Contributions
Abstract: EP1215
Type: E-Poster Presentation
Session title: Sickle cell disease
Background
Sickle cell disease (SCD) is an inherited, autosomal recessive disorder that leads to hemolytic anemia and vascular disease, with a range of acute and chronic complications driven by self-perpetuating cycle of vaso-occlusion and vaso-occlusive crises (VOCs).
Aims
CSL889, a human plasma-derived hemopexin, is being developed as a novel pharmacologic therapy to reduce toxic cell-free heme in patients with VOC, with the goal of reducing the duration and severity of acute VOC in adults and children with SCD.
Methods
The in-vivo toxicological program included 2-week repeat-dose tolerability studies in wild-type (C57BL/6) and Townes HbSS sickle cell mice (Hbbtm2(HBG1,HBB*)Tow), a 2-week repeat-dose toxicity study in rats and a 2‑week repeat-dose toxicity study in cynomolgus monkeys including cardiovascular safety pharmacology. The latter studies included a treatment free period of 7 days. A single dose safety pharmacology study in rats assessed effects on respiratory parameters. CSL889 was administered intravenously (IV) at dose levels of 50 to 500 mg/kg. All studies were conducted under applicable animal welfare standards and regulatory approvals.
Results
Repeat-dose administration of CSL889 every other day over two weeks was well-tolerated in cynomolgus monkeys and rats. There were no mortalities or adverse findings regarding clinical observations, body weights, ophthalmoscopy, electrocardiography, blood pressure, respiratory rate, clinical pathology, urine analysis, organ weights, gross pathology or histopathology attributable to treatment with CSL889. Non-adverse and transient effects which returned to baseline levels after the 7-day recovery period included an increase of the beta-globulin serum levels in cynomolgus monkeys, an increase of the alkaline phosphatase (ALP) serum levels which did not clearly follow the dose-response principle in rats, and a small but statistically significant decrease from baseline activated partial thromboplastin time (aPTT). The observed formation of anti-drug antibodies (ADAs) against CSL889 in both species is an expected immune reaction after repeated application of the heterologous human protein to animals and is not considered predictive for the clinical situation. ADA formation did not have an impact on safety or exposure of the study animals. Safety pharmacology evaluation did not show any deleterious effects of CSL889 on cardiovascular and respiratory functions in cynomolgus monkeys and rats. The NOAEL for rats and cynomolgus monkeys was at least 500 mg/kg under the conditions of the study.
Daily IV administrations of hemopexin for two weeks to wildtype mice was well tolerated and produced no adverse clinical signs at 160 mg/kg. While there were no findings after the first dosing occasions, high dose animals (500 mg/kg) showed a short-lived, transient clinical reaction, ie reduced mobility and body temperature to the treatment on Day 8. There was no clear evidence of treatment-related changes to hematology or clinical chemistry parameters in any dose group at the end of the dosing period.
Daily IV administration of hemopexin for two weeks or six days (500 mg/kg only) to Townes HbSS mice was generally tolerated. Similar to the reaction observed in wildtype mice immunological reactions were observed in some dosing groups after repeat administration, which are assessed as a result of the application of the heterologous human protein.
Conclusion
The toxicological program demonstrated that CSL889 has a favorable safety profile and supports the clinical development of hemopexin for the treatment of acute VOC in sickle cell disease.
Keyword(s): Safety, Sickle cell disease, Toxicity
Abstract: EP1215
Type: E-Poster Presentation
Session title: Sickle cell disease
Background
Sickle cell disease (SCD) is an inherited, autosomal recessive disorder that leads to hemolytic anemia and vascular disease, with a range of acute and chronic complications driven by self-perpetuating cycle of vaso-occlusion and vaso-occlusive crises (VOCs).
Aims
CSL889, a human plasma-derived hemopexin, is being developed as a novel pharmacologic therapy to reduce toxic cell-free heme in patients with VOC, with the goal of reducing the duration and severity of acute VOC in adults and children with SCD.
Methods
The in-vivo toxicological program included 2-week repeat-dose tolerability studies in wild-type (C57BL/6) and Townes HbSS sickle cell mice (Hbbtm2(HBG1,HBB*)Tow), a 2-week repeat-dose toxicity study in rats and a 2‑week repeat-dose toxicity study in cynomolgus monkeys including cardiovascular safety pharmacology. The latter studies included a treatment free period of 7 days. A single dose safety pharmacology study in rats assessed effects on respiratory parameters. CSL889 was administered intravenously (IV) at dose levels of 50 to 500 mg/kg. All studies were conducted under applicable animal welfare standards and regulatory approvals.
Results
Repeat-dose administration of CSL889 every other day over two weeks was well-tolerated in cynomolgus monkeys and rats. There were no mortalities or adverse findings regarding clinical observations, body weights, ophthalmoscopy, electrocardiography, blood pressure, respiratory rate, clinical pathology, urine analysis, organ weights, gross pathology or histopathology attributable to treatment with CSL889. Non-adverse and transient effects which returned to baseline levels after the 7-day recovery period included an increase of the beta-globulin serum levels in cynomolgus monkeys, an increase of the alkaline phosphatase (ALP) serum levels which did not clearly follow the dose-response principle in rats, and a small but statistically significant decrease from baseline activated partial thromboplastin time (aPTT). The observed formation of anti-drug antibodies (ADAs) against CSL889 in both species is an expected immune reaction after repeated application of the heterologous human protein to animals and is not considered predictive for the clinical situation. ADA formation did not have an impact on safety or exposure of the study animals. Safety pharmacology evaluation did not show any deleterious effects of CSL889 on cardiovascular and respiratory functions in cynomolgus monkeys and rats. The NOAEL for rats and cynomolgus monkeys was at least 500 mg/kg under the conditions of the study.
Daily IV administrations of hemopexin for two weeks to wildtype mice was well tolerated and produced no adverse clinical signs at 160 mg/kg. While there were no findings after the first dosing occasions, high dose animals (500 mg/kg) showed a short-lived, transient clinical reaction, ie reduced mobility and body temperature to the treatment on Day 8. There was no clear evidence of treatment-related changes to hematology or clinical chemistry parameters in any dose group at the end of the dosing period.
Daily IV administration of hemopexin for two weeks or six days (500 mg/kg only) to Townes HbSS mice was generally tolerated. Similar to the reaction observed in wildtype mice immunological reactions were observed in some dosing groups after repeat administration, which are assessed as a result of the application of the heterologous human protein.
Conclusion
The toxicological program demonstrated that CSL889 has a favorable safety profile and supports the clinical development of hemopexin for the treatment of acute VOC in sickle cell disease.
Keyword(s): Safety, Sickle cell disease, Toxicity