From clinical potential to meaningful therapies—Ovid Therapeutics is developing lifechanging therapies based on our deep understanding of key biological pathways and their central role in rare neurological diseases. We seek to develop medicines using novel and clinically relevant endpoints, to capture the real-world ways patients benefit from addressing underlying disorder pathology.
Angelman syndrome (AS) is a genetic disorder in which the still-developing brains of young children are overloaded with excitatory neuronal signals, leading to a range of severe neurological symptoms affecting behavior, sleep, learning, motor skills and communication, and which are present throughout life. Many individuals with AS also suffer from epilepsy. The key deficits are in:
• Behavior: Heightened hyperactivity and anxiety leading to maladaptive behaviors such as biting and pinching.
• Sleep: Increased nighttime awakenings and diminished total sleep time.
• Learning: Impaired cognitive performance and memory loss.
• Motor: Uncoordinated movements, tremors and an abnormal gait which limits mobility and independence walking.
• Communication: Significantly delayed development with little or no verbal speech, often leading to frustration and aggression.
• Epilepsy: Individuals with epilepsy most frequently experience atypical absences, generalized tonic-clonic, atonic or myoclonic seizures.
AS was first described in 1965—yet in more than 60 years not a single treatment option has been approved. There is an urgent need for effective, disease management treatment options. The neurological dysregulation in AS results in significant impairments that can be as difficult for individuals with AS to manage as it is for their caregivers to continuously manage:
• Living with AS: Individuals with AS require around-the-clock care and are unlikely to ever live independently
• Caring for individuals with AS: Caregivers constantly supervise their loved one with AS, often experiencing their own stress, anxiety and exhaustion in co-managing symptoms.
OV101 (gaboxadol) is a delta (δ)-selective GABAA receptor agonist. These receptors are thought to have a central role in tonic inhibition, a key physiological process of the brain believed to be a core pathophysiology underlying certain neurodevelopmental disorders.
Angelman syndrome (AS) occurs when a mutated gene, UBE3A, creates a nonfunctional protein of the same name. Without functional UBE3A proteins, the levels of GABA, one of the most important neurotransmitters in the brain, are lower than normal in the extrasynaptic space, which is a key area surrounding the space between nerves and where each nerve passes signals from one to the other. The absence of GABA in this area greatly reduces tonic inhibition, a critical process in neurons (brain cells) across the brain. Tonic inhibition is crucial as it modulates the ability of cells in the brain to distinguish a real signal from noise, and deficits in GABA levels or functioning has been associated with the symptoms of Angelman syndrome.1
While the ongoing open-label ELARA Study in Angelman syndrome will continue, Ovid Therapeutics will pause any additional clinical development of OV101 in Angelman syndrome pending a full review of the clinical trial data and discussions with regulators and investigators.
Fragile X syndrome (FXS) is an inherited disorder characterized by an overload of excitatory signals in the brain, leading to significant intellectual impairments that can be difficult to manage for both individuals and caregivers. The key disturbances are:
⦁ Behavior: Hyperactivity, anxiety and increased sensitivity to auditory stimuli
⦁ Sleep: Disrupted sleep patterns
⦁ Learning: Cognitive dysfunction
⦁ Motor: Reduced fine motor skills
⦁ Communication: Delayed speech development and impaired use of language (exacerbated by concomitant autism)
There is a significant unmet medical need as there are no approved therapies that treat the underlying cause of the condition. Current treatment options are limited to physical, behavior, communication, and symptomatic therapy—as such a large, multidisciplinary team is needed to care for individuals with FXS, including specialists in psychiatry, psychology, neurology and genetic counseling.
In certain cases, due to the severity of the condition, caregivers provide extensive support to their loved ones with FXS even for basic daily activities like feeding and bathing.
OV101 (gaboxadol) is a first-in-class, oral, highly selective extrasynaptic GABAA receptor (GABAAR) agonist. It passes the blood-brain barrier and binds tightly to the unique extrasynaptic GABAA receptors on neurons throughout the brain, restoring the levels of tonic inhibition that exist when intrinsic GABAA levels are low.
Fragile X syndrome is caused when the presence of a mutation on the FMR1 gene (located on the X chromosome) disrupts signaling pathways in nerve cells across the brain. This signaling shutdown causes the production of GABA, one of the most important neurotransmitters in the brain, to be reduced and plummet in key areas surrounding the space between nerves and where nerves pass signals from one to the other. The absence of GABA in this area greatly reduces a critical process in each cell and across all the brain, called tonic inhibition. Tonic inhibition is crucial as it modulates the ability of cells in the brain to distinguish a real signal from noise—and its absence can lead to the severe symptoms of Fragile X syndrome.1
OV101 is the only drug of its kind in clinical development for Fragile X syndrome and could potentially be the first to make a meaningful change for individuals with Fragile X syndrome and their families by addressing the severe symptoms of the condition.2
The Phase 2 study of OV101, known as the ROCKET study, has been completed and positive topline results have been released. OV101 met the study’s primary objective of safety and tolerability and produced statistically significant reductions in behavioral and functional symptoms in individuals with Fragile X syndrome. See press release >>
We go the extra mile to achieve and measure meaningful clinical results. While most individuals with Angelman syndrome have the same genetic mutation of the UB3A gene, the severity and range of symptoms across Angelman syndrome are unique to each individual. This variety and the heterogeneous manner in which symptoms express themselves in those with Angelman syndrome means in order to assess clinically meaningful effects of a medicine in individuals with Angelman syndrome, the measure needs to be tailored more to the individual, not patient populations—as is often the case in other diseases.
After careful evaluation of all available clinical tools, our independent clinical experts selected the well-established Clinical Global Impression (CGI) scales to objectively measure an individual with Angelman syndrome’s level of functioning at baseline before they are given OV101 (gaboxadol) and thereafter again to assess change during treatment. We have optimized the CGI scales for our Phase 3 NEPTUNE study to utilize clinical anchors specific to Angelman syndrome in order to reflect a range of development and symptomology that is specific to Angelman syndrome:
• Before treatment the physician assesses the CGI Severity Scale for Angelman syndrome (CGI-S-AS): Provides the baseline level of severity for each individual with Angelman syndrome based on that particular individual’s symptoms and measured before the person enters the treatment (or placebo) section of the clinical study.
• During treatment the physician assesses the CGI Improvement Scale for Angelman syndrome (CGI-I-AS): Measures the change in that individual’s symptoms after the participant starts treatment, relative to their baseline.
These scales help us track changes that are relevant to each individual patient and give us a measure of how the individual has improved overall.
OV935 (soticlestat) is a first-in-class oral compound that reduces brain 24-hydroxycholesterol levels by inhibiting an enzyme called cholesterol-24-hydroxylase. This candidate is being developed under a partnership with Takeda.
The human brain holds about 25% of the body’s cholesterol. It is constantly being metabolized and refreshed. One of the key enzymes that metabolizes this cholesterol is an enzyme found only in the brain, called cholesterol 24-hydroxylase (CH24H). CH24H metabolizes cholesterol to produce 24S hydroxycholesterol (24HC), a very active neurosteroid. This compound is a modulator of the NMDA receptor important in epilepsy. Too much 24HC can lead to abnormal cellular signaling mediated by a certain neurotransmitter, glutamate, in the brain. Excessive glutamate can potentially lead to the seizures experienced by individuals with developmental and epileptic encephalopathies (DEE), including CDKL5 deficiency disorder (CDD), chromosome 15q duplication syndrome (Dup15q), Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).1
OV935 restores appropriate modulation of glutamate neurotransmission, increases the health of the central nervous system (CNS), and reduces inflammation in preclinical models.2-5 For individuals with DEE, we believe OV935 has the potential to reduce seizure susceptibility and improve seizure control and may provide benefit where other mechanisms of conventional anti-epileptic drugs have not.
Ovid Therapeutics has designed a robust clinical program for individuals with developmental and epileptic encephalopathies (DEE). A Phase 1b/2a study has been completed and positive results have been released. Additionally, Ovid has recently completed two Phase 2 studies with OV935:
Interim results from the open-label ENDYMION extension study were also recently announced. The study is currently active and enrolling individuals who have successfully completed either the Phase 2 ARCADE or the Phase 2 ELEKTRA studies.
Tuberous sclerosis complex (TSC) is a genetic disease that can be inherited from one parent with TSC or can result from a spontaneous genetic mutation.
TSC can cause tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin, and lungs. The aspects of TSC that most strongly impact quality of life are generally associated with the brain: seizures, developmental delay, intellectual disability, and autism spectrum disorder.
One of the earliest forms of epilepsy that can occur in those diagnosed with TSC is infantile spasms. Infantile spasms can begin anytime in the first 2 years, but often peak between 4 and 6 months of age. They occur in 1 in 2,000 children from many different causes and in up to 35% of children with TSC.1
Reference: 1. Tuberous Sclerosis Alliance. Accessed February 18, 2021. https://www.tsalliance.org
OV329 (GABA aminotransferase inhibitor) is a preclinical compound being developed by Ovid Therapeutics for the treatment of seizures associated with Tuberous Sclerosis Complex and Infantile Spasms. OV329 functions by substantially reducing the activity of GABA aminotransferase (GABA-AT), a key enzyme responsible for the degradation of the brain’s major inhibitory neurotransmitter, GABA. By inhibiting the metabolism of GABA, OV329 leads to increased concentrations of GABA. Given that epilepsy is characterized by excessive neuronal excitation, the increased levels of GABA may suppress this excitatory signaling and may reduce seizures. We anticipate that if successful, OV329 could be used to treat seizures associated with Tuberous Sclerosis Complex and Infantile Spasms, and we are currently assessing this approach in the pre-clinical setting.
More about Tuberous Sclerosis Complex and Infantile Spasms »
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder where affected individuals experience neurodevelopmental delay and life-long neurological symptoms affecting behavior, sleep, learning, motor skills, and communication. Many individuals with AS also have seizures.
More about Angelman syndrome »
The genetic cause of AS is the loss of functional UBE3A protein in neurons due to a mutation in the maternal copy of the UBE3A gene coupled with the normal physiologic silencing of the paternal copy. This silencing of the paternal copy, unique to neurons, is mediated by a non-coding RNA sequence whose expression blocks transcription of the paternal UBE3A gene.
Boldly committed to the AS community, Ovid Therapeutics is developing interfering RNA (RNAi) therapeutics that interact with the non-coding RNA to inhibit the silencing of the paternal UBE3A gene. This research approach aims to activate the paternal copy of the UBE3A gene and lead to the production of UBE3A protein, potentially ameliorating many of the neurodevelopmental deficits associated with AS.
OV882, a short hairpin RNA (shRNA-551), is being developed as a potential disease-modifying gene therapy for Angelman syndrome by Ovid in collaboration with the University of Connecticut School of Medicine.
KIF1A Associated Neurological Disorder (KAND) is a rare and progressive neurodegenerative disorder caused by mutations in the KIF1A gene. Neurological symptoms vary greatly and affect behavior, sleep, learning, motor skills, vision, and communication. Many individuals also suffer from unpredictable seizure activity including continuous spikes and waves (CSWS) during sleep, which can be dangerous and lead to brain damage if not identified and treated. Currently, there are no approved treatment options for people with KAND.
KIF1A Associated Neurological Disorder (KAND) is a rare neurodegenerative disorder with a progressive course. KAND is caused by mutations in the KIF1A gene. The condition can affect both the brain and other areas of the body, such as the eyes, muscles, and nerves. There is a wide range of symptoms, that range in severity, that appear at birth or in early childhood.
Mutations in KIF1A can cause cognitive impairment, cerebellar atrophy, ataxia, spastic paraplegia, optic nerve atrophy, cortical vision impairment, peripheral neuropathy, and epilepsy.1
KIF1A is a motor protein that transports cargo along the microtubules of axons from the cell body toward the nerve terminals that synapse with neighboring neurons. Disruption of this cargo-transport process negatively impacts neurotransmission and leads to progressive neurologic deficits.1
Ovid is working closely with the Columbia University Irving Medical Center and the KAND community to develop treatments for KIF1A-related disorders. We are advancing genetic therapies to target mutations in the motor protein as well as the RNA precursor to reduce or eliminate the impact of the non-functional KIF1A protein to restore normal axonal transport of important cargo within the neuron.
Cause:
Genetic mutation: CDKL5 gene on X chromosome
Age of onset:
Birth to 3 months old
Prevalence:
• 1 in 40,000 to 1 in 60,000
• Mainly affects females
Symptoms:
• Extended, difficult seizures and periods of
repeated seizing
• Atypical EEG pattern (hypsarrhythmia)
• Repetitive hand movements
• Decreased muscle tone (hypotonia
FDA-approved Therapies:
None
Cause:
Genetic mutation: duplication on chromosome 15
Age of onset:
6 months old to 9 years old
Prevalence:
• 1 in 30,000
Symptoms
• Motor skill delays
• Autism spectrum disorder
• Anxiety disorders
• Progressive infantile spasms
• Decreased muscle tone (hypotonia)
FDA-approved Therapies:
None
Cause:
Primarily genetic mutation: 80% have mutation in Scn1a gene
Age of onset:
Birth to 1 year old
Prevalence:
• 1 in 15,000 to 1 in 21,000
Symptoms
• Seizures: prolonged focial progressing to
convulsive tonic-clonic
• Developmental delays
FDA-approved Therapies:
• Anticonvulsants (stripentol)
• Epidiolex® (cannabidiol)
Cause:
Multiple: includes genetic mutations, fetal/infant injury before/after birth
Age of onset:
2 to 5 years old
Prevalence:
• 1 in 11,000
• More common in males
Symptoms
• Multiple types of seizures, including drop
• Intellectual disabilities (with psychiatric comorbidities)
FDA-approved Therapies:
None
At Ovid, we know it takes a committed team to get breakthrough treatments into the hands of those who truly need them. Collaboration is critical in bringing impactful medicines to those who need it most. We seek like-minded potential partners driven to produce clinically impactful work for rare disease individuals and families. If you are a researcher, represent an academic medical center interested in collaborating or are interested in submitting an investigator-initiated trial (ITT), please contact us at clinical@ovidrx.com.
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