Chronic iron overload (CIO) is associated with anemias such as thalassemia that require blood transfusions as a chronic therapy. It is a serious and difficult to treat condition that is associated with multiple organ toxicities including of the liver, heart and endocrine glands. Untreated, CIO can lead to organ failure and death.
In 2005, the first oral iron chelator, deferasirox (DFX) in the form of a tablet for oral suspension (Exjade®), was approved in the United States for treating CIO. In 2015, a film-coated tablet (JadenuTM) was introduced as a more convenient formulation for patients.
Chirnomas, et al at Children's Hospital Boston (Blood, 2009) have previously published on a subgroup of transfusion dependent thalassemia patients in whom failure to achieve negative iron balance is linked to poor absorption of DFX into systemic circulation as compared to a control group that did respond to DFX.
DFX is a drug molecule with poor water solubility and large sensitivity to pH. It is practically insoluble in gastric fluid and very slightly soluble in intestinal fluid. These molecular traits of DFX likely contribute to its food effect and more importantly could lead to poor absorption of the drug in some patients (e.g., patients with more acidic GI tracts and/or on high doses).
Solid dispersion technology has been successfully used to address drug solubility challenges in a number of cases (e.g., ritonavir, etravirine, everolimus, ivacaftor). However, DFX as a molecule has a high melting temperature and poor solubility in organic solvents which together have precluded the use of traditional solid dispersion technology. A solid dispersion tablet formulation of deferasirox (DST-0509) was developed using a novel solid dispersion technology (KinetiSol®) that is able to process DFX.
DST-0509 was tested in 2 phase I studies, Study 101 and 102. Study 101, a single dose study in healthy volunteers, demonstrated improvements in the bioavailability of DST-0509 compared to Jadenu™ at a dose of 14 mg/kg. Furthermore, DST-0509 is the first deferasirox formulation to show no differences in total absorption between high-fat fed and fasted states.
Study 102 was a randomized, single dose, 3-period, 3-sequence crossover, oral bioavailability study of DST-0509 compared to Exjade® and Jadenu™ in fasted healthy volunteers at higher doses (25 - 33 mg/kg). The results showed less variability in Cmax and AUC with DST-0509 versus Exjade®, and meaningfully enhanced absorption versus Exjade® and Jadenu™. See Figure 1., "Comparative Bioavailability of DST-0509 to Exjade® and Jadenu™ in healthy subjects at high doses".
Future studies are planned to see if the enhanced bioavailability seen in these studies translates into superior iron control in patients not achieving target iron control on current deferasirox treatments.
Keen: DisperSol Technologies: Employment, Equity Ownership. Miller: DisperSol Technologies: Employment, Equity Ownership, Patents & Royalties. Tulloch: DisperSol Technologies: Consultancy; Capital Biopharma Consulting: Consultancy, Employment; Faraday Pharmaceuticals: Employment, Equity Ownership.
Asterisk with author names denotes non-ASH members.