We reported here that Memantine was found ineffective in an ALS clinical trial for the fifth time. Several articles about persistent failure in ALS clinical trials appeared in the last issue of The Lancet Journal. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00353-3/fulltext https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00407-1/fulltext
Scientists attribute Memantine's (and the many other drugs that were tried) lack of efficacy to the "complexity of the pathophysiological mechanisms."
In simpler words, they have no idea why it failed, yet it was tested for the fifth time in ALS, so in a rational world, they should, on the contrary, have expected it to fail. In addition, no pre-clinical studies have shown any special value of Memantine in ALS.
And it's not only about Memantine, hundreds of drugs with dozens of different mechanisms of action have been trialed in ALS, as well as in other neurodegenerative diseases. For example, in the same journal issue, there are the results of the ROCK-ALS phase II clinical trial which has a purported mechanism of action entirely different from the usual suspects (glutamate excitotoxicity, impaired proteostasis, autophagy, and neuroinflammation).
Clearly, scientists know nearly nothing about these diseases, otherwise, they would concentrate their efforts on specific drugs.
It is time to reconsider century-old and unquestioned assumptions about these diseases. What makes ALS patients die? Skeletal muscle wasting which leads to respiratory failure. Efforts should concentrate in this direction. We also know that ALS is not always a death sentence, for example Stephen Hawking lived 76 years and 55 years with the disease. We know that a BMI in the 27 range helps for survivability, yet publications on ALS metabolism in skeletal muscles represent only a tiny fraction of the huge amount of ALS publications. In 2023 there were only 23 publications on this topic, versus 2507 publications on ALS.
Why this situation? Laboratories and CRO are not organized to study whole-body mechanisms in large mammals. It would cost a lot, universities and biotech prefer to work on small rodents or even worse on immortalized cell lines.
There is also the question of the time span, most studies are conducted within 6 months, or even two months, because students are used as a cheap workforce. You can't detect any statistically meaningful clinical change in neurodegenerative diseases in two months.
Studies must last at least one year and use large mammals, if possible mammals which have a corticospinal tract similar to ours, with direct connection between upper and lower motor neurons for fine control of skeletal muscles such as in hands..