Dimebon is one of the more promising medications in clinical trials. It has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer's disease and Huntington's disease. New data shows how it may work by relieving oxidative stress. ( Currently, the most popular ways being explored to fight Alzheimer's are the reduction of beta-amyloid, tau and oxidative stress. )
An investigator and physicians said that Medivation's Dimebon may have some effect on the oxidative stress pathway. Dimebon is an orally-available small molecule that is a potential treatment for Alzheimer's, Huntington's and other neurodegenerative disorders.
There is data that indicates that the brain in Alzheimer's Disease (AD) is under increased oxidative stress, which may have a role in the pathogenesis of neuron degeneration and death in this disorder. There have also been studies that indicate that free radicals are possibly involved in the pathogenesis of neuron death in AD.
Any given cell has hundreds of mitochondria. This illustration shows two—a healthy mitochondrion and an oxidatively stressed and damaged one. The arrows indicate the movement of free radicals, which can spread easily from damaged mitochondria to other parts of the cell.
Free radicals are oxygen or nitrogen molecules that combine easily with other molecules (scientists call them “highly reactive”). Free radicals are generated in mitochondria, which are structures found in all cells, including neurons.
Mitochondria are the cell’s power plant, providing the energy a cell needs to maintain its structure, divide, and carry out its functions. Energy for the cell is produced in an efficient metabolic process. In this process, free radicals are produced. Free radicals can help cells in certain ways, such as fighting infection. However, because they are very active and combine easily with other molecules, free radicals also can damage the neuron’s cell membrane or its DNA. The production of free radicals can set off a chain reaction, releasing even more free radicals that can further damage neurons (see illustration "Mitochondria and Free Radicals"). This kind of damage is called oxidative damage. The brain’s unique characteristics, including its high rate of metabolism and its long-lived cells, may make it especially vulnerable to oxidative damage over the lifespan. The discovery that beta-amyloid generates free radicals in some Alzheimer's disease (AD) plaques is a potentially significant finding in the quest for better understanding of AD as well as for other neurodegenerative disorders and unhealthy brain aging.
Dr. Mark Smith, an investigator on Dimebon's trials who has studied the oxidative stress hypothesis for more than 15 years at Case Western Reserve University, said the clinical data on Dimebon looks very promising, especially if it is hitting mitochondria. "Obviously targeting mitochondria makes sense therapeutically, if you want to target the oxidative stress pathway." Oxidative modifications are a hallmark of oxidative imbalance in the brains of individuals with AD, according to one paper by Smith.
Dr. Eric Reiman, executive director of the Banner Alzheimer's Institute, said most of the mitochondrial pores and election transport chains are downregulated in regions of the AD brain. "That begs the question of whether the disease is a cause or consequence of dying neurons," he said.
"If I had to guess, I think something is going wrong in a patient's nerve endings in the brain," Reiman said. He added that Medivation's Russian study looks promising, but the US study will ultimately determine whether there will be a benefit.
A number of other studies are drawing more attention to metabolism and the effects on mitochondria, noted Reiman. Nerve terminals may play a role in early pathogenesis and presymptomatic disease - but oxidative changes also occur as a result of the normal aging process, and are not specific to AD, he cautioned.
Medivation's Dimebon is currently being tested as a symptomatic agent, and not a disease modifying therapy.
Smith is also a scientific advisor to Anavex Life Sciences, a company focused on Alzheimer's Disease (AD) drugs targeting oxidative stress, a similar mechanism of action to Medivation's Dimebon. He described Anavex's pre-clinical data as exciting, but noted that its drugs are obviously not as advanced in the pipeline.
Anavex are focused on sigma receptors, which have been shown to be neuroprotective, Smith said. Activation of sigma receptors have lead to alterations in memory in transgenic mice, and the downregulation of sigma receptors occurs at very early stage of the disease, he noted. None of the trials that targeted amyloid have worked so far, Smith noted. "I've written a lot of papers that both tau and amyloid are responses to the disease," he said, noting that the tau hypothesis is another place to look, but it does not mean everyone in the field should move into tau.
The compounds by Medivation and Anavex both lower oxidative stress levels, Smith noted. The APOE isoform is definitely a risk factor; there is a change in metabolism early on in Alzheimer's disease (AD) patients - which implicates mitochondrial dysfunction and oxidative stress. If oxidative stress is targeted in the right way, there will be a significant change in the progression of the disease, Smith added. Dr Gregory Jicha, a neurologist at the Sanders-Brown Center on Aging at the University of Kentucky, noted that IGF is also a compelling target, and there is a lot of preclinical clinical data in the AD population. "We actually submitted a grant that was shot down, because IGF was tested already in AD," he said.
"The caloric restriction data is extremely strong, but there is no agent necessarily associated with it," Jicha said. Hypoglycaemic agents, such as metformin, and PPARS are also in trials in AD, but while they may improve memory, there is a lot of potential risk.
Dimebon's preclinical data still has some flaws, Jicha noted. Animal models using the agent showed cholinergic deficits. If the drug indeed works through mitochondria, Jicha questioned why it doesn't show through a more generic cell death model.
Jeffrey M. Ostrove, Ph.D, president & CEO of Ceregene, said a deficiency of nerve growth factor, or other trophic factors, is among an alternative hypothesis for AD pathogenesis. Several lines of evidence support, but do not yet prove, this hypothesis, he said.
Numerous groups are attempting treatments to boost the levels of trophic factors for therapeutic purposes, and one of the most advanced trials involves the use of neurotrofin, an agent that is said to promote the release of trophic factors and cytokines. "We're looking at symptomatic improvement, because we don't know what is causing AD," he said.
Medivation is developing Dimebon as monotherapy, since the company can actually use the Russian trial data by doing that, Smith noted.
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