Safety Study of MP4CO in Adult Sickle Cell Patients
Safety Study of MP4CO in Adult Sickle Cell Patients
Sickle Cell Anemia 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 in the
 circulatory system, the deoxygenated abnormal hemoglobin S can begin to polymerize. When this
 occurs, the red blood cells can become sticky and elongated. These sickled red blood cells
 are less flexible and will obstruct small blood vessels and block normal red blood cells from
 traveling through the circulatory system, which limits oxygen delivery to tissues and organs.
 This is known as a "sickle crisis".

 Patients suffering from a sickle crisis experience severe pain and are at risk of stroke,
 heart attack or even death. By lowering the level of oxygen pressure at which sickling occurs
 and opening the vasculature and rapidly delivering oxygen directly to ischemic tissues, the
 addition of MP4CO to existing treatment protocols may alleviate pain associated with a sickle
 cell crisis, abort a crisis and/or potentially reduce the duration of a crisis. This could
 mean less time in the hospital and an improved quality of life for patients with sickle cell
 anemia.
To date, no specific agent has been approved to treat sickle cell crisis, to reduce the
 severity of a sickling crisis, or to shorten the duration of admission. Current therapy for a
 sickling 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. Carbon monoxide (CO) binds to Hb S and, while attached, prevents
 and reverses polymerization of Hb S chains and consequent distortion of the red blood cell.
 Carbon monoxide at very low doses also acts as a messenger to cells, reducing inflammation,
 reducing oxygen requirements, and preventing programmed cell death (apoptosis).

 The MP4 molecule can be modified to carry CO and other gases to enhance therapeutic benefit
 for certain patients. MP4CO is therefore designed to deliver therapeutic, non-toxic levels of
 CO, to provide an immediate metabolic signal to cells and to reduce inflammation. Once the CO
 is released from the compound, the MP4 molecule gets oxygenated in the lung and then delivers
 oxygen to ischemic tissues.

 Previously published studies provide a good foundation to postulate that a chemically
 modified hemoglobin such as MP4CO might have the ideal properties as an oxygen therapeutic
 agent for treatment or reversal of a sickling crisis. The initial release of CO from MP4CO is
 predicted to have a therapeutic effect including immediate stabilization of Hb S to prevent
 further polymerization and reverse existing sickling, vasodilation of capillaries, and
 anti-inflammatory properties. The subsequent circulation of the MP4 molecule as an oxygen
 therapeutic agent (after converting to MP4OX following oxygenation in the lungs) will help to
 1) preferentially oxygenate ischemic cells, 2) reverse partially sickled red cells, and 3)
 improve oxygenation of local tissues, thereby potentially ameliorating the painful VOC caused
 by red blood cell sickling. In addition, MP4CO has enhanced chemical stability, which enables
 storage at room temperature while minimizing methemoglobin formation.
Inclusion Criteria:

 -  Adult male or female patients (18 years of age or older) with diagnosed sickle cell
 disease based on Hb SS, or S/β0 Thalassemia genotype, who are clinically stable and
 not experiencing an acute episode of pain

 Exclusion Criteria:

 -  At least 4 painful VOCs within the preceding year requiring hospital treatment

 -  Urgent care facility, hospital treatment or admission for treatment of a painful VOC
 within the previous 2 months

 -  History of a painful VOC lasting longer than 2 weeks or > 12 pain episodes requiring
 intervention in a medical facility (emergency room, urgent care or clinic) in
 preceding year

 -  Baseline VAS pain score ≥ 4 cm

 -  Hemoglobin < 6 g/dL

 -  Transfusion of packed red blood cells within previous 4 weeks

 -  Currently on iron chelation therapy

 -  History of sickle cell disease-attributed CNS disease (including a) recent or past
 history of stroke; b) ongoing treatment with chronic transfusion therapy to prevent
 stroke; c. history of seizures or epilepsy; and d. evidence of or known overt cerebral
 vasculopathy or known cerebral vessel narrowing

 -  Evidence of pulmonary hypertension, based on an estimated systolic pulmonary artery
 pressure > 25 mmHg calculated from TRJ velocity from a transthoracic echocardiography
 (TTE) assessment at Screening visit or from a previous TTE assessment if it was done
 within 1 year prior to randomization

 -  Baseline oxygen saturation by pulse oximetry ≤ 90%

 -  History of a priapism within the last year

 -  History of hypertension requiring anti-hypertensive therapy

 -  Baseline bradycardia (heart rate < 60/min)

 -  History of myocardial infarction, myocardial ischemia, or angina

 -  Renal dysfunction or creatinine level within past 6 weeks of ≥ 1.2 mg/dL (≥ 106
 µmol/L) or a urine protein/creatinine ratio (PCR) > 50 mg/mmol

 -  Hepatic dysfunction (AST or GGT > 3x ULN, or ALT >2x ULN, or conjugated bilirubin > 2x
 patient's baseline within the last 6 weeks)

 -  Positive pregnancy test

 -  Any acute or chronic condition which would limit the patient's ability to complete the
 study

 -  Evidence of, or known to be chronically abusing illegal drugs or excessive quantities
 of alcohol

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

 -  Received any other investigational drug(s) within 30 days prior to randomization

 -  Professional or ancillary personnel involved with this study or in the employment of
 the investigator