We are developing our most advanced therapeutic candidate, tavapadon, for the treatment of both early- and late-stage Parkinson’s disease. Tavapadon was rationally designed as an orally-bioavailable, once-daily partial agonist that selectively targets dopamine D1/D5 receptor subtypes with the goal of balancing meaningful motor activity with a favorable tolerability profile. A chronic neurodegenerative disorder, Parkinson’s primarily results in progressive and debilitating motor symptoms, including decreased bodily movement, slowness of movement, rigidity, tremor and postural instability, all of which result from the death of dopamine-producing neurons in the brain.
About the Mechanism of Tavapadon
Dopamine is a neurotransmitter that drives motor function through a complex interaction between the striatum, the region of the brain responsible for motor control, the thalamus and the motor cortex. Patients with Parkinson’s lose dopamine-producing neurons in the region of the brain known as the substantia nigra, leading to increasingly reduced levels of dopamine in the striatum, which is believed to drive Parkinsonian motor symptoms.
Of the two types of dopamine receptor subtypes, D1/D5 receptor subtypes are expressed in a subset of neurons whose function is to modulate signaling from the thalamus to the cortex. This pathway is known as the direct motor pathway, and is responsible for the appropriate initiation of motor activity. D2/D3 receptor subtypes, expressed by a different group of neurons, signals via the indirect motor pathway, which indirectly regulates the signaling from the thalamus to the cortex. This pathway results in inhibition of motor activity. The balance between these two groups of neurons allows for proper motor control.
Tavapadon was designed to improve motor symptoms in Parkinson’s disease by selectively targeting and binding to dopamine D1/D5 receptor subtypes. Tavapadon differentially activates the direct motor pathway, potentially driving motor benefit while minimizing side effects typical of drugs that non-selectively stimulate dopamine, such as daytime sedation, or somnolence, compromised impulse control and risk of psychotic symptoms including hallucinations. Tavapadon is also designed to activate the D1/D5 receptor subtypes at levels that maximize motor benefit while reducing the prolonged receptor overexcitation and desensitization caused by full agonists, which can lead to dyskinesias and exacerbation of “off” time.