Ovid research is pioneering a scientific approach to develop therapies based on new understanding of key biological pathways and their central role in rare neurological disorders.
We seek to develop medicines using novel and clinically relevant endpoints to capture tangible patient benefits that emanate from addressing underlying disease pathology.
Our OV101 program focuses on a potential treatment for Angelman syndrome and Fragile X syndrome, two neurodevelopmental disorders caused by genetic mutations. In Angelman syndrome, the mutation is most commonly a microdeletion on chromosome 15 encompassing the ubiquitin protein ligase E3a (UBE3A) gene, which results in a loss of expression of the UBE3A protein. In Fragile X syndrome, mutations in the fragile X mental retardation 1 (FMR1) gene, located on the X chromosome, result in loss of expression of the Fmr1 protein (Fmrp). There are currently no approved drugs for either syndrome.
Our OV935 program focuses on developing potential therapies for people living with rare epilepsies, known as epileptic encephalopathies, that cause intractable seizures and are often associated with cognitive, neurologic and behavioral problems. In collaboration with Takeda, we are developing potential treatments for these rare disorders, including Dravet Syndrome, Tuberous Sclerosis Complex and Lennox-Gastaut Syndrome.
Developing BoldMedicine to Transform the Lives of People with Rare Neurological Disorders
“The cause is hidden.
The effect is visible to all.”
– Ovid, Metamorphoses
Rare Disorders of the Brain
About Angelman Syndrome
Angelman syndrome is a rare genetic disorder characterized by delayed development, intellectual disability, severe speech impairment, problems with movement and balance, seizures, sleep disorders and anxiety. The estimated prevalence of Angelman syndrome is between 1 in 12,000 to 20,000 people. The genetic cause of Angelman syndrome has been traced to mutations and other disruptions of the ubiquitin protein ligase E3A (UBE3A) gene. The first signs of Angelman syndrome are usually developmental delays, such as lack of crawling or walking, seen between the ages of 6 and 12 months. Due to its similarity to other disorders, it is frequently misdiagnosed.
About Fragile X Syndrome
Fragile X syndrome (FXS) is a genetic condition that results in intellectual disability, anxiety disorders, behavioral and learning challenges and various physical disabilities. FXS has an estimated prevalence of 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females. FXS is caused by mutations in the Fragile X mental retardation gene (FMR1), resulting in the lack of fragile X mental retardation protein expression that is required for normal brain development. The current standard of care relies on symptomatic treatments to address attention deficit, anxiety, irritability and sleep disorders, including antipsychotics and antidepressants. FXS patients also may experience seizures, which are treated with traditional anticonvulsants.
About Dravet Syndrome
Dravet syndrome is a severe form of childhood epilepsy that typically presents during the first year of life. It is largely caused by mutations in the SCN1A gene. Children experience frequent seizures, loss of muscle control, cognitive deficits and, in approximately 10 percent of cases, death before the age of 12 years. While some patients may survive into adulthood, their long-term intellectual development and seizure outcomes are typically extremely poor. The incidence of Dravet syndrome in the United States ranges from 1 in 15,700 to 1 in 20,900 births. Patients are frequently treated with combinations of classic anti-epileptic drugs, none of which are particularly effective. No drugs have been approved specifically for the treatment of Dravet syndrome in the United States and only one drug, the anticonvulsant stiripentol, has been approved in Europe.
Lennox–Gastaut syndrome is a rare disorder that is often diagnosed between three and five years of age. Patients diagnosed with Lennox–Gastaut syndrome experience multiple seizure types that are difficult to manage and have many of the same symptoms as other rare pediatric epilepsies. Studies estimate that Lennox–Gastaut syndrome affects approximately 14,500 to 18,500 children under the age of 18 and over 30,000 children and adults in the United States. It is also estimated that between 1 percent and 4 percent of childhood epilepsies are a result of Lennox–Gastaut syndrome. Only 10 percent of these patients have seizures that are fully controlled by existing therapies.
About Tuberous Sclerosis Complex
Tuberous Sclerosis Complex is a genetic disorder, often diagnosed in childhood, that causes non-malignant tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. The brain and skin are the most affected organs. Tuberous Sclerosis Complex results from a mutation in tumor suppression genes TSC1 or TSC2. Tuberous Sclerosis Complex is estimated to affect approximately 50,000 patients in the United States and occurs in 1 of 6,000 live births. The most common symptom of Tuberous Sclerosis Complex is epilepsy, which occurs in 60 to 90 percent of patients, of which 70 percent experience seizure onset in their first year of life. Despite available therapies, a significant number of Tuberous Sclerosis Complex patients have treatment-resistant seizures. Tuberous Sclerosis Complex is commonly associated with cognitive impairment in 50 percent of patients, autism spectrum disorders in up to 40 percent and neurobehavioral disorders in over 60 percent of patients.
Targeting Tonic Inhibition through OV101
Angelman syndrome and Fragile X syndrome are both rare neurogenetic conditions associated with developmental delays, physical characteristics and behavioral challenges.
It is believed that the symptoms of Angelman syndrome and Fragile X syndrome are a result of disrupted tonic inhibition.
What is Tonic Inhibition?
Tonic inhibition is what allows a healthy human brain to decipher signals correctly without being overloaded. A human brain is being constantly inundated with sensory information – sights, smells, sounds and touch – and tonic inhibition is what allows the brain to filter out the “white noise” and focus on the important information. If tonic inhibition is reduced, the brain becomes inundated with signals and loses the ability to separate background noise from critical information.
Tonic inhibition is key to the brain's ability to discriminate signal from noise.
GABA is a Key Player in Tonic Inhibition
The brain is composed of a vast network of interconnected neurons that facilitate the communication between cells. These communications are governed by the release of chemical signals, or neurotransmitters, across the synaptic gap (the physical gap separating two neurons). Neurotransmitters can create an excitatory signal – which carry messages that tell us how to move and speak – and inhibitory signals – which regulate how well, or not, we’re able to receive those signals. GABA is the primary inhibitory neurotransmitter in the human brain.
GABA signaling is involved in critical functions, like motor control, sleep, behavior and cognition. Under normal conditions, there is sufficient GABA present to stimulate synaptic and extrasynpatic (outside the synaptic gap) GABAA receptors. But in Angelman syndrome and Fragile X syndrome, the overall levels of GABA are reduced. This can lead to a situation in which there is not enough or insufficient GABA outside the synapse to stimulate the extrasynaptic receptors and maintain longer-term, or tonic, signaling. The decline in tonic inhibition triggered by the shortage of GABA leads to the chronic activation of the neurons receiving the signal and disruption of normal brain network activity.
In Angelman syndrome, there is a ubiquitin-protein ligase E3A (UBE3A) genetic defect that disrupts the cell’s normal maintenance function of tagging proteins for degradation. As a result, the GABA transport 1 (GAT1) protein is not tagged for degradation. The GAT1 protein is responsible for the reabsorption of GABA from the synaptic terminal into the presynaptic neuron. When not tagged for degradation, reabsorption of GABA into the presynaptic neuron continues, and GABA levels decrease in the synaptic terminal. This then leads to a loss of tonic inhibition.
In Fragile X syndrome, the fragile x mental retardation 1 (FMR1) genetic defect leads to a reduction of expression of the glutamate decarboxylase 65/67 (GAD 65/67) enzyme. This enzyme is responsible for the synthesis of GABA. In this syndrome, there is a reduced level of production of GABA within the presynaptic neuron. Hence, it is thought that there is a lower level of GABA available for release into the synaptic terminal which leads to a loss of tonic inhibition.
We believe our lead program, OV101 (gaboxadol), is the only clinically tested δ-selective direct-acting GABAA receptor agonist. This means it is able to bind to and activate this specific δ-subset of GABA receptors, which are found in the extrasynaptic space outside of the synapse. There are many types of GABA receptors in the brain, which help regulate neuronal activity, but tonic inhibition is specifically a function of the δ-subunit containing GABAA receptors.
The relationship between neural signaling and Angelman syndrome and Fragile X syndrome.
Ovid’s programs in rare epilepsy are focused on developing potential therapies for people living with epileptic encephalopathies. The term epileptic encephalopathy describes a group of epilepsy syndromes associated with severe cognitive and behavioral disturbances. These disorders vary in their age of onset, developmental outcome, etiologies, neuropsychological deficits, electroencephalographic (EEG) patterns, seizure types, and prognosis. These disorders typically present early in life and are often associated with severe cognitive and developmental impairment in addition to frequent seizures throughout the person’s lifetime.
OV101 (gaboxadol) is clinically tested δ-selective direct-acting GABAA receptor agonist. It is able to bind to and activate this specific δ-subset of GABA receptors, which are found in the extrasynaptic space outside of the synapse. There are many types of GABA receptors in the brain, which help regulate neuronal activity, but tonic inhibition is specifically a function of the δ-subunit containing GABAA receptors.
In Angelman syndrome and Fragile X syndrome, tonic inhibition is diminished; with OV101, we aim to restore that function. By signaling through the δ-selective GABAA receptor, OV101 can potentially make up for the loss of tonic inhibition, which we hope will relieve several of the symptoms of these disorders. In preclinical animal models, OV101 improved symptoms of Angelman syndrome and Fragile X syndrome, such as motor function, sleep and aspects of behavior and cognition.
Gaboxadol was originally being developed for sleep disorders and was acquired by Ovid from H. Lundbeck A/S in 2015.
1 J Neurosci. 2008 Feb 6;28(6):1421-6. doi: 10.1523/JNEUROSCI.4751-07.2008.
Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? Glykys J1, Mann EO, Mody I.
OV935 is a Phase 1 clinical stage compound that is part of the global collaboration between Ovid Therapeutics and Takeda and is being studied as a potential therapeutic option for people with various rare epileptic encephalopathies.
OV935, if approved, has the potential to become a first-in-class inhibitor of the enzyme cholesterol 24 hydroxylase (CH24H). CH24H is predominantly expressed in the brain where it has a central role in clearing cholesterol. CH24H converts cholesterol into a molecule called 24-hyroxycholesterol (24HC), which allows it to pass across the blood brain barrier, enter the circulatory system and be cleared from the body. As CH24H is predominantly expressed in the brain, there is a strong correlation between circulating blood levels of 24HC and brain levels of 24HC. The levels of 24HC in the blood may therefore serve as an indicator of CH24H activity in the brain, providing an important potential biomarker for OV935 development.
24HC has been demonstrated to impact key signaling pathways in the brain including glutamatergic signaling, or signaling by the neurotransmitter glutamate. Elevated levels of 24HC have been shown in various cellular and tissue models to lead to increased activation of the glutamate signaling pathway through one subtype of glutamate receptor called N-Methyl-D-Aspartate (NMDA). Activation of NMDA receptors has been implicated in a number of neurological disorders, including epilepsy, and is proposed to contribute to increased excitatory signaling in the brain. We believe that decreasing 24HC levels (through inhibiting CH24H with OV935) represents a plausible approach to addressing the underlying biology of epilepsy.
In preclinical models, OV935 has shown anti-seizure activity in genetic, pharmacologic and inflammation-induced seizure models. OV935 has been investigated across four Phase 1 clinical trials involving 86 healthy volunteers. Overall, OV935 appeared to be well tolerated in these clinical trials. Phase 1b/2a clinical trials of OV935 are anticipated to begin in 2017.
In working with foundations focused on Angelman syndrome, we have designed a double-blind, placebo-controlled, randomized Phase 2 clinical trial, named STARS, looking at safety parameters and exploratory efficacy endpoints in adults with Angelman syndrome. We are currently enrolling patients.
We called on the Angelman syndrome community to help us design the clinical trial, including identifying the trial endpoints. They also selected the final STARS clinical trial name and logo. The STARS logo was designed by Kaline, a proud parent of a child diagnosed with Angelman syndrome. The image “reaching for the STARS” is a depiction of her son, and every other person diagnosed with Angelman syndrome, standing with one foot firmly planted while using the “T” to stretch as far as they can to reach the brightest star in the sky.
Phase 1 Adolescent Pharmacokinetic (PK) Trial
In addition to the Phase 2 STARS trial, we are currently enrolling a Phase 1 trial in adolescents with Angelman syndrome and Fragile X syndrome. The primary goal of this trial is to identify doses for use in younger patients with these disorders as well as to assess safety and tolerability.
It is proposed that decreased tonic inhibition underlies many of the behavioral changes characteristic of Angelman syndrome and Fragile X syndrome. We believe that OV101 may provide an opportunity to provide a meaningful impact to patients with both these disorders.
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