GENEVA—Swiss biopharma Prexton Therapeutics believes it just may have found the key to treating Parkinson’s disease and other brain disorders following a recent Phase 1 clinical trial for an mGluR4 positive allosteric modulator, assessing lead compound PXT002331 to be “safe and well tolerated at doses well above those that produce robust effects in Parkinson’s disease animal models.” A Phase 2 clinical trial aimed at demonstrating the effectiveness of the compound is scheduled for 2017 in Europe with an enrollment of 120 patients.
Described by Prexton as a “new scientific approach” to treat Parkinson’s, PXT002331 has been tested and evaluated by 64 healthy volunteers in a historic Phase 1 study noted as the first in-man clinical trial for a drug of its kind.
PXT002331 is unusual in that it stimulates a compensatory neuronal system that is not impacted by central nervous system (CNS) conditions, compared to other treatments for Parkinson’s which typically target the affected dopaminergic system only. But traditional treatments fail to address all systems of CNS conditions and are often accompanied by a number of adverse effects, Prexton states.
“We are very happy with the completion of the first clinical trial with our lead compound PXT002331, which is the first mGluR4 PAM ever to enter a clinical phase—an important step for Prexton,” Francois Conquet, Prexton Therapeutics CEO, states in a news release. “This achievement ensures Prexton is in a solid position for a successful clinical development of PXT002331 as a novel treatment for Parkinson’s disease, and we look forward to moving in that direction.”
The lead compound “shows strong efficacy when compared to medications usually administered for Parkinson’s disease,” Conquet says. “In addition, Prexton’s product does not show any of the side effects observed with those medications. Therefore, we think that the ratio benefit/risk of our product will be significantly higher than existing treatments. We estimate that our compound may treat two-thirds of the total Parkinson’s population, which is approximately 2 million patients.”
The company aims to develop a group of first-in-class molecules that target the metabotropic Glutamate Receptor 4 (mGluR4), a protein belonging to the metabotropic glutamate receptor family. Preclinical data shows compelling evidence of the efficacy of Prexton’s molecule, indicating it has the potential to alleviate motor complications by modulating glutamate over activity in the central nervous system of Parkinson patients.
Parkinson’s disease is a progressive neurodegenerative disorder caused by loss of dopaminergic neurons in the basal ganglia, the brain center for movement initiation and coordination. The mGluR4 receptors are strategically localized to counteract neurotransmitter imbalance and restore motor behavior in patients.
Motor symptoms such as slowness in initiating and executing movements (akinesia and bradykinesia, respectively), muscular rigidity, resting tremor, postural instability, gait dysfunction and freezing are all a part of Parkinson’s disease.
These symptoms are caused by the degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine in the striatum, Conquet explains. In a healthy brain, there is a balance between the direct and indirect pathways of the basal ganglia. The direct pathway stimulates the initiation of movements through an activation of the thalamocortical neurons.
Current treatments are aimed at replacing dopamine or mimicking its effects by chronically administering patients with the dopamine precursor L-DOPA, inhibitors of dopamine catabolic enzymes or direct dopamine receptor agonists, he says. Although these treatments provide good symptomatic relief in the early to middle stages, they lose their efficacy as the disease progresses and their chronic administration is associated with invalidating side effects such as dyskinesia, motor fluctuations and even behavior disturbances.
“None of the compounds of the current pharmacopeia for Parkinson’s disease have demonstrated neuroprotection which would delay disease progression,” Conquet reports. “Therefore, to address these important unmet medical needs, efforts are required to develop new treatments that target the neurochemical systems downstream dopamine itself in the basal ganglia.”
Prexton researchers discovered by decreasing GABAergic and glutamatergic transmission in the indirect pathway, mGluR4 activation is expected to restore the equilibrium between the direct and indirect pathways, and then restore motor behaviors in Parkinson’s disease, as demonstrated in animal models, Conquet says.
“We are developing positive allosteric modulators, or PAMs, to increase mGluR4 activity while minimizing the likelihood of adverse effect,” he adds. “Several studies in animal models have demonstrated that this strategy is promising for the treatment of motor and non-motor symptoms of Parkinson’s disease, as well as for disease modification.”
Global figures show that 10 million people are affected by Parkinson’s disease, with 200,000 being diagnosed each year. The incidence of the disease is expected to rise as the average age of the population increases.
Today, the worldwide market for Parkinson’s disease is approximately $3.1 billion, according to Global Business Insight, 2015. The market is dominated by matured dopaminergic treatments, which frequently induce negative side effects. There is an overall consensus in the field supporting the development of more efficient approaches, while limiting or even abolishing the occurrence of adverse effects demonstrated after some traditional treatments.