Ovid Therapeutics 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 disorder 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
KINASE-LIKE 5 DEFICIENCY
About Angelman Syndrome
Angelman syndrome is a rare genetic disorder characterized by problems with movement and balance, delayed development, intellectual disability, severe speech impairment, seizures, sleep disorders and anxiety. The estimated prevalence of Angelman syndrome is 1 in 15,000 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.
About Lennox-Gastaut Syndrome
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.
About CDKL5 Deficiency Disorder
Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder, also known as CDD, is an ultra-rare, severe, neurological disorder caused by mutations in the CDKL5 gene on the X-chromosome. The CDKL5 gene provides instructions for making a protein that is essential for normal brain and neuron development, and may play a role in regulating the activity of other genes, including the MECP2 gene of Rett Syndrome. The true prevalence of CDD is unknown, however the number of CDD patients continues to grow as genetic testing for the disorder becomes more common. Of those diagnosed with CDKL5 deficiency disorder, 90 percent are females, however affected males tend to have more severe developmental disabilities. Symptoms of CDKL5 deficiency disorder include early onset and treatment resistant epilepsy, severe development delay and intellectual disability. Other common features of CDKL5 deficiency include poor fine motor skills, difficulty sleeping, scoliosis, visual impairment, microcephaly and various gastrointestinal difficulties.
About Dup15q Syndrome
Duplication 15q syndrome (Dup15q syndrome) is a rare, severe, neurological disorder that results from duplications of chromosome 15q11.2-q13.1. In most cases, the chromosome mutation is not inherited but occurs during formation of reproductive cells or during embryonic development. Those with Dup15q syndrome experience symptoms such as seizures, cognitive delays, hypotonia (poor muscle tone), and difficulty with motor skills, speech, and sensory processing. The severity of the condition and associated symptoms varies based on the size and location of the duplication and which genes are involved.
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.
Rare Epilepsy – Epileptic Encephalopathies
Inhibiting the enzyme CH24H with OV935 as a potential approach to epileptic encephalopathies
The term epileptic encephalopathy describes a group of epilepsy syndromes which typically present early in life and are associated with severe cognitive and behavioral disturbances. These disorders vary in their developmental outcome, cause of onset, neuropsychological findings, electroencephalographic (EEG) patterns, seizure types, and overall prognosis.
Ovid Therapeutics believes that decreasing 24-hydroxycholesterol (24HC) levels (through inhibiting cholesterol 24 hydroxylase (CH24H) with OV935) represents a plausible approach to addressing the underlying biology of epilepsy.
Understanding CH24H and 24HC
The enzyme CH24H is predominantly expressed in the brain where it has a central role in clearing cholesterol. CH24H converts cholesterol into a molecule called 24HC, which allows it to pass across the blood brain barrier, enter the circulatory system and be cleared from the body (Healthy Brain Function). As CH24H is predominantly expressed in the brain, there is a strong correlation between circulating blood levels of 24HC and brain levels of 24HC.
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.
Excessive extracellular glutamate and 24HC levels are thought to play roles in epilepsy. Glutamate can over activate the NMDA receptors and potentially cause symptoms associated with epilepsy. As the CH24H enzyme converts cholesterol to 24HC, the circulating levels of 24HC increase, and data suggests that it may further contribute to underlying disease processes.
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. In a Phase 1 clinical trial, OV101 was shown to be well tolerated in both adults and adolescents with Angelman syndrome and Fragile X syndrome. The Phase 2 STARS clinical trial in adults and adolescents met its primary endpoint of safety and tolerability and also showed a statistically significant improvement compared to placebo in the physician-rated clinical global impression of improvement (CGI-I) – an important measure that captures the constellation of clinical symptoms of Angelman syndrome. CGI-I was ranked first in the topline statistical plan. Subsequent topline analyses were conducted on a prespecified subset of scales across the domains of behavior, sleep and gait. While the analysis of these pre-specified subsets did not show a statistically significant difference from placebo, full data analyses on these domains are ongoing and will be communicated in the future.
Gaboxadol was originally being developed for sleep disorders and was acquired by Ovid Therapeutics 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.
Ovid Therapeutics and Takeda have joined in a global collaboration to develop OV935 for clinical development 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 CH24H. Preclinical studies with OV935 have shown anti-seizure efficacy in models relevant to the rare epileptic encephalopathies (EE) which are inadequately treated by current anti-epileptic medications (Treatment of Epilepsy with OV935).
We believe that OV935 will potentially address the underlying biology of epilepsy by decreasing 24HC levels by inhibiting CH24H.
OV101 Clinical Trials
Phase 2 STARS Trial
Working with foundations focused on Angelman syndrome, we designed the Phase 2 STARS study, the first industry-sponsored, international, randomized, double-blind, placebo-controlled clinical trial in adults and adolescents with Angelman syndrome. STARS investigated safety parameters as well as exploratory efficacy endpoints. In October 2018, Ovid announced comprehensive data from the STARS trial at the American Academy of Child & Adolescent Psychiatry’s 65th Annual Meeting. The trial met its primary endpoints of safety and tolerability and also showed a statistically significant improvement compared to placebo in the clinician-rated Clinical Global Impression of Improvement (CGI-I) – a common measure that allows the clinician to capture a constellation of clinical symptoms.
Planned Phase 3 NEPTUNE Trial
Based upon review and discussion with the U.S. FDA on the Phase 2 STARS trial results, the pivotal trial design, and the applicability of CGI-I as a primary endpoint, Ovid announced in December 2018 plans to move into the Phase 3 NEPTUNE trial, a randomized, double-blind, placebo-controlled, 12-week trial of OV101 in pediatric patients with Angelman syndrome. The trial is expected to enroll approximately 50 to 60 patients aged 4 to 12 years old. Enrollment for is expected to begin in the second half of 2019, pending FDA concurrence on the study protocol and supporting materials.
Ovid Therapeutics has also initiated trial activities for the ELARA trial, an open-label extension study for individuals with Angelman syndrome who have completed any prior OV101 study. ELARA will use once-daily dosing and will assess long term safety and tolerability in addition to efficacy measures.
Learn more about Angelman syndrome
Phase 2 ROCKET Trial
The Phase 2 ROCKET trial is a three-arm, double-blind, clinical trial designed to evaluate the safety and tolerability of OV101 in adolescent and young adult males, aged 13 to 22, who have been diagnosed with Fragile X syndrome. In addition to safety, the study will also assess changes in behavior during 12 weeks of treatment with OV101. Ovid Therapeutics is currently enrolling patients in the ROCKET trial.
Ovid Therapeutics also initiated SKY ROCKET, a non-drug study to assess the suitability of scales for the measurement of behavior, sleep and functioning in individuals with Fragile X syndrome. This trial is designed to provide additional data on the key endpoints that are being explored in ROCKET and provide comparative data on the benefit offered by the standard of care. The study will enroll 30 males ages 5 to 30 with Fragile X syndrome.
OV935 Clinical Trials
Phase 1b/2a Trial in Rare Epilepsies
OV935 is currently in development for the treatment of certain types of rare epilepsies. The Phase 1b/2a randomized, double-blind, clinical trial was designed to characterize the safety profile of OV935, measure 24HC plasma levels and determine changes in seizure frequency in adult patients with rare developmental and epileptic encephalopathies (DEE). DEE is a term for a specific group of rare epilepsy conditions that typically present early in life and are often associated with severe cognitive and developmental impairment in addition to frequent treatment-resistant seizures.
In December 2018, Ovid announced the trial met its primary endpoint of safety and tolerability and that signals of efficacy were observed in an exploratory analysis. Detailed findings from the trial are expected to be reported at an upcoming medical conference.
Phase 2 ARCADE Trial
The Phase 2 ARCADE trial is a multi-center, open-label, pilot study designed to evaluate OV935 in patients, aged 2 to 17 years old with CDKL5 deficiency disorder or Dup15q syndrome. This study is designed to assess the frequency of motor seizures in patients treated with OV935, as well as the safety, tolerability and PK of OV935. Ovid Therapeutics intends to enroll approximately 15 children with each condition. Ovid Therapeutics is now enrolling patients.
Phase 2 ELEKTRA Trial
The ELEKTRA trial is a Phase 2, international, multi-center, randomized, double-blind, placebo controlled, parallel-designed study designed to investigate OV935 in patients aged 2 to 17 years old with Dravet syndrome or Lennox-Gastaut syndrome. The study will evaluate the frequency of seizures in patients treated with OV935 compared to placebo, as well as the safety, tolerability and PK of OV935. Approximately 125 patients will be randomized to receive either OV935 or placebo. Ovid Therapeutics is now enrolling patients.
Open to all patients who have participated in a previous OV935 clinical trial, the ENDYMION trial is an open-label, extension study which will assess long term-safety and tolerability of OV935 in patients with rare epilepsies over a course of two years. The study will also evaluate the effect of OV935 on seizure frequency during the same time period. ENDYMION started to enroll patients in the third quarter of 2018.
Expanded Access Program (EAP)
The Ovid team is driven by the passion to improve the lives of patients and caregivers by working to develop new medicines for people living with rare and serious illnesses. As a company, we want to bring our medicines to the largest numbers of people who may potentially benefit from them. At the same time, we have a duty to balance this desire while ensuring that our investigational drugs are both safe and effective before making them available outside of the controlled setting of a clinical trial.
We understand that individuals with Angelman syndrome do not have many options to address their medical needs. Investigational clinical trials are the fastest path to bring forward a potential treatment for Angelman syndrome. Because our goal is to help as many patients as possible, as quickly as possible, access to the investigational therapy outside of a clinical trial must not adversely impact or delay the clinical trials involving the investigational therapy.
At times a health care provider may seek access to an unapproved drug candidate for a patient with a life threatening or serious disease who has exhausted all medical options. This use of a drug candidate outside of the context of a clinical trial is called expanded access, among other names. Currently, Ovid is evaluating the potential for an expanded access program for OV101 and will work with regulators to determine the best path forward.
The following is additional information regarding Ovid’s expanded access policy in accordance with the 21st Century Cures Act:
- Contact Information. If you have any questions regarding Ovid’s expanded access policy in general, please contact email@example.com. If you have any questions regarding potential participation in Ovid’s clinical trials, please contact us by email at firstname.lastname@example.org.
- General Criteria. If Ovid opens an expanded access program, we will update this policy and provide appropriate details.
- Response Timing. If you contact Ovid as described above, we anticipate that we will acknowledge receipt within five business days.
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