Phase 2 Study of MP4CO to Treat Vaso-occlusive Sickle Crisis
Phase 2 Study of MP4CO to Treat Vaso-occlusive Sickle Crisis
Sickle Cell disease is caused by an inherited hemoglobin disorder. Healthy red blood cells
 are discoid and can deform and move through small blood vessels to carry oxygen to all parts
 of the body. In Sickle Cell disease, as red blood cells circulate and oxygen is released, the
 deoxygenated abnormal Hemoglobin S can begin to polymerize and cause red cells to become
 sticky and elongated. These "sickled" red cells are less flexible and will obstruct small
 blood vessels and prevent normal red cells from circulating freely, which limits oxygen
 delivery to tissues and organs. This is known as a "sickling crisis" or "vaso-occlusive
 crisis" and is the leading cause of hospitalization in patients with Sickle Cell disease.

 Patients suffering from a sickle crisis experience severe pain and are at risk of stroke,
 heart attack or even death. Current therapy is limited to hydration and symptomatic pain
 relief. The administration of MP4CO as an adjunct treatment to standard therapy may alleviate
 pain associated with a sickling crisis and potentially reduce the severity and duration of a
 crisis. This may shorten the time in hospital and potentially improve the quality of life for
 patients with sickle cell anemia.
Sickle cell disease (SCD) is an autosomal recessive disorder of the β globin gene of the
 hemoglobin molecule. To date, no specific agent has been approved to treat a sickle cell
 crisis, to reduce the severity of a sickling crisis, or to shorten the duration of admission.
 Current therapy for a crisis is limited to hydration and symptomatic pain relief with opiates
 when pain is severe enough to cause admission to hospital. Administration of oxygen by
 inhalation alone has not proven effective. The carbon monoxide (CO) molecule binds to Hb S
 and, while attached, prevents and reverses polymerization of Hb S chains and the distortion
 of the red cell. CO at very low doses also acts as a cell-signaling molecule, and may reduce
 inflammation, decrease oxygen requirements, and prevent programmed cell death (apoptosis).

 MP4CO is designed as an ischemic rescue therapy to deliver non-toxic levels of CO, to provide
 an immediate metabolic signal to cells to help reverse red cell sickling, and to reduce
 inflammation.

 Previously published studies provide a foundation to postulate that MP4CO might have the
 appropriate properties for treatment or reversal of an acute sickling crisis. The initial
 release of CO from MP4CO is predicted to have a beneficial effect including immediate
 stabilization of Hb S to prevent further red cell polymerization and reverse existing
 sickling, dilation of capillaries to enhance tissue perfusion, and anti-inflammatory
 cell-signalling properties. The subsequent circulation of the MP4 molecule as an oxygen
 therapeutic (after converting to MP4OX following oxygenation in the lungs) will help to 1)
 preferentially oxygenate ischemic tissue, 2) reverse partially sickled red cells, and 3)
 improve perfusion and oxygenation of local tissues to potentially ameliorate the painful
 crisis caused by sickling of red cells. In addition, MP4CO has enhanced chemical stability,
 which enables storage at room temperature.
Inclusion Criteria:

 -  Signed Informed Consent (and assent as required for minors)

 -  Diagnosis of SCD (known HbSS or HbSß0)

 -  Sixteen years of age or older

 -  Prior history of at least one VOC requiring hospitalization within the last 24 months

 Exclusion Criteria:

 -  ≥ 5 VOCs within the preceding 6 months requiring Emergency Room (ER) visits or
 hospital admissions

 -  History of overt stroke or cerebral vascular accident within the previous 12 months

 -  Remained in the hospital for ≥2 weeks (14 days) for VOC management within the previous
 6 months

 -  Known pulmonary hypertension based on an estimated tricuspid regurgitant jet velocity
 (TRJV) >2.90 m/s or definitive diagnosis by prior right heart catheterization

 -  Baseline SaO2 level by pulse oximetry <92% on room air

 -  Systemic hypertension (baseline systolic pressure ≥ 160 mmHg or diastolic pressure ≥
 90 mmHg)

 -  History of myocardial infarction, myocardial ischemia, or angina

 -  On a chronic red blood cell transfusion therapy program (simple or exchange)

 -  Renal dysfunction presenting with a GFR<60 mL/min/1.73m

 -  Any diagnosis of a concurrent chronic debilitating disease that may affect the
 completion of the study or results of the study as determined by the investigator

 -  Currently enrolled in any other investigational treatment study

 -  Significant substance abuse.

 -  Known to have HIV, active hepatitis B, or C infection, or active tuberculosis