Question: Are we close to finding a drug to cure ALS? This illness has been around for so long. Why is it so difficult to find treatments?

ALS is a very complicated disease, and researchers have not yet figured out its root cause. That makes therapy development very difficult, as we do not have a genetic flaw to aim at fixing. In fact, there is no clear target at all, although researchers have a lot of possibilities. 

The underlying problems in ALS are in the brain and spinal cord. One of the biggest challenges in identifying the root cause of and targets for therapy development for ALS is the fact that it is very difficult to study the workings of the brain and spinal cord while someone is still alive. Whatever is causing motor neuron degeneration in ALS occurs at a chemical or molecular level, and we do not have tools to study these mechanisms in living people — even sophisticated tests such as MRIs can’t really tell us what is going on at a chemical level. Ideally, we would be able to study the brain or spinal cord in the laboratory, but we can’t take out pieces of the brain or spinal cord from a living person without causing severe injury such as a stroke or paraplegia. Therefore, we must rely on information gleaned from animal models of ALS, which are not perfect models for the disease, and from studying the brain and spinal cords of individuals who have died from ALS.   

But, despite these challenges, researchers have made a lot of progress, and there are some promising potential therapeutics under development. Unfortunately, most of these will not “cure” the disease, but even treatments that reduce or delay its effects will be very welcome. 

The most advanced treatment is, of course, riluzole, which is on the market for ALS, and increases survival a little. Knopp Neurosciences has been developing a drug, dexpramipexole, which was shown to be safe in a Phase II trial, and showed the potential for benefit (the trial was too small to be conclusive). This drug was designed simply to protect nerves from death — but the results look positive enough that Biogen Idec (a big pharmaceutical company) has licensed the drug and will start a much bigger trial in early 2011 to see how much of an effect the drug has on ALS progression. Trophos Pharmaceuticals also has a neuron-protecting drug in trials that has shown some promise. 

Other companies have drugs that affect specific aspects of ALS pathology. For example, arimoclomol, which is currently in a Phase II trial, is a drug designed to reduce aggregation (reducing the size of the clumps of protein typically seen in ALS spinal cords). Cytokinetics and Acceleron Pharma both have drugs that increase strength, which may improve quality of life. Cytokinetics’ drug has been shown to be safe in Phase I studies, and the company intends to test its efficacy in larger trials soon. Acceleron’s drug is currently in a trial for Duchenne muscular dystrophy, but the company suggests that it will be tested in those with ALS next. Isis Pharmaceuticals is developing a compound (developed by MDA grantee Tim Miller at Washington University) that aims to reduce the amount of toxic SOD1, the protein responsible for some forms of familial ALS.  

Stem cell therapies for ALS have been widely publicized. Currently, the most advanced stem cell treatment for ALS that is going through the FDA approval process is in a very early stage safety trial run by Neuralstem. This study is designed to find out if injecting the stem cells into the spinal cord is safe. No stem cell treatment has been in an efficacy trial for ALS, so no such treatment has been shown to work or be safe.

There are a lot of possible treatments in development at this time — we have only looked at the most advanced possibilities here. Unfortunately, the drug development process is fairly slow, as we need to be certain that a drug is both safe and effective before it should be prescribed to patients. If the most advanced therapies in development work, it still will be at least two years before they are available to patients outside of clinical trials. Nonetheless, there is hope on the horizon!

We do not want to give the impression that the above list includes the only possibilities of importance — there are actually any number of other possibilities out there that might work, and every day we learn of new possibilities. For example, someone in the MDA community pointed out that we left ceftriaxone (a compound currently in a Phase III trial) out of the above information. This was simply because we only mentioned one drug that acted through each mechanism, in each case the most advanced. The hypothesis is that ceftriaxone may reduce levels of glutamate (thought to be toxic to nerve cells), which is similar to how riluzole is thought to work. In no way did we mean to suggest that this Phase III trial was unimportant! In fact, we think the results will be very valuable, and the drug is as promising as any out there. In a short response like this, we couldn’t possibly mention every possibility (isn’t that a great place to be)! Clinical trials are an extremely important part of the therapy development process. But, before participating in any clinical trial, we suggest that you understand the pros and cons of a particular trial and what the researchers hope to learn from the trial. Make certain that all of your questions are answered before consenting to participate. For more about participation in clinical trials, see the Quest magazine article Being a Co-Adventurer.