A Novel Drug Shows Promise As Parkinson's New Treatment

Every year, nearly 90,000 people in the United States are diagnosed with Parkinson's, a condition in which brain cells that produce dopamine degenerate, leading to stiffness, slow movement, and balance problems. Currently, treatments fail to provide sustained relief from these symptoms without adverse events (such as nausea, confusion, hallucinations, and dizziness). Though these treatments may provide strong motor control, it's efficiency varies as the disease progresses. Therefore, patients often go through motor control fluctuations and unpredictable drop-offs in medicine effectiveness. In order to combat these challenges, researchers have looked into tavapadon, an oral medication.

Introduction - Current Treatments

The most prevalent treatments are:

• Dopamine precursors (substance the body uses to make dopamine)

• Dopamine agonists (acts like dopamine)

• Monoamine oxidase inhibitors (prevents dopamine from breaking down)

• Deep brain stimulation (a neurosurgical procedure that inputs a device into the brain that delivers needed electrical impulses)

• Disease-modifying treatments

  • Target the build-up of α-synuclein, which plays a role in the degeneration of dopamine neurons)

A specific, commonly recommended drug is levodopa, due to its strong effects. The treatment is administered multiple times a day, and because of that, effects often fluctuate. On the other hand, tavapadon may provide sustained and predictable motor control, which sets it apart from preceding medications. Researchers set out to find evidence for this claim.

Tavapadon, How Is It Better?

Figure 2. Comparison of tavapadon and levodopa (vehicle: patient with no treatment)

A big reason why tavapadon is so effective is due to it being a partial agonist. A partial agonist is a drug that binds to receptors but produces a weaker response compared to full agonists. This may sound counterintuitive, but this property makes tavapadon beneficial because adverse events are linked to full agonism. Prolonged receptor activation leads to an increase in the production of β-arrestin, leading to desensitization of the receptor. When receptors become desensitized, they become less reactive to treatments, and doses must be increased in order for the drug to be effective.

Further studies were performed on non-human primates, and researchers found that motor improvements were equal to levodopa, and were sustained for twice as long. This is strong evidence that tavapadon is even more effective than levodopa and will dependably provide relief.

Another reason why tavapadon is effective is due to how it targets D1/D5 dopamine receptors. Previous studies show that activating D1/D5 receptors caused enhanced responsiveness to treatment. Furthermore, animals were provided relief even when unresponsive to levodopa.

The activation of D1/D5 receptors also reduce the risk of dyskinesis, which is impairment of voluntary movement. Patients who had dyskinesias from long time levodopa exposure were administered tavapadon and found that their dyskinesias was reduced.

Moreover, patients with drugs targeting D2/D3 receptors sometimes expressed compulsive behavior (Impulse Control Disorder - ICD). Some patients even exhibit characteristics of a drug addict. Treatment use escalates, drug withdrawal is avoided, and drug intake continues even with adverse events. Studies on rodents and primates show that targeting D1/D5 receptors led to reduced relapsing behaviors.

Table 1. Published findings related to efficacy and safety of tavapadon

Discussion

There are still unmet needs for innovative Parkinson's treatment options, as there are no approved drugs to modify disease progression. Even with extensive research on Parkinson's that has led to a broad range of effective treatments, patients are often not satisfied to the unpredictability of these medical interventions. It is here that tavapadon holds promise. As phase 3 clinical trials continue to go on, researchers will continue to work toward providing more evidence to work toward getting tavapadon clinically approved.