Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Drugs acting on nondopaminergic systems have yet to prove their mettle in clinical trials.

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 axe clinical trials with vipadenant.

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. In the brain adenosine coordinates and controls motor function through regulating the release of neurotransmitters including glutamate and dopamine. Biogen 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.

Targeting Alpha-Synuclein

The abnormal proteins present in specific brain cells of patients with several neurodegenerative diseases including Alzheimer disease (AD), Huntington disease (HD), Lewy body dementia, and PD are attracting attention as potential drug targets. Controversy still exists, however, as to whether they are the root cause of these diseases or the result of upstream events. Yet, these proteins may prove to be more promising and discrete targets for new drugs than neurotransmitter systems.

Robert L. Nussbaum, M.D., and Christopher E. Ellis, Ph.D., pointed out, in a 2003 article in The New England Journal of Medicine, that the genetic mapping and gene-isolation tools created by the Human Genome Project greatly accelerated the rate of identification of genes involved in the rare inherited forms of PD and AD. These same tools and their more sophisticated descendents are now being used to determine the genetic contributions to the more common, multifactorial forms. They revealed alpha-synuclein as a neurotoxic in PD and believe that it may explain the pathogenesis not only of the inherited form of PD but also of the idiopathic form.

Alpha-synuclein is a major component of the filamentous inclusions called Lewy bodies, protein clumps that are the pathological hallmark of PD. The normal function of alpha-synuclein remains unknown, although it is thought to play an important role in synaptic function or lipid binding. Synuclein usually remains in an unfolded state but is highly prone to aggregation. 

The Michael J. Fox Foundation (MJFF) has invested about $12 million to date in alpha-synuclein. It supports researchers working to characterize the protein’s role in PD, assess its potential as a target for neuroprotective therapies, and develop drugs that inhibit aggregation of synuclein filaments into clumps.

No drugs targeting alpha-synuclein have reached the clinic, according to the MJFF. Some approved compounds, though, have been shown to stop synuclein clumping and to break up clumps in vitro. Even sirtuins are getting into the act, as investigators reported discovery of a potent sirtuin 2 (SIRT2) inhibitor that rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of PD.

Need for Better Animal Models

G. Linazasoro and colleagues at the faculty of medicine, University of the Basque Country, Leioa, pointed out that PD is a multisystemic disorder involving neurotransmitters other than dopamine. But even drugs acting on nondopaminergic systems, as in the case of vipadenant, have yet to prove their mettle.

Additionally, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems that have been assessed in human studies show negative, inconsistent, or unsatisfactory results, points out Dr. Linazasoro. Most of these drugs have been tested in two specific animal models: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys and 6-hydroxydopamine-lesioned rats.

As in many other diseases, the leap from animal models to man is hazardous. A major funding focus of the MJFF remains developing an animal model for PD. While current PD animal models may reproduce some features of the disease, the development of truly effective and safer treatments will require animal models that represent the full spectrum of biochemical and cellular lesions characteristic of the disease.

Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].

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