Clinical Trials and Black Market Statement
REcent News on FIP TreatmentS
FIP Cats Treated with New Antiviral Drugs in Clinical Trials Go Into Remission
Purina Pro Plan Spring 2019 issue reviewing the current state of the clinical trials.
Wet FIP treatment submitted to FDA
("Veterinary researchers and Anivive license antiviral drug for fatal cat disease", Kansas State University, September 20, 2018)
GC376 drug trial for Dry FIP
("Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis", Journal of Feline Medicine and Surgery, August 7, 2017)
GC376 and GS441524/GS5734 Policy
Anyone with true FIP knowledge and understanding, realizes the amazing progress made since the Bria Fund for FIP Research was founded in 2005. Also, they possess an appreciation for the complexity of FIP itself, and that there are no quick and easy solutions to treating or ending it. Over a decade ago, Julie Stanton, aided by a few Bria Fund supporters, created the FIP Fighters’ Group to support people going through the scary and horrible FIP experience. We had no one to go to when we lost our FIP angels and didn’t want others to be alone. No one wants an end to FIP more than we do, and with every precious life taken by FIP, our hearts break again.
There are other FIP groups on Facebook, but none of them possesses the collective depth of this group’s administrators and resources. We are knowledgeable about all aspects of FIP, including research. All credible FIP researchers are respected, and valuable information from them shared in the group, with the understanding that all researchers have egos and they don’t always agree with each other. FIP Fighters is a private group, with guidelines strictly enforced. To avoid conflicting information and confusion, we recommend a member belong to FIP Fighters or another group. In addition, other Facebook FIP groups may not be mentioned, nor conflicting information from those groups discussed. Belonging to FIP Fighters is a privilege, and by belonging, all members agree to accept our guidelines. We are an atypical social media vehicle guided by courtesy and respect for members and especially for our administrators who unselfishly devote valuable personal time to help others.
After a lot of discussion among administrators and consideration of relevant facts and information, we are issuing this FIP Fighters’ policy on GC376 and GS441524. Please read it carefully and follow it. Thanks.
FIP Fighters supports treatment and procedures supported by research studies published in peer reviewed scientific journals. We also advocate for participation in legitimate, humane clinical trials. FIP progress to date included initial, successful clinical trials using experimental drugs GC376 and GS441524. Both drugs are still experimental and neither approved or available to the general public. Additional FIP clinical trials using GC376 are underway, and GS441524/GS5734 is a human drug currently in a phase 2 clinical study. Neither drug is available as an approved drug on any market in the world.
Versions of both are being sold as chemical substances in China and elsewhere. These substances made by chemists are usually only legally available to restricted entities, such as research facilities. A chemical substance differs greatly from a drug approved for use in humans and cats. Approved drugs must go through a complex process, including clinical trials to ensure they work and are safe for use.
FIP Fighters’ guidelines are specific about acceptable discussion and prohibition of certain topics and information. Prohibition includes “Links to unlicensed providers for treatment purposes.” and “Soliciting for a product ex. book, remedy”. We do not permit links or messages of solicitation or referral for purchasing either GC5734 or GS441524. Members may no longer tell another member via the group to contact them for purchasing/obtaining these chemical compounds or for information related to precluded topics for discussion, like homeopathy. For the time-being, we will continue to allow individual members using GC376 and GS441524 to share updates and documents supporting improvement. We care about every cat and owner dealing with suspected or clinically diagnosed FIP.
Involvement of a veterinarian in all aspects of health care for cats with suspected or diagnosed FIP is critical. That includes any use of these experimental chemical substances. Individual owners and vets are ultimately responsible for treatment a cat and any legality.
Contaminated Generic Drugs
April 11, 2019
This article is about contaminated generics, but we think it explains and justifies some of FIP Fighters’ concerns about use of unapproved substances and drugs. Please read it thoroughly and carefully. It explains that generics are not the same as or identical to name brand drugs. Contamination problems were caused by active pharmaceutical ingredients manufactured in China and India. There are still manufacturing problems in those countries, and the FDA has stepped up its presence and manufacturing inspections in both countries.
Drugs alleging to be GC376 and GS441524 are not generic versions of the drugs in the clinical trials, nor have their safety and efficacy been established.
Contaminated Generic Drugs Reveal an Urgent Public Health Crisis
by Peter Pitts - 4/4/2019
Quality can be stipulated, but it cannot be assumed. Quality occurs by design; it cannot be tested into a product. Nowhere is this truer or more urgent than when it comes to generic drugs. Why generics? Because they represent 90 percent of the volume of medicine consumed by Americans.
Medications approved by the U.S. Food and Drug Administration (FDA) rest upon three pillars: safety, efficacy and quality. Up until recently, quality has been a silent partner—but that’s no longer acceptable. It often takes a crisis to propel important but overlooked issues to the forefront. Witness the recent public health imbroglio over valsartan, a widely prescribed angiotensin II receptor blocker (ARB), most commonly used to treat high blood pressure. Over the past few months, a dozen companies have recalled their generic versions of valsartan and other ARBs because of contaminated ingredients containing three different potential carcinogens.
How can such things happen? Isn’t a generic drug “identical” to its innovator reference product? Aren’t generic drugs approved by the FDA because they are just as safe and effective as the original brand? Alas, the answers to these questions are complicated.
First, as to generic drugs being “the same as” or “identical to” their brand cousins, the answer is they are not. Generic drugs are pharmaceutically equivalent (same active ingredient, dose and dosage form) and “bioequivalent” to the innovator brand. The fundamental regulatory assumption (as codified in the Hatch-Waxman Act) is that if two formulations are shown to be bioequivalent (resulting in equivalent blood levels of the drug), it is presumed that they will reach the same therapeutic effect, are therapeutically equivalent and can be used interchangeably. Bioequivalent doesn’t mean identical, and such differences are more important for certain types of medicine, specifically for medications that require a “narrow therapeutic index” for conditions such as epilepsy in which even a small difference can result in therapeutic failure.
Bioequivalence, however, was not the issue with valsartan. The problem was caused by contamination of the API (active pharmaceutical ingredients) manufactured in China and India. The FDA believes that genotoxic impurities may be generated by changes made in the API manufacturing process, but also may result from the reuse of materials, such as solvents.
According to the FDA’s website, more than 282 warning letters have been sent to pharmaceutical companies related to manufacturing problems since 2015. Of those, 70 involved active pharmaceutical ingredients.
Generic drugs are too important to America’s public health to allow anything less than complete confidence in their safety, efficacy and quality. Manufacturers unaffected by contamination issues have increased the price of valsartan at least twofold amid the recent recalls; Alembic Pharmaceuticals more than tripled the price of 17 of its valsartan formulations, with price hikes ranging from 329 to 469 percent. The bad actors who take advantage of recalls must be put on notice that such behavior, while not illegal, is certainly not in the public’s best interest.
This is why the FDA recently announced a plan to revamp its rules that govern how medicine is manufactured in an effort to ensure the safety of the nation’s drug supply, as recalls of contaminated imports from developing countries widen. Per outgoing FDA Commissioner Scott Gottlieb, “We’ve seen a lot of instances of adulterated products—contamination, impurities—recently… The underlying causes have been traced back to manufacturing, inadequate quality controls and generally poor management oversight.” The proposed rule changes will focus on the active pharmaceutical ingredients; however, Gottlieb said the overhaul is only now in its early stages and may take several years to complete.
An important inside-baseball but mostly overlooked move by the FDA was to develop a specific pharmaceutical inspectorate within the agency’s Office of Regulatory Affairs (ORA) rather than having district-based offices drive the process without the necessary authorities or resources.
According to Dr. Richard Kovacs, president of the American College of Cardiology, the recent ARB recalls have been “a bit of a reality check” in an era of easing regulatory constraints.
“If there is a silver lining to this, it’s going to be a measured approach to how we protect our drug supply in a global economy,” he said. “Certainly making everything in the U.S.—up to and including fill-and-finish—could be one solution, but that will have to be balanced against the cost of our drugs.”
“Inexpensive drugs are going to mean inexpensive manufacturing processes, and you would hope there wouldn’t be corners cut or quality controls that aren’t going to be kept, but the reality is it’s going to happen,” Kovacs said. “I think this is a societal question and an important regulatory question as to what the right balance of safety and efficacy is in this new framework.”
The bottom line is that generic manufacturers are going to be scrutinized more robustly and more regularly. Going forward, physicians and patients may start demanding products manufactured by specific generic companies that prioritize quality over cost.
As the Journal of Infection so aptly stated: “Nothing is more expensive than treatment failure.”
Peter J. Pitts, a former FDA associate commissioner, is president of the Center for Medicine in the Public Interest and a visiting professor at the University of Paris, Descartes Medical School.
Black-market Production and sale of GS-441524 and GC376
Niels C. Pedersen, DVM PhD
Distinguished Professor Emeritus School of Veterinary Medicine
University of California, Davis
April 26, 2019
A number of entities, largely in China, are manufacturing GS-441524 (GS) and GC374 (GC) for sale mainly to desperate owners of cats with FIP. Although the first effort was centered around GC, the emphasis of this black-market has rapidly shifted to GS. Although this sort of marketing and use of GS and GC is technically illegal and it could be considered unethical for veterinarians to assist in treating cats with such drugs, the companies holding patents on GC and GS have no effective means to halt this black-market use. The individuals and companies that are offering GS and GC are usually including a disclaimer to customers limiting the use of their compounds to what they call "for research use only - not to be used for human or veterinary use." This will effectively shield them from any "improper or illegal use." Owners purchasing such black-market products are under no legal obligation to abide by such limited use disclaimers. However, veterinarians that choose to assist owners with treating cats with such drugs may have no such protection against adverse situations that might arise from such unauthorized use. Therefore, some veterinarians are also requiring signed waivers from owners freeing them of any legal or ethical obligations for such treatment.
I have been opposed to the black-market use of GC or GS mainly because I have seen the "wild-west-like" situations that it creates. Although chemists producing these drugs indicate that they are highly pure, there is no testing for biological activity (i.e., antiviral effect). We already know that GC and GS are being made by an increasing number of individuals and that the quality on a mg/kg or molar dosage can greatly vary. We also know that the price of GC and GS can also vary greatly and that owners may pay many thousands of dollars for enough drug to complete a treatment. Purchasing sufficient drug, and soon enough to be of help, is only the first step. The drug may be purchased in a powder form, which requires more than average knowledge to successfully convert to a stable and injectable form. In response to this problem, some suppliers are offering GC or GS that has already been made into an injectable form. There is often no information on how this was done, what diluent was used, local and systemic toxicity, and its stability once in injectable. If owners or veterinarians insist on purchasing GS or GC on the black-market, usually at a very high price, they should expect some sort of information from the supplier as to biological (antiviral) activity on a molar basis, diluent used, and information on storage conditions and shelf-life.
The second problem with black market GS and GC involves how it is used, even if it should be equivalent in purity and biological activity to GS and GC described in peer-reviewed scientific publications. If the purity and anti-viral activity is the same as the drugs described in research publications, the published information can be directly applied. If they are not, then published information will not apply. It is also critical that the diagnosis of FIP be as strong as possible, as the disease is still frequently mis-diagnosed. Therefore, it is hoped that owners have access to a level of veterinary expertise that will assure that only cats needing such treatment will be subjected to a regimen of this emotional involvement, duration, cost, and need for proper monitoring. There is still a lack of knowledge of how to properly treat cats with the neurological and ocular/neurological forms of FIP. GC and GS penetrate into the brain with some difficulty. The only way to increase drug levels in the brain is to increase the blood level by using higher and higher dosage regimens. It does appear that higher dosages, especially with GS, can lead to complete or near complete remission of clinical signs, but relapses are common, and it is still uncertain whether every cat with neurological FIP can be cured. Because of these facts, cats with FIP and neurological involvement should be approached with far more caution than other forms of FIP. Cats treated for other forms of FIP, and later developing neurological signs, should be considered the same as cats with primary neurological FIP. The expense of retreating after relapses and using higher dosage of drug, with unknown expectation of cure, should be reason to carefully evaluate the pros, cons and unknowns of treating such cats.
I will continue to provide as much advice as possible for owners and veterinarians contemplating the use of black-market GS and GC to treat cats with FIP. However, I must make it clear that I would have preferred these drugs to be approved and commercialized in the normal manner. I am certain that this will happen within the next few years, and as it does, the black-market demand for drugs like GS and GC will disappear. In the meantime, UC Davis will continue to research new antiviral drugs for diseases like FIP and to share our findings in the conventional manner of peer-reviewed research publications. Our obligations are only to assure owners and veterinarians that our findings are accurate, reproducible, and applicable. We have no direct control of how our findings are ultimately applied.
Neurological and ocular FIP
Niels C. Pedersen, DVM PhD
Distinguished Professor Emeritus UC Davis
Center for Companion Animal Health
April 29, 2019
Many owners of cats with FIP have turned to the Chinese black market to obtain GS-441524. This black market is not entirely profit motivated as the FIP problem in China is horrendous. Pets are the in-thing in China, and expensive pedigreed Western breeds of cats produced locally are imported from abroad are especially valued. As a result of the associated FIP problem, Chinese were producing, selling, and applying drugs like GC376 and GS-441524 months before we were even able to publish our results. The reality is that the immediate need for drugs like GS-441524 has outpaced the official approval and commercialization process, which takes years. The result is a wild-west with new producers and suppliers entering the market weekly. Ultimately the black market will disappear as official suppliers come forward and patents are finally enforced. In the meantime, it is not beneficial for FIP anti-viral drug therapy to be given a bad name. Therefore, the purpose of this article of this communique is to discuss one of the main problems that has arisen, i.e., what to do with cats that have the neurological and/or ocular forms of FIP. This group of cats is increasingly a focus of my communications and also the type of cat that is most difficult to treat and requires a lot more clinical research.
The blood-to-brain and blood-to-eye barriers
The eye and nervous system are protected from harmful substances/agents by what is called the blood-to-eye and blood-to-brain barriers. These barriers have great evolutionary significance because they protect both brain and ocular functions from the effects of systemic toxins and infectious agents. Such barriers evolved over millions of years by positive selection for the fittest. The blood-to-brain barrier in cats will exclude around 80% of most drugs, while the blood-to-eye barrier excludes about 70%. Therefore, if a given dose of drug such as GS-441524 achieves an effective blood (plasma) level of 10 uM, the levels in the brain (cerebrospinal fluid) will be only 2 uM and the level in the eye (aqueous humor) only 3 uM.
There are several other aspects of these barriers that need to be considered. First, their efficiency at excluding unwanted substances and agents varies between individuals. Second, the efficiency of this barrier will decrease in inflamed tissues and increase as inflammation subsides. This is good for treatment in the early stages of disease but bad for treatment in the final stages when the inflammation is gone and only the virus is left. Thirdly, there is no simple, safe or effective means to decrease these barriers and the only way to increase drug levels in brain or eyes is to increase their levels in blood plasma with higher dosages.
How these barriers cause disease
Paradoxically, the ocular and neurological forms of FIP are also a result of these same barriers, but in this case of neurological and/o ocular FIP, the impediment is to the entry of antibodies and immune lymphocytes. The phenomenon of neurological disease following a common systemic virus infection is well known in humans and animals. The prime example is polio-encephalomyelitis in people and canine distemper in dogs. The polio virus is a common enteric pathogen and usually causes an inapparent or mild intestinal infection. However, in some people the virus also escapes to the brain and spinal cord. People mount a vigorous systemic immune response to the polio virus, which is highly effective in eliminating the virus in parts of the body except for the nervous system, where the blood-to- brain barrier limits is an impediment to immunity. These unfortunate people will develop the classical neurologic form of the infection. A similar phenomenon occurs with canine distemper. The canine distemper virus, which is closely related to the human measles virus, causes an acute respiratory infection in young dogs that manifests 7-14 days after exposure and lasts for a week or two. Most of these dogs will completely recover, but a proportion will develop neurological disease three or more weeks later. This highly fatal secondary form of canine distemper is caused by virus that escaped into the brain and spinal cord during the respiratory phase of infection and is shielded from the host's immune system by the blood-to-brain barrier.
What is FIP?
FIP is ultimately caused by a common and a largely innocuous enteric coronavirus, similar to coronaviruses causing diarrhea in humans, foals, calves and poultry. In about 10% of cats, mainly kittens, the enteric coronavirus will undergo specific mutations that allow it to escape the cells lining the lower intestine and infect the most basic cell of the immune system, the macrophage. This macrophage infection is eliminated in all but 0.3-1.4% of cats, which for unknown reasons are unable to develop the required protective immunity. The disease that occurs in this unfortunate small group of cats can clinically manifest within days, several weeks, sometimes months, and rarely a year or more. The form of disease that is manifested is referred to simply as wet (effusive) or dry (non-effusive). These two forms are easily distinguishable, although there may also be transition forms between the two. Some cats may present with signs of dry FIP but later develop wet FIP, or vice versa. Overall, about 75% of cats will present with wet FIP and 25% will present with dry FIP. Less than 5% of cats, usually those with milder forms of dry FIP to start, will survive longer than one year with the best symptomatic care.
Clinical manifestations of FIP
The clinical manifestations of wet (Table 1) and dry (Table 2) FIP vary according to the main site(s) of disease in the body. Wet FIP is characterized by the accumulation of large amounts of inflammatory fluid either in the abdominal cavity and/or chest cavity. Involvement of the central nervous system (CNS) and eyes is relatively uncommon in the wet form of FIP. The dry form of FIP is characterized, not by diffuse inflammation and fluid effusion, but rather by less numerous and larger tumor-like lesions (i.e., granulomas) in organs (e. g., kidney, cecum, colon, liver, lung, lymph nodes) within the abdominal or thoracic cavities, or in the eyes and brain. Whereas the brain and/or eyes are only involved in 9% of the cases, neurological and-or ocular disease is seen as the main presenting clinical sign in 70% of cats with dry FIP.
Table 1. Variability in clinical signs of effusive (wet) FIP from cats necropsied at UC Davis
Signs referable to: % affected Peritoneal cavity 58.0 Peritoneal & pleural cavity 22.0
Pleural cavity 11.0 Peritoneal cavity, eyes 2.8 Peritoneal cavity, CNS* 1.9 Peritoneal and pleural cavity, CNS 0.9 Peritoneal and pleural cavity, eyes 0.9 Pleural cavity, CNS, eyes 0.9 Peritoneal cavity, CNS, eyes 0.9 ________________ *Central nervous system (brain, spine)
Table 2. Variability in clinical signs of non-effusive (dry) FIP from cats necropsied at UC Davis
Signs referable to: % affected Peritoneal cavity 30 CNS 22 Eyes 14 CNS & eyes 8 Peritoneal cavity, eyes 7 Peritoneal & pleural cavities 4 Peritoneal & pleural cavities, CNS 3 Peritoneal & pleural cavities, eyes 2 Peritoneal cavity, CNS, eyes 2 Pleural cavity 1
The FIP virus spreads to sites outside of the body cavities through infected macrophages that have gained entry to the bloodstream. The main clinical signs of neurological FIP are fever, inappetence, weight loss, and incoordination (most intense in posterior). Some cats may also develop seizures and varying degrees of dementia. Ocular disease often accompanies neurological FIP due to the intimate relationship of eyes and brain. Ocular disease is most often manifested by inflammation of the anterior uveal tract (iris and ciliary body) with discoloration of one or both irises, precipitates on the back side of the cornea, and cloudiness of the aqueous humor. Ophthalmoscopic examination may also demonstrate inflammation in the retina and optic nerve.
Diagnosis of neurological and/or ocular FIP
The neurological and/or ocular forms of FIP can be confused with feline systemic toxoplasmosis, which is why so many cats with these forms of FIP are tested for toxoplasmosis and treated with Clindamycin or other antibiotics. However, systemic toxoplasmosis is an exceedingly rare disease of cats, especially when compared to FIP. FIP can be easily differentiated origin (cattery, foster/rescue, shelter), signalment (age, gender, breed), and basic blood test results. Deep fungal infections (coccidioidomycosis, blastomycosis, histoplasmosis) can cause similar clinical signs to dry FIP but are still uncommon even in their endemic regions. Lymphoma may also be a differential diagnosis for dry FIP, but this disease is usually sporadic and in older cats. The diagnosis of neurological and/or ocular disease is ultimately based on where a cat comes from the clinical signs, age, common changes in complete blood count (anemia, lymphopenia), serum protein changes (high total protein, high globulin, low albumin, low A:G ratio). The diagnosis may be confirmed if there is still doubt, by characteristic changes in cerebrospinal fluid (CSF) and aqueous humor (high protein, high cells, neutrophils, lymphocytes, macrophages), suggestive lesions on MRI, PCR or immunohistochemistry on CSF, or high serum coronavirus antibody titer by IFA (>1:3200). One must be careful, however, to follow the 70% rule, i.e., no single typical laboratory abnormality will occur 100% of the time. The rapid response of FIP to GS- 441524 is in itself a diagnostic indicator.
Treatment of neurological and/or ocular FIP
The only effective treatment for neurological and/or ocular FIP is an antiviral drug such as GS-441524. The minimum dosage regimen for this form of FIP should be 5 mg/kg, SC, q24 h for at least 12 weeks. We have found this treatment to cause a rapid reversal of clinical signs within days, a return to near normal within two weeks, and a return to full normalcy within 8 weeks or so. The best gauges of normalcy are weight gain, growth if retarded by the disease, and the ability to once again jump to previous heights without hesitation. Although GS-441524 is highly effective in reversing abnormal clinical signs in cats with neurological disease, it is not always curative. Relapses of disease following cessation of treatment have occurred within days to several weeks after stopping treatment and the relapse rate appears to be much higher than for cats suffering other forms of FIP. We have treated only six cats with neurological disease (four also with ocular disease). One cat relapsed with neurological disease after completing treatment at a dosage of 2 mg/kg, SC, q24h and was cured at a dosage of 4 mg/kg, SC, q24 h, while a second cat was treated twice at 2 mg/kg and relapsed each time. A third and fourth cat was treated at a dosage of 5 mg/kg and cured, while a fifth cat relapsed after two identical treatments at the same dosage. A sixth cat relapsed at 5 and 8 mg/kg and is now being treated at a dosage of 10 mg/kg. Cats that cannot be cured of FIP can be kept in a state of normalcy with indefinite treatment, but this can be a costly endeavor and with unknown long term side effects and the spectrum of drug resistance.
Can most cats with neurological FIP be cured?
The bottom line is that we do not know whether all cats with neurological FIP can be cured and in this regard, people treating cats with neurological FIP are definitely in a research mode. We feel that increasing the blood levels may be part of the solution based on very few cases. It is also interesting that ocular lesions in cats with neurological involvement are more amenable to treatment. We found that ocular disease signs can be eliminated at a dosage that is not sufficient to cure brain disease. This may reflect the greater permeability of the blood-to-eye barrier compared to the blood-to-brain barrier in cats.
The ability of drugs like GS-441524 to inhibit inflammation caused by FIPV infected macrophages may also be a two-edged sword. Increased vascular permeability in lesions may allow more drug to pass into tissues in the initial stages of treatment, while resolution of the inflammation may re-instate the barrier and prevent sufficient drug levels later in treatment.
Finally, the problem of drug resistance of FIP virus in brain has to be considered. We know from our field trial experience, and from the published research of others, that drug resistance occurs in a very small proportion of naturally infected cats and can be also induced by repeated passage in cell culture. There is additional evidence from the literature that different forms of the infecting virus can evolve in different tissues, so that virus in the brain may respond different to GS-441524 than virus in other parts of the body. The long-term exposure of variant viruses in the brain to low levels of drug could be conducive to the evolution of drug resistance. If drug resistance is present naturally or occurs after long term treatment, increasing drug dosage will not succeed.
From Niels Pedersen- BS, DVM, PhD
Center for Companion Animal Health, University of California - Davis
Medicine & Epidemiology
There is currently no effective treatment that is legally available for cats with confirmed FIP. Until new treatments can be approved and marketed, treatment remains largely symptomatic. A low to moderate dosage of prednisolone or prednisone (starting at 2 mg/kg, orally, once a day for two weeks and then 0.5-1 mg/kg indefinitely), coupled with a diet high in animal protein (e.g., 1/2 cooked chicken, turkey or rabbit and 1/2 a favorite commercial cat food) and a lot of personal care, is the simplest and possibly most effective symptomatic treatment. Symptomatic treatment ultimately depends on the cat's immune system to cure the infection. Some cats may have mild or subclinical disease isolated to a single intestinal lymph node, which may be detected as an abdominal mass upon routine physical examination or during a spay operation. Cats with more severe clinical signs will often go into a more chronic and less severe stage of disease after several weeks. As we gain more experience with treating rather than euthanizing cats when FIP is diagnosed, we begin to appreciate that a proportion of cats may survive for many weeks, months, and rarely a year or more. However, it is still fair to say that FIP is ultimately fatal to most cats if left to run its natural course.
There are misconceptions on the value of removing fluid effusions. Cats with chest involvement and breathing difficulties can benefit greatly by removal of pleural fluid. Chest fluid also tends to be slowly replaced, especially when cats are treated with prednisolone. Removal of abdominal fluid should be discouraged unless it is so massive that it interferes with breathing. Abdominal effusions tend to be rapidly replaced at the expense of body fluids and proteins. Owners can be encouraged to maintain symptomatic and palliative treatment for as long as weight and activity are maintained. This can be days, weeks, sometimes months, and rarely a year or more. However, owners should be apprised of the extremely high morality that occurs among cats with clinically active FIP.
There is some debate on whether certain non-steroidal anti-inflammatory drugs (e.g., TNF-alpha blockers such as pentoxifylline, thalidomide), specific immunomodulators (e.g., feline interferon omega, human recombinant alpha or beta interferon), and non-specific immunostimulants (e.g., several plant- or microbial-based biologics) have any efficacy against FIP. Although an initial study with feline interferon omega indicated efficacy, a subsequent large double blind and placebo-controlled trial showed it to be without efficacy. Human alpha and beta interferon are also of doubtless benefit and are immunogenic to cats and will be ultimately destroyed by the resulting antibodies. A similar large-scale trial with pentoxifylline also showed it to be non-effective against FIP.
Homeopathic treatments for FIP
Homeopathy involves the administration of sub-toxic doses of substances, usually plant based, which mimic the disease signs that are intended to be cured. There are several web sites that are offering various homeopathic medications for cats with FIP. They are basically dilute tinctures of various plant extracts. These extracts are quite expensive, and many desperate owners will be tempted to use them. One of these companies is in Australia -(http://www.naturalpaws.com.au/feline-infectious-peritonitis-fip-usefulinfo-112-false.html).
The use of non-specific immunostimulants has been popular in veterinary medicine for decades, usually for treating specific signs of feline leukemia and feline immunodeficiency virus infection such as anemia or low lymphocyte counts. There are occasional anecdotal reports of cats with “FIP” being cured or their lives prolonged by such treatments. These types of immunostimulants include substances such as Staphylococcal A protein, ImmunoRegulin (Propriobacterium acnes), Acemannan (mucopolysaccharide extract of Aloe vera leaves) and Imulan (lymphocyte T-cell immunomodulator). There is no evidence that these biologics have any beneficial effect on actual cases of FIP.
Peritan FP is a plant-based substance that is advertised for cats with FIP. Itt can be found at - http://www.greenpetdepot.com/products/peritan. Interestingly, advertised statements about the efficacy of Peritan for FIP conclude with the following statement – “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.” People should also be aware that some of the anecdotes attesting to the efficacy of a certain product for FIP are deliberately posted. Furthermore, many of the cats described may never have had FIP in the first place.
The most popular non-specific immunostimulant touted on the web to treat cats with dry FIP is an extract of tree leaves. Polyprenyl immunostimulant (PI) (https://vetimmune.com/pi-product-information/) is classed as a biologic by the USDA and is manufactured by Vetimmune (https://vetimmune.com/) (formally Sass and Sass, Inc.). PI has been given a conditional license by the USDA as therapeutic for “symptoms” of feline herpes virus infection. Although not currently approved for the treatment of FIP by the USDA, it is being widely used off label for prolonging the life of cats with milder forms of FIP. Polyprenyl immunostimulant as a potential treatment for cats with FIP has an interesting history that extends from Russia to the United States. The research and chemical structure of PI is based on a biologic "plant extract" called Phosprenyl, which is used in Russia to treat a wide range of viral infections in many animal species (http://www.2ndchance.info/fip-gamavite.pdf. The first publication on the use of PI for FIP outside of Russia was an article (http://www.vet.utk.edu/research/fip/FIPpolyprenyl.pdf) published by Dr. Al Legendre and colleagues. In this study, three cats with subclinical dry form FIP were treated with Polyprenyl Immunostimulant. Two of the three cats were alive and well 2 years after diagnosis. The results from these three cats were used to justify a much larger treatment trial on 58 cats presenting solely with dry FIP. The results of this study were presented in 2012 at the ACVIM forum. Twenty-two percent were alive at least 165 days and three cats lived longer than 365 days (5%), which was longer than what was expected. However, this study was faulted for not including a placebo control group and was subsequently published in more detail and including a historical control group - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306384/. This report described 60 PI treated cats with dry FIP and 59 cats with similar dry FIP from the literature that had not been treated. Eight of the 60 cats survived over 200 days, and 4 of 60 survived over 300 days No historical control cat that suffered solely from dry FIP and not treated with PI lived longer than 200 days. The conclusion was that PI treatment prolonged the life of cats with the dry form of FIP.
The published results with PI are difficult to interpret, but it can be safely concluded from the researchers words that cats with wet FIP are not responsive to treatment and that there may be a small increase in survival time for cats with the milder dry form of FIP. It is also important to note that the USDA has not added FIP to its list of approved diseases for PI treatment and that the makers of PI do not promote its use for FIP. However, it has gained a vocal following on the web that generates a considerable market for treating FIP. PI may cost over $400 a month if used on an average size cat and dosed accordingly and this expense can be magnified by associated veterinary expenses.
Non-specific anti-viral drugs
Common drugs such as cyclosporine, cholesterol inhibitors such as itraconazole, various antibiotics, and several herbal extracts inhibit FIP virus in cell-culture, but the anti-viral effect is weak and potential toxicity great. These substances have their biologic effects by inhibiting normal metabolic processes of cells and some of these processes are usurped by viruses to aid their own replication. The amount of drug required to achieve the needed level of virus inhibition would be toxic or damaging to the cells and thus to the host cat.
Targeted anti-viral drug therapy
The current hope for treatment of FIP rests with several of the same types of specific anti-viral drugs that have been used to treat viral infections of humans such as hepatitis C and HIV/AIDS. These are small molecules that are readily absorbed into cells and specifically target viral proteins that are essential for virus replication. Their toxicity for non-viral processes (i.e., cellular functions) is extremely low, making them both safe and efficacious. We have described our laboratory and field experiences with GC376, a viral protease inhibitor, in an article in the Journal of Feline Medicine and Surgery. An abstract of this article can be accessed at the PubMed website (https://www.ncbi.nlm.nih.gov/pubmed/28901812). The rights for GC376 have been obtained by Anivive and they are starting the lengthy process of obtaining FDA approval for treating cats with FIP and eventual marketing - https://www.k-state.edu/media/newsreleases/2018-09/fipantiviral92018.html.
We published our initial research studies on a second compound (nucleoside analog GS-441524- Gilead Sciences, Inc.) in 2018 and these results can be found at the Veterinary Microbiology journal open access article website - (https://www.sciencedirect.com/science/article/pii/S0378113518301603). The successful testing of GS-441524 in owned cats with a variety of forms of naturally-occurring FIP has just appeared in the Journal of Feline Medicine and Surgery - https://journals.sagepub.com/doi/full/10.1177/1098612X19825701. Similar reports will be forthcoming as other drugs go through experimental and field testing. We are convinced based on our research that anti-viral drugs of the type currently used for HIV/AIDS and hepatitis C virus (HCV) infection, and in test phase for Ebola, Marburg, MERS, SARS, and bat coronavirus infections will provide the best chance for curing this terrible disease of cats. These drugs include protease inhibitors, nucleoside analogs, RNA polymerase inhibitors, as well as other classes of anti-viral drugs that might target specific aspects of RNA virus replication.
Unfortunately, the research phase for these drugs has ended and no more field trials are contemplated at this time and no drug is legally available for veterinarians or owners. The processes involved in getting these new drugs FDA approved and commercialized is long and it may be 2-5 years before these, or similar drugs find their way to veterinarians for use in the treatment of cats with FIP. This delay has created a vigorous and growing black-market for drugs like GC376 and GS-441524. GC376 is being illegally produced in China and sold through subsidiaries in Europe and US. GS-441524 is also being produced illegally in China but has not yet appeared on the market. Manufacturers and secondary suppliers state that these drugs are to be used for research purposes only and not for use veterinary or human applications but are well-aware of their great demand and willingness of many cat owners to pay an extremely high price for them. We have no idea of the purity or biological activity of these black-market compounds and veterinarians have no experience with preparing them for treatment or using them to treat cats with FIP. The treatment period for naturally occurring FIP is a minimum of 12 weeks, not the two weeks based on treating cats with experimental FIP. Many owners have spent thousands of dollars on black-market drugs and have had to stop treatment before this time, even though their cats are responding, due to the cost. The FIP will relapse if treatment is stopped too soon. Owners and veterinarians using should be also aware of possible legal and ethical consequences arising from the use of black-market drugs.