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.
At Ovid, we are using emerging science to unlock the potential of small molecule compounds and genetic approaches to make medicines that will meaningfully improve the lives of people with rare neurological conditions.
OV350 and KCC2 portfolio: Potential first-in-class direct activators of the KCC2 transporter for epilepsies
Ovid’s KCC2 program is a portfolio of potential first-in-class direct activators of the KCC2 transporter. Ovid believes these activators may have therapeutic application in rare and common epilepsies, as well as other neuropathologies.
Ovid exclusively in-licensed the KCC2 portfolio from AstraZeneca in 2022.
The portfolio has the potential to reap multiple therapeutic development programs, including the current lead program, OV350. Studies indicate that OV350 works by binding with high affinity to KCC2 (potassium chloride cotransporter isoform 2) and increases its activity, reducing neuronal chloride accumulation and limiting the development of hyperexcitability. In animal models, OV350 restored the efficacy of benzodiazepines to treat refractory epilepsies and limit associated brain injuries.
LICENSED TO TAKEDA: Soticlestat for rare epilepsies
assessing an individual’s global functioning
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.
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 by our partner Takeda.
The role of glutamate in rare epilepsies
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 Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).1
Ovid Therapeutics designed and conducted a robust clinical program for individuals with developmental and epileptic encephalopathies (DEE). A Phase 1b/2a study was completed and positive results were released. Additionally, Ovid completed two Phase 2 studies with soticlestat:
The Phase 2 ARCADE study in individuals with CDKL5 deficiency disorder or Dup15q syndrome is complete and positive results have been reported.
The Phase 2 ELEKTRA study in individuals with Lennox-Gastaut syndrome or Dravet syndrome has been completed and positive topline results have been reported.
Further development and research of soticlestat will be led by our partner Takeda, including Phase 3 studies in children and adults with Dravet syndrome and Lennox-Gastaut syndrome. Additionally, the ongoing open-label ENDYMION extension study will continue under direction from our partner Takeda.
References: 1. Barker-Haliski M and White HS. Glutamatergic mechanisms associated with seizures and epilepsy. Cold Spring Harb Perspect Med. 2015; 5(8): a022863. 2. Nishi T et al. Poster presented at: SfN 2018. 3. Hasegawa S et al. Poster presented at: SfN 2018. 4. Nishi T et al. Poster presented at: AES 2017. Abstract 2.260. 5. Hawkins NA et al. Oral presentation at: AES 2018. Abstract1.286.
OV329, a next-generation GABA-aminotransferase inhibitor for potential treatment of rare and treatment-resistant forms of epilepsy and seizures
About Tuberous Sclerosis Complex and Infantile Spasms
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
OV329 is a next-generation GABA-aminotransferase (GABA-AT) inhibitor being developed for the potential treatment of rare and treatment-resistant forms of epilepsy and seizures, such as seizures associated with tuberous sclerosis complex, infantile spasms, and conditions with focal onset seizures. Low levels of GABA, the primary inhibitory neurotransmitter in the brain, have been linked to neuronal hyperexcitability. OV329 is believed to work by reducing the activity of GABA-AT, thereby increasing levels of GABA in the brain, and potentially suppressing neuronal hyperexcitability known to cause seizures. OV329 may be a potential best-in-class GABA-AT inhibitor that could offer: enhanced efficacy, an improved safety profile and more optimal dosing.
OV329 is currently enrolling healthy volunteers in a Phase 1 study to evaluate the safety and target engagement associate with single and repeated doses of OV329.
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.
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.
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.
Learn more about our shRNA candidate with University of Connecticut
OV815 for KIF1A Associated Neurological Disorder (KAND)
About KIF1A Associated Neurological Disorder (KAND)
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.
References: 1. KIF1A Foundation. KIF1A Associated Neurological Disorder. Accessed February 16, 2021. https://www.kif1a.org/kif1a-gene/kif1a-associated-neurological-disorder
2. Boyle L, Rao L, Kaur S, et al. Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A Associated Neurological Disorder. Hum Genet Genomics Adv. Published online January 2021:100026. doi:10.1016/j.xhgg.2021.100026
OV825 for HNRNPH2 (Bain Syndrome)
HNRNPH2, also known as Bain Syndrome, was first described in 2016. HNRNPH2 is an X linked gene, and most affected individuals are females. Heterozygous females with de novo mutations have delayed psychomotor development, intellectual disability, severe language impairment, seizures, behavioral abnormalities, acquired microcephaly, and feeding problems with poor overall growth. HNRNPH2 protein mis-localizes to the cytoplasm in cells from affected individuals.
HNRNPH2 encodes a member of the heterogeneous nuclear ribonucleoprotein. Proteins in the HNRNP family normally localize to the nucleus and shuttle pre-mRNA transcripts between the nucleus and cytoplasm for processing and transport.
Dravet syndrome (DS)
Lennox-Gastaut syndrome (LGS)
Primarily genetic mutation: 80% have mutation in Scn1a gene
Multiple: includes genetic mutations, fetal/infant injury before/after birth
Age of onset:
2 to 5 years old
• 1 in 11,000
• More common in males
• Multiple types of seizures, including drop
• Intellectual disabilities (with psychiatric comorbidities)
Calling all bold researchers!
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 firstname.lastname@example.org.