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We are conducting an EPM-treatment effectiveness study that will compare the treatment response between two drugs. The new drug is compared to a drug selected from those that are available commercially. The commercially available drug is called the Active, we will compare our treatment to an Active. The FDA’s Freedom of Information (FOI) Summary reports important information that was used to license a drug, this information is publicly available. The FOI’s found for EPM treatments show between 15 and 59% effectiveness. Studies were done in less than fifty evaluable horses. It is important to replicate the parameters used to determine effectiveness in the Active in order to compare the results between the studies.

The effectiveness of two products (ReBalance® and Protazil®) defined a successful treatment when the Western Blot test on CSF, compared before and after treatment, were negative. That means if a horse did not improve clinically, but antibodies weren’t detected by CSF-immunoblot after treatment, the horse was considered successfully treated. The ReBalance study used a total of 26 horses to determine effectiveness. Rebalance® was successful in 15% of the horses, that means 4.2 horses showed an improvement in clinical exam after 90 days. A few more ReBalance-treated horses, 42%, improved after 210 days. And, if clinical exam was evaluated with western blot conversion to negative as the criteria for success…at 210 days, a few more horses were considered successes. One interpretation is that if no antibodies were detected then the parasites are gone; the horse didn’t improve because there was irreversible neurological damage. Although commonly believed, that is not our working model of EPM. We believe that neuroinflammation can be reversed, if diagnosed and treated properly.

The Protazil® FOI shows 59% of horses are better at 48 days, unless a negative western blot test is included in the effectiveness analysis. In that case, effectiveness is 67%. An advantage to comparing our drug to Protazil® is the duration to an expected response. The FOI reports an improvement 20 days after the end of treatment, day 48. That is a darn site better than 90-210 days.

The folks testing Marquis® reported in their FOI that “Western Blot of the CSF did not appear to be a major factor in determining treatment success nor a reliable measure of treatment success”. They used gait exam as their assessment parameter and showed 59% improvement based on that exam.

Remember it was shown (Furr et. al. 2006) that prophylactic treatment with anti-protozoals delay antibody production in horses given oocysts as challenge, the challenge is similar to how horses are naturally infected. It was Dr. Furr and his co-workers that showed a delay in antibody production did not indicate that clinical signs would be prevented when horses were given ponazuril as a preventive treatment. The down side to Marquis® is 110 days to show an improvement, 82 days after the end of treatment, and that is a bit too long for our ideal comparison.

There is one notable reference in the new Marquis® flyer we just received and worth a digression from our current topic. The flier cites a paper published years before S. neurona was isolated from an EPM horse! This paper is offered as evidence that ponazuril “kills the parasite that causes EPM to stop it from inflicting further damage to the central nervous system (CNS)”! The paper really reports the effects of trianzinones on developmental stages of Eimeria in chickens, no mention of S. neurona, EPM or CNS stages of sarcocystis that cause EPM. Eimeria are coccidian parasites, don’t develop muscle cysts, and does not cause EPM. Eimeria is found and stays in the gut of a chicken. The flyer also cites coccidia in calves, lambs, and pigs as references. We side with Dr. Dirikolu (JAVMA, Vol 242, 2013) that reviews in vitro and in vivo studies to “clearly indicate the removal of triazines after appropriate treatment time results in regrowth of parasites…suggesting that stages are inhibited and retain the ability to begin development again once the drug is removed”. That means the action of the drug, in horses with S. neurona infections, is static, it doesn’t kill (cidal) all the stages. That is one explanation why horses relapse on this treatment. That is why it is important to test the drug against the species of organism in the animal species for which it was intended.

We are conducting the study, in horses, to show the field effectiveness against suspected S. neurona in horses. From the forgoing information our logical selection is Protazil® as our active placebo for our study. We will evaluate the clinical response to the treatment, not an antibody difference measured on a test before and after treatment.

We proposed a study using two treatments. Veterinarians call this kind of study an active control effectiveness study design, there is no placebo because the active control serves as the placebo. The advantage with this type of study is that a client feels more secure that a horse with EPM is getting a treatment and not a “sugar pill”. A veterinarian can enroll a horse and we have to have some assurance that there will be 4 cases/site over a couple of years. The site is the veterinarians practice.

Orogin® is a drug that is designed to treat Equine Protozoal Myeloencephalitis (EPM) due to S. neurona in horses. The Orogin® effectiveness study uses an active controlled parallel arm effectiveness design with animals randomly assigned to treatment groups and receive either the investigational drug (Orogin®) or the active control (Protazil®). The study for Orogin® is limited to 70 horses. This is a study that will be part of our Freedom of Information Summary and, because it is an FDA study, it has a few strings attached.

This is not a placebo controlled study, the horse will get a drug to treat EPM. The signed Owner Consent form, is required. The owner consent form informs the horse owner that this is an investigational drug. Your horse will not be considered for entry into the study without this form in place. If you haven't signed this form, you are not in this study. Horses can receive an alternate treatment at day 10, if there is no improvement. Any horse that is removed from the study drug before the end of the study will be called a treatment failure. The horses are examined again at 48 days, the expected time for Protazil® to exert an effect.

What does it take for a horse to qualify for enrollment? The documentation for qualification is called the Qualification Record. There are three conditions that must be met to qualify 1) the horse must have a provisional diagnosis of EPM due to Sarcocystis neurona. 2) The animal must exhibit a minimum of a Grade 2 deficit, and the easy one 3) the animal is 9.6 months to 30 years. A Grade 2 deficit is defined as “neurological deficit obvious at normal gaits or posture; signs are exacerbated with manipulative procedures.”

There is a second part for the qualification into the study and that is disqualification because there are situations that will disqualify a horse. The horse can't be in another study or be unsuitable for this study. The horse can't enroll if it has another disease. If the horse can't get up, grade 5, or the owner can't get medication into the horse (or multiple folks will treat the horse) it won't meet the study qualification standards.

There are some other forms (all one page with check boxes) for the veterinarian to fill out, the Physical Exam form at day 0 and 48, the Data Collection forms at day 0, 10, 27, and 48 and a Supplemental History form (these document the criteria used to support the diagnosis of EPM). There is a blood draw before treatment and day 10, the blood is collected in a couple of red top and lavender top tubes, accompanied by a Sample Collection form. Owners participate in the observations by completing check boxes on the Client Observation form that note behavior, appetite, respiration, and occurrence of diarrhea for 28 days, the end of the Protazil® therapy. Additional space is provided for owner comments.

So far, so good. But the first inclusion criteria, a provisional diagnosis of EPM, may be the most difficult requirement for this study. The diagnosis of EPM must be supported by testing, along with any other diagnostic testing used generally by the veterinarian for the horse. This ensures the diagnosis is correct. The FDA set the standard as CSF analysis by Western Blot to support the diagnosis.

We recognize that CSF taps are not generally obtained in the field and most veterinarians test serum, or don't test at all. We strongly hold that serum testing guides the correct treatment and that is so important. Hopefully data from this study will support that rationale, just like the Marquis® study, that CSF testing isn’t the best criteria to determine a horse that will respond to treatment. What we know now, that was not known a few years ago, is that diseases (like S. fayeri or autoimmune polyneuritis) look like EPM but will not respond to ReBalance®, Marquis®, or Protazil®. That is why treatinginflammation that is common to S. neurona, S. fayeri, or autoimmune polyneuritis is important. We want to use the serum analysis to make these points in our FOI.

However, until there is a paradigm shift at FDA the horse must have a CSF tap to participate. We provide a CE course (3 credits) and teach a technique to obtain a CSF tap, in the field, in a standing horse. Field sedation techniques, using drugs most veterinarians have on hand, allow a veterinarian to get a CSF sample from the side of the neck. With a bit of practice, the tap can be obtained in a couple of minutes. You can email us for the link or go to the Learn More tab and copy the link from the slide presentation that describes Pathogenes CE program. We will run the CSF testing at no cost.

We are far from finished in our quest to make EPM treatable and affordable and need your help with these studies. If you desire new equine treatments in the pipeline veterinarians and owners will need to be proactive. From idea, to models, to field testing and ultimate use, it's expensive and time consuming. It's also highly rewarding. This is our commitment to the horse community and any part you can play is appreciated. A veterinarian can call and discuss the protocol and time commitments.

 

We believe new treatments are transformational when talking about protozoal disease. What inspires transformational thoughts and ideas?  Some think it is a mysterious process, right out of the blue, a light comes on.  More likely, innovation springs from many years of questioning, hard work, vigorous testing, and careful analysis.

We have reached the proverbial 10,000 hours (ref: Malcolm Gladwell, Outliers) studying EPM, creating models, and we are ready for a final analysis.  Our research started using models that defined the disease process and indicated that we could develop a beneficial treatment.  Years later, it’s time to put the models aside and statistically test our model.  Our first placebo controlled study for NeuroQuel is available, limited to 60 horse owners.  This is a study that will be part of our Freedom of Information Summary and because it is an FDA study it has a few strings attached.

NeuroQuel is a drug that is designed to control the residual or recurrent clinical signs due to inflammation associated with Equine Protozoal Myeloencephalitis (EPM) following antiprotozoal therapy in horses.  The field study will enroll horses that have failed to improve, or have relapsed after licensed EPM treatment (Marquis, Protazil, or Rebalance). The horses will receive NeuroQuel and we will evaluate the response to the treatment.

This is a placebo controlled study.  The first form, the Owner Consent form, is required.  The owner consent form informs the horse owner that there is a chance (a statistically calculated chance, 1 out of 3) that the horse will receive a placebo treatment.  Your horse will not be considered for entry into the placebo controlled study without this form in place.  If you haven’t signed this form, you are not in this study.

Does the horse qualify for enrollment?  Not surprising, the documentation for qualification is called the Qualification Record. There are three conditions that must be met to qualify 1) the horse was previously diagnosed and treated for EPM.  2) The animal exhibits recurrent or residual clinical signs with a minimum of a Grade 2 deficit, and the easy one 3) the animal is 6 months or older weighing 600 pounds or more.  A Grade 2 deficit is defined as “a defect that is easily detected and exaggerated by backing, turning or neck extension.  The horse may sway at a walk.  There may be a wide based stance after tight circling.  The horse is weak on the tail pull-easily pulled off track and does not return to a normal walk for 3 steps.”

There is a second part for the qualification into the study.  There are situations that will un-qualify a horse.  The horse can’t be in another study or unsuitable for this study.  The horse can’t enroll if it has another disease.  If the horse can’t get up, or the owner can’t get medication into the horse (or multiple folks will treat the horse) it won’t meet the qualification criteria.

There are some other forms to fill out, the Physical Exam form, the Data Collection form at day 0 and day 14, and a Supplemental History form (these document the criteria used to support the original diagnosis of EPM).  There is a blood draw before and after treatment, the blood is collected in a couple of red top and lavender top tubes, accompanied by a Sample Collection form.  Owners participate in the observations by completing check boxes on the Client Observation form for behavior, appetite, respiration, and occurrence of diarrhea.  Additional space is provided for owner comments.

So far, so good.  But the first inclusion criteria is the most difficult requirement for this study.  The original diagnosis of EPM must be supported by testing and other diagnostic testing as needed. The FDA set the standard as CSF analysis to support the original diagnosis.  After bioassay for antibodies in the CSF the horse must have received a full course of an FDA approved treatment, per label instructions: dose, duration, and frequency, no loading doses or multiple treatments.  Treatment must be what the sponsor intended when they licensed their treatment.  Treatment must be within 90 days of enrollment.  At the end of the FDA approved treatment, if signs (minimum Grade 2) are present, then the horse will qualify for this study.  Also, if within 90 days the horse “relapses” with a Grade 2 deficit, then the horse will qualify for the study.

We recognize that CSF taps are not generally obtained in the field and most veterinarians  test serum, or don’t test at all.  We strongly hold that testing allows the selection of the correct treatment and can be accomplished by serum testing.  Hopefully data from this study will support that rationale, CSF taps aren’t the best criteria to determine a horse that will respond to treatment.

However, until there is a paradigm shift at FDA, we provide a CE course (3 credits) and teach a technique to obtain a CSF tap, in the field, in a standing horse.  Field sedation techniques, using drugs most veterinarians have on hand, allow a veterinarian to get a CSF sample from the neck.  With a bit of practice, the tap can be obtained in a couple of minutes. You can email us for the link or go to the Learn More tab and copy the link from the slide presentation that describes Pathogenes CE program.

We will continue to use models that advance our ideas because idea-modeling will result in more treatment options for horses and their caretakers.  For example we learned about the effect Sarcocystis fayeri, a common protozoal infection in horses, can have on neuromuscular disease.  Another example is the presence of autoimmune disease in horses, when treated early the horse can have several more years of useful life. A  limited enrollment, placebo controlled study gathers statistical data.  After the “reasonable expectation” of clinical benefit study a conditional license is issued and a larger field effectiveness study is conducted.

We are far from finished and need your to help in these studies if new equine treatments are desired in the pipeline.  From idea to models to field use, it’s expensive and time consuming.  It’s highly rewarding.  This is our commitment to the horse community and any part you can play is appreciated.

Between the dark and the daylight,

When the sun is ascending to power,

Comes a pause in the day's occupation

That is known as the Scientist's Hour.

It is dawn in tiny Fairfield, Florida, but Pathogenes is not sleeping in. Before daybreak, we begin to answer the emails which slithered in overnight when nobody was looking. It's also time to send out the documents which had gone directly to spam and to watch videos of ataxic horses from every state but Hawaii and Alaska, not to mention a few from our friends up North. We make early phone calls to our team of advisors across the country, wishing we had been more alert in Geography so that we'd recall that it is two hours earlier in the Mountain Time Zone. We are repaid for this failing later in the day when other poor Geography students telephone us at Pathogenes from Sacramento at ten p. m.

Our drop box at the end of the gated driveway oftentimes offers up samples from local vets and these are carried back to the lab. FedEx runs an early delivery route before the regular noon call so the gates must be opened well before eight a. m. The team arrives beginning at nine, a courier is dispatched to the small Farifield Post Office forthwith and the delivery trucks begin rolling in, culminating with UPS, the final visitor of the day, at seven p.m.

Our interpretations of the results from samples sent to us are the culmination of more than forty years of lab and field experience and fourteen years dedicated to EPM. And now we have yet another addition to the team. We call him Hal 9000P and he is tasked with test result interpretations and reporting.

 

Hal 9000’s people skills are renowned-- earning a top 100 award in his previous career, see his resume on Wikipedia. Hal 9000-P is a Cracker Jack at numbers, especially the numbers -1, 0 and 1. True/false and “not null” are Hal’s forte…beyond that Hal 9000 doesn’t read or speak. Austin trained Hal 9000-P to use our algorithm.

Submission Forms The submission form accompanies serum samples and gives us all the data we need to help you with your case of EPM. Our interpretation, coupled with a veterinarian’s neurological exam and field experience, simplifies treating equine protozoal myeloencephalitis. Sometimes, we find no submission form in the box, just a blood sample. Careful sleuthing by the lab crew can often reveal the source from the return address sticker. Failing that, we wait. Eventually, someone will call for the results.

Gait Assessment Score The veterinary exams are critical to a meaningful interpretation of our test. A trigger for “no interpretation” is absence of information on the submission form. A horse name and reporting email won’t give us anything to interpret—it may even trigger an email from Hal 9000.

It is well known that most horses in the United States are exposed to S. neurona resulting in serum antibodies, but yet there is no disease. This conundrum plagued EPM diagnosis for 25 years. We rely heavily on the gait assessment score (GAS), our hands are tied if there is no GAS on the form. A behavior problem should be scored as a “1”, issues such as head shaking and Horner’s (syndrome) make sense to us but Hal 9000 doesn’t interpret comments. He can evaluate a “1” listed as “Normal-deficit”, just check the box. We also need the submission form signed in order to use it for our FDA endeavors. You will get an interpretation without a signed submission, but the data is lost to our research. Be sure and download our newest, easy to fill out form on the services tab.

Send pre- and post treatment samples The follow-up sample is also critical to our analysis. If the second submission isn’t available, we won’t know how drugs. We hear that the once Grade 4 ataxic horse is now happily galloping in the meadow and can’t be caught…to us that is a treatment failure. We need that second signed submission form and blood sample.

Treatment response Initially our logic is based on the horse’s treatment history. If the horse has not been treated with an anti-protozoal AND there are antibodies to S. neurona then we want how the animal did clinically after treatment. Send us a quick email and let us know the response! Alternately, if there are no antibodies to S. neurona we still want your veterinarian to understand the disease process, this will lead to treatment options.

No S. neurona antibodies, GAS >0 We base our recommendations on statistics. We have tested and evaluated thousands of horses. We realize that some horses have no antibody; there are several situations could exist. No antibodies to S. neurona can indicate early infection (less than 17 days) or the horse has been exposed to anti-protozoals. Less likely reasons for lack of specific antibodies are that the animal has no ability to respond due to a defective immune system. This is a long held myth that there is a genetic predisposition to develop EPM—we don’t believe that. There is another theory…there are many unrecognized to S. neurona strains, thus all Sarcocystis may cause EPM—this is the Great Divide between our testing (specific) and the others (non-specific tests).

And, here is the most logical reason: it isn’t EPM. Yes, the horse can have neuroinflammation but not have active infection. In these cases we believe that a past infection with S. neurona, treatment of protozoa and not inflammation, is the problem. Our statistics show that in 80% of the cases without specific antibodies there is no infection. These cases can be treated. The numbers also indicate that 20% of the time we would miss early infections. When there is an early infection a post treatment test can determine active infection. A fourfold rise in titer (antibodies in the serum) indicates that there was active infection. The treatment decision is based on the veterinarian’s experience and risk assessment.

If a veterinarian is risk-averse, we offer C-reactive protein (CRP) testing. If the inflammation is due to ongoing S. neurona, Lyme, enteritis, gastritis, colitis, respiratory disease, tumor or other cause of inflammation the CRP will be high.

Treated The best time to retest is 8 weeks following treatment. We want to see that the antibodies are down to the undetected range. However, it the GAS is > 0 after treatment, we suggest determining the CRP and further treatment.

Relapse A relapse of EPM defined by us as insufficient treatment of IL6 mediated inflammation. Bute and banamine don’t work to treat this inflammatory path. A relapse can be due to incomplete removal of S. neurona, re-infection with S. neurona, or a reaction to another cause of IL6 mediated inflammation. We are documenting other reasons for IL6 inflammation, we recognize vaccination can induced ataxia in 0.3% of disease reported on our submission forms.

It’s the end of the day…we’ve used our lifetime of acquired knowledge to help you with your horse. We encourage you to forward your questions to Hal 9000…he’s waiting…