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

Abstract

BackgroundTreatment 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.MethodsAn 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.ResultsMusculoskeletal 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.ConclusionsThe 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.

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

“…In a human study (Phase I), SANGUINATE™ was found to be safe and well tolerated in healthy volunteers, and its half-life was dose dependent and ranged from 7.9 h to 13.8 h [82]. Interestingly, the half-life of SANGUINATE™ at a dose of 160 mg Hb/kg was prolonged in stable sickle cell anemia patients (about 20 h) compared to that in healthy volunteers (13.8 h) [83]. Although two cases where patients received SANGUINATE™ under emergency conditions were reported [78], large scale clinical trials in patients will be needed prior to clinical applications.…”

A phase Ib, open‐label, single arm study to assess the safety, pharmacokinetics, and impact on humoral sensitization of SANGUINATE infusion in patients with end‐stage renal disease

“…Our study is the first to evaluate an alternative to PRBC with a potential to ameliorate the burden of sensitization. SG has been studied and demonstrated to be safe and well tolerated in healthy volunteers (dose up to 160 mg/kg) and stable sickle cell disease patients (dose up to 320 mg/kg) . In both studies, there was an expected transient increase in the blood pressure due to SG.…”

“…Exclusion criteria included (i) blood product transfusion within 90 days from screening; (ii) ECG findings or symptoms suggestive of acute coronary syndrome, decompensated heart failure, third degree AV block or cardiac arrhythmias associated with hemodynamic instability; (iii) echocardiographic estimate of tricuspid regurgitant jet velocity of ≥2.8 m/s (based on data associating SG with pulmonary hypertension in stable sickle cell disease patients); (iv) severe or unstable cardiovascular, hemato‐oncologic, or neuropsychiatric illness; (v) elevated bilirubin (total bilirubin > 1.5 mg/dL) or transaminitis (ALT/AST >2 times the upper limit of normal); (vi) treatment with an investigational drug or immunosuppressive medications including corticosteroids within 90 days from screening; (vii) alcohol and/or illicit drug use and/or abuse; (viii) AIDS or seropositivity for HIV, hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody within a year from screening; (ix) innate or acquired immunodeficiency other than that associated with uremia; (x) uncontrolled diabetes mellitus (HbA1c > 9%); and (xi) any other condition that, in the opinion of the principal investigator, renders a patient unable to participate in the study.…”

“…Upon admission, they received three weekly, peripheral intravenous infusions of SG 320 mg/kg over 2 hours. Dosing was based on preclinical and clinical data of SG in healthy volunteers and stable sickle cell disease patients . Throughout the study, subjects were assessed for adverse events (AE), and blood samples for safety and PK analysis were drawn.…”

“…Dosing was based on preclinical and clinical data of SG in healthy volunteers and stable sickle cell disease patients. 4,8 Throughout the study, subjects were assessed for adverse events (AE), and blood samples for safety and PK analysis were drawn. Subjects were followed for 90 days after the initiation of their first SG infusion ( Figure 1).…”