Y

et another once-promising treatment for Alzheimer’s disease has come up short in the final stage of development, this time adding Wall Street drama to the familiar disappointment that has plagued the drug industry for decades.

A pill called intepirdine, developed by the biotech startup Axovant Sciences, failed to blunt the symptoms of Alzheimer’s in a large trial. The drug was never seen as a cure, but the company had hoped it would delay the worst symptoms of the disease, giving patients a few more months of health before needing around-the-clock care.

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  • All the complex biochemical explanations/theories (oxidation, nitration, inhibition of the synthesis of neurotransmitters, etc.) as to why Alzheimer’s disease develops are not very useful. This is because many studies have shown that it is HUMAN EXPERIENCE that results in structural changes in the brain and changes in biomarkers. For example, being subjected to psychological stresses, worries, rumination, etc., results in structural changes in the brain. Even animal studies have shown this. Mice subjected to various psychological stresses (e.g. being restrained) show adverse changes in the brain [see for example: Popoli M, et al. (2012). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nature Reviews Neuroscience. 2011;13(1):22-37] – these changes are reversible through psychological means (e.g. when stressed, restrained animals are released as described in the same article). There are many studies in humans as well. For example, the ‘Einstein Aging Study’ showed that psychological stress lead to cognitive impairment [see: Katz, M. J., et al. (2016). Influence of Perceived Stress on Incident Amnestic Mild Cognitive Impairment: Results From the Einstein Aging Study. Alzheimer disease and associated disorders, 30(2), 93-98.]. Even day-to-day experiences change the brain – studies have shown that as taxi drivers do their jobs (psychological causes), the brain changes. Jugglers gain more grey matter in certain areas of the brain as a result of engaging in juggling. Various psychological habits, choices, etc., can also change the brain. For example, research has also shown that impulsivity trait results in reductions in gray matter. On the other hand, mindfulness practices (that result in reductions in impulsivity) are known to change the structure and function of the brain in positive ways (e.g. increases in gray matter and cortical thickness), and even prevent plaque formation and Alzheimer’s Disease [see: Larouche, et al. (2015). Potential benefits of mindfulness-based interventions in mild cognitive impairment and Alzheimer’s disease: an interdisciplinary perspective. Behavioural brain research, 276, 199-212.]. The trouble with giving medicines (using a hit or miss approach) is that they can interfere with complex biochemical pathways of the brain with adverse effects in the long term, making matters much worse.

    • In a sense, you have confirmed my point. Psychological stress increases nitro-oxidative stress. One of the differences between mice and humans is that mice are only subjected to one of at most two causes of nitro-oxidative stress: amyloid (put into their brains) and/or psychological stress and partially for this reason, they do not develop full-blown Alzheimer’s disease (mice for example are not subject to various environmental toxins).

      Individuals with Alzheimer’s disease who have neuropsychiatric problems also have high levels of norepinephrine which is also the result of psychological stress.

      Certainly then mindfulness practices can reduce stress (both psychological and oxidative) and likely be helpful at least early in Alzheimer’s disease. Certain plant compounds such as ferulic acid can reduce levels of norepinephrine and thus potentially can help treat neuropsychiatric problems in Alzheimer’s disease, frontotemporal lobe dementia, and dementia with Lewy bodies.

      The key I believe is to see that there are many risk factors for Alzheimer’s disease but they all funnel into the same place (high levels of glutamate resulting in nitro-oxidative damage to the brain).

  • All the complex biochemical explanations/theories (oxidation, nitration, inhibition of the synthesis of neurotransmitters, etc.) as to why Alzheimer’s disease develops are not very useful. This is because many studies have shown that it is HUMAN EXPERIENCE that results in structural changes in the brain and changes in biomarkers. For example, being subjected to psychological stresses, worries, rumination, etc., results in structural changes in the brain. Even animal studies have shown this. Mice subjected to various psychological stresses (e.g. being restrained) show adverse changes in the brain (see for example: http://www.nature.com/nrn/journal/v13/n1/abs/nrn3138.html ) – these changes are reversible through psychological means (e.g. when stressed, restrained animals are released as described in the same article). There are many studies in humans as well. For example, the ‘Einstein Aging Study’ showed that psychological stress lead to cognitive impairment (see: https://www.ncbi.nlm.nih.gov/pubmed/26655068 ).
    Even day-to-day experiences change the brain – studies have shown that as taxi drivers do their jobs (psychological causes), the brain changes. Jugglers gain more grey matter in certain areas of the brain as a result of engaging in juggling. Various psychological habits, choices, etc., can also change the brain. For example, research has also shown that impulsivity trait results in reductions in gray matter. On the other hand, mindfulness practices (that result in reductions in impulsivity) are known to change the structure and function of the brain in positive ways (e.g. increases in gray matter and cortical thickness), and even prevent plaque formation and Alzheimer’s Disease (see: http://www.ncbi.nlm.nih.gov/pubmed/24893317 )
    The trouble with giving medicines is that they can interfere with complex biochemical pathways of the brain with adverse effects in the long term, making matters much worse.

  • It’s terrible ironic the Bill Cassidy was touting how important the “creative cures” of big Pharma are. Creative cures come from NIH and Universities, not Pharma. This was a tremendous waste of time and resources to try and save a poor investment. Anyone who cares for Alzheimer’s patients could tell you that this wasn’t going to provide significant benefit in addition to Aricept.

  • The boom and bust cycle of Alzheimer’s drugs and stocks continue. There always seems to be an explanation for earlier failures: not given soon enough, not given in the right dose, not combined with other drugs, etc. The explanation is never wrong mechanism.

    Alzheimer’s disease is a disease of oxidation and nitration. Oxidation damages most of the receptors for neurotranmitters and inhibits the synthesis of neurotransmitters themselves including those needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness. Axovant’s intepirdine modulated sertonergic receptors involved in mood and memory that were already damaged by oxidation. Efforts to modulate the main receptor involved in the retrieval of short-term memory–muscarinic acetylcholine receptors–are also doomed to failure for the same reason. Unless oxidation and nitration are partially reversed Alzheimer’s disease cannot be partially reversed. Unfortunately, there are very few drugs and natural products currently being studied for Alzheimer’s disease that do this.

  • I “hate” to say, I told you so

    And yet, Ramaswamy, Hung, and all the other highly respected professionals involved live on!

    After all, a sucker is born every minute, right?

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