By Richard Malik DVSc PhD FACVS FASM Centre for Veterinary Education, The University of Sydney 

Feline infectious peritonitis (FIP) is an infectious disease of cats, predominantly young cats. It occurs when feline enteric coronavirus multiplying in the intestines undergoes a critical mutation which changes its tissue tropism from enterocytes to macrophages. FIP virus then moves round the body in macrophages – the ultimate Trojan horse mechanism. This leads to a disseminated infection and the development of a fibrinoid necrotising vasculitis and serositis due to deposition of immune complexes consisting of cat antibodies and FIP viral antigens. 

Broadly speaking there are two forms of FIP – effusive (‘wet’) FIP and non-effusive (‘dry’) FIP. The actual disease process can occur in the abdominal cavity, the thoracic cavity, pericardium, the eyes, or the central nervous system. Mix and match combinations with different tissues involved, and dry and wet disease, are not unusual. 

Until recently, a diagnosis of feline infectious peritonitis (FIP) was a death sentence for a feline patient. But that notion has been turned on its head over the last few years as a result of the pioneering work of Professor Niels C. Pedersen and colleagues at UC Davis. 

Over the last 12 months, many vets in Australia have also successfully managed FIP cases using remdesivir and GS-441524. 

Omega-interferon (Virbagen) and polyprenyl immunostimulant (PPI) were the first drugs used to treat FIP and both had reasonable efficacy in some patients. Omega interferon was useful in cases of effusive (‘wet’) FIP, often combined with low dose prednisolone according to Ishida’s protocol, whereas PPI, pioneered by Al Legendre, was more useful in cases of non-effusive FIP. In some cases, both drugs were used in concert. The trouble was that both forms of therapy were often expensive especially when both drugs were used, so although patients improved and might have durable clinical remissions while receiving treatment, permanent clinical cures were rare. As a result, most vets still considered a diagnosis of FIP to be a prelude to euthanasia. 

That all changed a few years ago because of the culmination of a life-time of FIP research by Pedersen. Niels is an amazing veterinarian, a North American, with Danish heritage. He grew up on a chicken farm and initially wanted to be a large animal clinician, but with great foresight, decided a background in basic science would hold him in good stead. So, soon after graduation, he travelled to Canberra to the John Curtin School of Medical Research at ANU where he undertook an immunology PhD on kidney transplant rejection with Professor Bede Morris in the late 1960s, using sheep as the experimental model to study lymphocyte kinetics. 

When Niels returned to UC Davis as clinical faculty, he developed a special focus on infection and immunity. Although he contributed to a huge range of topics in canine and feline internal medicine and genomics, FIP was his favourite disease because of its commonness and also its complexity. His studies extended from the 1980s, when the focus was on diagnosis, virology, and pathogenesis, to the present day, with an increasing focus on therapy. 

Working with colleagues at Kansas State University, Niels showed that a purpose-designed protease inhibitor GC-376 could prevent and cure experimental FIP in research cats.[1,2] Clinical trials in the field using cats with naturally-occurring disease were disappointing, especially when cats had ocular or CNS disease. Not easily defeated, he moved onto a different drug - GS-441524[3,4] - a nucleoside analogue developed by the North American Pharma Gilead. This molecule proved to be much more effective than GC-376 for treating FIP, both in experimental infections and in spontaneous cases. Starting with pharmacokinetics, and then dose escalation studies using a wide range of clinical cases, Niels and colleagues determined that the dose required depended on whether the patient had dry or wet FIP and whether there was ocular or central nervous system (CNS) involvement.

GS-441524 For Cat FIPV

Surprisingly, Gilead, the manufacturer that developed GS-441524, has so far shown no interest in developing this molecule as a feline drug. So, to fill in the void for effective FIP therapy worldwide, various laboratories in China and eastern Europe started manufacturing GS-441524 and selling it on the black-market. 

The widespread availability of GS-441524, often of high quality, and initially very expensive, provided a way for dedicated cat owners to save cats with FIP. Studies by Samantha Evans a clinical pathologist at Ohio State University suggested a cure rate of approximately 80% in the field. Procuring the drug in the recent past was complicated and fraught with issues, which were circumvented at some level by help from various iterations of the Facebook collective ‘FIP Warriors’. Unfortunately for Australian cat lovers, the APVMA and Vet Boards eventually twigged to what was happening, and Border Force made it much more difficult to source GS-441524 and safely import it for veterinary use. Indeed, punitive warnings by the regulatory bodies and vet boards were directed at veterinarians who facilitated the treatment of cats with FIP using black-market drugs.

Ironically, the COVID 19 pandemic provided a novel solution to this problem. Gilead had developed remdesivir (GS-5734) as a drug for treating hepatitis C, Ebola, and human Coronavirus disease. Remdesivir is a prodrug of GS-441524, containing an extra chemical side chain (including a phosphate group) that is supposed to improve intracellular penetration (Figure 1B). Remdesivir (as the product Veklury) was given provisional registration (for two years) by the TGA in July 2020 for treatment of SARS-CoV-2 infections in human COVID-19 patients. This process of registration would normally have taken several years, but the severity of the pandemic expedited the process by relying on preliminary trial data. As remdesivir became a licensed human drug and Gilead licensed manufactures around the world, it has meant there are now more options of quality raw material available. This has circumvented problems with using a drug purchased on the black market, with the allied issues of unknown purity and consistency of product over time. 

In 2020, the animal compounding pharmacy BOVA Australia secured reliable supplies of remdesivir in a suitable format for IV and subcutaneous administration to cats. Studies in Australia have determined the shelf-life after reconstitution to be in excess of 12 days and confirmed efficacy in vitro against Coronaviruses using tissue culture. Drug analytic purity is regularly checked by HPLC. For the past year, veterinarians in every state of Australia have been using remdesivir for the treatment of cats with FIP. There has been a mixture of effusive and non-effusive cases, including some cats with ocular involvement (uveitis) and others with multifocal CNS disease. Based on approximately 500 cats treated between October 2020 and November 2021, remdesivir is proving to be highly effective at managing FIP infections. It is slightly easier to administer subcutaneously and seems a little less painful during injection compared to GS-441524 and does not cause the local injection site reactions seen with injectable GS-441524. Initially, remdesivir was used exclusively in Australia, although for the last 2 months it has also been available in Britain from BOVA UK. 

The molecular weight of remdesivir is 603 g/mol, while the molecular weight of GS-441524 is 291 g/mol. This might suggest that cats being treated with remdesivir require approximately twice the dose compared to GS-441524, although this does not account for possibly improved intracellular penetration of remdesivir in certain tissues compared to GS-441524. The suggested dose rate for remdesivir in human patients with COVID19 is a 200 mg loading dose intravenously (IV), followed by 100 mg IV daily. For a 70 kg human patient, this represents a daily dose of 1.3 mg/kg, so using allometric scaling, a dose of 5-10 mg/kg daily for a cat was considered to be in the right ballpark. Our experience over the first 500 cases , however, was that many cats ended up needing a higher dose of remdesivir for permanent cure, and so we have revised our dose recommendations upwards (see later). Remdesivir is provided by BOVA as a 10mg/ml sterile solution ready to use in a 10ml vial. 

Currently, Australia and the UK are the only countries where remdesivir is readily available via prescription for veterinary use. However, veterinarians in India, New Zealand, South Africa, and some parts of Europe, have also started accessing the drug using human suppliers.