Scientific articles about GS441524

The goal of this study was to formally evaluate the administration of unlicensed, crowdsourced antiviral GS-441524-like therapy for cats suspected to have feline infectious peritonitis (FIP), a previously fatal disease. Members of a large social media support and GS-441524-like drug distribution group were surveyed via the Internet. The survey was targeted toward owners who had treated their cats for at least 12 weeks with unlicensed GS-441524-like drugs. Of the 393 analyzed surveys which met inclusion criteria, 73.7% of owners utilizing this therapy were from the United States. Only 8.7% of owners reported receiving help from their veterinarian in administering the treatment to their cat. The mean cost of treatment was USD 4920. A majority of owners (88.2%) reported noticeable improvement in clinical signs within one week of initiating therapy. At the time of the survey, 96.7% (380 cats) were alive, with 54.0% of them considered cured and another 43.3% being monitored in the 12-week observation period. A total of 12.7% of the cats suffered a relapse of clinical signs of FIP, and 3.3% of the cats died despite GS-441524-like therapy. Reported complications were mostly related to owner administration of subcutaneous injections of the acidic GS-441525-like therapy, such as vocalization, pain, struggling, and injection-site wounds. Limitations of this study include a retrospective design, bias in case selection, reliance on owner-reported data, and inability to confirm the contents of unlicensed pharmaceuticals; however, important lessons can be learned from the experiences of these owners. While unconventional, and certainly not free from medical and legal risks, unlicensed, at-home GS-441524-like therapy, according to owner reports, can apparently offer benefits in the treatment of cats suspected of FIP.

Feline infectious peritonitis (FIP) is caused by a mutant biotype of the feline enteric coronavirus.

The resulting FIP virus (FIPV) commonly causes central nervous system (CNS)

and ocular pathology in cases of noneffusive disease. Over 95% of cats with FIP will succumb to disease in days to months after diagnosis despite a variety of historically used treatments. Recently developed antiviral drugs have shown promise in treatment of nonneurological FIP, but data from neurological FIP cases are limited. Four cases of naturally occurring FIP with CNS involvement were treated with the antiviral nucleoside analogue GS-441524 (5-10 mg/kg) for at least 12 weeks. Cats were monitored serially with physical, neurologic, and ophthalmic examinations. One cat had serial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis (including feline coronavirus [FCoV]) titers and FCoV reverse transcriptase [RT]-PCR) and serial ocular imaging using Fourierdomain optical coherence tomography (FD-OCT) and in vivo confocal microscopy (IVCM). All cats had a positive response to treatment. Three cats are alive off treatment (528, 516, and 354 days after treatment initiation) with normal physical and neurologic examinations. One cat was euthanized 216 days after treatment initiation following relapses after primary and secondary treatment. In 1 case, resolution of disease was defined based on normalization of MRI and CSF findings and resolution of cranial and caudal segment disease with ocular imaging. Treatment with GS-441524 shows clinical efficacy and may result in clearance and long-term resolution of neurological FIP.

Dosages required for CNS disease may be higher than those used for nonneurological FIP.

Objectives The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for cats suffering from various forms of naturally acquired feline infectious peritonitis (FIP).

Methods Cats ranged from 3.4–73 months of age (mean 13.6 months); 26 had effusive or dry-to-effusive FIP and five had non-effusive disease. Cats with severe neurological and ocular FIP were not recruited. The group was started on GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased when indicated to 4.0 mg/kg

SC q24h.

Results Four of the 31 cats that presented with severe disease died or were euthanized within 2–5 days and a fifth cat after 26 days. The 26 remaining cats completed the planned 12 weeks or more of treatment. Eighteen of these 26 cats remain healthy at the time of publication (OnlineFirst, February 2019) after one round of treatment,

while eight others suffered disease relapses within 3–84 days. Six of the relapses were non-neurological and two neurological. Three of the eight relapsing cats were treated again at the same dosage, while five cats had the dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a second time at the higher dosage, including

one with neurological disease, responded well and also remain healthy at the time of publication. However, one of the three cats re-treated at the original lower dosage relapsed with neurological disease and was euthanized, while the two remaining cats responded favorably but relapsed a second time. These two cats were successfully treated a third time at the higher dosage, producing 25 long-time survivors. One of the 25 successfully treated cats was subsequently euthanized due to presumably unrelated heart disease, while 24 remain healthy.

Conclusions and relevance GS-441524 was shown to be a safe and effective treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at least 12 weeks.

As previously demonstrated by our research group, the oral multicomponent drug

Xraphconn® containing GS-441524 was effective at curing otherwise fatal feline infectious peritonitis (FIP) in 18 feline coronavirus (FCoV)-infected cats. The aims of the current study were to investigate, using samples from the same animals as in the previous study, (1) the effect of treatment on fecal viral RNA shedding; (2) the presence of spike gene mutations in different body compartments of these cats; and (3) viral RNA shedding, presence of spike gene mutations, and anti-FCoV antibody titers in samples of 12 companion cats cohabitating with the treated cats. Eleven of the

eighteen treated FIP cats (61%) were shedding FCoV RNA in feces within the first three days after treatment initiation, but all of them tested negative by day 6. In one of these cats, fecal shedding reoccurred on day 83. Two cats initially negative in feces were transiently positive 1–4 weeks into the study. The remaining five cats never shed FCoV. Viral RNA loads in feces decreased with time comparable with those in blood and effusion. Specific spike gene mutations linked to systemic FCoV spread were consistently found in blood and effusion from treated FIP cats, but not in feces from

treated or companion cats. A new mutation that led to a not yet described amino acid change was identified, indicating that further mutations may be involved in the development of FIP. Eight of the twelve companion cats shed FCoV in feces. All but one of the twelve companion cats had anti-FCoV antibodies. Oral treatment with GS-441524 effectively decreased viral RNA loads in feces, blood, and effusion in cats with FIP. Nonetheless, re-shedding can most likely occur if cats are re-exposed to FCoV by their companion cats.

Feline infectious peritonitis (FIP) is a systemic, potentially fatal viral disease. The objectives of this

study were to review clinical and laboratory features and treatment of cats highly suspected of FIP

in Wuhan, China. The clinical records of 127 cats highly suspected of FIP were reviewed for history,

clinical signs, physical findings, and diagnostic test results. Sex, neutering status, breed, age, and

month of onset of disease were compared with the characteristics of the clinic population. Age and

neutering status were significantly correlated with FIP-suspicion. Sex, breed and onset month were

not associated with FIP. There were many more FIP-suspected cases in cats in young cats or male

intact cats. Effusion was observed in 85.8% of the FIP-suspected cats. Increased serum amyloid A

(SAA) and lymphopenia were common laboratory abnormalities in the FIP cases. Furthermore, 91.7%

of the cats highly suspected of FIP had an albumin/globulin (A/G) ratio < 0.6, while 85.3% had an A/G

ratio < 0.5. The mortality rate for FIP-suspected cats was 67%, and six submitted cases were confirmed

by FIP-specific immunohistochemistry. Of the 30 cats treated with GS-441524 and/or GC376, 29

were clinically cured. The study highlights the diverse range of clinical manifestations by clinicians

in diagnosing this potentially fatal disease. A/G ratio and SAA were of higher diagnostic value.

GS-441524 and GC376 were efficient for the treatment of FIP-suspected cats.

This article highlights knowledge of feline infectious peritonitis (FIP) as it evolved, starting at its recognition in 1963 to present time, and was prepared with veterinarians, cat rescuers and guardians, shelter staff, and cat lovers in mind. A brief mention is made of the causative feline coronavirus and its relationship to a ubiquitous and minimally pathogenic enteric coronavirus of felids, epizootiology, pathogenesis, pathology, clinical features, and diagnostics. Major emphasis is on risk factors affecting FIP prevalence, and the role of modern antiviral drugs in successful treatment.

Feline infectious peritonitis (FIP) is an important disease characterized by granulomatous changes in various organs including the ocular and central nervous system. FIP infection is referred as the best candidate for antiviral drug development studies due to the ineffectiveness of vaccines and being a cause of high mortality. The most important antiviral drugs developed against RNA viruses are nucleoside analogues such as GS-441524. In this study, GS-441524 was used in the treatment of three naturally infected cats with ocular lesions diagnosed with effusive FIP. The treatment of cats was planned as GS-441524 (5 mg / kg, SC, daily) administration for 12 weeks along with fluid therapy on the admission day. The treatment process included follow-ups with clinical and laboratory examinations on the admission 5 th , 15 th , 30 th , 60 th , 90 th and 120 th days. On the 5 th day, clinical signs including ocular abnormalities and on the 30 th day, laboratory findings were significantly improved in all 3 cats. While the cats were expected for monthly follow-ups, it was learned that the cats died on the 58 th , 60 th and 62 nd days. It was concluded that GS-441524 (5 mg/kg/day, SC) has been proven to be beneficial for improving clinical, laboratory findings and animal welfare. However, it was evaluated that clinical studies involving more cases are required in order to determine the clinical efficacy of nucleoside analogues and investigate the causes of deaths occurred on the 58 th , 60 th and 62 nd days of the treatment period with no symptoms that would grab the attention of the owners.

Feline infectious peritonitis (FIP) is a viral-induced, immune-mediated disease of cats caused

by virulent biotypes of feline coronaviruses (FCoV), known as the feline infectious peritonitis

virus (FIPV). Historically, three major pharmacological approaches have been employed to

treat FIP: (1) immunomodulators to stimulate the patient’s immune system non-specifically

to reduce the clinical effects of the virus through a robust immune response, (2) immunosuppressive

agents to dampen clinical signs temporarily, and (3) re-purposed human antiviral

drugs, all of which have been unsuccessful to date in providing reliable efficacious treatment

options for FIPV. Recently, antiviral studies investigating the broad-spectrum coronavirus protease

inhibitor, GC376, and the adenosine nucleoside analogue GS-441524, have resulted in

increased survival rates and clinical cure in many patients. However, prescriber access to

these antiviral therapies is currently problematic as they have not yet obtained registration

for veterinary use. Consequently, FIP remains challenging to treat. The purpose of this review

is to provide an update on the current status of therapeutics for FIP. Additionally, due to

interest in coronaviruses resulting from the current human pandemic, this review provides

information on domesticated cats identified as SARS-CoV-2 positive.

Feline infectious peritonitis (FIP) is a complex and historically fatal disease, though recent

advances in antiviral therapy have uncovered potential treatments. A newer therapeutic option,

unlicensed molnupiravir, is being used as a first-line therapy for suspect FIP and as a rescue therapy

to treat cats who have persistent or relapsed clinical signs of FIP after GS-441524 and/or GC376

therapy. Using owner-reported data, treatment protocols for 30 cats were documented. The 26 cats

treated with unlicensed molnupiravir as a rescue therapy were treated with an average starting

dosage of 12.8 mg/kg and an average ending dosage of 14.7 mg/kg twice daily for a median of

12 weeks (IQR = 10–15). In total, 24 of 26 cats were still living disease-free at the time of writing.

One cat was euthanized after completing treatment due to a prolonged seizure, and the other cat

underwent retreatment for relapsed clinical signs. Few adverse effects were reported, with the most

notable—folded ears (1), broken whiskers (1), and severe leukopenia (1)—seen at dosages above

23 mg/kg twice daily. This study provides a proof of principle for the use of molnupiravir in cats

and supports the need for future studies to further evaluate molnupiravir as a potentially safe and

effective therapy for FIP.

This is the first report on a clinical follow-up and postmortem examination of a cat that

had been cured of feline infectious peritonitis (FIP) with ocular manifestation by successful treatment

with an oral multicomponent drug containing GS-441524. The cat was 6 months old when clinical

signs (recurrent fever, lethargy, lack of appetite, and fulminant anterior uveitis) appeared. FIP

was diagnosed by ocular tissue immunohistochemistry after enucleation of the affected eye. The

cat was a participant in a FIP treatment study, which was published recently. However, 240 days

after leaving the clinic healthy, and 164 days after the end of the 84 days of treatment, the cured

cat died in a road traffic accident. Upon full postmortem examination, including histopathology

and immunohistochemistry, there were no residual FIP lesions observed apart from a generalized

lymphadenopathy due to massive lymphoid hyperplasia. Neither feline coronavirus (FCoV) RNA

nor FCoV antigen were identified by quantitative reverse transcription polymerase chain reaction

(RT-qPCR) and immunohistochemistry, respectively, in any tissues or body fluids, including feces.

These results prove that oral treatment with GS-441524 leads to the cure of FIP-associated changes

and the elimination of FCoV from all tissues.

Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent

studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may

be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a

pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and

RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic

in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK

cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined

the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood

levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease

signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent

toxicity.

Feline infectious peritonitis (FIP) caused by feline coronavirus (FCoV) is a common dis-ease

in cats, fatal if untreated, and no effective treatment is currently legally available. The aim of this

study was to evaluate efficacy and toxicity of the multi-component drug Xraphconn® in vitro and as

oral treatment in cats with spontaneous FIP by examining survival rate, development of clinical and

laboratory parameters, viral loads, anti-FCoV antibodies, and adverse effects. Mass spectrometry and

nuclear magnetic resonance identified GS-441524 as an active component of Xraphconn®. Eighteen

cats with FIP were prospectively followed up while being treated orally for 84 days. Values of key

parameters on each examination day were compared to values before treatment initiation using

linear mixed-effect models. Xraphconn® displayed high virucidal activity in cell culture. All cats

recovered with dramatic improvement of clinical and laboratory parameters and massive reduction

in viral loads within the first few days of treatment without serious adverse effects. Oral treatment

with Xraphconn® containing GS-441524 was highly effective for FIP without causing serious adverse

effects. This drug is an excellent option for the oral treatment of FIP and should be trialed as potential

effective treatment option for other severe coronavirus-associated diseases across species.

Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The disease has a spectrum of clinical presentations including an effusive (“wet”) form and non-effusive (“dry”) form, both of which may be complicated by neurologic or ocular involvement. The feline coronavirus (FCoV) biotype, termed feline infectious peritonitis virus (FIPV), is the etiologic agent of FIP. The objective of this study was to determine and compare the in vitro antiviral efficacies of the viral protease inhibitors GC376 and nirmatrelvir and the nucleoside analogs remdesivir (RDV), GS-441524, molnupiravir (MPV; EIDD-2801), and β-D-N4-hydroxycytidine (NHC; EIDD-1931). These antiviral agents were functionally evaluated using an optimized in vitro bioassay system. Antivirals were assessed as monotherapies against FIPV serotypes I and II and as combined anticoronaviral therapies (CACT) against FIPV serotype II, which provided evidence for synergy for selected combinations. We also determined the pharmacokinetic properties of MPV, GS-441524, and RDV after oral administration to cats in vivo as well as after intravenous administration of RDV. We established that orally administered MPV at 10 mg/kg, GS-441524 and RDV at 25 mg/kg, and intravenously administered RDV at 7 mg/kg achieves plasma levels greater than the established corresponding EC50 values, which are sustained over 24 h for GS-441514 and RDV.

PICO question In cats with feline infectious peritonitis (FIP), does treatment with the nucleoside analogue GS-441524 or the protease inhibitor GC376, compared to supportive measures alone, lead to longer survival times? Clinical bottom line Category of research question Treatment The number and type of study designs reviewed Five studies, including four uncontrolled interventional studies and one case-series were critically reviewed Strength of evidence Moderate Outcomes reported The reviewed studies collectively provide moderate evidence in support of the application of GS-441524 or GC376 to extend the survival time of cats suffering from feline infectious peritonitis Conclusion While these antiviral drugs are considered the most likely options for FIP treatment, more robust evidence should be obtained through well-designed randomised controlled trials to verify the observed positive effects in treating various forms of the disease and the potential long-term side effects. However, the ethical dilemmas of conducting double blinded placebo-controlled trials, which by necessity include untreated cats with an invariably fatal disease are recognised How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.