OV4071 & KCC2 Portfolio
KCC2 portfolio overview
Ovid’s potassium-chloride cotransporter 2 (KCC2) portfolio is designed to build a first-in-class franchise targeting restoration of excitatory/inhibitory balance in the brain, which may offer therapeutic benefit across multiple neurological and neuropsychiatric disorders. The portfolio of direct KCC2 activators includes an intravenous (IV) tool program (OV350) that supports the advancement of Ovid’s pipeline of optimized direct oral KCC2 activators led by OV4071.
KCC2 is a “master switch” for neurological disorders where hyperexcitability is core to pathophysiology
KCC2 is a neuron-specific chloride transporter that maintains inhibitory balance in the brain. The cotransporter plays a central role in regulating neuronal excitability by enabling gamma-aminobutyric acid (GABA) to exert its inhibitory effect. Direct activation of KCC2 is intrinsically self-limiting, supporting potential chronic use.
By restoring KCC2 function, it may be possible to reset a fundamental control point in brain circuitry, turning down pathologic hyperexcitability at its source rather than treating symptoms in isolation. This mechanism-based approach has the potential to unlock new treatments across a spectrum of neurodegenerative, neurodevelopment and psychiatric disorders in which disrupted inhibitory/excitatory balance is a shared driver of disease.
Direct activation of KCC2 matters
KCC2 is a fulcrum for rebalancing inhibitory/excitatory signaling across many diseases of the brain. Direct activation of KCC2 represents a novel, differentiated, mechanism-based approach to treating serious neurological and neuropsychiatric conditions in which neuronal hyperexcitability is central to disease and symptom manifestation. Ovid’s molecules are designed to bind directly to the KCC2 transporter and modulate its function independently of upstream signaling cascade. This direct mechanism enables dose-controlled, rapid and predictable pharmacodynamics, with the goal of avoiding tolerability and safety limitations seen with broader potassium–chloride transporter modulators.
Advancing a first-in-class portfolio of oral KCC2 direct activators
OV4071 is the lead oral direct activator in the KCC2 portfolio. Ovid plans to advance OV4071 into a Phase 1/1b safety and proof‑of‑concept clinical study for the treatment of psychosis associated with Parkinson’s disease and Lewy body dementia. These conditions have high unmet need, validated endpoints, an established regulatory pathway, and traditional atypical antipsychotics are typically contraindicated.
The advancement of OV4071 is supported by OV350, the first-in-human KCC2 direct activator, which served as a clinical tool program that provided important human safety validation of KCC2 as a druggable target. In a randomized, placebo‑controlled, Phase 1 study in healthy volunteers, OV350 IV met its primary safety, tolerability and pharmacokinetic objective, reinforcing the potential for further clinical development of KCC2 direct activators, including OV4071, which performs with twenty-fold greater potency than OV350 in pharmacodynamic models.
Additionally, Ovid is planning to characterize the pharmacodynamic effects of OV4071 and relevant mechanisms in additional neuropsychiatric conditions, such as schizophrenia and psychoses or agitation associated with other neurodegenerative conditions including Alzheimer’s disease. In parallel, Ovid is advancing a proprietary library of next‑generation KCC2 activators optimized for both oral and injectable use and designed to expand the KCC2 platform across a broad spectrum of neurological, neurodevelopmental and psychiatric conditions driven by neuronal hyperexcitability.
Ovid hosted a KCC2 Download Day in November 2024. For information about the session, please click here.