Studies Published in Cell Reports Medicine Validate the Potential of Direct KCC2 Activation in Resistant Seizures

  • OV350 is the first reported compound that directly binds to and activates the KCC2 co-transporter, a target implicated in neuronal excitation, including epilepsies
  • Two preclinical seizure models suggest that OV350 mitigates neuronal hyperexcitability by reducing intracellular chloride accumulation
  • OV350 shown to arrest benzodiazepine resistant seizures and limit subsequent neuronal injury in an animal model of status epilepticus

NEW YORK, March 08, 2023 (GLOBE NEWSWIRE) -- Ovid Therapeutics Inc. (NASDAQ: OVID), a biopharmaceutical company developing medicines designed to conquer epilepsies and meaningfully improve the lives of people affected by brain disorders, today announced the publication of multiple preclinical studies of OV350 in Cell Reports Medicine. The preclinical studies indicate that OV350 directly activates the potassium chloride cotransporter isoform 2 target, known as KCC2, and suggest that OV350 confers therapeutic efficacy in resistant epilepsy models and may offer a neuroprotective benefit.

“These findings provide us with increased confidence that our unique program of KCC2 activators directly bind to the target and, as a result, may deliver significant seizure reduction in treatment-resistant epilepsies, such as status epilepticus. We continue to further characterize our KCC2 activator compounds across several modes of delivery and explore them in models of epilepsies and other conditions associated with neuronal excitation,” said Manoj Malhotra, Chief Medical Officer of Ovid Therapeutics.

The paper presents data characterizing the mechanistic target engagement of OV350 and evaluates its potential in several translatable, animal seizure models. Publication of the data was led by Dr. Stephen Moss and a team at the Tufts Laboratory for Basic and Translational Neuroscience Research, as well as a team of researchers at AstraZeneca. Ovid in-licensed AstraZeneca’s portfolio of approximately 100 KCC2 activator compounds from AstraZeneca in January 2022, and continues to work with Dr. Moss related to the development of KCC2 activators and other small molecule antiseizure programs.

Mechanistic Engagement Findings

Several mechanistic studies articulated in Cell Reports Medicine suggest that OV350:

  • Directly binds to the KCC2 co-transporter with high affinity and potentiates KCC2 activity without modifying its plasma membrane accumulation or key regulatory phosphorylation sites.
  • Is brain-penetrant and does not show overt effects on behavior in mice. Following subcutaneous injection, OV350 was detected in the brain at 30 minutes, reached a maximal concentration at 4 hours, and maintained that level at 8 hours. During this time, there were no observable changes in animal behavior, including no sedative effect as commonly seen with many antiseizure medicines.
  • Increases KCC2 activity in neurons and efficiently reduces Cl-accumulation to moderate hyperexcitability.

Potential Anticonvulsant & Neuroprotective Properties

Data published from multiple animal models suggest that OV350, at a consistent studied dose, provided significant anticonvulsant properties. Additionally, when OV350 was prophylactically administered, it appeared to prevent seizures in a mouse model.

Results were reported from two validated pharmacological screening models: the convulsant pentylenetetrazole (PTZ) model and the kainate-resistant status epilepticus model. These findings suggest OV350:

  • Terminated ongoing resistant status epilepticus and restored the efficacy of benzodiazepines. In this model, mice were administered kainate, a convulsant that induces status epilepticus-like seizures, which are typically resistant to benzodiazepines. These seizures are then monitored by electroencephalogram (EEG). Initially, 62% of mice exhibited insensitivity to diazepam, a common benzodiazepine, and continued to experience status epilepticus. When an intravenous dose of OV350 was injected in tandem with diazepam, the resistant status epilepticus was effectively arrested. Levels of OV350 that were sufficient to activate KCC2 remained present in the brain for at least 15 hours.
  • Prevents the development of benzodiazepine resistant status epilepticus. In a separate kainate model, mice that had received pre-treatment of OV350, versus diazepam alone, exhibited delayed onset of the first seizure and spent less time experiencing seizure activity than mice that had received pre-treatment with the comparator vehicle and diazepam. The mice that received OV350 were significantly more responsive to treatment with diazepam, suggesting OV350 may provide a synergistic potentiation.
  • Reduces neuronal cell injury and death following status epilepticus. In kainate-induced seizure models, neuronal cell death across brain regions is commonly observed in animals up to 72 hours post-treatment. However, in mice treated with OV350 at 48 hours post-treatment, no cell mortality was seen. The same animal cohort showed a reduced number of dead brain cells post-mortem.
  • KCC2 activation protects against PTZ-induced motor seizures. In a mouse model, OV350 was shown to freely distribute in the brain and protect against late-stage seizures induced by PTZ.

“These data support the hypothesis that activating the KCC2 co-transporter may have significant implications for mitigating conditions caused by neuronal hyperexcitability, such as seizures and additional neurological conditions. With our colleagues at Ovid, we are excited to explore the independent properties of this portfolio of compounds, as well as their potential ability to restore the therapeutic efficacy of benzodiazepines,” stated Dr. Moss.

Findings from some of the published models were previously presented at the American Epilepsy Society (AES) Annual Meeting in December 2022, and published in Cell Reports Medicine publication in February 2023. Click here to read the scientific paper in its entirety.

About The KCC2 Portfolio & OV350
Ovid is developing a portfolio of potential first-in-class direct activators of the KCC2 (potassium chloride cotransporter isoform 2) transporter. Ovid believes these compounds may have therapeutic application in common and rare epilepsies, as well as other neurological conditions. Ovid seeks to develop multiple programs from the KCC2 portfolio amenable for various modes of administration. The lead compound in the portfolio is an intravenous formulation of OV350 that is being actively characterized in preclinical studies.

About Ovid Therapeutics
Ovid Therapeutics Inc. is a New York-based biopharmaceutical company striving to conquer seizures and brain disorders with courageous science. Ovid’s pipeline of small molecule and genetic medicines candidates seek to meaningfully improve the lives of people and families affected by epilepsies. Ovid is developing OV329, a GABA-aminotransferase inhibitor that is in early clinical development for treatment-resistant seizures, and OV350, a direct activator of the KCC2 transporter, for potential treatment of epilepsies. In addition, Ovid maintains a significant financial interest in the future regulatory development and potential commercialization of soticlestat, which Takeda is responsible for advancing globally. Soticlestat is a cholesterol 24-hydroxylase inhibitor, which is currently in Phase 3 trials for Dravet and Lennox-Gastaut syndromes. For more information about these and other Ovid research programs, please visit www.ovidrx.com.

Forward-Looking Statements
This press release includes certain disclosures that contain “forward-looking statements,” including, without limitation: the potential development and use of OV329, OV350, the portfolio of KCC2 activator compounds, and the status of Takeda’s two pivotal Phase 3 trials evaluating soticlestat for Lennox-Gastaut and Dravet syndromes. You can identify forward-looking statements because they contain words such as "anticipates," "believes," "expected," "intends," "plan," "potentially," and "will," and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances). Forward-looking statements are based on Ovid’s current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, without limitation, uncertainties inherent in the preclinical and clinical development and regulatory approval processes, the risk that Ovid may not be able to realize the intended benefits of its technology. Additional risks that could cause actual results to differ materially from those in the forward-looking statements are set forth under the caption “Risk Factors” in Ovid’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 8, 2022, and in future filings Ovid makes with the SEC. Any forward-looking statements contained in this press release speak only as of the date hereof, and Ovid assumes no obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law.

Contacts
Investors and Media:
Ovid Therapeutics Inc.
Meg Alexander
917-943-6681
malexander@ovidrx.com

OR

Investors:
Argot Partners
Maeve Conneighton
212-596-7231
ovid@argotpartners.com


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