FIP Antivirals

1.12.2020, Translation 1.5.2021
Original Cornell University blog post: FIP Antivirals

Summary

• For families living with a diagnosis of feline infectious peritonitis (FIP) and the veterinarians involved in their care, we understand that the decision to use black market treatment for an otherwise necessarily fatal disease is the ethical dilemma of choosing the lesser of the two evils.
• Due to concerns about the safety and efficacy of black market GS-441524 counterfeits, combined with the fact that veterinary supervision of such use is full of legal and ethical dilemmas, we cannot currently recommend the use of such treatment.
• We strongly warn against the widespread use of antiviral therapy as monotherapy in farms and shelters with endemic feline enteric coronavirus (FECV). Widespread use in these conditions is expected to generate antiviral-resistant FIP strains.

Opinion

We received many questions regarding the use of GS-441524 in the treatment of FIP. Here is a summary of GS-441524 and our position on its current use. Research into the use of this compound was first published by Dr. Niels Pedersen of UC Davis in 2018. Team Dr. Pedersen published a follow-up study documenting the use of GS-441524 in naturally occurring cases of FIP in 2019. The results of both studies were unprecedented with the 100% (10/10) recovery rate reported in experimentally infected cats and the 84% (25/31) recovery rate in naturally infected cats. Owned cured cats reported returning to "near normal" within two weeks of treatment. The fever usually subsided during the first 12-36 hours, accompanied by a return of appetite. The effusions subsided within 10-14 days and the jaundice gradually subsided within 2-4 weeks. The conclusion of the 2019 study proposes an optimized treatment protocol for the use of GS-441624 at a dose of 4.0 mg / kg given as a subcutaneous injection once a day for at least 12 weeks.

Although managing a natural infection has been shown to be more challenging than an experimental infection, most cats in the study have responded to treatment. Dr. Pedersen is a pioneer in the field of FIP research and there is no doubt about the legitimacy of its work. Unfortunately, there are many issues surrounding the current use of GS-441524. Most of these concerns are directly related to the fact that this medicine cannot be legally purchased from a regulated source. In addition to blocking consumers' access to the medicine, it has also blocked research into best practice and marginalized the role of veterinarians in treatment decisions.

GS-441524 is owned by Gilead Sciences, an American biopharmaceutical company focused on the development of antiviral drugs. Gilead provided GS-441624 Dr. Pedersen for use in his 2018 and 2019 studies, but refused to market the drug for use in cats because of his close relationship with another promising antiviral drug, remdesivir. Prior to the SARS-CoV-2 pandemic, remdesivir was tested for the treatment of Ebola. In a story complicated by human drug licensing challenges, Gilead feared that any adverse effects of GS-441524 reported in cats would harm remdesivir in the FDA approval process. The veterinary medicine market - even as promising as GS-441524 - is negligible compared to a potential human blockbuster. Gilead considered the use of GS-441524 for the treatment of FIP as an unnecessary risk that could harm the chances of remdesivirus success and refused to license it for use in cats.

This created a black market with GS-441524, led by overseas businessmen in an effort to take advantage of the despair caused by the FIP diagnosis. Treatment is expensive, ranging from $ 1,000 to $ 10,000. There is no formal regulation of these suppliers or their products on the black market. Veterinary professionals may be at legal risk if they recommend, dispense or administer these unapproved medicines. This combination of factors can prevent treated cats from receiving optimal care. We understand that FIP is otherwise a deadly disease, so these risks may seem acceptable, but we warn that unregulated use of GS-441524 has the potential to develop antiviral resistance and jeopardize the success of FIP treatment in the future.

GS-441524 is a nucleoside analog. When viral RNA polymerase integrates GS-441524 into the viral genome, the replication mechanism is blocked and transcription is terminated prematurely, making it difficult for the virus to replicate. We know from experience with nucleoside analogues designed to treat HIV that these drugs do not completely suppress viral replication. The use of single-drug therapy leads to the development of resistant strains. Our most successful experience with antiviral therapy includes combination therapies targeting various aspects of viral replication. Such combination therapies lead to excellent viral suppression and reduce the incidence of antiviral resistance.

The oral form of the nucleoside analog GS-441524 is currently marketed as a supplement to support the feline immune response. Preliminary study Dr. Dianne Addie states that this treatment stops the secretion of the original enteric coronavirus, also known as FECV. This work investigates the prophylactic use of a nucleoside analog in a multi-cat environment where cats have a high risk of developing FIP. Although these results appear to be positive at first sight, they are a matter of deep concern due to the development of antiviral resistance. Although there is preventive prophylaxis for people at high risk of contracting HIV, it is important to emphasize that this medicine, known as Truvada, is a combination antiviral treatment. Decades of experience with HIV have shown that monotherapies are much more likely to result in resistant antiviral strains.

Dr. Addie presents compelling arguments for involving veterinarians and researchers in the use of new FIP therapies. We would like to add that there is an obligation to discourage any use that should lead to the development of antiviral resistance. According to "one-health", both wild and domestic cats appear to be susceptible to SARS-CoV-2. This has implications for both the veterinary and human worlds: coronaviruses are well known for their ability to recombine in susceptible hosts, and there is a possibility that we will find ourselves in an uncharted area with recombinant viruses generated under selective antiviral pressure.

One of the bright spots in the dark cloud of the SARS-CoV-2 pandemic is that we will probably soon be able to put aside concerns about the use of the GS-441524 from the black market. A close relative, remdesivir, recently obtained FDA approval for use in a pandemic SARS-CoV-2 infection in humans. Now that the main obstacle to licensing has been clarified, we are optimistic that this will pave the way for the legal and scientifically based use of GS-441524 in cats. While initial studies of GS-441524 have proven to be very promising, important research is still needed in the wider field. Initial data on the efficacy of remdesivir for treatment with COVID-19 illustrated better results than those found in the larger study. WHO, where the drug has only a slight effect on the results at best.

With regard to combination therapy, other potential antiviral drugs for FIP are possible, in particular the protease inhibitor GC376 has a completely different mechanism of action and is a promising component of combination therapy. (Although not mentioned here, the GC376 black market is a very similar case to GS-441524.) Research into the treatment of COVID-19 in humans will undoubtedly lead to the development of promising therapies for cats. Dr. Pedersen posted preliminary data about 25 such compounds, some of which have shown potential for combination therapy. While awaiting GS-441524 approval, there will be questions regarding the off-label use of remdesivir in cats. We warn that the effects of drugs on different species can be unpredictable and that laboratory research is needed to determine safety and efficacy parameters.

For families living with a diagnosis of feline infectious peritonitis (FIP) and for the veterinarians involved in their care, we understand that the decision to use black market treatment for an otherwise necessarily fatal disease is the ethical dilemma of choosing the lesser of the two evils. We hope that this statement provides a useful reference framework for the history of GS-441524, while emphasizing the potential of antiviral resistance in its unregulated use. Pedersen posted own comment to use FIP antivirals from the black market, which provides more detailed information on current use strategies. At Whittaker Lab, we are continuing our basic research into the mechanisms that coronaviruses use to expand their cellular tropism in order to better understand the factors that lead to diseases such as FIP and COVID-19. We are committed to working in solidarity with our fellow researchers, veterinarians and cat owners to create a future without FIP.