ReAlta Clinical PipelineReAlta is a clinical stage company working towards FDA approval for four indications. These four areas of focus (pulmonary, CNS, hematology, immunology) are closely linked to the potential to address an additional 15 indications. The initial indications are:
- ALI (Acute Lung Injury) Related to COVID-19
- HIE (Hypoxic Ischemic Encephalopathy)
- HTR (Hemolytic Transfusion Reaction)
- AIHA (Autoimmune Hemolytic Anemia)
Acute Lung Injury
Acute lung injury (ALI) associated with COVID-19 is the most frequent cause of death related to the infection, with limited benefit shown from current treatments. ALI ensues following the triggering of the complement cascade and innate immune response. RLS-0071 downregulates both processes by acting on the earliest stages of the inflammatory cascade preventing escalation and tissue damage.
Preclinical data in our proprietary two-hit animal model shows dramatic decreases of inflammatory cytokines IL-1b, IL-6, TNFa after prophylactic or rescue dosing. RLS-0071 decreases neutrophil infiltration by 59% after single IV injection, preventing lung tissue damage.
In July 2020, ReAlta announced that the U.S. Food and Drug Administration (FDA) accepted its Investigational New Drug (IND) application for RLS-0071 for the treatment of acute lung injury secondary to COVID-19. ReAlta expects to begin a Phase 1 randomized, double-blind, placebo-controlled clinical trial of RLS-0071 in adult patients with pneumonia and early respiratory failure in the third quarter of 2020.
In parallel, ReAlta is exploring the ability of RLS-0071 to decrease the risk of acute lung injury from other viral infections such as RSV and influenza.
Hypoxic Ischemic Encephalopathy
ReAlta is initially focusing PIC1 technology on significantly improving outcomes from Hypoxic Ischemic Encephalopathy (birth asphyxia brain damage). Brain injury due to birth asphyxia (HIE) is implicated in 23% of four million infant deaths worldwide. Over 50% of neonates experiencing HIE do not survive, the rest are left with moderate to severe mental and physical disabilities. ReAlta objectives are to:
- significantly increase the survival rate of HIE neonates world-wide
- enhance the neurocognitive outcomes of HIE survivors, and
- make the PIC1 drug product available to professionals and families around the world.
Based on results from the “gold standard” HIE animal model, PIC1 decreases the area of brain infarction by 50% and dramatically improves neurocognitive outcomes, even to adult age. As can be seen below, there is little visible difference between the normal rat pup brain and the brain of a rat treated with PIC1, while untreated rats and rats treated with hypothermia show large areas of dead brain tissue.
PIC1 also dramatically improves neurocognitive function of hypoxia-induced, treated rats. Below are test results of rat ability to remember escape hole locations. Hypoxia-induced rats treated with PIC1 are clearly smarter.
There are currently no pharmaceutical approaches to treat birth asphyxia. PIC1 is the first anti-inflammatory/anti-oxidant compound studied for HIE. As such, PIC1 represents a new treatment approach with a focus on preventing brain damage. PIC1 will decrease reperfusion injury via Complement activation, Myleoperoxidase activity, Neutrophil Extracellular Trap formation and anti-oxidant activities.
The current standard of care for HIE is hypothermia (reducing neonatal body temperature). While this treatment has a small positive (11%) impact on fatality, there is no improvement in IQ (<70) at school age. This therapy must be initiated within a few hours of birth at a facility with special equipment and highly trained professionals. We expect PIC1 to become the primary treatment for HIE and eventually be available in the delivery room of every hospital in the world. Administration will not require specialized knowledge, training or sophisticated equipment.
Hemolytic Transfusion Reactions
Hemolytic Transfusion Reactions--Acute Intravascular Hemolytic Transfusion Reactions (HTRs) are life-threatening complement-mediated disease processes with no current clinical intervention and thus constitute a critical unmet medical need. Situations like mass casualty or battlefield trauma can stress transfusion services due to high demand for blood products and minimal time to cross-match. This is critical when O-negative red blood cell (RBC) availability may be limited and the chance of an ABO incompatible blood transfusion is increased. Currently there are no prophylactic or intervention treatments for HTRs.
PIC1 Impact on prevention of HTRs:
- PIC1 maximally inhibits the intravascular destruction of mismatched RBCs and acute kidney injury in an animal model of AIHTR
- PIC1 inhibits complement-mediated opsonization of mismatched RBCs slowing extravascular hemolysis
- PIC1 also inhibits free hemoglobin toxicity to kidneys
Autoimmune Hemolytic Anemia
Autoimmune Hemolytic Anemia (AIHA) is a heterogeneous group of rare, acquired immune disorders characterized by autoantibody-mediated destruction of red blood cells (RBC) resulting in hemolytic anemia. The incidence in adults has been estimated at 1-3 cases per 100,000/year.
The pathogenesis of AIHA generally involves the production of IgG, IgM, and sometimes IgA autoantibodies that bind to RBC surface antigens, initiating red blood cell destruction via the complement system and reticuloendothelial system. Complement plays an important role in mediating cell lysis. Patients with AIHA usually present with symptoms of anemia. In the case of severe hemolysis, there may be fever, pallor, jaundice, hepatosplenomegaly, hemoglobinuria and signs of heart failure and/or renal failure, and death has been reported in up to 11% (Lechner and Jager, 2010).
Glucocorticoids continue to be considered as first-line treatment, but relapses are not uncommon, and complications are of particular concern in patients with underlying diabetes in whom treatment-related death from infection is a major risk. For those who fail to respond or who relapse, splenectomy may be considered. PIC1 has the potential to stabilize AIHA patients more rapidly than glucocorticoids without the associated negative side-effects.