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A Big Reach

We’ve been reading a lot about amyotrophic lateral sclerosis (ALS) lately.  One thing is abundantly clear and that is there will be no single treatment to cure this disease.  There are inherited forms of ALS, fALS, and then there are sporadic cases, sALS. Our take on the overall picture of ALS is that no matter the inciting event at some point there is a final common pathway…that is inflammation.

Dogs get late onset fALS.  We suspect horses get fALS as well.  Is someone looking for it?  It would be very rare and most likely, with no treatment options, the horse would be euthanized before a clinician would think of ALS. Horses get subclinical inflammation presenting as a peripheral neuropathy.  After some time passes the neuromuscular disease progresses to the lower motor neurons (polyneuritis equi) and then it affects the upper motor neurons if the horse lives long enough. Diagnosis is the big issue here, to recognize a case of equine ALS.

The sporadic form of ALS seems more insidious…the sub-clinical pathways probably take a long time to surface into clinical disease.  The dysregulated systems that are forefront in human fALS are being targeted with specific small molecules-it is unlikely they will target sALS patients.  Even after years of failed attempts to find the cure for ALS the approach is the same: one path-one drug. New molecules come along, and so far they failed, even if they showed promise in mice that develop ALS.

The newest platform is skipping the animal step and moving right into people with promising drugs or small molecules. The entry criteria for the studies using novel small molecules targeting fALS are not available to sALS.  The treatments are super expensive. These approaches will never translate into an equine therapy.

Back to our hypothesis that it will take multiple drugs to combat presumptive equine ALS (eALS).  And this is a huge problem.  If one decided on a cocktail that was effective, the licensing process for the therapy would be impossible to get through FDA.  The effectiveness trial is mind boggling…we are suggesting the cocktail may involve 5 drugs at a minimum. The safety trial alone would cost at least a million dollars, our one-drug safety trial was nearly a half-million alone.

How does one start to evaluate therapeutic cocktails for a rare disease such as ALS?   Initially an animal model of the disease is necessary.  And a non-subjective test to evaluate if the disease is present in the animal.  And then one needs to identify the drugs that could be beneficial based on a firm understanding of the disease process. After all this is complete, it would be possible to approach FDA.

After our experiences with a simple and direct treatment using two well known drugs with specific actions for a specific disease with a defined and useful animal model, we can absolutely say the task for licensing a putative five drug ALS cocktail is insurmountable.

Ah, but a man’s reach should exceed his grasp, Or what’s a heaven for? (Robert Browning)

We have an approach that just may be doable.  And that is finding single therapies that hit multiple targets.  Our idea will rest upon finding a useful diagnostic test to ascertain effectiveness.  We aren’t afraid to try our approach in ALS models and compare the results to multiple drugs that target dysfunctional ALS pathways. Of course, testing multiple drugs together is a huge step that is outside the box thinking.  Out of the box thinking is what it will take to tackle ALS.

Our reach is big.  We’ll let you know how it goes.