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

Niels C. Pedersen, DVM Ph.D., Distinguished Professor EmeritusSchool of Veterinary MedicineUniversity of California, Davis 

April 26, 2019

Several entities, mainly in China, manufacture GS-441524 (GS) and GC374 (GC) for sale, mainly to desperate owners of cats with FIP. Although the first effort centered around GC, this black market's emphasis has rapidly shifted to GS. Although this 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 offering GS and GC usually include a disclaimer to customers limiting 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 who choose to assist owners with treating cats with such drugs may have no protection against adverse situations from such unauthorized use. Therefore, some veterinarians also require signed waivers from owners freeing them of any legal or ethical obligations for such treatment.

I have been opposed to GC or GS's black-market use mainly because I have seen the "wild-west-like" situations it creates. Although chemists producing these drugs indicate they are highly pure, there is no testing for biological activity (i.e., antiviral effect). We already know that an increasing number are making GC and GS of individuals and that the quality of an mg/kg or molar dosage can significantly vary. We also know that GC and GS's prices can vary greatly, and owners may pay thousands of dollars for enough drugs to complete treatment. 

Purchasing sufficient drugs, 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 convert to a stable and injectable form successfully. In response to this problem, some suppliers offer 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. Suppose owners or veterinarians insist on purchasing GS or GC on the black market, usually at a very high price. In that case, they should expect some information from the supplier regarding biological (antiviral) activity on a molar basis diluent used and information on storage conditions and shelf-life.

The second problem with the black market GS and GC involve their use, even if it should be equivalent in purity and biological activity to GS and GC described in peer-reviewed scientific publications. The published information can be directly applied if the innocence and antiviral activity are the same as the drugs described in research publications. If they are not then published, the information will not apply. It is also critical that FIP diagnosis be as firm as possible, as the disease is frequently misdiagnosed. 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 treat cats properly with FIP's neurological and ocular/neurological forms. GC and GS penetrate 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. However, 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 more cautiously than other FIP forms. 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 a higher dosage of drugs, with an unknown expectation of cure, should be a 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 using black-market GS and GC to treat cats with FIP. However, I must clarify that I would have preferred these drugs to be approved and commercialized commonly. I am sure 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 medications for diseases like FIP and share our findings in the conventional manner of peer-reviewed research publications. We have no direct control over how our conclusions are ultimately applied. Our obligations are only to assure owners and veterinarians that our findings are accurate, reproducible, and applicable. 

Dr. Pedersen Spring 2019 Research Update

To the numerous cats with FIP owners 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 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 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). Anivive has obtained the rights for GC376, 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.). These results can be found on 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 undergo experimental and field testing. Based on our research, we are convinced that antiviral drugs of the type currently used for HIV/AIDS and hepatitis C virus (HCV) infection, and in the test phase for Ebola, Marburg, MERS, SARS, and bat coronavirus infections will provide the best chance for curing this terrible cat disease. These drugs include protease inhibitors, nucleoside analogs, RNA polymerase inhibitors, and other classes of antiviral drugs that might target specific aspects of RNA virus replication. I wish there were currently available treatments for FIP, but none have proven curative, and treatment remains 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 ahead of the procedures necessary to bring them safely and economically to the marketplace. It takes 2-7 years to get approvals and market a drug after it is researched in Western countries, and the global 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 illegally produced in China and sold through subsidiaries in Europe and the US. GS-441524 (EV0984) is also being made illegally in China but has recently started appearing on the market. Manufacturers and secondary suppliers state that these drugs should be used for research purposes only and not for veterinary or human applications. However, they are well aware of many cat owners' great demand and willingness to pay a high price. Many owners pay $25K or more for enough drugs to treat their cats for at least 12 weeks. We have no idea of the purity or biological activity, and veterinarians have no experience preparing them for treatment or using them to treat cats with FIP. I believe it is unethical for veterinarians to use drugs obtained in this manner for their patients, even though the owners purchase them. Therefore, owners and veterinarians using such drugs should be aware of possible consequences arising from illegal and unapproved drugs.