PEGylated Carboxyhemoglobin Bovine (SANGUINATE): Results of a Phase I Clinical Trial

Abstract

PEGylated carboxyhemoglobin bovine (SANGUINATE) is a dual action carbon monoxide releasing (CO)/oxygen (O2 ) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE's efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients.

Sanguinate's effect on pial arterioles in healthy rats and cerebral oxygen tension after controlled cortical impact

“…In a rat cerebral ischemia model (Klaus et al, 2010;Zhang et al, 2012), an even faster infusion rate (30 mL/h) and similar dose (10 mL/kg) resulted in only a minor rise in MAP. On the other hand, a clinical trial of healthy human volunteers (Misra et al, 2014) showed increases in MAP. Since we measured only blood pressures, other physiological changes besides volume expansion could play a role in the blood Table 2 Total Hb, PaO 2 , PaCO 2 and pH (mean ± SEM) in TBI rats.…”

Toxicology and Safety Determination for a Novel Therapeutic Dual Carbon Monoxide and Oxygen Delivery Agent

“…A phase I study has been completed and is consistent with the preclinical studies. SANGUINATE was found to be safe and well-tolerated in healthy human volunteers at doses of 80 mg/kg, 120 mg/kg, and 160 mg/kg [12]. Multiple doses of SANGUINATE have been used in Sickle Cell patients as well [13,14].…”

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

“…Pharmacokinetic results found that SANGUINATE (160 mg/kg) had a prolonged T 1/2 in stable SCA patients (19.56 h) compared to that found in healthy volunteers (13.75 h) 7 . In the Phase I study with healthy volunteers, it was observed that haptoglobin levels were significantly reduced following SANGUINATE administration.…”

“…SANGUINATE is a novel construct of hemoglobin that contains carbon monoxide and pegylated bovine carboxyhemoglobin. It has been shown to reduce infarct volume in animal models7, 8 and has been administered under multiple emergency Investigational New Drugs (eINDs) 9, 10 11 and demonstrated the transfer of oxygen to hypoxic cells.…”