoPharma Inc.: Employment. Tsang:ApoPharma Inc.: Employment. Fradette:ApoPharma Inc.: Employment. Tricta:ApoPharma Inc.: Employment.

Description: Background: Patients with sickle cell disease (SCD) or other rare anemias whose care includes chronic blood transfusions must receive iron chelation to prevent the morbidity of iron overload. Currently, only deferoxamine (DFO) and deferasirox (DFX) are approved chelators in these patient populations. This randomized open-label trial evaluated if the efficacy of deferiprone (DFP) was non-inferior to DFO. DFO was used as the comparator product since DFX was not approved as first-line treatment for SCD at trial initiation. Methods: Participants at 27 sites in 8 countries were randomized in a 2:1 ratio to receive either DFP or DFO for up to 12 months. Those with lower transfusional iron input and/or less severe iron load were prescribed either DFP 25 mg/kg of body weight t.i.d. or DFO 20 mg/kg (children) or 40 mg/kg (adults); those with higher iron input and/or more severe iron load received either DFP 33 mg/kg t.i.d. or DFO up to 40 mg/kg (children) or 50 mg/kg (adults). Dosages could be adjusted over the course of the trial if necessary. Efficacy endpoints were the changes from baseline in liver iron concentration (LIC), cardiac iron, and serum ferritin (SF) at Month 12. The primary endpoint was based on LIC, and for the demonstration of non-inferiority of DFP to DFO, the upper limit of the 95% confidence interval for the difference between treatments had to be no more than 2 mg/g dry weight (dw). All patients had their neutrophil count monitored weekly, whereas other safety assessments and compliance with study therapy were evaluated monthly. Acceptable compliance was defined as taking 80% to 120% of the prescribed dosage. Results: A total of 228 of the targeted 300 patients were dosed with 152 receiving DFP and 76 receiving DFO, to assess non-inferiority. There were no significant differences between the groups in any demographic measures: in each treatment group, 84% of patients had SCD and the remainder had other, rarer forms of transfusion-dependent anemia. Mean age at enrollment was 16.9 years (± 9.6); 53.1% of patients were male; and 77.2% were white, 16.2% black, and 6.6% multi-racial. Over the course of the study, 69% of patients in the DFP group and 79% in the DFO group had acceptable compliance with treatment. Based on the Pocock's α spending function, a more stringent confidence level of 96.01% was applied to the calculation of confidence interval for the evaluation of non-inferiority. For the primary efficacy endpoint, the least squares (LS) mean change in LIC (measured as mg/g dw) was -4.04 for DFP, -4.45 for DFO; the upper limit of the 96.01% confidence interval for the difference was 1.57, thereby demonstrating non-inferiority of DFP to DFO. The upper limit for the subpopulation of patients with SCD also met the non-inferiority criterion. For the secondary endpoints, the change in cardiac iron (measured as ms on MRI T2*, log-transformed) was approximately -0.02 for both; and for SF (measured as μg/L), it was -415 vs. -750 for DFP vs. DFO, respectively. The difference between the groups was not statistically significant for both endpoints. With respect to safety, there was no statistically significant difference between the groups in the overall rate of adverse events (AEs), treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis was seen in 1 DFP patient vs. no DFO patients, while events of less severe episodes of neutropenia occurred in 4 vs. 1, respectively. All episodes of agranulocytosis and neutropenia resolved. There was no significant treatment group difference in the rates of any of the serious AEs. Conclusion: The efficacy of DFP for the treatment of iron overload in patients with SCD or other rare anemias is not inferior to that of DFO, as assessed by changes in liver iron concentration. non-inferiority was supported by the endpoints on cardiac iron load and SF. The safety profile of DFP was acceptable and was similar to that previously seen in thalassemia patients, and its use was not associated with unexpected serious adverse events. The results of this study support the use of DFP for the treatment of iron overload in patients with SCD or other rare transfusion-dependent anemias. Note: The authors listed here are presenting these findings on behalf of all investigators who participated in the study. Disclosures Kwiatkowski: Terumo: Research Funding; Imara: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Apopharma: Research Funding. Fradette:ApoPharma: Employment. Kanter:Sangamo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Modus: Consultancy, Honoraria. Tsang:Apotex Inc.: Employment. Stilman:ApoPharma: Employment. Rozova:ApoPharma: Employment. Sinclair:ApoPharma: Employment. Shaw:ApoPharma: Employment. Chan:ApoPharma: Employment. Toiber Temin:ApoPharma: Employment. Lee:ApoPharma: Employment. Spino:ApoPharma: Employment. Tricta:ApoPharma: Employment. OffLabel Disclosure: Deferiprone is an oral iron chelator.

Description: Introduction: Agranulocytosis/severe neutropenia is an established adverse event during deferiprone (DFP) use. Less is known about milder episodes, which are frequently transient despite continuous deferiprone use. To provide further insight into this topic, we compared the incidence of neutropenia during DFP or deferasirox (DFX) treatment in the randomized Deferiprone Evaluation in Paediatrics (DEEP-2) trial, where blood neutrophil count was regularly monitored in patients randomized to be treated with DFP or DFX. Methods: DEEP-2 was a multicenter, randomized, 12-month, open-label trial comparing DFP vs DFX in pediatric (

Description: Cynomolgus monkeys and rats have been the species of choice for evaluation of general toxicity during the non-clinical development of iron chelators. Each model has its advantages in safety assessment studies, although the relatively poor conservation of iron in rats and other differences in their iron handling compared with primates, including man, have raised questions about their appropriateness. It was reported that in a study in cynomolgus monkeys conducted during the early development of deferiprone, doses greater than 150 mg/kg caused deaths when given orally once daily for c. 20 days of a scheduled 3-month treatment period. We present results from a 12-month oral toxicity study of deferiprone in naive and iron-loaded cynomolgus monkeys, using twice daily dosing and compare them with findings in a similar study in rats. Cynomolgus monkeys (4–6/sex/group) and rats (20/sex/group), iron loaded by intraperitoneal injection of iron dextran, were given deferiprone as two equal daily oral doses totalling 0, 75, 150 and 200 (250 after 3 months in monkeys) mg/kg/day; naive monkeys were given 0 and 150 mg/kg/day for 12 months. Measurement of all standard parameters, including toxicokinetics, was included. No mortalities, no adverse clinical signs, and no effects on body weight gain, food intake, cardiovascular function or eye morphology, were observed in either iron-loaded or naive monkeys. Haematological and plasma chemistry parameters were largely unaffected by treatment with deferiprone; intermittent increases in serum activities of some hepatic enzymes were related to iron loading. Similarly, histopathological changes were limited to those associated with iron deposition in tissues. Plasma deferiprone concentrations achieved were significantly in excess of clinical exposures. Both naive and iron-loaded rats were less tolerant of long-term administration of deferiprone. Both divided daily dosing and iron loading may have contributed to the markedly better survival of monkeys in the 12-month study compared with the earlier investigation, and the results of this work confirm the value of the model in the evaluation of the safety of iron chelators.

Description: Transfusion-dependent iron overload, such as occurs in beta-thalassaemia (Cooley’s Anaemia), leads to lethal cardiac toxicity in the second decade of life if not treated by iron chelation, but even with subcutaneous desferrioxamine (DFO) cardiac disease remains a problem, although delayed by 1–2 decades. As we design novel iron chelators, we are testing them in various animal models of iron overload. While assessing outcomes we have observed relatively sparse reports of systematic studies on organs, tissues, cellular, or subcellular iron distribution. Therefore we initiated a series of studies to characterize iron distribution using various approaches. Multiple intraperitoneal injections of iron dextran, 200 mg/kg/week X 4 − 16 weeks, followed by an equilibration period of minimum 1–2 weeks was studied as a means of increasing total body iron load in hundreds of rats under various conditions. Sacrifice varied from 6 weeks to 1 year post iron loading and the concentration of iron in liver, heart, and other tissues, organs, cells and subcellular organelles was examined. Quantitatively, in untreated rats (no chelators), the liver/heart iron ratio was about 10:1, consistent with the accumulation observed in post-mortem studies in humans prior to extensive use of iron chelation. Much less-well described has been the distribution of iron in lymphatic tissues. Our studies revealed that lymph nodes become visibly enlarged. In addition, randomly distributed brown spots appeared in the omentum. Such changes persisted up to one year after iron loading, regardless whether they were treated daily with chelators (DFO or deferiprone) in standard doses for four months. Even after a single intraperitoneal iron-dextran injection of 200 mg/kg, changes were visible. Histopathological analysis (hematoxilin-eosin for general histology and Perl’s Prussian Blue for iron) showed extensive iron accumulation in the omentum, and in the cortical and subcortical regions of the enlarged lymph nodes. Electron microscopy revealed cellular (macrophages) and subcellular (mitochondria) iron localization in the lymph nodes. When iron was administered as iron sucrose (single ip dose), iron accumulation was more extensive in the omentum and in the peritoneal fat in comparison to iron dextran, but the enlargement of the lymph nodes was not observed. Quantitative iron measurement (via validated HPLC method) in the liver and heart after a single iron dextran (N=30, up to 29th day) and iron sucrose dose (N=6 up to 50th day) was in agreement with the histological observations. Iron accumulation in the omentum and lymph nodes after four months of chelation treatment and one year after iron loading indicated the resistance of these unusual iron “pools” to chelation therapy. These studies confirm that different iron formulations may result in different patterns of iron distribution and they also raise questions about the suitability of rats as an animal model for transfusional iron overload in humans.