Our polyneuritis (PNE) field study was a multi-site historical controlled, GCP (VICH GL9) study conducted under field conditions to determine field safety and effectiveness for NeuroQuel®.
We already completed the laboratory safety study required by FDA for licensing the equine treatment and the chemical manufacturing (CMC) section of the submission. The last piece of this long endeavor is the field safety study.
Eligible horses were enrolled into our field study if they met the inclusion criteria and were not excluded. The main criteria for contacting veterinarians about cases was a positive Fordyce score and willingness to participate in the study. Seventeen hundred and seventy six potential cases from multiple geographic locations within the United States were identified and contacted using our algorithm.
The algorithm selected animals that we knew were seronegative for S. neurona antibodies against recombinant SAG 1, 5, and 6 antigens. Keep in mind that nearly all horses are infected with S. fayeri and 85% of horses in the United States are seropositive for S. neurona. But they do not have EPM. Surprisingly, 91.6% of horses with a demyelinating polyneuropathy are seropositive for S. neurona! Five hundred and ninety three (593) responses to our email indicated that the horses did not meet the Study inclusion criteria.
A primary concern with regulatory medicine folks is that the correct population is selected for participation into the study and their opinion was that horses should be S. neurona seronegative to enroll. Potential cases also were within a specific weight and age with clinical signs consistent with a diagnosis of PNE. The current defining signs of PNE are based on the Fordyce, Edington, Bridges, Wright and Edwards 1987 paper titled Using an ELISA in the differential diagnosis of cauda equina neuritis and other equine neuropathies.
Veterinarians did not respond to one thousand one hundred and forty eight (1148) solicitation letters indicating our emails went to spam, or these veterinarians don’t recognize PNE or the importance of bringing a therapy to their patients. We will try to teach them what we know.
Polyneuritis equi is a rare condition and it is not recognized often enough by veterinarians. The presumptive diagnosis of EPM is foremost on the differential diagnosis list of neuropathies with upper motor neuron signs distinguishing them from PNE that starts with lower motor neuron signs. PNE can have UMN signs in the terminal stages of disease. Horses with PNE do not respond to antiprotozoals. Chronic antiprotozoal therapy in these horses results in relapses, progressive disease and eventually death.
Why was a change in Fordyce Score the key evaluator for the study? In 1987 researchers examined 27 potential neuropathies using an ELISA assay employing myelin P2 from bovine or equine myelin as the capture protein and then used post-mortem exam to confirm a diagnosis. Their ELISA test detected all cases of PNE with caudal involvement using antibody against myelin P2 as the analyte (what they were testing). Fordyce et. al. found their test was limited in differentiating neuropathies involving only cranial or other peripheral nerves.
Once the caudal nerves are calcified or fibrosed there is no hope of treatment. Our goal is to identify early stages of PNE that we believe can be treated. It was shown a few years after the Fordyce report that recombinant proteins are superior to minced nerve tissue, just as recombinant ELISA’s are superior to western blots. When you hear others tried and failed to identify PNE horses with their “tests” be sure and question the source of the antigen(s). We use recombinant P2 and most importantly, the sequence of amino acids that are neuritogenic—the part of the equine myelin P2 that corresponds to the cytokine IL6 receptor. In human medicine the comparison of antibodies against these two proteins are predictive of disease progression. It works for us.
The Fordyce team did recognize that the signs of PNE included tail paralysis, urine retention, rectal dysfunction, perineal analgesia, muscle wasting over the hindquarters and any sign associated with a cranial nerve neuropathy, ear droop, inability to blink and masticatory muscle wastage. They recognized the pathology as inflammation of the nerve roots in any peripheral nerve involved. They also documented remyelination in the process, they saw destructive and reparative lesions being juxtaposed, just as others had. That means if the distructive process is halted the nerve can repair.
The recently completed study allowed us to add some signs that were observed by Owners that are not on the Fordyce list. It is possible including these signs can identify horses that can be treated before the damage is irreversible. We will ask the Agency if they will consider inclusion of these additional signs for a more rigorous study that can further define PNE.
The presence of disease detected by anti-myelin P2 antibody did not determine the cause of disease for the Fordyce team. The reason is any inciting agent that sets off an IL6 response can result in a demyelinating polyneuropathy. PNE has multiple causes with similar pathology. Vaccines that use equine dermal cells will cause PNE in 3% of the cases that we evaluated. Fordyce recognizes the link to experimental allergic neuritis, the model to induce that disease is giving dermal cells.
Sarcocystis neurona can cause a polyneuritis, we showed that in our Trojan Horse model experiments. It is expected that Borrelia will do the same and this organism will ultimately be associated with PNE as “post-treatment Lyme disease syndrome”, as it is in people. We are asserting any organism (bacteria, virus, protozoa) that elicits an IL6 mediated innate immune response, that becomes dysregulated, may result in PNE. Some organisms will be more inclined to elicit a PNE reaction, possibly S. neurona is one of them.
The take home message is that the presence of antibody to P2 in horses suffering from PNE is a useful diagnostic indication of the condition, just as it was thirty-six years ago. The term we use is a demyelinating polyneuropathy. The value of testing for antibody to P2 as a prognostic indicator is undetermined, however adding the neuritogenic peptide to the analysis may get us there. Antibody levels to P2 will not be correlated with clinical severity, just as the antibody levels against S. neurona don’t correlate with clinical severity or detect the presence of parasites in the CNS. Antibody levels do correlate with duration of infection in S. neurona, increasing and decreasing titers are important to assess clinical course of the disease. Changing P2 titers in horses with PNE are also important to assess the clinical course of disease. It is possible that our next study will provide a missing piece of the PNE association with S. neurona.
If you have a horse with signs of PNE be sure to call us and discuss the case. Help us associate serotype of S. neurona to PNE and most important, when we open another study please see if you have a horse that will qualify.