A Phase I study to determine safety, pharmacokinetics, and pharmacodynamics of ANF-RHO™, a novel PEGylated granulocyte colony-stimulating factor, in healthy volunteers.

Patients receiving pegfilgrastim (Neulasta®) for the treatment of neutropenia can experience bone pain following the injections required to achieve effective neutrophil levels. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of ANF-RHO™, a novel pegylated granulocyte colony stimulating factor, were assessed in a randomized, controlled, double-blind Phase 1 clinical study in healthy volunteers. Subjects received a single subcutaneous dose of ANF-RHO over a range of 6 doses (5-50 µg/kg), placebo (saline), or the recommended clinical dose of pegfilgrastim administered at the labeled fixed 6 mg dosage (equivalent to 80-100 µg/kg). The primary outcome measure was safety and tolerability. Secondary outcomes included PK and PD effects on absolute neutrophil count (ANC) and number of CD34+ progenitor cells. Severity of bone pain was also assessed. In healthy volunteers, ANF-RHO was administered at ascending doses up to 50 µg/kg without significant adverse effects; appeared to be better (5 to 30 µg/kg) or equally well (50 µg/kg) tolerated, and had lower mean bone pain scores as compared to pegfilgrastim. ANF-RHO achieved CD34+ and ANC numbers at significantly lower doses, and had a significantly longer circulating half-life than pegfilgrastim. These results suggest that ANF-RHO can be provided less frequently, at a lower dose, and with fewer side effects. ANF-RHO had unique, prolonged PK/PD attributes as compared to marketed pegfilgrastim, suggesting that it may provide an improved clinical benefit in further clinical studies in patients with chemotherapy-induced or chronic idiopathic neutropenia.

A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia.

BACKGROUND: Treatment of sickle cell anemia is a challenging task and despite the well understood genetic and biochemical pathway of sickle hemoglobin, current therapy continues to be limited to the symptomatic treatment of pain, supplemental oxygen, antibiotics, red blood cell transfusions and hydroxyurea. SANGUINATE is a carbon monoxide releasing molecule and oxygen transfer agent under clinical development for the treatment of sickle cell anemia and comorbidities. METHODS: An open-label randomized Phase Ib study was performed in adult sickle cell anemia patients. Two dose levels of SANGUINATE were compared to hydroxyurea in 24 homozygotes for Hb SS. Twelve subjects received either a low dose (160mg/kg) of SANGUINATE or 15mg/kg hydroxyurea. Another 12 subjects received either a high dose (320mg/kg) of SANGUINATE or 15mg/kg hydroxyurea. The primary endpoint was the safety of SANGUINATE versus hydroxyurea in sickle cell anemia patients. Secondary endpoints included determination of the plasma pharmacokinetics and assessment of hematologic measurements. RESULTS: Musculoskeletal related adverse events were the most common. Transient troponin I levels increased in three patients, one of whom had an increase in tricuspid regurgitant velocity; however, no clinical signs were noted. Following an assessment of vital signs, tricuspid regurgitant velocity, electrocardiogram, serum biochemistry, hematology, urinalysis, and analysis of reported adverse events, SANGUINATE was found to be safe in stable sickle cell anemia patients. CONCLUSIONS: The clinical trial met its primary objective of demonstrating an acceptable safety profile for SANGUINATE in patients with sickle cell anemia. This trial established the safety of SANGUINATE at both dose levels and permitted its advance to Phase II trials.

A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia

Abstract Background: Treatment of sickle cell anemia is a challenging task and despite the well understood genetic and biochemical pathway of sickle hemoglobin, current therapy continues to be limited to the symptomatic treatment of pain, supplemental oxygen, antibiotics, red blood cell transfusions and hydroxyurea. SANGUINATE is a carbon monoxide releasing molecule and oxygen transfer agent under clinical development for the treatment of sickle cell anemia and comorbidities. Methods: An open-label randomized Phase Ib study was performed in adult sickle cell anemia patients. Two dose levels of SANGUINATE were compared to hydroxyurea in 24 homozygotes for Hb SS. Twelve subjects received either a low dose (160 mg/kg) of SANGUINATE or 15 mg/kg hydroxyurea. Another 12 subjects received either a high dose (320 mg/kg) of SANGUINATE or 15 mg/kg hydroxyurea. The primary endpoint was the safety of SANGUINATE versus hydroxyurea in sickle cell anemia patients. Secondary endpoints included determination of the plasma pharmacokinetics and assessment of hematologic measurements. Results: Musculoskeletal related adverse events were the most common. Transient troponin I levels increased in three patients, one of whom had an increase in tricuspid regurgitant velocity; however, no clinical signs were noted. Following an assessment of vital signs, tricuspid regurgitant velocity, electrocardiogram, serum biochemistry, hematology, urinalysis, and analysis of reported adverse events, SANGUINATE was found to be safe in stable sickle cell anemia patients. Conclusions: The clinical trial met its primary objective of demonstrating an acceptable safety profile for SANGUINATE in patients with sickle cell anemia. This trial established the safety of SANGUINATE at both dose levels and permitted its advance to Phase II trials.