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Endpoints in clinical trials have to be relevant

How do you know when something is meaningful or just a conincidence?Meaningful veterinary clinical trials that lead to drug licensing have to be reviewed by the Center for Veterinary Medicine, CVM, or “the Agency”. We clarify veterinary because we are in this same process with FDA for a human drug to treat neuroinflammation in amyotrophic lateral sclerosis (ALS). We are happy to say the drug we invented for ALS is starting the first-in-human dosing in an FDA clinical trial. The drug has roots in our levamisole story and engages some of the same innate immune receptors we target with our veterinary drug. We will write the book after a few more steps are completed. However, the path isn’t as easy as imagined.

For the drug licensing processes, veterinary and human, there is an expectation of effectiveness bar that has to be achieved and this is not as easy as imagined. We are deeply immersed in the science of why our treatments are appropriate or worth the work to develop the drug. The folks at the Agency are not, they must be convinced. The Agency says that there are a variety of sources of information that can be used to support effectiveness, in some cases a field effectiveness study may be the clearest way to demonstrate the effect of the drug. They want to be sure there is cause and effect in the treatment and not just a coincidence. In both venues, human and animal, clinical trial trumps all. These studies start with a protocol and the Agency will concur. Concurrence will not guarantee acceptance of the data, however.

In humans there are Phase 1, Phase 2 and Phase 3 trials that go from expensive to prohibitive. Obtaining data for veterinary clinical trials is within reach and are expensive for a small company. A feasibility study kicks off the data accumulation process and often these data are published, hopefully you have read our studies. The next step is to move on to safety studies, these are emotionally hard to do because the animals are sacrificed. Of course, in humans the pre-clinical data is done in animals (that are sacrificed). We are pleased that FDA is moving toward non-animal data to support the pre-clinical steps and hope someday no animals will be sacrificed in the licensing of any pharmaceuticals.

With the foregoing under ones belt it’s time to take the second step in diseased animals and provide data that the drug works as we intend. Concurrence selecting the target population in animals is difficult. In humans it’s easier. Once the target population is defined, its time to select the primary outcome variable. What will measurably change, clinically, when the patient is dosed? We know from the pre-clinical work and the feasibility studies what will change—but there is a catch!

The primary outcome variable must have statistical relevance to a clinical observation. The regulatory agencies don’t like biomarkers, unless the biomarker is specific to the disease processes-that would be called a pathognomonic biomarker. For example, in a drug to treat equine protozoal myeloencephalitis (EPM) a change in titer against S. neurona isn’t acceptable (S. neurona is related to EPM) but a change in a clinical neurological assessment score is acceptable. For a drug to treat polyneuritis equi (PNE) a change in a biomarker is not acceptable but a change in clinical signs is acceptable. We know that PNE is related to myelin protein antibodies and think this is pathognomonic for demyelinating polyneuropathy, neurofilament light is pathognomonic for axon damage, but not a specific neurodegenerative disease.

A non-human, clinically relevant parameter is a huge, and so far, an unsurmountable obstacle in ALS. What is acceptable would be a primary outcome variable that has been tied to a clinically relevant outcome in humans. The Catch 22 is that no drug that is effective in ALS animal models has been effective in humans. No drug that is effective in vitro has been effective in humans. And some biomarkers that are important in the disease process, like cytokine levels or neurofilament light (NfL), have not been statistically significant in human trials.

Recently FDA accepted NfL as a biomarker to assess drug effectiveness in ALS clinical studies. But as yet there isn’t a drug that changes NfL that shows a statistically relevant treatment effect in the ALS-treated population. We are working with a company that is doing ground breaking work called a human-on-a-chip assay that is intended to show a clinically relevant outcome variable that could move our human drug development forward. The Holy Grail we seek is a primary outcome variable in vitro that is shown in the literature to be statistically relevant and clinically meaningful in human ALS.

The major issue is that neurological diseases, human and horse, have clinical signs that relate to multiple diseases…now we are back to the clinically relevant population for our studies. That is the main reason veterinarians need to conduct thorough exams, conduct appropriate testing, and then select a treatment appropriate to the disease. A post-treatment exam is likely to show a relevant changes.

There are no equine models for PNE that would be acceptable to CVM that are affordable to conduct. In 2015 we conducted a feasibility study providing evidence that horses diagnosed with EPM (upper motor neuron disease or chronic relapsing motor neuron disease and antibodies against S. neurona) by a veterinarian have serum antibodies against a reactive site of equine myelin protein 2, a peripheral neuropathy marker. Anti-equine myelin protein 2 antibodies are linked to PNE and horses with anti-equine myelin protein 2 antibodies are found predominantly (over 90%) in horses with S. neurona antibodies. This isn’t enough evidence to prove cause (sarcocystosis) and effect (PNE). The statistitian says it could be conincidence.

These data lead us to conclude that chronic sarcocystosis can result in a demyelinating polyneuropathy and can be a factor in PNE. Other researchers reported the reactive site on myelin protein 2 is a reactive T cell epitope that corresponds to the cytokine Il6 receptor and expression of the IL6 receptor can be changed by levamisole HCl treatment. We provided data to show that levamisole HCl resulted in a clinical benefit in horses with and without antibodies against myelin protein 2. In another published study we provide data that suggests as C-reactive protein (CRP) values increase the likelihood of a seropositive myelin protein 2 test. We relate the increase in anti-myelin protein to a dysregulated CRP-IL6 pathway and may be a biomarker we can propose for clinical studies. Stay tuned!


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