Safety and Tolerability Of MP4CO: A Dose Escalation Study In Stable Patients With Sickle Cell Disease
Authors: Howard Jo , Thein Swee Lay , Galacteros Frederic , Inati Adlette , Reid Marvin , Keipert Peter E. , Small Tania N. , Booth Frank 
Published: October 2019

Abstract

Introduction
Vaso-occlusive crises (VOC) remain the hallmark of Sickle Cell Disease (SCD) yet to date no agent has been approved to hasten the resolution of an acute painful event. MP4CO, a pegylated hemoglobin-based carbon monoxide (CO) carrier, has demonstrated potential in non-clinical studies for the prevention and reversal of red cell sickling and has exhibited anti-adhesive, anti-oxidant, anti-inflammatory and anti-apoptotic properties at circulating carboxyhemoglobin (CO-Hb) levels < 10% (Belcher: BLOOD, Aug 2013). These cellular protective effects are expected to limit the progression of vascular occlusion and mitigate the consequences of ischemic tissue damage and inflammation. The beneficial effects of MP4CO can be ascribed to 5 postulated mechanisms: 1) downregulation of ICAM-1, VCAM-1 and NF-κB 2) upregulation of Heme-Oxygenase-1 and Nrf2 leading to further increase in anti-inflammatory mediators, biliverdin and CO 3) delivery of oxygen to ischemic tissues 4) intravascular volume expansion and improved perfusion of ischemic tissue and 5) possible prevention and reversal of polymerization and sickling of red blood cells

Methods
We conducted a Phase 1b prospective, double-blind, comparator controlled, dose escalating, multi-center study designed to assess the safety profile of MP4CO in clinically stable adult sickle cell patients not experiencing painful crises at the time of testing.
Patients with HbSS and S/β0 Thal genotypes, 18 years of age and older, meeting eligibility criteria were randomized to receive either MP4CO or normal saline (NS) in a sequential series of 6 escalating doses (Cohorts A-F). Each cohort included 4 patients; 3 patients per cohort received MP4CO (treated group) and 1 patient per cohort received NS (control group). Cohorts A through D received single dose IV infusions ranging from 15 mg/kg/dose (0.35 mL/kg infusion) to 172 mg/kg/dose (4 mL/kg infusion). Cohorts E-F, received fractionated doses of 172 mg/kg or 344 mg/kg (4-8mL/kg administered as two daily intravenous infusions of 2 mL/kg separated by 24 hours).
Physical examination, vital signs, pulmonary artery pressure/TRJV, ECGs, pulse oximetry, venous blood co-oximetry, free plasma hemoglobin, pain assessments and laboratory measurements were conducted at defined intervals throughout the study. Safety variables were evaluated by an unblinded independent medical safety monitor from randomization through Day 28 for each cohort.

Results
Twenty-four patients were randomized. Eighteen subjects were exposed to MP4CO and 6 subjects received NS. Overall, 16/24 subjects (66.7%) reported mild to moderate adverse events (AEs) with 13/18 subjects (72%) from the MP4CO group and 3/6 subjects (50%) in the NS group. No serious adverse events (SAEs) were experienced and no deaths were reported. The most common AEs (reported by >2 subjects) included headaches (mostly mild and transient), dizziness, fatigue, and rash at the application site of the Holter electrodes
No treatment-emergent abnormalities were noted throughout the study. Vital signs, ECG readings, standard laboratory values and pulmonary pressures remained within normal limits. The maximum increase in of CO-Hb level was only 2% which returned to pre-dosing levels within 8 hours after the completion of infusion. Mean increase in free plasma hemoglobin (an index of MP4CO dose) ranged from 0.2 to 0.35 g/dL in the two highest dosed cohorts with no significant change in total whole blood hemoglobin. There was no symptomatic or clinical evidence of renal dysfunction observed in either group based on serum creatinine and urinary albumin results. While two subjects had elevated levels of renal biomarkers, β2M and NAG at Hour 72, levels normalized at follow up visits. Both subjects had documented intercurrent illnesses during the trial and further testing of stored urine samples were within normal limits supporting the hypothesis that the β2M and NAG changes were reflective of a more generalized inflammatory state than of direct tubular injury.

Conclusion
MP4CO appears to be well tolerated at doses up to 344 mg/kg. Results of this Phase 1b safety study showed no obvious or concerning safety signals or clinical evidence of abnormal organ dysfunction/injury. Together with nonclinical evidence, this study supports the decision to proceed with further efficacy and safety evaluation of MP4CO in a larger phase 2 study for treatment of a painful VOC.

Disclosures:
Howard: Sangart: Membership on an entity’s Board of Directors or advisory committees. Galacteros:Sangart: Consultancy. Inati:Sangart: Consultancy. Reid:Sangart: Consultancy. Keipert:Sangart: Employment, Equity Ownership. Small:Sangart: Employment, Equity Ownership. Booth:Sangart: Employment, Equity Ownership.