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Alzheimer’s Disposes of Another Idea

In case you were wondering, you can add “MAO-B inhibition” to the long, long list of Things That Don’t Do Any Good For Alzheimer’s. I’m not sure how much hope anyone had for that program (at either Roche or Evotec), but the potential payoff is so huge that a lot of marginal ideas get tried. At least this was in Phase II, and not Phase III; there’s always that. . .

19 comments on “Alzheimer’s Disposes of Another Idea”

  1. MoBio says:

    I’m a bit surprised that they went at all with that compound for AD as there was scant reason to suspect that particular mechanism would have any chance of success.

  2. Anonymous says:

    @1, well the mechanisms where people suspected things might work have not fared any better.
    What would the equivalent to a broad street pump for this disease?

  3. Anonymous says:

    @1… I wonder what preclinical support they had, if any…
    Does anyone know?

  4. MoBio says:

    @3: there is literature showing that MAO-B may be a marker for astrocyte increases as a result of neurodegeneration and general evidence that MAO-B inhibition could inhibit oxidative stress but difficult to imagine how this would be construed to specific or relevant to AD.

  5. Yashar says:

    Roche conducted PhIII trials in AD with another compound, lazabemide, which was stopped for liver toxicity after completion of the trials.
    They probably saw some signal in those trials

  6. a. nonymaus says:

    Do any other organisms develop Alzheimer’s? If not, what is different between elderly people and aged bonobos (aside from a tendency to enjoy golf on television)? Several species of whales live longer than people on average and are also mammals, but the epidemiology is difficult to do unless your name is Ahab.

  7. MoBio says:

    A bit more about lazabemide:
    “Although the course of patients’ deterioration did slow somewhat, the decline was not statistically significant enough for FDA approval, Bowden concluded. Lazabemide delivered only a 1.5-point advantage on the test of cognitive skills, falling short of the 2-point hurdle. That disappointment, and the fact that a few patients had liver problems, perhaps because of the drug, killed lazabemide.”
    This is quite a small effect and even a 2-point effect would only be marginally significant to patients.

  8. Anonymous says:

    Plenty of marketed MAO inhibitors used in PD have failed in AD already. Wasn’t expecting much of this

  9. Lane Simonian says:

    @6 Dogs get a condition very similar to Alzheimer’s disease (canine cognitive dysfunction). The cause (oxidative damage) and the treatment (antioxidants) of cognitive dysfunction in dogs is very similar to that of people with Alzheimer’s disease.
    http://www.ncbi.nlm.nih.gov/pubmed/12392784

  10. Anonymous says:

    The Degu – a type of guinea pig gets AD

  11. DN says:

    One plausible mechanism is that AD seems to be part of normal senescence, and an awful lot of human developmental clocks are powered by dopamine in the hypothalamus/pituitary.

    Another, wackier, idea is that catecholamines are made using tetrahydrobiopterin (BH4), which is a very sensitive oxidation detector, and seems to be widely involved in senescence. Both vascular aging and graying of hair are also mediated by oxidation of BH4. It’s conceivable that fixing a positive feedback loop involving the catecholamines might mitigate oxidative damage more widely.

    But we already knew these were Hail Mary ideas. People with Parkinson’s disease are not known for developing magical de-senescence.

  12. Lane Simonian says:

    The idea that BH4 oxidation plays a role in Alzheimer’s disease is actually quite plausible.
    http://www.ncbi.nlm.nih.gov/pubmed/17191137

  13. Yashar says:

    @7 – that statement is not true – Roche never disclosed the data
    @8- most published trials were very small – the only trial with decent sample size gave a signal in severe patients (Sano & Thal)

  14. Yashar says:

    @7 – Roche never disclosed the data – don’t know where that statement comes from
    @8- most published trials were very small – the only trial with decent sample size gave a signal (in severe patients, Sano & Thal)

  15. Anonymous says:

    How about any animals who develop something similar to Parkinson’s disease upon aging?
    Does anyone know?
    As much as these neurodegenerative disorders may come with normal aging, not all humans end up getting it…

  16. Lane.Simonian says:

    Bad link. I will try again. Here’s the title of the article in case it fails again.
    Parkinson’s disease in Dogs Symptoms and Treatment: Tips & Suggestions
    http://www.petmanage.com/dog-diseases/parkinson%E2%80%99s-disease-in-dogs.html

  17. Lane Simonian says:

    Reducing oxidative stress is indeed the primary rationale for testing MA0-B inhibitors for the treatment of Alzheimer’s disease.
    In Alzheimer’s disease, oxidative stress inhibits the synthesis of dopamine, serotonin, and melatonin. Oxidative and nitrative stress restrict the transport of choline and depress the activity of choline acetyltransferase. Cysteine oxidation of g protein-coupled receptors limits the release of acetylcholine, dopamine, melatonin, serotonin, and oxytocin further adversely affecting short-term memory, alertness, sleep, mood, and social recognition. The nitration of NMDA receptors and the oxidation of glutamate transport system contributes to DNA damage and neuronal cell death.
    As long as the brain’s antioxidant systems are not exhausted (especially glutathione levels), a person can have the same levels of amyloid and neurofibrillary tangles in their brain as a person with Alzheimer’s disease, but be cognitively “normal.”
    The level of oxidative damage is less in mice than in human beings, so many antioxidants that will work in mice will be much less effective in human beings with Alzheimer’s disease (in particularly many mice strains used to study Alzheimer’s disease don’t exhibit excitotoxicity).
    MAO-B inhibitors will increase dopamine levels and partially reverse oxidation but not enough to substantially slow down Alzheimer’s disease. A compound like eugenol that increases dopamine, serotonin, and melatonin levels through MAO-A inhibition and is a strong antioxidant in its own right likely represents a better compound for the treatment of Alzheimer’s disease.

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