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. 2021 Nov 5;13(11):2228.
doi: 10.3390/v13112228.

Curing Cats with Feline Infectious Peritonitis with an Oral Multi-Component Drug Containing GS-441524

Daniela Krentz  1 , Katharina Zenger  1 , Martin Alberer  2 , Sandra Felten  1 , Michèle Bergmann  1 , Roswitha Dorsch  1 , Kaspar Matiasek  3 , Laura Kolberg  2 , Regina Hofmann-Lehmann  4 , Marina L Meli  4 , Andrea M Spiri  4 , Jeannie Horak  5 , Saskia Weber  6 , Cora M Holicki  6 , Martin H Groschup  6   7 , Yury Zablotski  1 , Eveline Lescrinier  8 , Berthold Koletzko  5 , Ulrich von Both  2   9 , Katrin Hartmann  1
Affiliations

Curing Cats with Feline Infectious Peritonitis with an Oral Multi-Component Drug Containing GS-441524

Daniela Krentz et al. Viruses. .

Abstract

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.

Keywords: FCoV; FIP; GS-441524; Mutian; Xraphconn®; antiviral chemotherapy; feline coronavirus; therapy; treatment.

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Conflict of interest statement

The authors declare that they have no conflict of interest. The oral multi-component drug Xraphconn® was provided by Mutian Life Sciences Limited, but Mutian played no role in the interpretation of study data or the decision to submit the manuscript for publication. No commercial conflict of interest exists as the information is solely for scientific dissemination.

Figures

Figure 1
Figure 1
Flow diagram illustrating enrollment, inclusion, allocation process to high-dose treatment (10 mg/kg) for cats with neurological/ocular signs or low-dose treatment (5 mg/kg) for cats without neurological/ocular signs (based on the package inserts, Supplementary File S1), and outcome of cats in the study.
Figure 2
Figure 2
Feline coronavirus (FCoV) replication inhibition by Xraphconn®. (A) FCoV cycle threshold (ct) values in supernatants collected from infected Crandell-Rees Feline Kidney (CRFK) cells (multiplicity of infection (MOI = 0.01) treated with the indicated active compound concentrations were collected at 24 h post infection (n = 4). Significance levels compared to the results for untreated cells were determined by the Bonferroni’s multiple comparisons test and are indicated as follows: *, p ≤ 0.05; ****, p < 0.0001. (B) Data from four biological replicates were used to calculate the half maximal effective concentration (EC50) value by non-linear regression analysis.
Figure 3
Figure 3
Timeline visualizing improvement of clinical parameters throughout the study course. Figures show average predictive values and 95% confidence intervals of each parameter. Grey shading marks the reference ranges of the parameters. Red asterisks mark significant difference (p ≤ 0.05) of the parameters on different days of treatment when compared to day 0 (before treatment) measured by a linear mixed-effects model (for temperature) and by robust linear mixed-effects models. (A) Karnofsky’s score modified for cats. (B) Body weight. (C) Body temperature. (D) Amount of effusion subjectively evaluated during abdominal/thoracic ultrasound and paracentesis (grades 0 (no fluid) to 4 (massive effusion)).
Figure 4
Figure 4
Timeline visualizing improvement of clinicopathological parameters throughout the study course. Figures show average predictive values and 95% confidence intervals of each parameter. Grey shading marks the reference ranges of the parameters. Red asterisks mark significant difference (p ≤ 0.05) of the parameters on different days of treatment when compared to day 0 (before treatment) measured by a linear mixed-effects model (for albumin) and by robust linear mixed-effects models. (A) Hematocrit. (B) Lymphocyte count. (C) Bilirubin concentration. (D) Total protein concentration. (E) Albumin concentration. (F) Globulin concentration. (G) Albumin/globulin ratio. (H) Serum amyloid A (SAA) concentration.
Figure 4
Figure 4
Timeline visualizing improvement of clinicopathological parameters throughout the study course. Figures show average predictive values and 95% confidence intervals of each parameter. Grey shading marks the reference ranges of the parameters. Red asterisks mark significant difference (p ≤ 0.05) of the parameters on different days of treatment when compared to day 0 (before treatment) measured by a linear mixed-effects model (for albumin) and by robust linear mixed-effects models. (A) Hematocrit. (B) Lymphocyte count. (C) Bilirubin concentration. (D) Total protein concentration. (E) Albumin concentration. (F) Globulin concentration. (G) Albumin/globulin ratio. (H) Serum amyloid A (SAA) concentration.
Figure 5
Figure 5
Feline coronavirus (FCoV) viral RNA loads in blood and effusion samples and serum anti-FCoV antibody titre measurements. (A) FCoV RNA loads in EDTA anticoagulated blood. (B) FCoV RNA loads in effusions. (C) Serum anti-FCoV antibody titres. FCoV RNA loads were determined by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) (A,B). Antibody titers were determined by indirect immunofluorescence assay (IFA). NT, not tested.
Figure 6
Figure 6
Viral load in blood and effusion throughout the study course. Figures show visualization of data using nonparametric bootstraps. (A) FCoV RNA loads in EDTA anticoagulated blood. (B) FCoV RNA loads in effusions.
Figure 7
Figure 7
Comparison of the Ultra-High-Performance-Liquid Chromatography Electro-Spray QTRAP Mass Spectrometry (UHPLC-ESI-QTRAP-MS/MS) spectra of GS-441524 and the active component of Xraphconn® extracted from the tablet. The compounds in both test solutions were not only isobaric with [M + H]+ m/z 292.1040, but exhibited identical fragmentation spectra. Mass spectra were generated at a collision energy of 50 eV with positive ionization using the Multiple Reaction Monitoring with Information Dependent Acquisition and Enhanced Product Ion (MRM-IDA-EPI) scan mode. Cps, counts per second.
Figure 8
Figure 8
13C spectrum of the analyzed sample. Labels refer to the assignment of carbons in the active component of Xraphconn® depicted above. All signals above 100 ppm belong to the cyano-group and nucleobase in the identified compound. Some additional signals of uncharacterized impurities were observed below 80 ppm (indicated with *). Ppm, parts per million.
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