Feline Infectious Peritonitis and the Black-Market Production and Sale of GS-441524 (EVO984) and GC376

Black-Market Production and Sale of GS-441524 (EVO984) and GC376

Niels C. Pedersen, DVM PhDDistinguished Professor EmeritusSchool of Veterinary MedicineUniversity of California, DavisApril 26, 2019A 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.

Dr. Pedersen Spring 2019 Research Update

To the numerous owners of cats with FIP that contact us daily:  I am sorry but our field trials on GC376 and GS-441524 have been completed and we are no longer accepting cats with FIP for treatment.  We also cannot dispense these drugs, free or for a charge, as that would not be legal or ethical.  Both drugs have shown promise in curing cats with FIP and are now in various stages of being commercialized. This is a complex process that involves intellectual property rights and ultimately identifying potential companies interested in taking a drug through FDA approval and licensing.  This is not a simple task and could take one to two years before one or more drug is approved and made available for use by licensed veterinarians.  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.We have also published our initial research studies on a second compound (nucleoside analog GS-441524- Gilead Sciences, Inc.) and these results can be found at the Veterinary Microbiology journal open access article website (https://www.sciencedirect.com/science/article/pii/S0378113518301603).  We are in the process of publishing field trial results with this very promising viral RNA inhibitor in the Journal of Feline Medicine and Surgery.  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.  I wish that there were currently available treatments for FIP, but none have proven curative and treatment remains basically symptomatic and targeted at extending a reasonable quality of life. -N. C. Pedersen DVM, PhD

Note: There is a desperate need for these drugs, but the demand has gotten way ahead of the procedures necessary to bring them safely and economically to the market place.  It takes 2-7 years to get approvals and market a drug after it is researched in Western countries and the worldwide problems with FIP are only getting worse.  This is especially true in advancing countries where the demand for purebred kittens has gone through the roof and the conditions favoring FIP have gone with it.  GC376 is being illegally produced in China and sold through subsidiaries in Europe and US. GS-441524 (EV0984) is also being produced illegally in China but has just recently started to appear 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 a high price. Many owners are paying $25K or more for enough drug to treat their cat for at least 12 weeks.  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. I believe that it is unethical for veterinarians to use drugs obtained in this manner for their patients, even though they are purchased by the owners.  Therefore, owners and veterinarians using such drugs should be aware of possible consequences arising from the use of illegal and unapproved drugs.