A recent GlobalData report stated that Parkinson disease (PD) drug development in general, focused as it is on the dopamine pathway, is “increasingly hampered by a lack of innovation.” Compounds in late-stage development aim at the symptomatic treatment of the disease, as do current medications. Any company developing treatments for PD will need to overcome prevailing product weaknesses including psychiatric side effects and obsessive compulsive behaviors as well as limited efficacy, the report pointed out.
This played out most recently on July 16 when Vernalis and Biogen Idec reported their decision to discontinue vipadenant development for the treatment of PD. Although the companies achieved positive results in Phase II studies, a review of preclinical toxicology studies raised some red flags, prompting the companies to halt clinical trials.
Side effects comprise the biggest challenges preventing most products in company pipelines, all 181 of them in various stages of development, from reaching the market, the GlobalData report pointed out.
About four million individuals worldwide suffer from PD, which results from the death of neurons that produce dopamine in a specific area of the brain. The loss results in muscle rigidity, uncontrollable tremors, and slowing or loss of voluntary movement. One third of PD patients also develop a form of dementia.
Blocking the A2A Adenosine Receptor
Currently used drugs aim to increase brain dopamine levels or prevent its breakdown, and others stimulate the same receptors as dopamine. While helpful in the short run, these treatments have significant side effects and lose efficacy over time.
Since A2A adenosine receptor signaling regulates dopaminergic tone, it was hoped that Vernalis’ drug, because it acts to block these receptors, would improve PD symptoms with fewer side effects. Adenosine coordinates and controls motor function in the brain through regulating the release of neurotransmitters including glutamate and dopamine. Biogen Idec paid Vernalis $10 million in 2004 to license vipadenant and a back-up compound as well as gain option rights to Vernalis’ entire research program surrounding A2A antagonists.
The firms expect to progress a second-generation A2A antagonist for PD treatment into Phase I studies in early 2011. The discontinuation of the Phase II trial, however, was a significant blow to Vernalis, as the company had reported negative results from another clinical trial about four months prior. On March 10, Vernalis said that idantadol for diabetes-related neuropathic pain missed its primary endpoint.