Takeda Pharmaceutical Company Limited (TSE:4502) (“Takeda”) and Ovid Therapeutics Inc. (NASDAQ:OVID) today provided an overview of their TAK-935/OV935 broad clinical development program. The companies plan to initiate three clinical trials: in pediatric patients with Dravet syndrome and Lennox-Gastaut syndrome, in pediatric patients with CDKL5 deficiency disorder (CDD) and Duplication 15q (Dup15q) syndrome, and an extension trial for patients with developmental and epileptic encephalopathies (DEEs) who participated in a previous TAK-935/OV935 clinical study. These trials join the clinical development program that includes a fully enrolled Phase 1b/2a trial of adults with DEE. Together, these trials will further investigate the potential of TAK-935/OV935 to modulate the N-Methyl-D-Aspartate (NMDA) signaling receptor, which has been implicated in several neurologic disorders.
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 throughout the person’s lifetime. These disorders vary in age of onset, developmental outcomes, etiologies, neuropsychological deficits.
“Takeda and Ovid believe that TAK-935/OV935, with its novel mechanism of action, may have the potential to treat rare epilepsies,” said Emiliangelo Ratti, Head of the Neuroscience Therapeutic Area Unit at Takeda. “The expansion of our clinical program to include pediatric populations, and additional rare epilepsies, exemplifies our joint commitment to identify an innovative treatment option for DEE.”
TAK-935/OV935 is a potent, highly-selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) being investigated as an anti-epileptic drug (AED). CH24H is predominantly expressed in the brain, where it plays a central role in cholesterol homeostasis. CH24H converts cholesterol to 24-hydroxycholesterol (24HC), which then exits the brain into the blood plasma circulation. Glutamate is one of the main neurotransmitters in the brain and has been shown to play a role in the initiation and spread of seizure activity. Recent literature indicates CH24H is involved in over-activation of the glutamatergic pathway through modulation of the NMDA channel, implying its potential role in central nervous system diseases such as epilepsy. Ovid and Takeda believe that its novel mechanism of action may potentially treat rare epilepsies by inhibiting CH24H to decrease 24HC levels, effectively decreasing glutamate hyperactivity. This mechanism of action may be especially important in CDD and Dup15q since the NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of these syndromes. To Ovid and Takeda’s knowledge, TAK-935/OV935 is the only molecule with this mechanism of action in clinical development.
In previouse Ph I studies, TAK-935/OV935, demonstrated an acceptable safety profile and was well tolerated. Following once daily doses of up to 400 mg for 14 days in healthy subjects plasma 24HC concentrations decreased by 47 to 63 percent from baseline in a dose-dependent fashion and achieved steady state levels by day 7. As part of Takeda and Ovid’s development strategy, plasma 24HC is being assessed as a potential biomarker for TAK-935/OV935.