Pipeline

Drug Development for Neurological Disorders

ONP-002 for the Treatment of Traumatic Brain Injury

ONP-002 is a First-in-Class Enantiomeric-Neurosteroid being developed for the treatment of mild Traumatic Brain Injury (mTBI) aka concussion. A mTBI can occur following a direct hit to the head or a whiplash movement of the cervical spine. The injury is defined by stretching of the brain cells that leads to small tears in brain tissue including neurons and microvasculature. While many individuals recover within two-weeks of the injury there is a population of approximately 20% that can remain symptomatic for months or years, this is referred to as Post-Concussion Syndrome (PCS) and is linked to chronic neurological diseases including Alzheimer’s, Parkinson’s, and Chronic Traumatic Encephalopathy (CTE).

• Animal and cell culture models of neuronal injury show neuroprotective molecular and behavioral effects of ONP-002 within hours

• Animal studies have shown the drug to have an excellent safety profile when given intranasally and intravenously

• Intranasal administration in animals showed quick and significant distribution to all regions of the brain

• The intranasal formulation has been developed as a novel spray dried nanoparticle to enhance absorption and access to the brain parenchyma, bypassing the burdensome blood brain-barrier (BBB)

• The IP includes structure, synthetic preparation, and methods of use for ONP-002

ONP-002 - Mechanism of Action and Clinical Studies

ONP-002 diffuses intracellularly to induce steroid receptors found in neurons, glia, and the endothelium of the blood brain-barrier. The induction of the ONP-002 receptors activates multiple gene response elements leading to the production of mRNA transcripts and subsequently proteins that reduce inflammation, oxidative stress, and swelling. In addition, ONP-002 induces macro-autophagy to reduce the build-up of extra- and intra-cellular debris that can cause chronic neurological diseases associated with dementia. Since ONP-002 is not a GABAergic compound, it does not cause fatigue.

Oragenics has completed a SAD/MAD Phase I human safety study. ONP-002 was well-tolerated with no severe adverse events. PK studies showed a dosage increase in ONP-002 in blood plasma with overall low plasma levels due to intranasal delivery versus predicted higher levels with other forms of administration such as intravenous or oral.

Oragenics is currently preparing the launch of a Phase II clinical study evaluating the feasibility of using ONP-002 in the acute ER setting while analyzing blood biomarkers for prognosis and enrolment of more severe concussion along with cognitive, visual motor, patient reported outcomes, and disability scores to establish proof of concept for the use of ONP-002 - 2X a day for 5-days post brain injury.

ONP-001 for the Treatment of Rare Leukodystrophies

ONP-001 is a First-in-Class Enantiomeric-Neurosteroid being developed for the treatment of rare Leukodystrophies. There are over 50 rare Leukodystrophies which are generally defined as genetic disorders that cause the accumulation of lipids aka fat in the brain and subsequently lead to the impairment of myelin. Myelin is required for proper electrical signaling in brain cells. Some Leukodystrophies are classified as Lysosomal Storage Disorders due to specific pathological mechanisms that cause lipid trafficking to fail within brain cells.

• Animal and cell culture models show ONP-001 to be neuroprotective and increase the molecular expression of P-Glycoprotein, a known activator of macroautophagy which is needed to metabolize excessive intra and extra-cellular lipids including cholesterol

• Animal models of neuronal injury show positive effects on cognition and motor performance, two of the classical signs of neurological impairment in leukodystrophies and associated Lysosomal Storage Disorders

• Animal studies have shown the drug to have a large safety margin when given intranasally and intravenously

• The IP covers methods of preparation and methods of use

ONP-001 – Mechanism of Action and Preclinical Studies

ONP-001 binds to intracellular steroid receptors. The ONP-001 receptor is an intracellular receptor found in neurons, glia and the endothelium of the blood brain-barrier. The induction of the ONP-001 receptor activates gene response elements leading to the transcription of P-Glycoprotein (PGP), which pumps cholesterol and lipid debris, out of the brain cells and the extracellular compartments of the brain.

Acute and sub-acute dose ranging studies were executed in rats – intranasal and intravenous. No drug-related effects were noted in hematology, blood chemistry, or histopathology. Additional IND-enabling studies are underway. These studies will be followed by a Phase I safety trial in preparation for Phase II studies for feasibility and proof-of-concept in human leukodystrophies. Niemann Pick, Type C disease will be the first disorder to be evaluated using ONP-001 in Phase II trials.

Novel Intranasal Device for the Treatment of Brain Disorders

Oragenics has developed a novel breath-propelled device for the treatment of brain disorders. The nasal end of the device houses the spray-dried nanoparticle drug formulation.

Intranasal delivery through breath propulsion causes the soft palate to elevate which closes the back of the nasopharynx - trapping the powdered drug in the nasal cavity. The powder sticks to the wet mucosa giving it ample time to be absorbed. Targets within the nasal cavity that enhance brain delivery include the superior nasal turbinate and superior nasal roof where the olfactory region is located. Direct flow of drug occurs along the trigeminal nerve, olfactory nerve, and within the perivascular system from the nose to the brain in minutes. Lipophilic compounds such as ONP-001 and ONP-002 are hydrophobic and more readily cross the epithelium of the intranasal lining further improving brain drug delivery.