SBIR-STTR Award

Omniox is developing a new oxygen delivery therapeutic (H-NOX) that has the potential to dramatically reduce the damage associated with stroke. Stroke causes the largest number of quality-adjusted years lost in the U.S. In ischemic stroke, arterial occlusion reduces blood supply and oxygen to the brain, leading to tissue death (infarction). H-NOX is small enough to penetrate past vascular occlusions, can oxygenate ischemic tissue, and avoids toxicities associated with previously tested hemoglobin-based oxygen carriers (HBOCs). Thus, H-NOX represents a safer oxygen carrier that could revolutionize therapy for stroke patients. Preclinical studies with HBOCs have established that small proteins can penetrate the occluded artery and the ischemic penumbra to extend oxygenation beyond the reach of red blood cells in ischemic and reperfused brain tissue. HBOCs exhibit remarkable efficacy in stroke models, showing reductions in infarct volume up to 70%. However, HBOCs cause unacceptable side effects in patients due to their high chemical reactivity with nitric oxide (NO), an essential myocardial-, renal- and vaso-regulator. HBOCs induce cardiovascular dysfunction, renal toxicity, hypertension, and a range of other serious side effects that have halted their regulatory approval by the FDA. Omniox'class of H-NOX oxygen carriers are not reactive with NO and to date show no cardiovascular, renal or hypertensive toxicities when compared with a polymeric HBOC. Preliminary in vivo studies in ischemic wounds and hypoxic tumors show that H-NOX monomers can penetrate and oxygenate tissue. In this proposal, H-NOX monomers that have been shown to oxygenate ischemic tissue will be trimerized to increase their circulation half-life for extended brain oxygenation. The trimers will be evaluated for their ability to penetrate into ischemic brain tissu and relieve ischemia. Efficacy will be tested in a well-established model of stroke to quantify reduction in brain infarct volume and preservation of neurological function.

Public Health Relevance:
Omniox has developed an oxygen delivery therapeutic that has the potential to reduce neuronal death after an acute stroke, without the dramatic toxicities associated with hemoglobin-based oxygen carriers (HBOCs). The oxygen-carrying protein is small in size (comparable to HBOCs of 60-150 kDa that extravasate into cerebral tissue), has an oxygen affinity allowing it to release oxygen in ischemic brain tissue, and has none of the NO- related toxicities associated with hemoglobin-based oxygen carriers. This proposal will develop Omniox'H- NOX oxygen delivery platform into a lead candidate that meets the necessary criteria for approval as a new agent in the treatment of acute stroke. !"#$%&'#(%)*+",-./01+%-23+4+5677+ #"(+$"8+&%9(8%:;(%"#+

About half of stroke patients present with penumbra, defined as the tissue immediately surrounding an ischemic area in which blood flow is compromised due to vascular occlusion. The penumbra tissue may remain viable for several hours after an ischemic event due to collateral vessels that provide sufficient oxygen and nutrients to maintain neuronal structure but not enough to support function. As time elapses after stroke onset, the scarcity of oxygen supply causes the penumbra tissue to infarct, resulting in neurological deterioration. Omniox has engineered a safe first-in-class oxygen carrier (OMX) that improves brain oxygenation after stroke to preserve the neuronal and glial cell network viability within the oxygen-deprived penumbra tissue, resulting in the amelioration of neurological function. Because there is a high unmet need for therapeutics that preserve penumbra viability in stroke patients, OMX is a promising therapeutic candidate. In SBIR Phase I studies, Omniox has successfully achieved each of the milestones set out in accordance with the Stroke Therapy Academic Industry Roundtable (STAIR) and RIGOR guidelines demonstrating: 1) accumulation of OMX in the oxygen-deprived brain areas in stroke models of transient and permanent occlusion of the middle cerebral artery (tMCAO and pMCAO), 2) penetration of OMX into the brain parenchyma of the larger brain of a dog stroke patient; 3) sustained improvement of brain oxygenation and reduction of brain cell death; 4) prevention of infarct growth and long-term increase of neuronal survival; 5) significant amelioration of sensorimotor function in aged rats for at least a month after stroke onset. Importantly, OMX is efficacious in tMCAO stroke models in which penumbra exists. Therefore, these data support clinical translation of OMX in a well-defined patient population in which penumbra tissue can be salvaged using mechanical devices that remove the clot and restore blood flow. Since penumbra is detected in a majority of ischemic stroke patients, OMX could fundamentally change the landscape of stroke treatment. This Phase ll proposal builds upon our Phase I data to further explore the potential of OMX to benefit an expanded patient population presenting salvageable penumbra as well as complete additional STAIR criteria to demonstrate the translational potential of OMX. To do so, we will test OMX in multiple species and stroke models with varying spatio-temporal profiles of penumbra and infarct volume that mimic a range of clinical stroke scenarios such as: 1) a permanent occlusion model to support treating patients ineligible for recanalization (Aim 1), 2) a clot-based model to mimic thrombolytic recanalization with IV tPA in patients (Aim 2), and 3) a transient occlusion model in a non-human primate model with a large gyrencephalic brain suitable for longitudinal imaging to model the complexity of the human brain (Aim 3). These Phase II studies will guide the dose, therapeutic window, and selection of patient population for future clinical trials. CONFIDENTIAL (c)2015 Omniox, Inc. For review purposes only.

Public Health Relevance Statement:


Public Health Relevance:
Omniox has developed a breakthrough oxygen-delivery protein, OMX, which can delay or prevent the progressive death of oxygen-deprived brain tissue (penumbra) after ischemic brain injury. If left untreated, oxygen-deprived brain cells die over time, resulting in the expansion of the initial cerebral infarct. By improving oxygenation of the brain tissue after stroke, OMX prolongs neuronal survival, attenuates infarct growth, and ameliorates neurological function. This SBIR Phase II project will focus on testing OMX in additional stroke models and species to validate OMX as an emergency stroke treatment that can benefit the majority of stroke patients who present with salvageable oxygen-deprived tissue. CONFIDENTIAL (c)2015 Omniox, Inc. For review purposes only.

NIH Spending Category:
Brain Disorders; Cerebrovascular; Neurosciences; Stroke

Project Terms:
Acute; Affect; aged; Area; Attenuated; base; Behavioral; behavioral outcome; Biochemical; Blood flow; Blood Vessels; Brain; brain cell; Brain Injuries; brain parenchyma; brain tissue; Canis familiaris; Cell Death; Cerebral Infarction; cerebral oxygenation; Cessation of life; Chairperson; Clinical; Clinical Trials; Coagulation Process; Combined Modality Therapy; Consultations; Data; deprivation; design; Deterioration; Devices; Diffuse; Dose; Emergency Situation; Engineering; Event; Future; Generations; Growth; Guidelines; Hour; Human; Image; imaging modality; improved; in vitro activity; in vivo; Industry; Infarction; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lead; Left; Life; Long-Term Effects; Magnetic Resonance Imaging; Mechanics; Middle Cerebral Artery Occlusion; Modeling; Motor; Nervous System Physiology; Neuroglia; Neurologic; neuron loss; neuronal survival; Neurons; Nitric Oxide; nonhuman primate; Nutrient; Oryctolagus cuniculus; Outcome; Oxygen; patient population; Patients; Penetration; Phase; phase 1 study; phase 2 study; prevent; Prevention; Proteins; public health relevance; Rattus; Safety; Sensorimotor functions; Sensory; Small Business Innovation Research Grant; stroke; stroke therapy; stroke treatment; Structure; Technology; Testing; Therapeutic; Time; tissue oxygenation; Tissues; Translations