fotostorm
Alzheimer’s is like a puzzle made up of jagged pieces. Instead of putting these pieces together, researchers spend their time isolating and analyzing the puzzle piece that looks the most promising to them. The puzzle as a whole, then, is a brainteaser. If we continue to pursue this path, we will never put the puzzle together, and the problem will remain insoluble. (From Alzheimer’s, Aromatherapy, and the Sense of Smell)
As clinical trials using anti-amyloid and anti-tau drugs keep failing, considerable attention has turned to inflammation as the cause of Alzheimer’s disease. There are a number of companies utilizing this approach. Some like Alector (ALEC) and INmune Bio (INMB) promise to promote brain-saving immune responses while blocking neuron-killing inflammatory responses. Neuroinflammation does indeed contribute to the progression of Alzheimer’s disease, but it itself is the product of oxidative stress. Thus, drug candidates that address neuroinflammation without also addressing oxidative stress are not likely to perform that much better than anti-amyloid and anti-tau drug candidates.
Alector’s AL002 – a TREM2 activator (triggering receptor expressed on myeloid-2 cells) – inhibits apoptosis (cell death) and neuroinflammation, while promoting a healthy immune response via the phosphatidylinositol-3 kinase/Akt pathway (study). INmune Bio’s XPRO1595 neutralizes soluble Tumor Necrosis Factor-alpha which limits apoptosis and neuroinflammation while leaving the beneficial transmembrane Tumor Necrosis Factor-alpha intact (mechanism of action). Transmembrane Tumor Necrosis Factor-alpha acting through the Tumor Necrosis Factor Receptor 2 has also been tied to the neuroprotective phosphatidylinositol-3 kinase/Akt pathway. It is this pathway that is responsible for increased blood flow in the brain, regeneration of neurons in the hippocampus, and autophagy (removal of cellular debris). Both approaches, then, make sense in theory for the treatment of Alzheimer’s disease. However the phosphatidylinositol-3 kinase is largely inactivated by nitration in Alzheimer’s disease, so it is uncertain whether activating TREM-2 or maintaining transmembrane Tumor Necrosis Factor-alpha does much good. Or to put it another way, the nitration of the phosphatidylinositol 3-kinase would have to be reversed, before Alector’s AL002 and INmune Bio’s XPRO1595 could work more effectively.
More importantly, neuroinflammation in Alzheimer’s disease is driven by oxidation. It is the damage to molecules by oxidants (hydrogen peroxide during the very early stages of the disease and then by peroxynitrite) that leads to the upregulation of various inflammatory mediators, including Tumor Necrosis Factor-alpha. Various insults to the brain, including exposure to environmental toxins, chronic bacterial, viral, and fungal infections, an unhealthy diet (high in sugar and other carbohydrates, salt, saturated fats, cholesterol, and high fructose corn syrup), and psychological stress can all lead to oxidative and nitrosative damage. And while subsequent neuroinflamation adds to that damage, it is not the initial trigger. The probable sequence of events in Alzheimer’s disease then is oxidation – neuroinflammation – oxidation and not neuroinflammation – oxidation – neuroinflammation. Treating neuroinflammation in Alzheimer’s disease is thus unlikely to do much more than modestly slow down the progression of the disease.
The evidence continues to mount that specific antioxidants are key to the treatment of Alzheimer’s disease. This includes Anavex’s (AVXL) 2-73/blarcamesine, Cyclo Therapeutics (CYTH) Trappsol Cyclo, panax ginseng, and aromatherapy. The conclusion from a recent placebo-controlled clinical trial for aromatherapy for Alzheimer’s disease makes this point well:
Aromatherapy can improve sleep, alleviate psychobehavioural symptoms and improve quality of life in patients with AD, which may be related to reducing the level of oxidative stress in patients and inhibiting inflammatory factors [including Tumor Necrosis Factor-alpha]; it is a non-drug intervention that can be widely applied. (clinical trial)
Indeed, oxidation and nitration are the pieces of the puzzle that tie the features of Alzheimer’s disease together.
Like most companies developing drug candidates for Alzheimer’s disease, Alector and INmune Bio have the resources to complete their current trials for Alzheimer’s disease. Alector, in particular, has attracted a considerable amount of investment. As of May 2022, it has $868.6 million in cash, cash equivalents, and marketable securities (strong financial position). By comparison, as of March 2022, INmune Bio had $14.5 million in debt, but $66.7 million in cash (solid financial position). The company has run into a snag in terms of manufacturing issues with the FDA, however, it is still likely to have data available from its phase 2 clinical trial by the second half of 2023. The projected completion date for Alector’s phase 2 clinical trial is January 2024.
The financial numbers and completion dates, though, mean less than the probable results. Tumor Necrosis Factor-alpha is a major cytokine but not the only cytokine involved in Alzheimer’s disease. TREM-2 is an activator but not the only activator of the neuroprotective phosphatidylinositol 3-kinase/Akt pathway. And again, the activation of this pathway is largely disabled due to nitration in Alzheimer’s disease. Most importantly, neither company’s drug candidate appears to directly address the critical problem of oxidation. Therefore, it is probably unwise to invest in either company.
Be the first to comment