Phase Chart for Clinical Pipeline for PP-007
The widely known PEGylation process attaches repeating units of polyethylene glycol (PEG) typically to a polypeptide drug. Our PEGfinity™ process creates hemoglobin conjugated with PEG, acting as a nano-sized oxygen carrier, substituting for red blood cells in supplementing oxygen in hypo-oxygenation pathologies and vasoconstricted or obstructed areas. In PP-007, the novel PEGylation pattern modifies the bHb hemoglobin saturation profile, skewing it towards selective oxygenation of severely hypoxic tissue.
We believe that oxygen delivery alone does very little to address the comorbidities of disorders caused by anemia or hypoxia/ischemia, such as the vaso-occlusive crisis of sickle cell disease. These comorbidities include vaso-occlusive (pain) crisis, acute chest syndrome, leg ulcers, and pediatric and adult stroke.
Carbon monoxide (CO) is naturally produced at low concentrations in our bodies through the catalysis of heme by Heme Oxygenase-1 (HO-1), which act as endogenous signaling molecules to reduce excessive pro-inflammatory cytokine expression. Exogenous treatment with carbon monoxide-releasing molecules (CORMs) has previously shown inhibition of apoptosis and inflammation, reducing oxidative stress, and providing an anti-vasoconstrictive in several distinct animal models. The release of CO by PP-007 into the microcirculation has been shown to limit/prevent vasoconstriction of the pial arteries acute ischemic stroke animal models. The CO release is anticipated to function along with other supportive therapies addressing the complex cascade of disorders stemming from ischemia/reperfusion injury, which is a leading cause of organ damage following an acute ischemia/hypoxia event as often observed in stroke and myocardial infarction (Cipolla 2018, Kawaguchi AT 2018).
By combining bovine hemoglobin with both PEG to improve perfusion and CO to prevent vasoconstriction and inflammation during ischemia/hypoxia, PP-007 works holistically to achieve vascular and tissue homeostasis, unlike other oxygen carrier therapeutics that only treat the symptomatic condition and not underlying root cause of a disorder (Abuchowski A. 2017).
PP-007 is a clinical stage investigational medicine product being evaluated in conditions of ischemia/hypoxia. Prolong has completed 12 clinical trials including the treatment of over 250+ individuals. PP-007 was previously made available for life-threatening compassionate use (i.e. eIND) in severe anemia when blood was not an option (BNAO) – either due to incompatibility or personal choice. The diverse underlying health conditions of these severe anemia patients varied widely and included examples of hemoglobin loss due to intravascular hemolysis or hemorrhage. The BNAO case reports provided foundational evidence for PP-007 to rapidly improve cardiovascular dynamics, and the capacity to “bridge” these patients through hemodynamic crisis.
- ACUTE ISCHEMIC STROKE (AIS)
AIS occurs when a blood clot blocks the blood flow (ischemia) in the brain resulting in brain injury resulting from loss of tissue oxygenation (hypoxia). Agents that dissolve the clot (thrombolysis) or mechanical removal (thrombectomy) have improved outcomes of numerous stroke patients. However, there are time limitations and other factors that limit the widespread use of these treatments. With over 750,000 AIS each year in the US, additional treatments are urgently needed. Prior studies in stroke animal models have shown PP-007 can improve microcirculation perfusion (cerebral perfusion), tissue oxygenation and reduced inflammation that collectively resulted in reduced infarct volumes and improved neurological outcomes (Cipolla MJ. 2018).
We are dedicated to our mission to bring a proven therapeutic to market that can treat the debilitating impacts of ischemic stroke and help relieve physical blockage for a comprehensive treatment. Additionally, a prior PP-007 clinical study in patients at risk of delayed cerebral ischemia (DCI) following subarachnoid hemorrhagic stroke revealed evidence of brain tissue oxygenation at the 320 mg/kg dose level (Dhar R 2017 and Tallarico RT 2018).
Prolong is also dedicated to aiding in multi-therapeutic situations in conditions such as hemorrhagic stroke, where PCHB was dosed several times along with other supportive therapies to stabilize (bridge) a critically ill anemic patient for lifesaving interventions without adverse effects.
- Sickle Cell Disease (SCD)
SCD is an inborn genetic disease resulting from a single mutation in the human beta globin gene. The mutated hemoglobin structure is altered, which forces the red blood cells (RBC) to form a sickle shape. The mutation (E6V) affects the shape of hemoglobin, compromising its ability to transport oxygen. Currently there are agents approved to reduce the frequency of vaso-occulsive episodes (VOE), but not for use during an active VOE. Prior non-clinical, clinical safety and Proof of Concept studies in SCD have shown PP-007 can reverse sickled RBCs both in vitro and in vivo. A recent phase 2 vaso-occulsive crisis (VOC) study showed unsickling in 66% of PP-007 treated individuals that also reduced inflammatory gene expression. (NCT02411708)
PP-007 has been widely studied in several clinical studies that included Sickle Cell Disease (SCD) and Beta-thalassemia (β-thal) subjects (Table 1 – Completed PP-007 Clinical Trials). These safety and Proof of Concept studies showed PP-007 was well tolerated. The majority of SGSC-005 subjects treated with PP-007 showed a decrease of intravascular RBC sickling and reductions in markers of systemic inflammation as compared to saline controls. This novel, rapid capacity for PP-007 to promote RBC “unsickling” may provide for rapid treatment of VOC events or more serious exacerbations including Acute Chest Syndrome.
- BLOOD NOT AN OPTION (BNAO)
PP-007 has unique resuscitative properties that has been shown to improve organ function and survival in animal models of severe hemorrhagic and hypovolemic shock (Guerci P 2020, Macko A 2020, Nugent WH. 2019). RBC transfusions are the standard of care treatment for low blood hemoglobin levels resulting from an acute event such as massive blood loss or complications of chronic anemia. However, many individuals do not receive RBC transfusions for personal choices including religious beliefs and allogeneic incompatibility. Several subjects received single or multiple PP-007 treatments to “bridge” their recovery from life-threatening anemia (Brotman I 2019, DeSimone RA 2018, McConachie S 2018, Thenuwara K 2017). Many of the treated individuals had suffered severe hemorrhage and significant drops in Hb levels (Bachert SE 2020, McConachie SM 2020). Other conditions treated included liver transplantation and recipient’s thrombotic thrombocytopenic purpura (Holzner MI 2018, Sam C 2017).
Collectively these data add further support the mechanisms of action for PP-007 to provide for improving patient hemodynamics during periods of extreme acute injury.
Table 1. COMPLETED PP-007 CLINICAL TRIALS. The safety and efficacy of PP-007 was evaluated in single and multiple dose administration settings in acute and chronic conditions. Overall the product was well tolerated with efficacy observed in studies where measured. In total, 272 individuals received PP-007 treatment in 12 clinical trials conducted between 2013 and 2017.
- CYSTIC FIBROSIS
CF is an inborn genetic disease resulting from mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The mutations affect the CFTR protein function that promotes a build-up of mucus and hyperinflammation in the lungs. There are a limited number of currently approved therapeutics, but none directly targeting lung inflammation. Pre-clinical in vitro and in vivo studies in CF models challenged with Lipopolysaccharide (LPS) or Pseudomonas aeruginosa (PA) showed that PP-007 could promote HO-1 production and yield a coordinated reduction in lung neutrophils, alveolar macrophage inflammation without reducing the CF mouse antibacterial activity (Di Pietro C, 2020).
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