We are developing our second most advanced therapeutic candidate, darigabat, for the treatment of both epilepsy and anxiety. Darigabat was rationally designed as an orally-bioavailable, twice-daily positive allosteric modulator (PAM) that selectively targets GABAA receptors containing alpha-2/3/5 subunits.
About the Mechanism of Darigabat
Gamma-aminobutyric acid (GABA) is the major main inhibitory neurotransmitter in the central nervous system that dampens down neuronal hyperexcitation through hyperpolarization. GABA-producing neurons are distributed throughout the brain and play a fundamental role in processing and integrating most neuronal functions. GABA binds GABAA receptors, which are comprised of five individual subunits. Upon activation, GABAA receptors open and allow chloride to move into the neuron. This action inhibits the neuron’s activity and reduces signal transmission.
Balance in GABA signaling is crucial for controlling brain hyper-excitability hyperexcitation. Non selective inhibition can lead to sedation or amnesia. Epilepsy and anxiety are two examples of neuroscience diseases that show evidence of impaired GABA neuronal transmission.
Benzodiazepines (BZDs) are non-selective PAMs of the GABAA receptor, enhancing the effect of GABAA receptors containing alpha-1/2/3/5 subunits. Alpha-1 subunit-containing GABAA receptors are broadly expressed throughout the brain and their modulation is believed to underlie many tolerability issues associated with BZD use (including sedation, motor and cognitive impairment) and contribute to desensitization and tolerance. Selectively minimizing alpha-1 subunit activation by targeting other alpha receptor subunits presents an attractive treatment option for epilepsy.
By having minimal activity via the alpha-1 subunit-containing GABAA receptor, we believe darigabat can minimize the negative side effects of sedation and potential for addiction seen with traditional non-selective GABAA receptor modulators, such as BZDs. Darigabat is designed as a PAM to increase the effect of endogenous GABA without blocking or overexciting normal neural activity and with a lower propensity for development of tolerance. Based on these differentiating features, we believe darigabat has the potential for anti-epileptic activity comparable to currently available BZDs but with reduced tolerance, sedation and withdrawal liabilities, which may enable chronic use. To our knowledge, darigabat is the only alpha-2/3/5-selective GABAA receptor PAM being evaluated in clinical trials for epilepsy.
For information on clinical trials please visit realizestudy.com.