A recent publication poses a question that has become increasingly pressing in the face of numerous unsuccessful trials for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. "Why is the treatment and management of amyotrophic lateral sclerosis so difficult?"
The article suggests that when a phase II clinical trial succeeds while its phase III trial fails, it's because they have a different profile of patient population.
The authors argue that because they recruit fewer patients, the characteristics of patients enrolled in phase II trials are more homogeneous than those in phase III trials, which aim to recruit hundreds of participants. This is contrary to what statistics teaches.
I also find this hypothesis unlikely, given the constraints on patient recruitment and the sensitivity of principal investigators to the fragility of ALS diagnoses and the variability of patient phenotypes.
The authors also propose specifically that edaravone and Relyvrio (AMX0035) phase II studies yielded better results than their phase III studies. However, the phase II trials for these two drugs did not provide clear evidence of a therapeutic benefit, only showing marginal improvements in the ALSFR-R criterion, which is known to be influenced by non-medical factors such as access to better equipment. Relyvrio/AMX0035 in particuliar benefited from the intense pressure by ALS organisations. It should be noted that one of these organisations would have financially greatly benefited in a market authorization.
Furthermore, post-hoc analyses, which are often favored by drug manufacturers, are statistically unreliable. It is too easy to select favorable results from a small sample and attribute them to a common characteristic, which is why large-scale clinical trials are necessary.
In my opinion, it is time to recognize that we are on the wrong track in relying on molecular biology experts to develop treatments for neurodegenerative diseases. The current pharmacological approach is heavily influenced by our understanding of communicable diseases, where identifying the pathogen and suppressing it can lead to recovery. Molecular biology is conceptually far removed from medicine, as it ignores cellular mechanisms, tissue-level interactions, physiological systems, and the complex interplay between organs.
I believe that we would be better served by acknowledging that neurodegenerative diseases are the result of a complex interplay of factors, including a patient's medical history, lifestyle, and environmental exposures. Each patient over the age of 50 likely has a unique combination of age-related neurological diseases, with some having a history of strokes, high-intensity sports, environmental toxins, or head trauma. Some may have also had a history of substance abuse or smoking.
In summary, I believe that neurodegenerative diseases are the result of a complex interplay of factors in a patient's history, rather than a single molecular event. Therefore, funding for most molecular biology efforts should be gradually shifted to regenerative medicine, which addresses the restoration of damaged tissues and organs.