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. We make that argument to FDA, let’s leave out that post-treatment CSF test. 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. Our 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. Our experience shows that an owner will know within 10 days if the drug is working, that means 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 our treatment is different, we treat the inflammation that is common to S. neurona, S. fayeri, or autoimmune polyneuritis. 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.