MEDIVATION’S DIMEBON HAS PROBABLE EFFECT ON OXIDATIVE STRESS PATHWAY, INVESTIGATOR AND PHYSICIANS SAY By Kimberly Ha in New York
Medivation’s (NASDAQ:MDVN) Dimebon for the treatment of Alzheimer’s disease (AD) may have some effect on the oxidative stress pathway, an investigator and physicians said. Dimebon is an orally-available small molecule that has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer’s disease and Huntington’s disease, making it a potential treatment for these and other neurodegenerative disorders.
There is data that indicates that the brain in 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.
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 theUSstudy will ultimately determine whether there will be a benefit.
Medivation did not return calls seeking comment.
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.
Dr Samantha Budd, director of neurology strategy at AstraZeneca (NYSE:AZN), said AstraZeneca has a broad effort in AD, but does not have approaches on oxidative stress or neuroprotection. “We like to approach the underlying approaches of the disease earlier in the disease progression, rather than treating symptoms,” she said.
Medivation’s Dimebon is currently being tested as a symptomatic agent, and not a disease modifying therapy.
There is a lot of literature on oxidative pathways, but very little clinical data, Budd said. “But it would be interesting to see if there is clinical success that could be coupled to oxidative stress in AD,” she noted.
Smith is also a scientific advisor to Anavex Life Sciences (OTCBB: AVXL), a company focused on AD drugs targeting oxidative stress, a similar mechanism of action to Medivation’s Dimebon. He described Anavex’s pre-clinical data as exciting, noted that but 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 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 theSanders-BrownCenteron Aging at theUniversityofKentucky, 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 necessary 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. “Everyone in theUSis asking what’s the interaction of Dimebon with other AD drugs,” he said.
“Unless you get to the target, the key to the disease – you’re always chasing after the side reactions,” said Smith.
Medivation has a market cap of USD 547m.
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