Basic information Feline infectious peritonitis (FIP) is a viral disease of cats caused by certain strains of the coronavirus that has a high mortality rate.
The goal This case series reports the results of treatment of cats with FIP with molnupiravir.
The animals Eighteen cats diagnosed with FIP at You-Me Animal Clinic, Sakura-shi, Japan between January and August 2022 and whose owners gave informed consent for this experimental treatment.
Methods In this prospective observational study, molnupiravir tablets were prepared directly at the You-Me Animal Clinic. Owners administered 10-20 mg/kg PO twice daily. The standard duration of treatment was 84 days.
The results Of the 18 cats, 13 cats had effusive FIP and 5 cats had non-effusive FIP. Three cats had neurological or ocular signs of FIP before treatment. Four cats, all with effusive FIP, died or were euthanized within 7 days of starting treatment. The remaining 14 cats completed treatment and were in remission at the time of writing (139-206 days after initiation of treatment). Elevated serum alanine transaminase (ALT) activity was found in 3 cats, all on days 7–9, and all recovered without intervention. Two cats with jaundice were hospitalized, 1 during treatment (day 37) and 1 with severe anemia at the start of treatment.
Conclusions and clinical significance This case series suggests that molnupiravir may be an effective and safe treatment for domestic cats with FIP at a dose of 10–20 mg/kg twice daily.
1. Introduction
Feline infectious peritonitis (FIP) is a viral infectious disease occurring mainly in domesticated cats.1, 2 FIP is an aberrant immune response to infection with feline coronavirus (FCoV), which is ubiquitous, especially in breeding and rescue breeds, usually with no or mild clinical signs. Fecal-oral transmission of FCoV often occurs, especially in environments with multiple cats3 and the incidence of FIP in cats exposed to FCoV is up to 14 %.4, 5
Feline infectious peritonitis is usually classified as either effusive or non-effusive based on clinical presentation.1, 6, 7 Until the development of specific antiviral therapy, the case fatality rate associated with FIP was high, and most affected cats died within weeks to months of the onset of clinical signs.
Some nucleoside analogs, including remdesivir (GS-5734) and its active metabolite GS-4415248, inhibit viral RNA synthesis and have high antiviral activity against FCoV causing FIP in cats.9, 10 Despite the expectations of veterinarians and cat owners, the developer decided not to apply for approval of GS-441524 for the treatment of FIP. As a result, many cats with FIP are being treated with the unapproved drug GS-441524, and concerns have been raised about the quality, purity, and efficacy of the unapproved products available on the world market. Mutian has excellent efficacy and safety.11-14 Although the manufacturer did not disclose the chemical structure of the active substance and its exact concentration, its active substance is GS-441524.12
Molnupiravir is an oral nucleoside antiviral prodrug with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). As of 2021, molnupiravir is approved in Japan to treat people with COVID-19. There are published reports on the efficacy and safety of molnupiravir in cats15 , but sufficient data on the use of molnupiravir in cats with FIP are lacking. Due to the lack of treatment options for FIP, we began offering molnupiravir to clients at our clinic, using small tablets prepared in-house for easy administration to cats. Here we present the results of the first 18 cats that underwent this FIP treatment in our clinic.
2 MATERIALS AND METHODS
2.1 Cats
All cats attending the You-Me Animal Clinic in Sakura-shi, Japan since January 2022 diagnosed with FIP and whose owners provided informed consent were included in this case series. Feline infectious peritonitis was diagnosed based on a combination of clinical signs (decreased appetite, enlarged abdominal lymph nodes, weight loss, fever, effusions, or uveitis) and laboratory test results for anemia and hyperglobulinemia, including the albumin-to-globulin (A/G) ratio and values of α1-acid glycoprotein (AGP). The presumptive diagnosis of FIP was based on the identification of FCoV RNA in samples from abdominal or pleural effusion (effusive FIP) or whole blood (non-effusive FIP), or from fine needle aspiration (FNA) of pyogranulomatous lesions. Virus detection was performed by reverse transcription polymerase chain reaction (RT-PCR) in the following testing laboratories: abdominal effusion and FNA samples at IDEXX, Japan (using a LightCycler 480 System II, Roche Diagnostics KK, Basel, Switzerland) and whole blood at Canine Lab., Japan (using CFX Connect, Bio-Rad Laboratories, Inc, Irvine, CA, USA). Abdominal or pleural effusion samples (1 ml each) were taken by ultrasound-guided abdominocentesis, respectively. by thoracentesis and were evaluated for the total number of nucleated cells, protein content, A/G ratio and cytology. Whole blood samples (1 ml) were collected and sent in ethylenediaminetetraacetic acid (EDTA) tubes.
2.2 Preparation of the medicine
Tablets containing molnupiravir 20 mg were prepared at the You-Me Animal Clinic. Briefly, molnupiravir powder was extracted from 20 commercially produced molnupiravir 200 mg capsules (MOVFORE, Lot No. HH2201001 [HETERO HEALTHCARE, Hyderabad, India]) and mixed with powdered cellulose (microcrystalline cellulose powder, NICHIGA, Takasaki, Japan) using a mortar and pestle (Matsuyoshi Medical Instruments Co, Ltd, Tokyo, Japan) to make a total of 12 g of powder mixture. The powder was shaped into approximately 200 6 mm wide sectional scored tablets using a generic tablet press made in China.
2.3 Treatment
Treatment with molnupiravir was initiated when FIP was highly suspected on the basis of clinical presentation or when FCoV RNA was detected by PCR; this date was marked as the first check. The following dosages were chosen: 20 mg/kg/d (10 mg/kg twice daily) for cats with effusive type, 30 mg/kg/d (15 mg/kg twice daily) for cats with non-effusive type and cats with pyogranulomatous lesions, and 40 mg/kg/d (20 mg/kg twice daily) for cats with neurological or ocular signs of FIP. Dosage may be increased or decreased in animals showing clinical deterioration or adverse reactions. Dosage was chosen based on estimated animal dosages listed on the Internet16, 17 and based on the adult human COVID-19 dose of molnupiravir, which is 800 mg every 12 hours.18 This would correspond to a dose per kilogram of 10 to 13.3 mg/kg twice daily for adults weighing 60 to 80 kg. As no pharmacokinetic information is available in relation to cats, we have chosen the dosage for cats based on the assumption that metabolism of drugs in cats is equivalent to metabolism in humans.
Owners were instructed to administer the tablets twice a day with 12 hours between doses. The expected standard duration of treatment was 84 days according to study GS-441524.10
2.4 Measurements
Owners were instructed to record body weight, body temperature, physical activity, appetite, and voiding/urinating daily and were asked to visit the clinic at 1, 2, 6, and 10 weeks. The following laboratory tests were required at each visit: red and white blood cell count, hemoglobin, hematocrit (HCT), AGP, total protein, albumin, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, creatinine, blood urea nitrogen (BUN ) and the A/G ratio. Samples were analyzed in the clinic using a Catalyst One chemistry analyzer and a ProCyte One hematology analyzer (both IDEXX Laboratories, Westbrook, Maine). The A/G ratio was determined either from a whole blood plasma sample or from a fractionated protein sample. We performed abdominal and thoracic ultrasound evaluation of each cat at baseline and after 2, 6, and 10 weeks of treatment using a Prosound α7 (Aloka, Japan), including assessment of cardiac function (fractional shortening, left atrial to aortic diameter ratio, and valvular regurgitation).
2.5 Adverse Events
Any abnormal laboratory test values or medical events that occurred during treatment were considered adverse events and decisions were made to continue/discontinue treatment.
2.6 Statistical analysis
As this is a case series, no statistical calculations were performed other than descriptive statistics.
2.7 Ethics
All owners provided written informed consent prior to initiation of treatment. The experimental use of molnupiravir was approved by our Institutional Animal Study Review Committee.
3 RESULTS
3.1 Characteristics of the disease and treatment
Eighteen cats completed treatment by August 4, 2022 and are included in this summary report.
The presentation of the 18 cats is summarized in Table 1 and Table S1. The median age was 6.5 (range: 3-93) months. All 18 cats had a low serum A/G ratio, 16 cats had a loss of appetite, and 14 cats had mild to severe anemia by hemoglobin level and HCT. Thirteen cats had effusive FIP and 5 cats had non-effusive FIP. Neurological or ocular signs suggestive of FIP were present in 3 cats before treatment, including epileptic seizures/neurological signs (No. 8), blunted postural reflexes (No. 10), and slow pupillary reflex (No. 18) (Table S1). All but 2 cats (#8 and #15) were treated exclusively on an outpatient basis. Cat no. 8 was hospitalized from day 37 for 3 days due to jaundice. Cat no. 15 required hospitalization for 5 days after starting treatment due to anemia and jaundice accompanied by increased bilirubin concentration and ALT activity. During hospitalization, the cat received molnupiravir as scheduled, was hydrated with Ringer's solution, and treated with oral ursodeoxycholic acid (Towa, Japan) 10–15 mg twice daily to reduce bilirubin. There was no evidence of intravascular hemolysis (HCT remained stable), and microscopic examination of blood smears was negative for hemotropic mycoplasma infection.
TABLE 1. Basic characteristics of the cats in the described case series.
Age at disease onset, months, median (range)
6.5 (3-93)
Breed, n (%)
Housecat
9 (50.0)
Exotic shorthair
2 (11.1)
British Shorthair
2 (11.1)
Other
5 (27.8)
Sex, n (%)
Male not neutered/male neutered
4 (22.2)/7 (38.9)
Female not spayed/female spayed
2 (11.1)/2 (11.1)
Weight in kg, mean (SD)
2.72 (0.77)
Duration from onset of illness to initiation of treatment, days, median (range)
16.5 (2-49)
Effusive type, n (%)
13 (72.2)
Pyogranulomatous lesions in the abdominal cavity, n (%)
5 (27.8)
Neurological manifestations of FIP, n (%)
2 (11.1)
Ocular symptoms of FIP, n (%)
1 (5.6)
Temperature, °C, mean (SD)
39.3 (0.9)
Hematocrit, %, mean (SD)
27.3 (8.1)
Albumin/globulin ratio, mean (SD)
0.35 (0.10)
Sample type, n (%)
Abdominal effusion
11 (61.1)
Pleural effusion
1 (5.6)
FNA of a pyogranulomatous lesion
2 (11.1)
Full blood
3 (16.7)
None
1 (5.6)
The attending physician decided to extend the treatment to 99 days for cat no. 1. Consciousness disturbances appeared on day 8 in this cat and the dose was subsequently increased to 40 mg/kg. This symptom disappeared on the 15th day; however, the A/G ratio with the fractionated protein sample did not return to normal. On day 99, although the A/G ratio was still below the reference range (0.6), the clinician decided to stop treatment because the cat showed no clinical progression or deterioration.
3.2 Outputs
Clinical response in 14 cats was rapid. Dosing, findings during treatment, and outcomes in these animals are summarized in Tables S2 and S3. The fever subsided and the appetite returned within 2-3 days after the start of treatment. Remissions were also achieved in cats with severe clinical signs. Among them were cats no. 8, 17 and 18, which had pyogranulomatous lesions ≥ 2 cm in size, cat no. 4, which had severe anemia and a low A/G ratio, cat no. 14, which had a pleural effusion and difficulty breathing, and cat no. 15, who had an enlarged kidney. The pyogranulomatous lesions shrank or were undetectable on ultrasound in all 5 cases, and laboratory values returned to normal in all cats. Three cats had neurological signs of FIP before treatment. Cat no. 12 had no neurological symptoms of FIP before treatment, but had an epileptic seizure on day 7. The dosage was subsequently increased to 40 mg/kg. On the 2nd day, on the slit lamp at cat no. 7 found anisocoria that was probably related to uveitis. The dosage of molnupiravir was increased to 40 mg/kg from day 15, and all neurological or ocular signs of FIP resolved within 15 days.
Of the 14 cats that achieved remission, no relapses occurred through August 3, 2022, during 55 to 107 days of post-treatment follow-up. Three cats died (No. 2, No. 11 and No. 16) and one (No. 13) was euthanized; all these cats had the effusive form of FIP but had no neurological or ocular signs of the disease. All died within one week of starting treatment.
3.3 Security
Alanine transaminase activity higher than the reference value was found in 4 cats; the value of each of them was 286 U/l (cat #8 on day 37), 283 U/l (cat #9 on day 9), 154 U/l (cat #10 on day 7), and 117 U/l (cat No. 17 on the 9th day). Three cats with early ALT elevations on days 7 to 9 recovered without the need for intervention. In cat no. 8 developed jaundice on day 37 and was hospitalized for 3 days.
No abnormalities in BUN or creatinine concentrations were noted during treatment with molnupiravir.
4 DISCUSSION
In our series of cats with presumptive FIP treated off-label with a molnupivir compound, 14 of 18 cats achieved remission and remained in remission for up to 107 days of observation at the time of writing. Four cats showed signs of potential hepatic adverse effects; 3 cats developed ALT activity above the reference range during the first 7 to 9 days of treatment, all of which resolved without treatment, and 1 cat developed jaundice requiring hospitalization on day 37 of treatment.
The approved human formulation of molnupiravir is in 200 mg capsule form, but for animals it must be divided into smaller doses to facilitate administration of an appropriate dose based on body weight. We decided to prepare molnupiravir in the form of small tablets to simplify administration. We hypothesized that cats might refuse to swallow the drug in powder form or in aqueous solution, and it might be difficult for owners to administer the entire powder dose each time.
The minimum effective dose of molnupiravir in FIP is recommended to be 4.5 mg/kg PO every 12 hours for cats without neurological/ocular signs of disease, increasing to 12 mg/kg PO every 12 hours for cats developing ocular or neurological signs. symptoms of FIP.17 Others recommend a dose of 25 mg/kg every 24 hours for dry/wet FIP, 37.5 mg/kg every 24 hours for ocular FIP, and 50 mg/kg every 24 hours for neurological FIP.16 Since none of these recommended dosages have been established in prospective controlled studies, the dosage in this case series was determined by the author based on these estimates, adult dosages, and his experience. Nevertheless, the dosage used in our case series (10 mg/kg twice daily for cats with effusive FIP, 15 mg/kg twice daily for cats with non-effusive FIP or pyogranulomatous lesions, and 20 mg/kg twice daily for cats with neurological or ocular signs FIP) appears to be effective and safe and may help guide dosing in future clinical trials.
Four cats died during this study. Each of these cats had the effusive type of FIP; however, considering that some cats that survived had symptoms as severe or even more severe than those that died, no signs were found to predict early death. Unfortunately, the attending veterinarian was given little information about the deaths of the 3 cats that died at home, and no post-mortem examinations were performed. One cat (#2) died after vomiting the drug on day 6, so it is possible that this animal had swallowing problems.
The use of GS-441524 in 31 cats with FIP, of which 26 cats completed at least 12 weeks of treatment, resulted in remission in 25. 10 Eight of the 26 cats relapsed or became reinfected within 3 to 84 days after this period. . The length of observation in our case series is shorter than in study GS-44152410; however, observation of cats in our series is currently ongoing and more cats with FIP are being treated with molnupiravir. Further observation will provide data on longer-term efficacy. The major adverse events reported with injection in study GS-441524 were injection site reactions in 16 of 26 cats.10 Because the treatment in our study was administered orally, no injection site reactions occurred in any of the cats in our series. In our series, the most frequent adverse event during treatment was an increase in ALT activity. However, longer-term follow-up is necessary to more adequately assess liver-related reactions, and a larger group of animals is needed to more fully assess the adverse effects of molnupiravir.
Molnupiravir is active against SARS-CoV-2 and other RNA viruses19 and in cell culture it creates only low resistance.20 – 22 The efficacy of oral molnupiravir was evaluated in a phase 3 randomized control trial in 1,433 people with COVID-19, with a lower percentage of hospitalizations or deaths by day 29 in the molnupiravir group compared to placebo.18 Another important clinical question is whether molnupiravir-resistant viruses can develop and how many cats relapse or reinfection after treatment.
All owners who provided informed consent to participate were included in this study, so the risk of any bias should be minimal. Nevertheless, selection bias should be considered as this case series was enrolled in a single center in Chiba Prefecture, Japan. Another potential limitation of our case series is that the diagnosis of FIP was probable in all cases. Cats can have FCoV viremia without FIP, so RT-PCR detection of FCoV RNA is not specific for FIP.7 although this technique has a high sensitivity (90 %) and specificity (96 %) for FIP when applied to FNA specimens.23 In our series, the combination of RT-PCR with clinical signs and other serum biochemical tests, including a low A/G ratio, was highly suggestive of FIP.7 This case series suggests that molnupiravir may be an effective and well-tolerated treatment for FIP.
Table S1. Feline demographics and disease status before treatment. Table S2. Overview of the course of treatment. Table S3. Test values obtained at the first visit and the last test, based on which the decision was made to stop treatment.
References
Addie D, Belák S, Boucraut-Baralon C, et al. Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg. 2009; 11: 594-604.
Wang YT, Su BL, Hsieh LE, Chueh LL. An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Vet Res. 2013; 44: 57.
Addie DD, Toth S, Murray GD, Jarrett O. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. Am J Vet Res. 1995; 56: 429-434.
Foley JE, Poland A, Carlson J, Pedersen NC. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Am Vet Med Assoc. 1997; 210: 1313-1318.
Murphy BG, Perron M, Murakami E, et al. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018; 219: 226-233.
Pedersen NC, Perron M, Bannasch M, et al. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019; 21: 271-281.
Jones S, Novicoff W, Nadeau J, Evans S. Unlicensed GS-441524-like antiviral therapy can be effective for at-home treatment of feline infectious peritonitis. Animals (Basel). 2021; 11: 2257.
Krentz D, Zenger K, Alberer M, et al. Curing cats with feline infectious peritonitis with an oral multi-component drug containing GS-441524. Viruses. 2021; 13: 2228.
Katayama M, Uemura Y. Therapeutic effects of Mutian([R]) Xraphconn on 141 client-owned cats with feline infectious peritonitis predicted by total bilirubin levels. Vet Sci. 2021; 8: 328.
Katayama M, Uemura Y. Prognostic prediction for therapeutic effects of Mutian on 324 client-owned cats with feline infectious peritonitis based on clinical laboratory indicators and physical signs. Vet Sci. 2023; 10: 136.
Roy M, Jacque N, Novicoff W, Li E, Negash R, Evans SJM. Unlicensed molnupiravir is an effective rescue treatment following failure of unlicensed GS-441524-like therapy for cats with suspected feline infectious peritonitis. Pathogens. 2022; 11: 1209.
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in non-hospitalized patients. N Engl J Med. 2022; 386: 509-520.
Agostini ML, Pruijssers AJ, Chappell JD, et al. Small-molecule antiviral β-dN (4)-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J Virol. 2019; 93:e01348.
Dunbar D, Kwok W, Graham E, et al. Diagnosis of non-effusive feline infectious peritonitis by reverse transcriptase quantitative PCR from mesenteric lymph node fine-needle aspirates. J Feline Med Surg. 2019; 21: 910-921.
Although currently the most widely used active substance in the treatment of FIP is the nucleoside analog GS-441524, in fact there are already several agents with antiviral activity that can be successfully used in the treatment of FIP. In this article, I would like to introduce you to currently used antivirals, or recommendations for their use.
Due to the absence of clinical studies other than GS-441524 and GC-376, unless otherwise stated, the recommended duration of treatment for FIP is still 12 weeks. This does not mean that the treatment cannot be shorter for a specific individual, but at the same time there are also cases where the treatment must be extended. It should also be noted that the treatment should always be terminated only after the assessment of the cat's clinical condition and the results of the blood test.
GS-441524
Currently the most widely used antiviral drug for the treatment of FIP. Nucleoside analog GS-441524 has been the subject of several clinical studies. The first to prove its effectiveness in the treatment of FIP was Dr. Niels Pedersen and his team. You can find his pioneering clinical study here. The subject of this clinical study was injection form active substance, but it didn't take long, and tablet forms of the drug also appeared on the market. The originally determined dosage was gradually increased over time along with the decreasing price of the treatment, and nowadays it is good to stick to the values listed below. In addition, GS-441524 is a very safe antiviral, and because of minimizing the risk of relapse, it is better overdose, such as underdosing.
Unfortunately, the patent holder of GS-445424, Gilead, never licensed it to another company (with the exception of Bova), and is not even trying to commercialize this substance. For this reason, practically all medicines containing GS-441524 come from the black market.
In the case of a severe condition, it is possible and even advisable to use at least the first 3 days of the so-called booster dosage at the dosage level for neurological FIP, even if the cat does not have neurological FIP. There are even opinions that it is good to use neurological dosage for the first 14 days even in non-neurological forms of FIP (Dr. Addie).
FIP type
GS-441524 - injection solutions
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
6 mg/kg once a day sc
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)
8 mg/kg once daily SC
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)
10 mg/kg once daily SC
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)
12 mg/kg once daily SC
Relapse of FIP (usually associated with neurological manifestations)
15 mg/kg once daily SC
Arrival tablets The dosage for treatment has become a bit confusing, because some manufacturers have started to list the so-called equivalent GS content for tablets, so that the dosage used is "compatible" with injections, while other manufacturers list the real GS content. It is believed that the oral bioavailability of the drug is only about 50% compared to injections, so in practice it is necessary to count on double the dosage for such tablets compared to injections, or simply use tablets with a known real GS content as tablets with half the equivalent GS content. There is only one company that has a license to use GS-441542 in tablet form in veterinary practice, and that is the British company Bova. Its tablets with a GS content of 50 mg are used for the legal treatment of FIP in Australia and Great Britain. Unfortunately, they are very expensive. It is necessary to count on the price of 1 tablet of about 1000 CZK. For this reason, similarly to injectable solutions, in practice tablets from the Chinese black market are mainly used for treatment.
Note that for neurological FIP, the recommendation is to split the dose twice a day. This is due to the presumed reduced absorption capacity of the drug in the digestive tract at an equivalent dosage higher than 10mg/kg.
FIP type
GS441524 - tablets with the specified real GS content
GS441524 - tablets with the stated equivalent GS content
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
10-12 mg/kg once a day
6 mg/kg once a day
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)
12-16 mg/kg once a day
8 mg/kg once a day
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)
20 mg/kg once a day or 10 mg/kg twice a day
10 mg/kg once a day or 5 mg/kg twice a day
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)
12 mg/kg twice a day
6 mg/kg twice a day
Relapse of FIP (usually associated with neurological manifestations)
15 mg/kg twice a day
7.5 mg/kg twice a day
As already mentioned, GS-441524 is a safe antiviral, but on the other hand, neutropenia is very often observed after treatment, which can last for a very long time (up to several months). In the case of long-term and very significant neutropenia, the application of filgrastim - a factor that stimulates the formation of hematopoietic cells - can be considered.
GC376
Protease inhibitor GC376 is actually a first generation anti-FIP drug. Its effectiveness has been proven in the treatment of wet and dry FIP, but due to the significantly reduced ability to penetrate through the blood-ocular and blood-brain barrier, it is not suitable for the treatment of ocular or neurological forms of FIP. Given that very shortly after pilot study GC376 was lost to Dr. Niels Pedersen with the nucleoside analog GS-441524, the importance of the protease inhibitor GC376 has declined significantly. However, it turns out that it can be, and probably will be in the future, an important component of the combined treatment of FIP, for example together with GS-441524, where the effect of both active substances is mutually potentiated, and as a result is much more pronounced than with each active substance alone . Currently, the company is trying to launch GC376 on the market Anivive.
FIP type
GC376 - solution for injection
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
15 mg/kg 2x daily sc
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)
15 mg/kg 2x daily sc
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)
it is not used
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)
it is not used
Relapse of FIP (usually associated with neurological manifestations)
it is not used
GC376 is a safe antiviral, but its most significant side effect is a delay in the development of permanent teeth in young cats.
Remdesivir
This is another drug from Gilead. In fact, it is the so-called prodrug of the above GS-441524. After the application of remdesivir, intracellular metabolism to GS-441524 occurs in the organism. Remdesivir was marketed by Gilead under the trade name Veklury and has played a significant role in the treatment of Covid-19 in humans. However, its use in veterinary practice is very questionable and impractical. Firstly, it lacks approval for veterinary use and secondly, it is very expensive. Application is also a weak point of the drug, as it is intended for intravenous administration. The concentration of Veklura after reconstitution is only 5mg/ml.
The company Bova managed to obtain a license for the use of remdesivir for veterinary use and produces a product with a concentration of 10 mg/ml, which can be used in the form of subcutaneous injections. Unfortunately, the price is very high, so it is not used much in common practice. Remdesivir has approximately 2x the molecular weight of GS-441524, so the dosage of remdesivir must be approximately 2x higher than that of GS-441524.
FIP type
Remdesivir - solution for injection
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
10-12 mg/kg once a day iv/sc
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)
10-12 mg/kg once a day iv/sc
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)
15 mg/kg once daily iv/sc
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)
20 mg/kg once a day iv/sc
Relapse of FIP (usually associated with neurological manifestations)
25 mg/kg once a day iv/sc
Molnupiravir
Antiviral with a long history primarily intended for the treatment of Covid-19 in humans. Molnupiravir (EIDD-2801) is incorporated into the genome of RNA viruses and causes random mutations resulting in the so-called virus bug disaster. The drug exists in the form tablets or capsules. Most legally manufactured drugs (e.g. Lagevrio) contain capsules containing 200 mg of the active substance, and re-encapsulation of the drug is necessary for use in the treatment of FIP. Of course, Chinese manufacturers also produce tablets intended for direct use in animals. Although molnupiravir is not strictly the drug of first choice in the treatment of FIP, it shows great potential in the treatment of FIP relapses, resistance to GS-441524, or can be an important part of FIP combination therapy.
FIP type
Molnupiravir
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
10 mg/kg twice a day
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)
10 mg/kg twice a day
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)
12 mg/kg twice a day
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)
12 mg/kg twice a day
Relapse of FIP (usually associated with neurological manifestations)
15 mg/kg twice a day
With molnupiravir, as with GS-441524, neutropenia can often be observed after the end of treatment, especially at high dosages.
Mefloquine
Mefloquine is an interesting substance that has its primary application in the treatment of malaria in humans. It is not effective as a monotherapy in the treatment of FIP, but it is shown that it can play an important role in the adjunctive treatment of FIP, for example with GS-441524. It mainly makes it possible to reduce the price of FIP treatment or reduce the risk of relapse. The normal length of treatment using GS-441524 is about 12 weeks, but in principle it is possible to shorten this treatment to about 8 weeks and use mefloquine for the next 4 weeks. In Europe, mefloquine is available under the trade name Lariam. One tablet contains up to 250 mg of active substance. In practice, the drug is administered at a dose of 12.5 mg/kg twice a week, or 62.5 mg twice a week for one cat. This corresponds to 1/4 tablet of Lariam twice a week (for example, Monday and Thursday). Lariam must be given with food, otherwise there is a higher probability of the cat vomiting.
I strongly reiterate the fact that mefloquine is not intended for the treatment of FIP as a monotherapy, and should always follow as a supplement after the treatment of FIP with one of the above-mentioned antivirals, or in combination with them.
FIP type
Mefloquine (Lariam)
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
62.5 mg per cat twice a week
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)
62.5 mg per cat twice a week
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)
62.5 mg per cat twice a week
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)
62.5 mg per cat twice a week
Relapse of FIP (usually associated with neurological manifestations)
62.5 mg per cat twice a week
Other antivirals
It turns out that there is actually up to several dozen of potentially suitable antivirals applicable to the treatment of FIP. Unfortunately, no clinical studies have yet been conducted for many of them, which are important not only for the verification of effectiveness, but mainly for the determination of cytotoxicity. The goal, of course, is to cure the animal without causing poisoning or other health problems that would lead to the cat's death.
Combined therapies
The currently used FIP treatment usually takes the form of monotherapy, that is, the drug contains only one active substance. Unfortunately, this approach has the disadvantage that it is only a matter of time before resistance to the used antiviral begins to manifest itself. The way out of this situation is combined therapy, when 2 or more antivirals are used simultaneously for the treatment of FIP. It is not an entirely simple issue, as in some combinations the therapeutic effect is significantly strengthened, but there are also combinations where, on the contrary, the therapeutic effect is weakened. Currently, the most likely drug combinations are the pairs GS-441524 and Molnupiravir, or GS-441524 and GC376. Regarding the second named combination, it has already taken place in China study, the result of which is really encouraging. In addition to curing all cats, the treatment time was reduced from 12 weeks to 4 weeks. It turns out that a dosage of GS-441524 5mg/kg/24h and GC-376 20mg/kg/12h could be used to achieve a therapeutic effect. However, this combination therapy still needs further independent verification of efficacy.
Meagan Roy 1, Nicole Jacque 2, Wendy Novicoff 3, Emma Li 1,Rosa Negash 1 , Samantha JM Evans 1 *
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
Independent Researcher, San Jose, CA 95123, USA
Departments of Orthopedic Surgery and Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
* Author to whom correspondence should be addressed.
Academic editors: Alessia Giordano and Stefania Lauzi Pathogens 2022, 11(10), 1209; https://doi.org/10.3390/pathogens11101209 Received: 19/09/2022 / Revised: 9/10/2022 / Received: 19/10/2022 / Published: 20/10/2022 (This article is part of a special issue of Advances on Feline Coronavirus Infection)
Feline infectious peritonitis (FIP) is a complex and historically fatal disease, although recent advances in antiviral therapy have revealed treatment options. A newer therapeutic option, unlicensed molnupiravir, is used as first-line therapy for suspected FIP and as salvage therapy for cats that have persistent or recurrent clinical signs of FIP after treatment with GS-441524 and/or GC376. Treatment protocols for 30 cats were documented based on owner-reported data. 26 cats treated with unlicensed molnupiravir as rescue therapy were treated with a mean starting dose of 12.8 mg/kg and a mean final dose of 14.7 mg/kg twice daily for a median period of 12 weeks (IQR = 10-15). A total of 24 of the 26 cats were still living without signs of disease at the time of writing this report. One cat was euthanized after treatment due to persistent seizures and the other cat underwent retreatment due to relapse of clinical signs. Few adverse effects have been reported, with the most prominent - drooping ears (1), broken whiskers (1) and severe leukopenia (1) - occurring at doses above 23 mg/kg twice daily. This study provides 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.
Keywords: FIP; coronavirus; antiviral drug; EIDD-2801; black market
1. Introduction
Feline infectious peritonitis (FIP) is a complex and historically fatal disease caused by mutation of the ubiquitous feline enteric coronavirus (FECV) [1]. Recent advances in feline and antiviral medicine have revealed potential treatment options for FIP. The 3C-like protease inhibitor GC376 was the first targeted antiviral therapy used against this disease [2]. GC376 was highly effective in improving clinical signs of FIP in 19 of 20 naturally infected cats, but showed limited ability to manage long-term disease [2]. Pedersen et al. continued to investigate the antiviral compound GS-441524, a nucleoside analog and active metabolite of remdesivir (GS-5734). GS-441524 demonstrated superior ability to treat and control disease in naturally infected cats compared to GC-376, with 25 of 31 cats disease-free at the time of writing [3]. Since these discoveries, cat owners worldwide have obtained these mostly unlicensed drugs to treat their FIP cats with remarkably high success rates [4]. Legal FIP treatment is in high demand in the United States due to ethical and legal concerns regarding the unlicensed drugs GC376 and GS-441524. In addition, some cats with FIP have exhausted all current treatment options due to disease relapse and/or treatment failure after GS-441524, GC376 and/or combination therapy. Therefore, an effective and legal treatment option for FIP is urgently needed. In connection with the recent outbreak of SARS-CoV-2, a number of new antivirals have entered the market. Molnupiravir (EIDD-2801), manufactured by Merck, is currently available under an emergency use authorization (EUA) from the FDA for the treatment of COVID-19 in adults [5]. It is an oral prodrug of the nucleoside analog BD-N4-hydroxycytidine, which increases guanine to adenine and cytosine to uracil nucleotide transition mutations in coronaviruses [6]. This mechanism increases the rate of mutations above the accepted limit, which in turn inactivates the virus [7]. Molnupiravir has been found to be safe and well tolerated at doses up to 800 mg twice daily in patients with COVID-19 [8]. Some studies have reported significant reductions in hospitalizations and deaths in mild-to-moderate COVID-19 patients, although efficacy appears to be lacking in severe COVID-19 patients [7].
Because of molnupiravir's strong potential to treat other coronavirus infections, cat owners have begun using unlicensed molnupiravir (or its active metabolite EIDD-1931) purchased over the Internet to treat FIP. However, the use of molnupiravir for the treatment of FIP is currently not documented in any scientific literature. Unlicensed molnupiravir can be used as first-line therapy for suspected FIP, but also as rescue therapy to treat cats that have persistent or recurrent clinical signs of FIP after GS-441524 and/or GC376 therapy. The aim of this study is to document this use and provide proof of principle for molnupiravir as a potential treatment for FIP based on owner-reported data.
2. Materials and methods
The survey was conducted using the Qualtrics XM program (Qualtrics Version May-August 2022, Provo, UT, USA) under license from Ohio State University. The survey (Supplementary Data S1) was written in English and consisted of 94 multiple-choice and free-response questions asking about FIP diagnosis, clinical signs, initial therapy (used before molnupiravir), molnupiravir treatment, adverse events, duration of treatment, and remission time. The number of free-response questions was limited to limit recall bias. The survey also allowed owners to upload relevant documents (eg veterinary medical records and laboratory results). The survey was formatted using questions from previous studies to maintain consistency of language and style, as well as newly developed questions specific to the experience of molnupivir treatment. The logic of the survey dictated that some questions appeared only after a particular answer was selected, while others were skipped when a particular answer was selected. This conditional logic was used to reduce questionnaire completion bias and questionnaire fatigue. The survey took approximately 20-30 minutes to complete and could be saved and completed later if needed. This study was approved by the Ohio State University Institutional Review Board (Protocol No. 2021E0162).
The survey was distributed to participants individually by email and data were collected from June to August 2022. Participants were selected from a subset of owners seeking molnupiravir therapy for their cat with suspected FIP through popular FIP therapy and social media support groups. Inclusion criteria were surveys of cats suspected of having FIP based on veterinary diagnosis, failure to respond to initial therapy, or recurrence of clinical signs after completion of initial therapy other than molnupiravir (eg, GS-441524 or GC376) and completion of 8–10 weeks of oral molnupiravir therapy (or those who subsequently died or were euthanized during therapy). This study also included a small group of cats that received molnupiravir for 8-10 weeks as initial and sole therapy, which will be referred to as first-line therapy in the rest of this paper, when FIP is suspected. Exclusion criteria were surveys with incomplete data or cats not diagnosed with FIP by a veterinarian.
3. Results
3.1 Demographic data
A total of 80 potential participants were identified through a social media FIP support group and 37 invitations to complete the questionnaire were sent to those participants with available contact details. A total of 33 questionnaires were mailed and 21 participants were sent follow-up emails to obtain complete questionnaire data. Seventeen owners attached relevant documents to the submitted questionnaires and two additional owners sent relevant documents containing veterinary medical records, laboratory results and diagnostic images to the study email address. These submitted documents were used to document adverse reactions reported by one participant. One response was a refusal to participate. Two cases were excluded because the cats did not have a diagnosis of FIP from a veterinarian (one of them was reported to have been diagnosed based on the loss of a sibling due to FIP and the other was examined by a veterinarian who concluded that blood tests were not consistent with FIP). A total of 30 cats with suspected FIP were therefore included in this study, 4 of which had not received any treatment prior to molnupiravir administration. These four cats were included as a separate small cohort of first-line molnupiravir treatment. A flow chart of these cases is shown in Figure 1. The countries of origin represented were the United States (25), Germany (2), Poland (2), and Sweden (1). The sex/neuter status of the cats at the time of diagnosis was 40 % neutered males, 40 % spayed females, and 20 % intact males. The mean age at diagnosis was 9.7 months, with a range of 1 month to 6 years. The majority of cats were of mixed or unknown breed (70 %); These included seven purebred cats and two special crossbreeds (e.g., a Balinese-Ragdoll-Siamese cross). Responses that referred to the cat as "American Shorthair" or "American Longhair" were instead categorized as mixed breed, given the commonly reported confusion among American owners regarding the nomenclature of this breed.
Figure 1. This flowchart represents the number of cases in each treatment block.
Regarding comorbidities, feline leukemia virus was reported in only one cat and calicivirus was reported in one cat. Several cats also had a history of external and/or internal parasitic infections (3), conjunctivitis/ocular infections (2), and bacterial skin infections (pyoderma) (1). A total of 16 cats had neurological signs of FIP. Three cats had both neurological and ocular manifestations of FIP, and two cats had only ocular manifestations of FIP. Of the remaining cases, seven were effusive, while five cases were non-effusive. The full breakdown of FIP types is shown in Table 1.
Cat
Age at diagnosis (months)
Sex/castration status at diagnosis
Tribe
Previous medical conditions
Country of origin
FIP form
Duration of initial treatment (weeks)
Disease-free period
Second therapy
Duration of the second therapy (weeks)
Disease-free period
The third therapy
Duration of the third therapy (weeks)
Disease-free period
1
4
Male
European shorthair
parasitic infections, URI at an early age
Germany
neurological
injectable oral GS-441524
8
none
injectable and oral GS-441524
15
none
2
15
neutered cat
Burmese
none
Sweden
effusive, non-effusive, neurological
injectable GS-441524
12
less than 4 weeks
injectable GS-441524
14
17 days
oral GS-441524
5 weeks
none
3
9
neutered cat
British Shorthair
none
Poland
effusive, neurological, ocular
injectable GS-441524
13
less than 2 weeks
injectable GS-441524
12
more than 6 months, less than 1 year
4
5
neutered cat
Abyssinia
none
USA
effusive
injectable GS-441524
12
less than 2 weeks
injectable GS-441524
14
less than 4 weeks
5
4
neutered cat
Balinese/Ragdol mix
calicivirus, conjunctivitis, giardiasis, tapeworm, URI
USA
non-effusive
injectable GS-441524
13
less than 8 weeks
6
7
neutered cat
Siamese
none
USA
neurological
injectable and oral GS-441524, injectable GC, injectable and oral molnupiravir
12
none
7
7
neutered cat
American Shorthair
none
USA
non-effusive
injectable and oral GS-441524
5
none
8
6
neutered cat
American Shorthair/Siamese mix
tapeworm, FCoV
USA
effusive, neurological
injectable and oral GS-441524
5
none
9
4
neutered cat
Homemade mixed
broken pelvis
USA
effusive
injectable and oral GS-441524
14
less than 6 months
oral GS-441524
13
less than 4 weeks
oral GS-441524/injectable GC
6 weeks in combination then 6 weeks of oral GS
none
10
4
neutered cat
Homemade mixed
none
USA
effusive
injectable GS-441524
23
less than 4 weeks
11
72
neutered cat
Homemade mixed
FeLV
USA
non-effusive
oral GS-441524
12
less than 6 months
12
5
Male
Homemade mixed
none
USA
non-effusive, neurological, ocular
injectable and oral GS-441524
17
none
13
01.V
Male
Savannah
none
USA
effusive, neurological
injectable and oral GS-441524
24
less than 6 months
injectable and oral GS-441524
12
less than 4 weeks
14
4
neutered cat
Homemade mixed
Skin and eye infections, fleas
Poland
non-effusive, neurological
injectable GS-441524
12
less than 2 weeks
injectable GS-441524
17
less than 4 weeks
15
12
neutered cat
American Shorthair
none
USA
effusive
injectable GS-441524/GC
01.V
none
16
5
neutered cat
Homemade mixed
none
USA
effusive, neurological
injectable GS-441524
12
less than 4 weeks
17
4
Male
American longhair
none
USA
ocular
injectable and oral GS-441524, GC376
13
none
18
6
neutered cat
Homemade mixed
none
USA
effusive
injectable GS-441524
12
none
19
12
neutered cat
Homemade mixed
none
USA
non-effusive
injectable and oral GS-441524
12
less than 2 weeks
injectable GS-441524
12
none
20
6
neutered cat
Unknown
none
USA
non-effusive, neurological
injectable GS-441524
4
none
oral GS-441524
3
none
21
4
neutered cat
Norwegian forest
none
USA
neurological
injectable GS-441524
12
less than 6 months
injectable GS-441524
01.V
none
Molnupiravir, GS-441524, GC
12 weeks
none
22
6
neutered cat
Homemade mixed
none
USA
neurological, ocular
oral GS-441524
3
none
23
12
neutered cat
Unknown
none
Germany
neurological
injectable GS-441524
16
less than 6 months
24
3
Male
Homemade mixed
none
USA
neurological
injectable GS-441524
12
less than 6 months
25
6
neutered cat
American Shorthair
none
USA
effusive
oral GS-441524
13
less than 1 week
26
1
Male
Unknown
none
USA
non-effusive
injectable GS-441524
12
less than 1 week
27
7
neutered cat
Homemade mixed
none
USA
non-effusive, neurological
Molnupiravir
12
less than 1 week
*Molnupiravir
28
24
neutered cat
Homemade mixed
none
USA
effusive
Molnupiravir
29
12
neutered cat
Homemade mixed
none
USA
non-effusive, ocular
Molnupiravir
30
24
neutered cat
Homemade mixed
none
USA
neurological
Molnupiravir
Table 1. Signaling and initial therapy characteristics of all 30 cats treated with unlicensed molnupiravir for suspected FIP.
3.2. Initial treatment before initiation of molnupiravir
A total of 26 of 30 cats received initial treatment for suspected FIP with unlicensed GS-441524 or a drug combination containing unlicensed GS-441524 as the main base drug (GS-441524-based). Half (13) of the cats were treated with injectable GS-441524. Only three cats were treated with oral GS-441524, while the other seven cats were treated with a combination of injectable and oral GS-441524 throughout the treatment period. Two cats were treated with a combination of the unlicensed drug GS-441524 and the unlicensed drug GC376. Cube no. 6 was treated with all previously mentioned drugs along with molnupiravir for 12 weeks of a very complicated regimen (Supplementary Data S2). Dosing of combination drugs used as part of primary therapy (eg, GC376 and molnupiravir) was not determined. Reported initial doses of the unlicensed GS-441524 ranged from 2 mg/kg to 10 mg/kg; the most frequently reported dosages were 5-6 mg/kg (eight cats) and 10 mg/kg (seven cats). Most (21) cats received a dose once a day. Only four were dosed twice daily, and one cat was dosed twice daily for one week at first, then switched to once daily dosing. The median duration of treatment based on GS-441524 was 12 weeks (IQR = 12-13). In fifteen cats, a change in daily doses was reported during treatment. For several cats, the daily dose was increased by body weight to maintain the same dosage in mg/kg. Others increased the mg/kg dosage because of insufficient clinical response or a change in route of administration (eg, from injectable to oral GS-441524). No participant reported dose reduction during treatment.
A total of 6 of 26 cats completed a shorter than average 12-week treatment with GS-441524 due to insufficient clinical response and were immediately started on another treatment. Two of the six cats initiated a different route or dose of unlicensed GS-441524 treatment as shown in Table 1. One cat switched from injectable to oral GS-441524 treatment on the second treatment. In the second cat, the dose of GS-441524 was simply increased during the second treatment. The remaining four cats started treatment with unlicensed molnupiravir at this time, as shown in Table 2. Of the 20 cats that completed at least 12 weeks of treatment with GS-441524, 16 experienced clinical remission. All 16 were in remission for less than 6 months, with 2 cats in remission for less than a week before clinical signs returned. All 16 started a second round of treatment, with 10 receiving a second round of GS-441524-based treatment and 6 starting molnupiravir at this time. Four cats that completed treatment with GS-441524 but did not achieve clinical remission were immediately started on molnupivir. A total of 26 cats received primary treatment with GS-441524 and all 26 relapsed or did not respond adequately. A total of 10 of 26 completed a second round of GS-441524-based treatment and 16 started molnupivir treatment.
Cat
Clinical symptoms at the beginning of treatment
Brand name
Initial dosage and frequency
Final dosage and frequency
Duration of treatment (weeks)
Time to improve
Persistent clinical symptoms
The result
Adverse effects
1
diarrhea, vomiting
Aura Plus
11 mg/kg twice daily
11 mg/kg twice daily
12
less than 1 week
none
clinical remission
none
2
none reported
Aura
12 mg/kg twice a day
12 mg/kg twice a day
12
uncertain
none
clinical remission
none
3
anisocoria, colored spots in the eye, polydipsia, pica, weight loss
Aura 2801
28 mg/kg twice daily
14 mg/kg twice a day
12
within 2 weeks
none
clinical remission
none
4
anorexia, lethargy, weight loss
EIDD
7 mg/kg twice a day
7 mg/kg twice a day
12
less than 1 week
none
clinical remission
none
5
colored spots in the eye, diarrhea, hiding and lack of socialization
Aura 2801
6 mg/kg once daily
13 mg/kg once daily
10
within 2 weeks
none
clinical remission
none
6
anisocoria, constipation, anorexia, fecal and urinary incontinence, lethargy, paralysis, seizures, pale gums, weight loss
Aura 2801
20 mg/kg twice a day
20 mg/kg twice a day
11
less than 1 week
none
clinical remission
none
7
anorexia, difficulty walking, hiding, lack of socialization, jaundice, lethargy
anorexia, heavy walking, hiding, lack of socialization, lethargy, unusual timidity
Aura 2801
11 mg/kg twice daily
16 mg/kg twice a day
18
more than 4 weeks
nothing physical but the MRI is still not normal
clinical remission
none
15
blindness, constipation, anorexia, diarrhea, enlarged abdomen, hiding, lack of socialization, lethargy, pale gums, weight loss
Aura 2801
16 mg/kg twice a day
16 mg/kg twice a day
12
less than 1 week
none
clinical remission
none
16
anorexia, difficulty walking, lethargy, seizures, tremors, weight loss
Aura 2801
14 mg/kg twice a day
14 mg/kg twice a day
12
less than 1 week
none
clinical remission
none
17
cough, anorexia, difficulty breathing, hiding, lack of socialization, lethargy, vomiting, weight loss
Aura 2801 and Aura 1931
12 mg/kg twice a day
17 mg/kg twice a day
20
within 3 weeks
anorexia
clinical remission
nausea/vomiting, anorexia
18
constipation, anorexia, difficulty walking, hiding, lack of socialization, weight loss
Aura 2801
12 mg/kg twice a day
12 mg/kg twice a day
8
within 2 weeks
none
clinical remission
none
19
lethargy, anorexia
Aura 2801
12 mg/kg twice a day
12 mg/kg twice a day
7
within 2 weeks
none
clinical remission
none
20
trembling/shaking
Aura 2801
10 mg/kg twice a day
23 mg/kg two to three times a day
10
less than 1 week
in remission about 1 1 weeks before the onset of seizures
euthanasia
decreased appetite when dosed three times a day, severe leukopenia, loss of beard, scaly skin on ears
21
difficulty walking, fecal incontinence
Aura 2801 and Aura 1931
13 mg/kg twice a day
30 mg/kg twice a day
14
less than 1 week
difficult walking, difficult jumping, fecal incontinence persisted during the study (1 week post treatment)
relapse and euthanasia
drooping ear tips, muscle weakness
22
colored spots in the eye, anorexia, difficulty walking, hiding, lack of socialization, lethargy
Aura 2801
16 mg/kg twice a day
19 mg/kg twice a day
9
within 2 weeks
none
clinical remission
none
23
difficulty walking, anorexia, loss of balance
EIDD aura
12 mg/kg twice a day
15 mg/kg three times a day
10
within 2 weeks
heavy walking
clinical remission
none
24
blindness, colored spots in the mouth, anorexia, difficulty breathing, difficulty walking, enlarged abdomen, urinary incontinence, jaundice, lethargy, paralysis, tremors
Aura 2801
15 mg/kg twice a day
15 mg/kg twice a day
16
less than 1 week
none
clinical remission
none
25
difficulty breathing, difficulty walking, hiding, lack of socialization, lethargy, URI
Aura 2801
7 mg/kg twice a day
7 mg/kg twice a day
16
within 2 weeks
none
clinical remission
none
26
lethargy, anorexia
Aura 2801
14 mg/kg twice a day
14 mg/kg twice a day
15
less than 1 week
neurological twitches, elevated liver enzymes
clinical remission
none
Table 2. Treatment and outcome characteristics of 26 cats receiving unlicensed molnupiravir as rescue therapy.
3.3. The second round of treatment before the initiation of molnupiravir
Overall, 10 of 26 cats that received initial GS-441524 treatment and subsequently relapsed were reported to have received a second round of unlicensed GS-441524 treatment prior to initiation of molnupiravir. Again, most cats received injectable GS-441524 (6), with two receiving oral GS-441524 and two receiving both injectable and oral GS-441524. Reported dosages ranged from 4-5 mg/kg to 15 mg/kg; the most frequently used dosages were 7-8 mg/kg (two cats) and 15 mg/kg (two cats). Most cats were dosed once daily (seven cats), one cat was dosed twice daily and one cat was dosed three times daily. In most cats, the dose was varied during treatment. The two doses were weight-adjusted to maintain the same dosage in mg/kg. Dosing in mg/kg was increased in five cats that did not respond adequately or developed new clinical signs (eg, neurological signs). The median duration of treatment was 12.5 weeks (IQR 9.75–14.25). Only two cats did not undergo at least 12 weeks of therapy. One of the two added GC376 and molnupiravir to current GS-441524 therapy, and the other started molnupiravir as sole therapy. Of the eight cats that completed at least 12 weeks of GS-441524 therapy, two did not achieve clinical remission. Both cats started treatment with unlicensed molnupiravir at that time. The remaining six cats were reported to achieve clinical remission after a second round of treatment with GS-441524. Five of the six cats were in remission for less than 4 weeks, with the exception of one cat that was in remission for more than 6 months but less than a year. Seven out of ten cats started taking unlicensed molnupiravir at this time.
3.4. The third round of treatment before starting molnupiravir
The remaining three cats received a final round of GS-441524-based treatment before switching to molnupiravir. Cat no. 2 received oral GS-441524 for 5 weeks prior to initiation of molnupiravir. Cat no. 9 was treated for 6 weeks with oral and injectable GS-441524 and then continued for 6 weeks with oral GS-442524 alone. Dosing and frequency in both cats are unknown, as the survey collected data on only two therapies prior to molnupivir. Cat no. 21 received a combination of GS-441524, GC376 and molnupiravir for 12 weeks. The dosage, frequency and duration of each varied radically over the course of 12 weeks (Supplementary Data S3). All three cats started treatment with molnupiravir without clinical remission from this third round of treatment.
3.5. Molnupiravir as rescue therapy
Of the 26 cats receiving unlicensed molnupiravir as rescue therapy, most were using the Aura brand, with only 2 cats using a different brand of molnupiravir. More than 81 % cats (18) were treated with Aura 2801, 1 cat was treated with Aura 1931, and another 2 cats were treated with both Aura preparations. The mean initial dosage was 12.8 mg/kg twice daily. One cat was dosed only once a day and two cats were dosed 2 to 3 times a day. The most commonly used initial dosage was 12 mg/kg twice daily. Dosage ranged from 6 to 28 mg/kg twice daily. 11 dosage changes were reported, all but one being an increase in dosage. Reduction of dosage in cat no. 3 was not explained in any way. The mean final dosage was 14.7 mg/kg twice daily, with the same three cats differing in dosing frequency. The most common final dosage was also 12 mg/kg twice daily. The dosage range was 7 to 30 mg/kg twice daily.
Median duration of treatment was 12 weeks (IQR 10-15). Overall, a wide range of 7-20 weeks was reported. Only eight cats were treated for less than 12 weeks. A cat that completed only 7 weeks of treatment was reported to have discontinued treatment due to achieving clinical remission. All 26 cats completed treatment at 7 weeks or longer and all 26 cats survived. No cases of missed doses of molnupiravir have been reported.
Owners reported improvement in clinical signs in more than 92 % cats within three weeks of initiation of molnupiravir treatment, with 84.6 % cats showing improvement within two weeks and nearly half (46.2 %) within one week. Only two cases were reported differently, with one cat showing no signs of improvement for up to 1.5 months, and the owner of the other cat being unsure of the timescale and degree of improvement in clinical signs. A total of seven cats with persistent clinical signs of FIP were reported. In one of them, the disappearance of clinical symptoms was reported after one week of the observation period. Others are thought to have had residual symptoms such as difficulty walking or jumping, tremors, MRI changes and fecal incontinence. The full range of persistent clinical signs is shown in Table 2. Only three cats reported adverse reactions in response to molnupiravir, including nausea/vomiting, anorexia, drooping ear tips (Figure 2), brittle whiskers, leukopenia, scaly skin and muscle wasting. At the time of publication, 24 of 26 cats are living in clinical remission of FIP after oral molnupiravir treatment. One cat reportedly died 1 week after discontinuation of molnupiravir due to a prolonged seizure, and the other cat (No. 21) was disease-free 4 weeks before relapse. Cat no. 21 then started a second round of molnupiravir at the same dose, but was subsequently euthanized due to insufficient response to treatment.
Figure 2. Dropped ear tips were reported as an adverse effect of unlicensed molnupiravir treatment in cat no. 21.
In cat no. Severe leukopenia was reported in 22 cases. Through veterinary records, it was found that cat no. 22 has moderate panleukopenia with lymphopenia, neutropenia, and normal hem and thrombograms on 4 of 5 sequential complete blood counts, which were confirmed through veterinary records of sequential complete blood counts. The initial white blood cell count recorded was 10,700 cells per microliter (reference range 3,500–16,000 cells per microliter). Four more complete blood tests showed white blood cell counts ranging from 1,200 to 1,900 cells per microliter. The initial neutrophil count was 8560 cells per microliter (reference range 2500-8500 cells per microliter). The other four neutrophil counts ranged from 696 to 1292 cells per microliter. The initial lymphocyte count was 1177 cells per microliter (reference range 1200-8000 cells per microliter). The other four lymphocyte counts ranged from 330 to 532 cells per microliter.
3.6. Molnupiravir as primary therapy
A small group of four cats were treated with unlicensed molnupiravir as sole therapy for suspected FIP, as shown in Table 3. Three of them reportedly chose molnupiravir over the unlicensed counterpart GS-441524 due to financial constraints. Cat no. 29 received 12 weeks of oral molnupiravir 12 mg/kg twice daily prior to the treatment shown in Table 3. This cat was disease-free for less than one week prior to restarting oral molnupiravir 19 mg/kg twice daily for 10 weeks.
Cat
Clinical symptoms at the beginning of treatment
Brand name
Initial dosage and frequency
Final dosage and frequency
Duration of treatment (weeks)
Time to improve
Persistent clinical symptoms
Conclusion
Adverse effects
* 27
Hiding, lack of socialization, lethargy, anorexia, URI, vomiting, weight loss
Aura 2801
19 mg/kg twice a day
19 mg/kg twice a day
10
less than 1 week
none
clinical remission
none
28
Anorexia, difficulty walking, distended abdomen, hiding, lack of socialization, lethargy
Aura 2801
8 mg/kg twice a day
8 mg/kg twice a day
13
in two weeks
none
clinical remission
none
29
Anisocoria, blindness, eye color changes, anorexia, hiding, lack of socialization, urinary incontinence, lethargy,
Aura 2801
10 mg/kg twice a day
10 mg/kg twice a day
13
in two weeks
none
clinical remission
none
30
Hiding, lack of socialization, lethargy, pale gums, weight loss
Aura 2801
10 mg/kg twice a day
12 mg/kg twice a day
10
in two weeks
none
clinical remission
none
Table 3. Treatment and outcome characteristics of 4 cats receiving unlicensed molnupiravir as primary therapy.* They received two rounds of molnupiravir treatment; the first round is documented in Table 1.
All four cats were treated with oral molnupiravir Aura 2801 at a mean starting dose of 11.75 mg/kg twice daily (range 8-19 mg/kg) and a mean final dose of 12.25 mg/kg twice daily (range 8-19 mg/kg ). The median duration of treatment was 11.5 weeks (IQR 10-13), with two cats treated for 10 weeks and two cats treated for 13 weeks. A Mann-Whitney test was performed and no significant difference was found between the median duration of molnupivir as rescue therapy (12) and the duration of molnupivir as initial therapy (11.5) (p = 0.692). All owners reported seeing clinical improvement within two weeks and one cat showed improvement within one week. All cats survived the treatment, were disease-free at the time of publication, and no adverse effects of the treatment were reported.
3.7. Molnupiravir by type of FIP
The above information was collected for all 30 cats and then further divided according to the clinical forms of FIP. First, 16 cats with a reported neurological form of FIP were evaluated. Subsequently, the other cats were divided according to ocular (2), effusive (7) and non-effusive (5) forms. The mean starting dose of molnupiravir in the neurological form of FIP was 14.4 mg/kg twice daily, with two cats treated 2-3 times daily. The mean final dosage was 16.4 mg/kg twice daily, with two cats treated 2-3 times daily. The most commonly used initial and final dosage was 12 mg/kg twice daily. Median duration of treatment for neurological FIP was 12 weeks (IQR 10-12,641).
In the two remaining cases of ocular FIP, the mean initial dose was 11 mg/kg twice daily and the mean final dose was 13.5 mg/kg twice daily. The treatment lasted an average of 16.5 weeks. Seven cases of effusive disease were treated with a mean initial dose of 10.5 mg/kg twice daily and a mean final dose of 11.1 mg/kg twice daily. Treatment lasted an average of 13 weeks (IQR 12–16). Five non-effusive cases were treated with a mean initial dose of 10.6 mg/kg twice daily and a mean final dose of 12.8 mg/kg twice daily. One cat was treated once a day. The average duration of treatment was 10 weeks (IQR 8.5-13.5).
3.8. Costs and owner satisfaction
The majority of cats in this study were switched to unlicensed molnupiravir due to treatment failure/relapse or insufficient response. In addition to cats that relapsed or did not respond to unlicensed GS-441524-based therapy, one cat did not tolerate the injectable form of GS, and three owners were restricted due to the cost of treatment. Owners were not required to disclose the financial cost of treatment; this information was provided on a voluntary basis only. In addition, “0” responses reported in the report were not included in the calculation of the following averages because it was not possible to distinguish whether “0” represented no cost or unknown cost. The average reported cost for the first round of GS-441524-based therapy was $3448.83, and similarly, the average reported cost for the second round of GS-441524-based therapy was $3509.09. Only 4 owners reported paying for molnupiravir treatment, while 16 others reported “0” (or no cost/cost unknown). The overall average for the 20 owners who responded to the survey question regarding financial costs (including “0” responses) for molnupiravir was $209. The average cost for the four owners who did not respond with a “0” response was $1045. While 90 % owners reported being “very” or “somewhat” satisfied with their experience of their cat’s molnupiravir treatment, three were “very dissatisfied” with their experience. Unfortunately, no explanation was provided for the reported dissatisfaction.
4. Discussion
In this work, we describe the first known use of unlicensed molnupiravir for the treatment of suspected FIP in cats based on owner-reported data. For the treatment of cats using unlicensed molnupiravir as primary therapy for suspected FIP, the combined data from this study suggests that dosing at 12 mg/kg twice daily for approximately 12 weeks is effective in achieving clinical remission. For the treatment of cats receiving molnupiravir as rescue therapy when failing or relapsing after GS-441524-based therapy, the combined data from this study suggests that dosing at 12-15 mg/kg twice daily for 12-13 weeks is effective in achieving clinical remission. However, when broken down by clinical form of FIP, it was found that neurological cases of FIP were generally treated with a higher dosage than the average for all types of FIP. Ocular, effusive and non-effusive cases were treated with a dosage of around 12 mg/kg twice daily, with some variations. Therefore, dosing of 15 mg/kg molnupiravir twice daily for 12 weeks appears to be effective for neurological cases of FIP. For ocular, effusive, and non-effusive cases, 12 mg/kg molnupiravir twice daily for 12–13 weeks appears to be effective.
These data are somewhat inconsistent with the proposed treatment protocol of the company manufacturing the unlicensed molnupiravir under the trade name HERO Plus 2801. The recommended dosage in the package insert is 25 mg/kg once daily for effusive and non-effusive FIP, 37.5 mg/kg once daily for ocular FIP, and 50 mg/kg once daily for neurological FIP [9]. The package insert for HERO Plus 2801 also reports preliminary results from a study entitled “Effect of Oral Nutrition Therapy on Survival and Quality of Life in Feline Infectious Peritonitis,” which included 286 cats diagnosed with FIP. According to this package insert, 28 cats were cured after 4 weeks of treatment and 258 cats were cured after 8 weeks of treatment, with no deaths at the time of writing [9]. Data from this study have not yet been published in the scientific literature.
However, the cats in this study were using molnupiravir from a different supplier, Aura, which did not provide specific treatment recommendations. The treatment protocols used were therefore based on advice and information shared in groups on social networks, worksheets published on the Internet [10,11] and information on possible adverse effects contained in information published as part of human drug approval applications [12].
The molnupivir treatment protocol derived from this study more closely matches an independently designed protocol [10] published on the Internet. Based on data from in vitro cell cultures of EIDD-1931 and EIDD-2801, laboratory and field studies of GS-441524, and human pharmacokinetic studies, these authors extrapolated the effective dosage of oral molnupiravir [10]. Their calculations suggested a dosage of 4.5 mg/kg every 12 h for effusive and non-effusive FIP, 8 mg/kg every 12 h for ocular FIP, and 10 mg/kg every 12 h for neurological FIP [10]. Although the dosage in this study was generally higher than the dosage suggested by the cited authors, the high survival rate and low relapse rate at the time of the study termination suggest that the manufacturer's unlicensed recommendations may not represent the lowest effective dosage. Ultimately, controlled scientific experiments are greatly needed to evaluate the lowest effective dosage of molnupiravir in cats with suspected FIP.
Several cats were treated with Aura 1931, which is the active metabolite of molnupiravir, EIDD-1931. The reported dosages used were in a similar range to those reported for molnupiravir. Nominally, because the molecular weight of EIDD-1931 is lower than that of EIDD-2801, these cats received more active drug than cats using molnupiravir. However, a previous study showed decreasing oral bioavailability with increasing doses in mice. Therefore, the difference in bioavailability may not be proportional [13]. Pharmacokinetic studies of both molnupiravir and EIDD-1931 in cats are unfortunately unknown.
No adverse effects were reported in the package insert for HERO Plus 2801, which is contrary to what was reported in this study. Among the reported side effects of molnupiravir, the most prominent were drooping ears, hair loss, and severe leukopenia. No skin or follicular lesions have been reported in the human medical literature to match the whisker shedding or ear folding reported here. However, it should be noted that the cats that experienced these side effects received the two highest doses of molnupiravir shown in this study: 23 mg/kg three times daily and 30 mg/kg twice daily.
Severe bone marrow toxicity was reported in dogs during a 28-day study that was discontinued due to severe drug effects [12]. At the dosage of 17 mg/kg/day and 50 mg/kg/day, all hematopoietic cell lines were affected [12]. Cat no. 22 received a maximum dosage of 23 mg/kg three times daily, which was much higher than the toxic dosage in dogs of 17 mg/kg once daily. In the study group with a dose of 17 mg/kg, the possibility of reversibility was noted when the treatment was stopped [12].
There are concerns about the content of unlicensed brands of molnuviravir, as these brands are not currently regulated and often do not list the actual ingredients. The Hero brand (same manufacturer as HERO Plus 2801) shown in Figure 3 was analyzed by our group in December 2021 through Toxicology Associates Inc. (Columbus, OH). It was found to contain 97.3 % of molnupivirus, with no other contaminants detected. The Aura 2801 product used by the majority of participants in this study was analyzed in September 2022 by the same laboratory. It was found to contain 96.8 % of pure molnupivirus. A more controlled assessment of the actual content and purity of the unlicensed preparations of both GS-441524 and molnupiravir is of great interest to the veterinary community and is an active research topic in our group.
Figure 3. Images of Hero brand unlicensed molnupiravir packaging.
Some limitations of this study result from the retrospective nature and legality of the therapies used. First, all data used in this study were obtained based on owner reports. Working closely with the owners and administrators of the social media websites that supported this group enabled a better understanding and interpretation of many of the survey responses. Due to the lack of a definitive ante-mortem diagnosis of FIP available for practical use, it was also not possible to confirm that the cats included in this study had FIP. In addition, the data are likely to be biased toward positive outcomes and may be burdened by recall error. During the distribution phase, a potential study participant responded by requesting to be removed from our email list and stating that he did not wish to participate in the study. Their cat did not respond to molnupiravir treatment and was eventually euthanized. We assume that others may have had the same feeling, since three other potential participants did not respond to the invitation to the study. This may have narrowed the number of participants with an adverse outcome and falsely inflated apparent survival rates. Therefore, the data presented here are intended to serve as evidence of the feasibility of using molnupiravir as primary or rescue treatment for FIP, not as an indication of the true rate of efficacy.
In cats using unlicensed molnupiravir as rescue therapy, the cause of failure to respond or relapse after GS-441524-based therapy was not determined. It could be related to the quality of the drug, the resistance of the virus or another factor. As there is currently no testing or regulation in the US, unlicensed versions of GS-441524 or GC376 may be of insufficient purity or concentration, leading to treatment failure. Another possible cause is natural or acquired resistance to GS-441524. These two causes may also be linked, as acquired resistance may be promoted when an insufficient amount of antiviral is used in treatment, for example with low-quality drugs.
A recent paper found no drug-induced viral mutations of SARS-CoV-2 during molnupivir treatment [14]. This suggests that SARS-CoV-2 is unlikely to develop resistance to molnupiravir. Therefore, treatment with molnupiravir may be similarly unlikely to induce FIPV resistance, making it an attractive therapeutic option.
However, there is clearly a need for (1) a legal (in the United States and elsewhere) alternative to unlicensed treatment with GS-441524 and (2) the availability of alternative rescue drugs, either alone or in combination, after failure of GS-441524 treatment. Molnupiravir has the potential to fill both of these gaps, and this is the first known report of its use in cats in the literature. Nevertheless, unlicensed preparations may continue to be used for the treatment of FIP given the cost and the widely established networks available for their acquisition.
In conclusion, according to owner-reported data, unlicensed molnupiravir appears to be an effective treatment for suspected FIP, both as a first-line and rescue treatment. At a dose of 12–15 mg/kg every twelve hours, minimal side effects are reported and it provides a survival benefit with clinical resolution of FIP. Although the experiences of these owners in treating and possibly curing cats with FIP are unconventional and potentially illegal, they are undeniably remarkable and there is much to learn from the experiments these “citizen scientists” are conducting. In reporting these experiences, we aim to provide a basis for investigating molnupiravir for use in cats with suspected FIP and to document a phenomenon of “group health” that our profession should not ignore.
Supplementary materials
The following supplementary information can be downloaded at https://www.mdpi.com/article/10.3390/pathogens11101209/s1 Supplementary Data S1: retrospective review of molnupiravir trials; additional data S2: abbreviated diary of clinical history cat. no. 6; supplementary data S3: Cat #21 abbreviated clinical history log.
References
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The development of FIP treatment with GS441524 was such that, since its discovery, it started with the use of an exclusively injectable form, to which a tablet form of the drug was later added. However, the existence of two forms using the same active substance brought a bit of confusion, which is related to the difference in absorption (biological availability - usability) of the active substance during injection and oral use. While almost 100% of the drug is used during injection, it is only about 50% for GS when administered orally. In order to be able to use the same dosage for both injectable and tablet forms of medicine, most manufacturers who produce both forms of medicine list the so-called equivalent GS content, which already takes into account the reduced availability of the drug administered orally. In this way, it is possible to easily switch from injections to tablets and vice versa. So, for example, if a tablet from the well-known manufacturers Lucky, Spark, or Hero etc... is equivalent (corresponding to the injectable form) let's say 16mg of GS, in fact it contains double the amount of GS, i.e. 32mg... But we can safely use 16mg in the calculation and follow the dosage recommendations for injectable use. However, due to the fact that many different manufacturers want to grab their piece of the GS pie on the market, many of them often state the real GS content for marketing reasons, because of course such a tablet looks financially more attractive than a tablet with the stated equivalent GS content... For such tablets but you really have to to know for sure from the manufacturer, what GS content it actually states, because if it states, for example, 40mg real content of GS in the tablet, when calculating the dose according to the generally valid recommendations for injections, you only have to use half tablet content… In other words, you use a 40mg GS tablet in your calculations as a 20mg tablet…
At this point, I would like to emphasize that GS-441524 is proven and safe by clinical studies and hundreds of thousands of cured cats worldwide, with minimal side effects, and is therefore used as a medicine first choice.
Recommended approximate dosage of GS-441524 at injection application or for tablets with the stated equivalent containing GS441524. The stated dosage applies to 1kg / 24h:
6 mg/kg q24h – Wet FIP
8 mg/kg q24h – Dry FIP
10 mg/kg q24h – Ocular FIP
12 mg/kg q24h – Neurological FIP
15 mg/kg q24h – Neurological relapse
Recommended approximate dosage of GS-441524 for tablets with the stated real containing GS441524. The stated dosage applies to 1kg / 24h:
12 mg/kg q24h – Wet FIP
16 mg/kg q24h – Dry FIP
20 mg/kg q24h – Ocular FIP
24 mg/kg q24h – Neurological FIP
30 mg/kg q24h – Neurological relapse
When you buy tablets yourself, pay extra attention to find out the information about whether the indicated content of the active substance in the tablet is real, or so-called. equivalent.
Note: Given that there is a reasonable assumption of an absorption limit of GS441524 in the digestive tract, it is recommended for dosages in equivalent 10mg/kg or more when taken orally, divide the dose into 2x a day.
In connection with the treatment of Covid-19, an antiviral drug called Molnupiravir has appeared on the market, which is just a more understandable name for the substance labeled EIDD-2801. Unlike GS-441524, this antiviral drug is used exclusively in oral form. Although its bioavailability (absorption ability) in the digestive tract is similar to that of GS441524, i.e. around 50%, due to the absence of an injectable form, no "equivalent" content of the active substance is used in the recommended dosage by manufacturers and practically all of them state its real content. Thus, no conversion to 50% content is used. A 40mg tablet is simply 40mg, and this must also be taken into account when calculating the dose based on the recommended dosage. And there is one more very important thing... The pharmacokinetics of Molnupiravir is different from that of GS, and therefore Molnupiravir must be administered 2 times a day.
Recommended approximate dosage of EIDD-2801 tablets at 1kg / 12h:
6 mg/kg q12h – Moist FIP
8 mg/kg q12h – Dry FIP
10 mg/kg q12h – Ocular FIP
12 mg/kg q12h – Neurological FIP
15 mg/kg q12h – Neurological relapse
Although at first glance this dosage may seem the same as that of GS, do not forget the essential difference. This is a dosage of 12 hours (as opposed to 24 hours for GS441524).
Given that no official clinical trial has yet been conducted for the use of Molnupiravir in the treatment of FIP (one is currently underway at UC Davis), its use is recommended only in cases of apparent resistance to GS441524, thus Molnupiravir will find application mainly in severe neurological relapses. Keep in mind that the side effects of Molnupiravir are not yet accurately mapped and one of the most feared is the potential mutagenic effect leading to cancer. There is no need to panic, but it is necessary to realize that in the current state of knowledge it is better to use Molnupiravir only in cases where it is really necessary. Time will tell if the possible side effects are a real threat or will never be confirmed.
An interesting paradox occurred in connection with the drugs GS441524 and Molnupiravir (EIDD-2801).
Efficacy and safety of GS441524 in the treatment of FIP was indeed confirmed clinical study, but due to the licensing policy of the patent owner (Gilead company) there is no legal the source of medicines and practically all production is concentrated in China.
On the other hand, the efficacy and safety of Molnupiravir in the treatment of FIP has not yet been confirmed no official clinical study, it exists but is legally available a form of medicine primarily intended for the treatment of Covid-19. In the Czech Republic/SR, it is distributed under the name Lagevrio in packs of 40 capsules, each containing 200 mg of the active ingredient, which is too much. Therefore, for use in cats, the drugs must be decapsulated. Of course, EIDD-2801 is already produced by several Chinese companies that also produce GS441524. Since the drug is not officially intended for the treatment of FIP, it is used off-label.
You are all familiar with the standard treatment for FIP in Australia which uses remdesivir (IV or SCI), GS-441524 (tablets) and mefloquine. These three drugs represent the basic equipment for feline veterinarians in Australia, although the specific details and treatment regimens vary from cat to cat according to their clinical signs and the preferences of the attending physician and the financial resources of the owner. Remdesivir has the advantage of being suitable for both intravenous and subcutaneous treatment, which may be useful in some cases of advanced disease or in cases where the abdominal disease is so extensive that there is concern about how much GS-441524 will be absorbed. I suppose no one uses the polyprenyl immunostimulant anymore despite recent work by the Edinburgh group showing some effectiveness.1
Figure 1: Hong Kong British Shorthair cat with moist (effusive) FIP. Photos courtesy of Chris Simpson.
In fact, some doctors and clients prefer to skip remdesivir altogether and go straight to GS-441524 tablets, which are less expensive, forgoing the need for high-cost hospitalization for several days of intensive treatment. The optimal timing of parenteral administration of remdesivir before switching to GS-441524 tablets is debated. We initially recommended two weeks of parenteral treatment, but for example colleagues at the Royal Veterinary College give remdesivir intravenously for 4-5 days and then switch to oral GS-441524.
Mefloquine is a useful drug that can be used in combination with GS-441524, or it can be given when owners can no longer afford the high cost of treatment, at a time when the cat is doing well but is probably not yet cured. There is some debate about the best dosing regimen for this repurposed drug. The original work suggested that ¼ tablet of Larium (62.5 mg) given twice weekly was adequate, while I prefer 20 to 25 mg per cat once daily. I often start this dose in cats near the end of GS-441524 treatment, and I give mefloquine for several months to give the cat’s immune system a little more time to “clear out” any FIP virus that is hiding in the mononuclear phagocytic cells.
Figure 2: High protein fluid from the abdominal cavity of the cat in Figure 1.
I have found that treatment regimens based on these drugs usually result in successful treatment of kittens and cats with FIP, although individual cases can be very challenging.
In my opinion, the biggest obstacle to successful treatment is the very high cost of treatment. Another problem is the requirement of 84 days of treatment to completely eliminate the virus.
The drugs themselves are very expensive, especially in adult cats or patients with CNS disease (which require higher mg/kg doses for drugs to penetrate the CNS), and this includes not only the very high cost of the drugs, but also the cost of initial stabilization and ongoing consultations for monitoring. As a result, treatment is financially unaffordable for many owners, often from the outset, and if resistance to the FIP virus develops during treatment, the requirement for very high doses, often over a long period of time, makes treatment difficult for even the most dedicated owner.
The owners tried to circumvent the high cost of treatment by using the black market drug GS-441524, which is commonly available from many suppliers. Although it is not legal, owners and especially cat breeders have obtained it in large quantities and many cats have been saved by these drugs.2 The problem is that we are not sure of the actual doses or the quality or the product that is given in different colored tablets, and our testing has shown that the dose, even if indicated on the package, may be higher or lower than the value indicated by the manufacturer. In addition, we cannot assess the differences between individual batches of black market drugs. Therefore, most Australian vets advise clients to use legal products provided by BOVA Australia and the supply chain is reliable and regular quality control ensures that each tablet contains 50mg of GS-4415624 as stated.
Figure 3: X-ray of the cat from Figure 1 with wet FIP.
The COVID pandemic has led to tremendous research into the prevention and treatment of coronavirus disease, and two oral products for the oral treatment of human patients infected with SARS-CoV2, namely molnupiravir and paxlovid, are now commonly available in Australia and elsewhere.3 Niels Pedersen provided the SOC FIP on his website a summary of the history of molnupivirus that I have attached to this monograph. The key part is cut and pasted below (with some editing):
As expected, molnupiravir was recently tested in cats with FIP by at least one Chinese vendor of GS-441524, and preliminary results were reported on the FIP Warriors CZ/SK website. The field study consisted of 286 cats with various forms of naturally occurring FIP seen at companion animal clinics in the US, UK, Italy, Germany, France, Japan, Romania, Turkey and China. There were no deaths among the 286 cats that participated in the tests, including seven cats with ocular (n=2) and neurological (n=5) FIP. Twenty-eight of these cats were cured after 4-6 weeks of treatment and 258 after 8 weeks. All treated cats remained healthy after 3-5 months, which is the period during which cats that were not successfully treated would be expected to relapse.
These data provide compelling evidence for the safety and efficacy of molnupiravir for cats with various forms of FIP. However, we hope that this field study will be written up in manuscript form, submitted for peer review and published. Nevertheless, it is now marketed to owners of cats with FIP. At least one other major marketer of GS-441524 is also interested in using molnupiravir to treat FIP, indicating demand for additional antiviral treatment in cats with FIP.
The safe and effective dosing of molnupiravir in cats with FIP has not been published. However, at least one vendor from China provided some pharmacokinetic and field test data for molnuparivir in cats with naturally occurring FIP in their promotional leaflet for a product called Hero-2801. In 28/286 cases, they received this drug at a dose of 30-40 mg/kg every 24 hours, ie the equivalent of 15-20 mg/kg every 12 hours. For comparison, the dose for humans is 800 mg every 12 hours or about 10 mg/kg per day.
Figure 4: Data provided on “Hero 2018” by FIP Warriors CZ/SK – EIDD-2801 (Molnupiravir). https://www.fipwarriors.eu/en/eidd-2801-molnupiravir/
Dosage recommendations seem to vary. It was originally proposed:
FIP: 25mg/kg q24h
Ocular FIP: 37.5 mg/kg q24h
Neurological FIP: 50 mg/kg q24h
The duration of treatment is 5-10 weeks, depending on the severity of the disease and the specific cat.
Later, this proposal was modified based on input from Niels Pedersen and the UC Davis group:
FIP: approximately 5-7 mg/kg q12h for 84 days.
Ocular FIP: 8-10 mg/kg q12h for 84 days.
Neurological FIP: 10-15 mg/kg q12h for 84 days.
These recommendations are based on assumptions based on published information and more field experience with molnupiravir is needed. Sam Evans has just presented some data on the use of molnupiravir for salvage therapy at the ISCAID conference in Glasgow. An active clinical trial involving Brian Murphy and Krystal Regan is underway at the University of California, Davis, to determine the optimal dosage and dosing interval for molnupiravir, beginning in July 2022.
It is questionable whether molnupiravir will prove safer and more effective than GS-441524 in the treatment of FIP, but a third antiviral could prove extremely useful in preventing resistance to GS-441524 (as a cocktail of antivirals with different resistance profiles) or in treating cats that they no longer respond well to GS-441524. The big unknown is whether molnupiravir will be free of long-term side effects.
As the dosages given in the trials seem to be somewhat questionable, I used 10mg/kg twice daily, but note that test cats are claimed to have received 100mg/kg once daily with no detectable adverse effects (see Figure 4) .
Key fact: I have been using molnupiravir in selected patients for about 2 months at a dose of 10 mg/kg twice a day. It may be prudent to increase this dose to 15 mg/kg twice daily, particularly in CNS disease. Higher doses seem likely to be safe and possibly more effective, but I'm reluctant to recommend them until we get more long-term data.
Finally, and really on a side note, paxlovid is a combination of two drugs given at the same time, with one used to inhibit the metabolism of the other; I can find no precedent for its use in cats, which is a shame because in humans it is the more effective of the two oral drugs available for COVID. It costs about the same in Australia as molnupiravir, but is comparably more expensive than molnupiravir when purchased from websites in India. It could prove to be a very useful drug for treating FIP if it is proven safe. In humans, one of the problematic side effects is a foul taste in the mouth, so-called “paxlovid mouth”, which could prove disastrous if it were to occur in cats, as they tend to foam at the mouth.
So what is the place of molnupiravir in the therapy of kittens and cats with FIP? How to get it? How much does it cost?
Anyone can buy molnupiravir for personal use or for use in cats by obtaining a prescription and presenting it at a pharmacy. The price is approximately $1,146.39 (https://www.pbs.gov.au/medicine/item/12910L) subject to pharmacy surcharge. The trade name is Lagevrio (Merck Sharp & Dohme) and the box contains 40×200 mg capsules. The drug was provisionally approved by the TGA in February 2022 for the treatment of COVID-19 in adults who do not require oxygen and are at risk of progression to severe COVID-19.
To treat a 4 kg cat at 10-15 mg/kg bid, you need 80 mg to 120 mg daily for 84 days or 6,720 to 10,080 mg. A box of 40x200 mg capsules is 8,000 mg, so if you factor in the preparation fee for a suitable dose for a cat - the high dose treatment costs about $1100-$2200, which is quite a bit cheaper than GS-441524 or remdesivir. So now we have an alternative treatment to the one we are currently using. What is the evidence? Are pharmacokinetics well known in cats? The answer to both is - we don't know for sure because the evidence hasn't been peer-reviewed, but compelling unpublished anecdotal information suggests it's an effective therapy. And we'll probably have good PK info from the Davis group within a year.
And now it gets a little more complicated! Australia has a system that allows people to import medicines from overseas for their own personal use and that of their family members. The reason is that human patients who are prescribed expensive unregistered medicines, and therefore medicines not covered by the PBS, have to find their own way of getting these medicines. It is not known how many Australians import medicines, but it is legal under the personal import scheme. Perhaps the best example is the “FixHepC Buyers Club” (https://fixhepc.com/), founded by Australian infectious disease doctors and general practitioners Drs John and James Freeman.5 Before hepatitis C drugs were subsidized by the PBS, thousands of Australians used this buyers' club to import affordable hepatitis C drugs at 1-2 % of the retail price. The initiative was supported by the Australian Society for HIV, Viral Hepatitis and Sexual Health Medicine, and many Australian doctors directed patients to buy their medication this way.
"They each paid $1,000 to $2,000 to get better, instead of the $84,000 that Gilead Sciences charged in America. It's still expensive, but at least it's affordable for many."
However, it comes with some risk. The online market for medicines is poorly regulated, operating across jurisdictions and substandard products are common. Some estimates suggest that up to 25% of medicines in circulation outside high-income countries are substandard. The biggest risk is insufficient quantities of the active substance, which can lead to unintentional undertreatment. This is a difficult area for doctors to navigate, both clinically and medico-legally. It is unclear how far a doctor’s duty of care extends. The current code of conduct states that good medical practice includes “upholding the patient’s right to access the necessary level of healthcare and, wherever possible, assisting them to do so.” There is no reason to believe that this would not also include helping patients to import medicines they would otherwise be unable to afford, if it is clearly in their best interest to do so.
My own opinion is that this is the same situation for small animal vets involved in the treatment of cats with FIP, and the vet oath taken by recent graduates would support this claim.
So how can a client order molnupiravir to treat their cat with FIP?
Figure 5; Screenshot of correspondence with the manufacturers of Molcovir 200 mg
Go to the internet and find the URL of the website called IndiaMART https://www.indiamart.com/ and search for Molcovir 200mg - currently the URL is: https://m.indiamart.com/isearch.php?s=Molcovir +200mg&prdsrc=1&countryiso=AU&qu-cx=1&stype=attr=1
They will take your information and ask what medicine you are interested in. They will then send your inquiry to several pharmacies and ask you for quotes. The manufacturers we have the most experience with are Dolphin pharmaceuticals and Mediseller, one of which accepts payment via PayPal instead of using your credit card. They will advise you that customs is your own business, but they will do their best to help you label the medication so that it is clear that it is not an illegal drug. You can't buy anything until the quote comes back to you. Figure 5 shows a screenshot of the correspondence with the company. Once you accept the quote, they will then arrange payment and then shipping. Currently, a five-pack purchase costs US$30 (AU$42) per pack plus US$65 shipping. Treating a 4kg cat with FIP CNS at 10-15mg/kg bid for 84 days is likely to be in the range of AUD$100-150. The cost of treating the same cat with remdesivir/GS-441524 is $6,550 when drug costs alone are considered.
So the cost of treating a cat with molnupiravir from India under the personal importation scheme will be about 2 % of the cost of conventional GS-441524 treatment. This means that no cat has to be euthanized due to the high cost of treatment –
Figure 6; Generic molnupiravir (Molcovir 200 mg capsules) purchased from IndiaMART and imported to Australia after customs clearance
The practical question is how to obtain molnupiravir in time. When purchased from this website, it takes approximately 3 weeks for the drug to reach Australia and clear customs. One option would therefore be to start treatment with remdesivir and/or GS-441524 and switch to molnupiravir as soon as the drug arrives. An alternative is to set up a “buyers’ club”, perhaps with the support of the Australian and New Zealand College of Veterinary Science Pharmacology chapter, to be the source of molnupiravir until the client can arrange to import their own supplies. Another option would be for a compounding pharmacy to import the drug from a reliable manufacturer and adapt it to a size suitable for cats and kittens, perhaps as a 60 mg metered tablet that can be split in half.
What is the best way to treat a cat with FIP in 2022 in Australia?
This question is not as simple as it might seem. Remdesivir and GS-441524 have had much success as a treatment for FIP in kittens and cats, and we are also comfortable with low-dose mefloquine as an add-on to consolidate treatment. However, most of us who have assisted in the treatment of cats know of cases where the FIP virus has developed acquired mutational resistance during treatment. This can often be worked around by increasing the doses of GS0-441524 administered, but many owners simply cannot afford this procedure.
Thus, the routine use of combination therapy of FIP cases using GS-441524 and molnupiravir can be recommended, and it is indeed possible that the combination therapy could be more effective and faster because it attacks two different targets in the FIP virus, and this could potentially lead to a shorter duration of treatment. The idea of 84-day therapy comes from the seminal work of Neil Pedersen and perhaps the assumption that the lifespan of macrophages in tissues is about 84 days, so to completely eliminate all the intracellular virus that is hiding in the mononuclear phagocyte system, we need to treat for longer than 84 days of lifespan macrophage.
However, for many clients, the huge cost of treatment is an insurmountable problem, and for many, and I dare say most clients, the ability to treat their kitten or cat for $200 (drug costs) will be the most important argument.
What is the disadvantage of molnupivir? The big unknown is whether molnupiravir will not have long-term toxic effects, since the active substance, N4-hydroxycytidine, is an extremely potent mutagen and the treatment time for FIP is much longer than the 5 days recommended for the treatment of Covid-19 in human patients. The probability of side effects is therefore theoretically higher. To me, that's a completely theoretical risk, but it's something we have to monitor in the patients we treat, being aware of the possibility of later cancer in some cases.
References
1. Černá, P.; Ayoob, A.; Baylor, C.; Champagne, E.; Hazanow, S.; Heidel, RE; Wirth, K.; Legendre, AM; Gunn-Moore, DA Retrospective Survival Analysis of Cats with Feline Infectious Peritonitis Treated with Polyprenyl Immunostimulant That Survived over 365 Days. Pathogens2022, 11, 881. https://doi.org/10.3390/pathogens11080881
2. Jones, S.; Novicoff, W.; Nadeau, J.; Evans, S. Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for At-Home Treatment of Feline Infectious Peritonitis. Animals2021, 11,2257. https://doi.org/10.3390/ani11082257
3. Atmar RL, Finch N. New Perspectives on Antimicrobial Agents: Molnupiravir and Nirmatrelvir/Ritonavir for Treatment of COVID-19. Antimicrob Agents Chemother. 2022 Aug 16;66(8):e0240421. doi: 10.1128/aac.02404-21. Epub 2022 Jul 12. PMID: 35862759; PMCID: PMC9380556.
4. https://ccah.vetmed.ucdavis.edu › files › inline-files (this is a fantastic review of this subject, although some of the arithmetic is wrong. Highly recommended for people who are interested in drug development and action.)
Feline infectious peritonitis (FIP) is a highly fatal viral disease of cats with a worldwide incidence. Several antiviral agents have recently been shown to be promising in the treatment of cats with FIP. Despite these findings, there is currently no legal FIP treatment approved by the Food and Drug Administration (FDA), so many owners turn to unlicensed antivirals purchased online. Due to the ongoing COVID-19 pandemic, several antiviral drugs have recently been approved for oral use in human patients. One of these antivirals is the nucleoside analog EIDD-2801 (molnupiravir). EIDD-2801 causes hypermutation of developing viral RNA, effectively terminating the viral replication of many different RNA viruses. This antiviral agent has been developed for oral use in human patients at home. The use of EIDD-2801 in human medicine may facilitate veterinary use. An orally administered antiviral compound would be advantageous for the treatment of cats with FIP administered to a client. We will determine the effective oral dosage of EIDD-2801 and evaluate the efficacy of this compound in the home treatment of cats owned by a client with naturally occurring effusive FIP.
(Bria Fund)
Grant ID: EC22-007 Status: Active Year: 2022 Grant amount: $33,550 Investigator: Brian Murphy, DVM, PhD, Dip ACP; Krystle Reagan, DVM, PhD, Dip ACVIM (SAIM); University of California, Davis
Abbreviations: SC - subcutaneous IV - intravenous IM - to the muscle PO - per os - orally SID - once a day BID - 2x this q24h - once every 24 hours q12h - once in 12 hours
Introduction
Antiviral resistance is well documented in diseases such as HIV / AIDS and hepatitis C. In some cases, this resistance is present in the infecting virus, but is more often due to long-term drug exposure. Resistance to GC376 [1] and GS-441524 [2] has also been documented in cats with naturally acquired FIP. Resistance develops based on mutations in regions of the viral genome that contain targets for the antiviral drug. For example, several amino acid changes (N25S, A252S or K260N) were detected in the GIP376-resistant FIPV isolate (3CLpro). [3]. A change in N25S in 3CLpro was found to cause a 1.68-fold increase in 50 % GC376 inhibitory concentration in tissue cultures [3]. Resistance to GC376, although recognized in initial field trials, has not yet been described. GC376 is less popular in the treatment of FIP and is not recommended for cats with ocular or neurological FIP. [1].
Natural resistance to GS-441524 was observed in one of 31 cats treated for naturally occurring FIP [2]. One of the 31 cats in the original GS-441524 field study also appeared to be resistant, as viral RNA levels did not decrease throughout the treatment period and the symptoms of the disease did not abate. Although this virus has not been studied, resistance to GS-5734 (Remdesivir), a prodrug of GS-441524, has been established in tissue culture by amino acid mutations in RNA polymerase and corrective exonuclease. [4].
Resistance to GS-441524 has been confirmed in a number of cats that have been treated for FIP with GS-441524 in the last 3 years, especially among cats with neurological FIP [5]. Resistance to GS441524 is usually partial and higher doses often cure the infection or significantly reduce the symptoms of the disease during treatment. Interestingly, resistance to GS-441524 has also been found in patients with Covid19 treated with Remdesivir [12]. An immunocompromised patient developed a prolonged course of SARS-CoV-2 infection. Remdesivirus treatment initially alleviated symptoms and significantly reduced virus levels, but the disease returned with a large increase in virus replication. Whole genome sequencing identified an E802D mutation in nsp12 RNA-dependent RNA polymerase that was not present in pre-treatment samples and caused a 6-fold increase in resistance.
Although the history of molnupiravir and its recent use in the treatment of FIP has been described [6], there are currently no studies documenting natural or acquired resistance to molnupiravir. Molnupiravir has been shown to function as an RNA mutagen causing several defects in the viral genome [7]while remdesivir / GS-441524 is a non-binding RNA chain terminator [8], which suggests that its resistance profile will be different.
Overcoming resistance to GS-441524
Drug resistance can only be overcome in two ways: 1) by gradually increasing the dose of the antiviral to achieve drug levels in body fluids that exceed the resistance level, or 2) by using another antiviral that has a different mechanism of resistance, either alone or in combination. So far, the first option has been chosen, which has proved effective in many cases. However, resistance to GS-441524 may be complete or so high that increasing the dose is no longer effective. In such cases, the second option is increasingly used. Currently available alternatives to GS-441524, although still from an unapproved market, are GC376 and molnupiravir.
Antiviral drug treatment regimens for resistance to GS-441524
GC376 / GS-441524
The combined GS / GC regimen has been shown to be effective in cats treated with GS-441524 at doses up to 40 mg / kg without cure due to resistance to GS-441524. It is better to intervene as soon as resistance to GS-441524 is detected, which will allow the cat to be cured sooner and at lesser cost to the owner.
Rainman is the current supplier of GC376, which comes in 4 ml vials at a concentration of 53 mg / ml.
GS / GC dosage: The dose of GS (SC or PO equivalent) in combination antiviral therapy is the same as the dose needed to adequately control the symptoms of the disease. This is usually the last dose used before the end of treatment and relapse. To this dose of GS-441524, GC376 is added at a dose of 20 mg / kg SC q24h regardless of the form of FIP. This is sufficient for most cats, including many cats with neuro FIP, but some will need higher doses. If remission of clinical signs is not achieved or blood tests are of concern, the dose of GC376 is increased by 10 mg / kg up to 50 mg / kg SC q24h.
Duration of treatment: An eight-week combination GC / GS treatment is recommended, which is added to previous GS monotherapy. Some cats were cured at 6 weeks of combination therapy, but relapse is more likely than at 8 weeks.
Side effects: Most cats have no serious side effects. However, about one in five cats may experience nausea or discomfort at the beginning of treatment and sometimes longer. These side effects do not appear to be dose dependent and can be treated with anti-nausea drugs such as Cerenia, Ondansetron or Famotidine. Ondansetron appears to have performed better in some cats.
Molnupiravir
Molnupiravir has been reported to be effective in monotherapy in cats with FIP by at least one Chinese retailer GS-441524 [9], but there are no reports of its use in cats with resistance to GS-441524. However, resistance to GS-441524 is unlikely to spread to molnupiravir. The fact that it has been found to be effective as an oral medicine also makes it attractive for treatment alone, as many cats resistant to GS-441524 have suffered from injections for a very long time.
A field study of molnupiravir reportedly consisted of 286 cats with various forms of naturally occurring FIP, which were examined in pet clinics in the United States, the United Kingdom, Italy, Germany, France, Japan, Romania, Turkey and China. Among the 286 cats that participated in the trial, no deaths occurred, including seven cats with ocular (n = 2) and neurological (n = 5) FIP. Twenty-eight of these cats were cured after 4-6 weeks of treatment and 258 after 8 weeks. All treated cats remained healthy 3-5 months later, a period during which cats that were not successfully cured would be expected to relapse. These data provide convincing evidence of the safety and efficacy of molnupiravir in cats with various forms of FIP. However, we hope that this field study will be written in the form of a manuscript, submitted for review and published. Nevertheless, it is now sold to cat owners with FIP. At least one other major retailer of GS-441524 is also interested in using molnupiravir for FIP, indicating a demand for further treatment of cats with FIP antivirals.
Molnupiravir dosage: The safe and effective dosing of molnupiravir in cats with FIP has not been established based on closely controlled and monitored field studies such as those performed for GC376 [1] and GS-441524. [2]. However, at least one seller from China in his flyer for a product called Hero-2801 [9] provided some pharmacokinetic and field trial data for Molnuparivir in cats with naturally occurring FIP. This information does not clearly state the amount of molnuparivir in one of their “50 mg tablets” and the actual dosing interval (q12h or q24h?). The dose used in this study also seemed too high. Fortunately, an estimated starting dose of molnuparivir in cats with FIP can be obtained from the published studies of EIDD-1931 and EIDD-2801 [15] in vitro on cell cultures and laboratory and field studies GS-441524 [14,18]. Molnupiravir (EIDD-2801) has an EC50 of 0.4 μM / μl against FIPV in cell culture, while the EC50 of GS-441524 is approximately 1.0 μM / μl. [18]. Both have a similar oral absorption of approximately 40-50 %, so an effective subcutaneous (SC) dose of molnupiravir would be approximately half the recommended starting dose of 4 mg / kg SC q24h for GS441524. [14] or 2 mg / kg SC q24h. The oral (PO) dose would be doubled to account for less effective oral absorption per 4 mg / kg PO q24h dose. The estimated initial effective oral dose of molnupiravir in cats with FIP can also be calculated from the available Covid-19 treatment data. Patients treated with Covid-19 are given 200 mg of molnupiravir PO q12h for 5 days. This dose was, of course, calculated from a pharmacokinetic study performed in humans, and if the average person weighs 60-80 kg (70 kg), the effective inhibitory dose is 3,03.0 mg / kg PO q12h. The cat has a basal metabolic rate 1.5-fold higher than humans, and assuming the same oral absorption in both humans and cats, the minimum dose for cats according to this calculation would be 4.5 mg / kg PO q12h in neocular and non-neurological forms of FIP. If molnupiravir crosses the blood-brain and blood-brain barriers with the same efficacy as GS-441524 [3,18], the dose should be increased to 1,51.5 and 2,02.0-fold to ensure adequate penetration into aqueous humor and cerebrospinal fluid for ocular cats (88 mg / kg PO, q12 h), respectively. neurological FIP (~ 10 mg / kg PO, q12 h). These doses are comparable to those used in ferrets, where 7 mg / kg q12h maintains sterilizing blood levels of the influenza virus drug (1.86 μM) for 24 hours. [10]. Doses in ferrets of 128 mg / kg PO q12h caused almost toxic blood levels, while a dose of 20 mg / kg PO q12h caused only slightly higher blood levels. [10].
Molnupiravir / GC376 or Molnupiravir / GS-441524
Combinations of molnupiravir with GC376 or GS-441524 will be used more and more frequently, not only to synergy or complement their individual antiviral effects, but also as a way to prevent drug resistance. Medicinal cocktails have been very effective in preventing drug resistance in HIV / AIDS patients [11]. However, there is currently insufficient evidence on the safety and efficacy of the combination of molnupiravir with GC376 or GS-441524 as initial treatment for FIP.
Case studies
Rocky - DSH MN Neuro FIP
A 9-month-old neutered domestic shorthair cat obtained as a rescue kitten had several weeks of seizures with increasing frequency, ataxia and progressive paresis. The blood tests were unremarkable. FIP treatment was started at a dose of 15 mg / kg BID GS-441524, which decreased to SID for about a week. The cat showed improvement, seizures stopped, and mobility increased within 24 hours of starting treatment. Within 5 days of treatment, the cat was able to move again. However, approximately 2 weeks after the start of treatment, the cat experienced loss of vision, decreased mobility, recovery of seizures and difficulty swallowing. Dose adjustments of levetiracetam and prednisolone were made, as well as a change in the composition of GS-441524, followed by a temporary improvement in motility and swallowing and a reduction in seizures, but overall the cat's condition worsened. The dose of GS-441524 was gradually increased to 25 mg / kg, with little or no improvement. At this point, GS was taken orally at a dose of 25 mg / kg (estimated to be approximately 12.5 mg / kg) and within 3 days, the cat began to move, improved vision, and stopped seizures with increased energy and appetite. Improvement in cats continued for approximately 4 weeks with oral administration of GS-441524, then stopped for approximately 3 weeks before rapidly progressing paresis. Oral doses up to 30 mg / kg SC equivalent have been tested but have no effect. GS-441524 was then injected at a dose of 20 mg / kg and the cat was able to move again within 4 days with good appetite and energy. After 2 weeks, a dose of GC376 20 mg / kg BID was added to the dosing regimen. The cat terminated 6 weeks of the GS441524 and GC376 combination therapy and then discontinued the treatment. Although the cat has certain permanent neurological deficits, its condition is stable, it has good mobility, appetite and activity for 9 months after the end of antiviral treatment.
A four-month-old neutered domestic shorthair cat obtained as a rescue kitten was presented with a monthly history of lethargy and a progressive history of ataxia, hind limb paresis, spades, uveitis, anisocoria, and urinary and stool incontinence. Blood tests were mostly uncommon, with the exception of mild hyperglobulinemia. The A / G ratio was 0.6. The cat was treated with 10 mg / kg GS-441524 SC SID for 3 weeks. Activity, mentation and uveitis improved within 72 hours of starting treatment. During the first 2 weeks, a slow improvement in mobility and eye symptoms was observed, but then a plateau was reached. After 3 weeks, the dose of GS-441524 was increased to 15 mg / kg GS-441524 SC SID due to persistent neurological and ocular deficits. In addition, enlargement of the left eye due to glaucoma was noted at this time and the eye continued to swell until it was removed at week 8 of treatment. Due to persistent weakness / lack of pelvic coordination and increasing lethargy, dose GS-441524 was increased to 20 mg / kg SC SID [or equivalent oral dose] at week 9 and 20 mg / kg SC BID was added to the regimen a few days later. GC376. Significantly increased activity and willingness to jump on elevated surfaces occurred within 48 hours of starting GS376 treatment. The combination treatment of GS-441524 and GC376 was maintained for 8 weeks. The cat has residual incontinence problems after treatment, but is otherwise clinically normal 6 months after treatment.
Boris - Maine Coon MI wet eye FIP
The five-month-old intact (uncastrated) Maine Coon cat, obtained from the breeder, had lethargy, anorexia, abdominal ascites, cough, anemia and neutrophilia. No biochemical analysis was performed to establish the diagnosis. The cat was treated with 6 mg / kg GS-441524 SC SID for 8 weeks. After six weeks of treatment, X-rays revealed nodules in the lungs, and after 8 weeks, hyperglobulinemia persisted. The GS-441524 dose was then increased to 8 mg / kg SC SID for 4 weeks. There was little improvement in blood tests and X-rays and the dose of GS-441524 was increased to 12 mg / kg SC SID over 4 weeks, followed by an increase to 17 mg / kg over 11 weeks, 25 mg / kg over 4 weeks and 30 mg / kg for 4 weeks. After 25 weeks of treatment, ultrasound revealed pleural abnormalities on the left side and X-rays showed no improvement in the pulmonary nodules. In addition, uveitis and retinal detachment have been reported in the right eye. Pulmonary aspirates that showed FIP-compliant inflammation were collected. After 33 weeks of treatment, 20 mg / kg SC BID GC376 was added to the regimen and the combined treatment of GS-441524 and GC376 was continued for 12 weeks. Increased activity was noted over several days. Over the course of 5 weeks, the weight gain accelerated, the cough subsided and the energy level increased. Blood tests showed an improvement in the A / G ratio, and chest X-rays showed a reduction in the lungs. After 84 days of combination antiviral therapy, the A / G ratio was 0.85 and the cat appeared clinically normal. The cat is currently 3 months after treatment.
References
Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg. 2018; 20 (4): 378-392.
Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H. efficacy and safety of the nucleoside analog GS-441524 for the treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019; 21 (4): 271-281.
Perera KD, Rathnayake AD, Liu H, et al. Characterization of amino acid substitutions in feline coronavirus 3C-like protease from a cat with feline infectious peritonitis treated with a protease inhibitor. J. Vet Microbiol. 2019; 237: 108398. doi: 10.1016 / j.vetmic.2019.108398
Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to the antiviral remdesivir (GS5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio 2018; 9. DOI: 10.1128 / mBio.00221-18.
Pedersen NC. 2021. The neurological form of FIP and GS-441524 treatment. https://sockfip.org/the-neurological-form-of-fip-and-gs-441524-treatment/
Pedersen NC. The long history of beta-d-n4-hyroxycytidine and its modern application to treatment of covid019 in people and FIP in cats. https://sockfip.org/the-long-history-of-beta-d-n4-hydroxycytidineand-its-modern-application-to-treatment-of-covid-19-in-people-and-fip-in- cats /.
Agostini, ML et al. Small-molecule antiviral beta-dN (4) -hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J. Virol. 2019; 93, e01348.
Warren, TK et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016; 531, 381–385.
FIP Warriors CZ / SK - EIDD-2801 (Molnupiravir) https://www.fipwarriors.eu/en/eidd-2801-molnupiravir/
Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, Plesker R, Barrena AH, Reddy PG, Mitchell DG, Shean RC, Bluemling GR, Kolykhalov AA, Greninger AL, Natchus MG, Painter GR, Plemper RK . Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci Transl Med. 2019; 11 (515): eaax5866.
Zdanowicz MM. The pharmacology of HIV drug resistance. Am J Pharm Educ. 2006; 70 (5): 100.doi: 10.5688 / aj7005100
Gandhi, S, Klein J, Robertson A, et al. De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report. medRxiv, 2021.11.08.21266069AID
Beta-d-N4-hydroxycytidine is a small molecule (nucleoside) that was studied in the late 1970s in the former Soviet Union as part of biological weapons research [2]. The weaponization of diseases such as smallpox was a worldwide threat, but the danger of using the smallpox virus for this purpose was too great. Smallpox was eradicated from the world, virtually all stocks were destroyed and further research was banned. This led the US and the Soviet Union to research other RNA viruses as biological weapons and antivirals to defend against them. The Venezuelan equine encephalomyelitis virus (VEEV) was one of the first viruses to be seriously considered for use as a biological weapon. [3]. VEEV is transmitted to humans by mosquito bites and causes high fever, headaches and encephalitis with swelling that can be fatal. Beta-d-N4-hydroxycytidine has been found to inhibit not only VEEV replication but also a wide range of alphaviruses, including Ebola, chikungunya, influenza virus, norovirus, bovine diarrhea virus, hepatitis C virus and respiratory syncytial virus. [3-8]. The first reports of an inhibitory effect of beta-d-N4-hydroxycytidine on human coronavirus NL63 date back to 2006 [9]. Recent studies have confirmed its inhibitory effect on a wide range of human and animal coronaviruses [8].
An important part of the recent history of beta-d-N4-hydroxycytidine is associated with the Emory Institute for Drug Development (EIDD) [1], where he received the experimental designation EIDD-1931. The US government has provided significant financial support for the study of antivirals against alphaviruses in institutions such as Emory since 2004. [10]. In 2014, the Defense Threat Reduction Agency provided institutional support to find an antiviral compound against VEEV and other alpha-coronaviruses. "N4-Hydroxycytidine and its derivatives and antiviral uses" were included in U.S. Patent Application 2016/106050 A1 of 2016 [11]. Additional funding in 2019 was provided by the National Institute of Allergies and Infections for fellowship of the esterified beta-d-N4-hydroxycytidine precursor (EIDD-2801) for the treatment of influenza. [10]. The stated purpose of the chemical changes of EIDD-2801 was to increase its oral bioavailability, which would ultimately allow beta-d-N4-hydroxycytidine to be administered as pills and not as injections. In 2019/2020, the focus of research changed from influenza to SARS-CoV-2 [2]. The commercialization of EIDD-2801 was entrusted to Emory's Ridgeway Biotherapeutics subsidiary, which subsequently worked with Merck on a lengthy and costly FDA approval process. The current version of EIDD-2081 for field testing was named Molnupiravir.
Beta-d-N4-hydroxycytidine, the active substance in Molnupiravir, exists in two forms as tautomers. In one form, it acts as a cytidine with a single bond between the carbon and the N-OH group. In its other form, which mimics uridine, it has an oxime with a double bond between the carbon and the N-OH group. In the presence of beta-d-N4-hydroxycytidine, viral RNA-dependent RNA polymerase reads it as uridine instead of cytidine and inserts adenosine instead of guanosine. Switching between forms causes inconsistencies during transcription, which results in numerous mutations in the viral genome and a cessation of viral replication. [8].
Merck's commitment to conditional and full FDA approval of Molnuparivir continues. In its statement, Merck stated: [12]"In anticipation of the results of the MOVe-OUT program, Merck manufactures Molnupiravir at its own risk. Merck expects to produce 10 million therapeutic doses by the end of 2021, with more expected to be produced in 2022. Merck is committed to providing timely access to Molnupiravir worldwide, if authorized or approved, and plans to introduce access to tiered prices based on World Bank admission criteria that reflect countries' relative ability to fund their pandemic health response. As part of its commitment to extend the global approach, Merck has previously announced that it has entered into non-exclusive voluntary licensing agreements for Molnupiravir with established generic manufacturers to accelerate the availability of Molnupiravir in more than 100 low and middle income countries (LMICs) following approval or emergency approval by local regulatory agencies. . " This "generosity" is unlikely to apply to use in animals.
Drugs to inhibit the current Covid-19 pandemic have been the subject of accelerated field trials in the last two years, and one of them, Remdesivir, has been approved for use in hospitalized patients in record time. Last year, Molnupiravir was submitted for conditional approval as an oral medicinal product for home treatment of the infection at an early stage. [12]. However, anti-coronavirus compounds have been developed previously for another common and serious feline disease, feline infectious peritonitis (FIP). These drugs include a protease inhibitor (GC376) [13] and an RNA-dependent RNA polymerase inhibitor (GS-441524), which is an active ingredient of Remdesivir [14]. The success of antiviral drugs in the treatment of FIP prompted a recent study by EIDD-1931 and EIDD-2801 for their ability to inhibit FIPV in tissue cultures. [15]. The effective EC50 concentrations for EIDD-1931 against FIPV are 0.09 μM, EIDD-2801 0.4 μM and GS441524 0.66 μM [15]. The percentage of cytotoxicity at 100 μM is 2.8, 3.8 and 0, respectively. Therefore, EIDD-1931 and EIDD-2801 are slightly more effective at inhibiting viruses, but also more cytotoxic than GS-441524. These laboratory studies suggest that EIDD-1931 and EIDD-2801 are excellent candidates for the treatment of FIP.
Although EIDD-1931 and EIDD-2801 are a great promise for the treatment of FIP, there are several obstacles that will make the legal use of these compounds unlikely in the near future. GS-441524, the active form of Remdesivir and patented by Gilead Sciences, was investigated for use in cats with FIP shortly before the Covid-19 pandemic. FIP research [14] therefore stimulated the potential use of Remdesivir against Ebola and not SARS-like coronavirus [14]. Although these studies were conducted in collaboration with scientists from Gilead Sciences, the company refused to grant GS-441524 rights to treatment in animals as soon as it became clear that there was a much larger market for Covid-19 in humans. [16]. Similarly, my attempts over the past 2-3 years at Emory, Ridgeback Biotherapeutics, and Merck Veterinary Division to investigate EIDD-1931 and EIDD2801 for the treatment of FIP in cats have either remained unanswered or rejected, no doubt for similar reasons why Gilead refused to grant rights for GS-441524. However, the great worldwide need for FIP treatment quickly supported the unapproved market for GS-441524 from China. The same need to treat FIP has recently aroused interest in Molnupiravir, also from China.
Situation with EIDD-1931 vs. EIDD-2801 / Molnupiravir and GS-441524 vs. Remdesivir raises the question of why some medicines are being converted to prodrugs for marketing purposes [17]. Remdesivir was reportedly esterified to increase antiviral activity, although studies in cats showed that GS-441524 and Remdesivir had similar viral inhibitory activity in tissue culture. [18]. However, Remdesivir was found to be poorly absorbed by the oral route and was therefore conditionally approved for injectable use only. EIDD-2801 was designed to increase the oral absorption of EIDD-1931, although previous research has shown that EIDD-1931 is well absorbed orally without esterification. [6]. The motives for the commercialization of Remdesivir instead of GS-441524 for human use have been scientifically questioned, as it appears to be better in several ways without further modification. [17]. Why EIDD-2801 was chosen for commercialization, when EIDD-1931 would be cheaper, 4 times more effective against viruses and one third less toxic than EIDD-2801 [15]? The strength of patent rights and the longevity of patents may be more important factors in these decisions. [16,17,19].
One of the problems in the treatment of FIP in cats is the blood-eye and blood-brain barriers, which become very important when the disease affects the eyes and / or the brain. [13, 14, 20]. This problem has been largely overcome in the treatment of ocular and neurological forms of FIP with GS-441524 by gradually increasing the dose to increase blood levels and thus drug concentrations in the ventricular fluid and / or brain. [20]. GC376, one of the most effective antivirals against FIP virus in culture [17], is not effective against ocular and neurological FIP due to the inability to get enough drug to these sites, even if the dose is increased several times[14]. Fortunately, it appears that EIDD-1931 can reach effective levels in the brain, as indicated by studies in horses with VEEV infection. [3]. Drug resistance is another problem that now occurs in some cats treated with GS-441524, especially in individuals with the neurological form of FIP. Long treatment procedures and difficulties in transporting enough drug to the brain support the development of drug resistance.
The short-term and long-term toxic effects of the drug candidate on the test person or animal are crucial. GS-441524 showed lower toxicity in cell cultures than GC376, EIDD-1931 and EIDD-2801 [15]. Most important, however, is the toxicity that manifests itself in vivo. GC376 is one of the drugs with the highest coronavirus inhibitory effect [15], but slows the development of adult teeth when given to young kittens [13]. No serious toxicity was observed during nearly three years of field use of GS-441524, reflecting the complete absence of cytotoxic effects in vitro at concentrations up to 400 µM. [18]. However, EIDD-1931 and EIDD-2801 show significant cytotoxicity at 100 μM [15]. Therefore, the ability of EIDD-1931 to make fatal mutations in RNA has been raising a number of questions for some time. [8, 21, 22]. This was the main reason why the application for the treatment of diseases was still delayed. However, the current recommended duration of treatment with Covid-19 Molnupiravir is only 5 days at the initial stage of treatment. [10]. However, the recommended duration of FIP treatment with GS-441524 is 12 weeks [14], which represents a much longer time for the manifestation of toxicity. Therefore, close observation of cats during treatment with EIDD-1931 or EIDD-2801, whether short-term or long-term, will be important.
All existing antiviral drugs have led to the development of drug resistance through mutations in the viral genome. Although Remdesivir appears to be less susceptible to such mutations compared to drugs used in viral diseases such as HIV / AIDS, resistance is well documented. [23-25]. Resistance to GS-441524 in cats treated for FIP was observed at a higher frequency, especially in cats with neurological FIP, where it is more difficult to deliver sufficient drug to the brain [13, 14, 20]. Resistance to GS-441524 in cats is also likely to be a major problem, as cats with FIP are often treated for 12 weeks or longer, while Remdesivir (and Molnupiravir) are recommended for only five days during the initial viremic stage of Covid-19. [16]. The problem of drug resistance in HIV / AIDS treatment is effectively addressed by using a cocktail of different drugs simultaneously with different resistance profiles. Mutants resistant to one drug will immediately inhibit other drugs, thus preventing their positive selection during treatment. Inhibition of resistance is particularly strong when the two drugs attack different proteins involved in virus replication. For example, GC376 is a protease inhibitor [13], while GS-441524 acts on an RNA-dependent RNA polymerase [18]. However, GC376 is not as well absorbed across the blood-brain barrier. Although the necessary research has not yet been performed, there appears to be no cross-resistance between GS-441524 and Molnupiravir and is as effective as GS-441524 in crossing the blood-brain barrier. [3]. This makes Molnupiravir (or 5-hydroxycytidine) an important contribution to the future treatment of FIP.
As expected, Molnupiravir has recently been tested on cats with FIP by at least one Chinese retailer, GS-441524, and preliminary results are available on the FIP Warriors website. [26]. Field trials included 286 cats with various forms of naturally occurring FIP observed at pet clinics in the United States, the United Kingdom, Italy, Germany, France, Japan, Romania, Turkey, and China. The 286 cats that participated in the study, including seven cats with ocular (n = 2) and neurological (n = 5) FIP, did not die. Twenty-eight of these cats were cured after 4-6 weeks of treatment and 258 after 8 weeks. All treated cats were healthy after 3-5 months, a period during which relapses would be expected to relapse unsuccessfully. These data provide convincing evidence of the safety and efficacy of Molnupiravir in cats with various forms of FIP. However, we hope that this field study will be written in manuscript form, submitted for review and published. Either way, Molnupiravir is already marketed to owners of cats with FIP. At least one other major retailer of GS-441524 is also interested in using Molnupiravir for FIP, indicating a demand for additional antiviral drugs for cats with FIP.
Safe and effective dosing for Molnupiravir in cats with FIP has not been published. However, at least one vendor from China provided certain pharmacokinetic and field test data for Molnuparivir in cats with naturally occurring FIP in a leaflet for the product Hero-2081. [26]. However, this information does not clearly indicate the amount of Molnupiravir in one of their "50 mg tablets" and the actual dosing interval (q12h or q24h?). Fortunately, the estimated starting dose of molnupiravir for cats with FIP can be obtained from published in vitro cell culture studies of EIDD-1931 and EIDD-2801. [15] and laboratory and field studies GS-441524 [14,18]. Molnupiravir (EIDD-2801) has an EC50 of 0.4 μM / μl against FIPV in cell culture, while the EC50 of GS-441524 is about 1.0 μM / μl. [18]. Both have a similar oral absorption of about 40-50 %, so the effective subcutaneous (SC) dose for Molnupiravir would be approximately half the recommended 4 mg / kg SC every 24 hours of the initial dose for GS441524. [14] or 2 mg / kg SC q24h. The per-os (PO) dose would be doubled to account for less effective oral absorption at a dose of 4 mg / kg PO every 24 hours. The estimated initial oral dose of molnupiravir for cats with FIP can also be calculated from the available Covid-19 treatment data. Patients treated for Covid-19 are given 200 mg of molnupiravir PO q12h for 5 days. This dose was evidently calculated from a pharmacokinetic study performed in humans, and if the average person weighs 60-80 kg (70 kg), the effective inhibitory dose is 3,03.0 mg / kg PO q12h. The cat has a basal metabolic ratio 1.5 times higher than humans, and assuming the same oral absorption in both humans and cats, the minimum dose for cats according to this calculation would be 4.5 mg / kg PO every 12 hours. Assuming that molnupiravir crosses the blood-brain barrier and the blood-brain barrier as efficiently as GS-441524 [3,18], the dose would be increased ~ 1.5 and ~ 2.0-fold to allow adequate penetration into the aqueous humor and cerebrospinal fluid for cats with ocular (~ 8 mg / kg PO, q12 h) or neurological FIP (~ 10 mg / kg PO, q12h). The treatment will last 10-12 weeks and the monitoring of the response to treatment will be identical to GS-441524 [14, 20]. These recommendations are based on published data assumptions and further experience with Molnupiravir will be required in this area. Molnupiravir is unlikely to be safer and more effective than GS-441524 in the treatment of FIP, but a third antiviral drug may be particularly useful in preventing resistance to GS-441524 (as a cocktail of antivirals with different resistance profiles) or in treating cats that no longer respond. good on GS-441524. It is largely unknown whether Molnupiravir will be without long-term toxic effects, as the active substance N4-hydroxycytidine is an extremely potent mutagen. [21] and the duration of FIP treatment is much longer than with Covid-19 and there is a likelihood of major side effects.
It is a pity that EIDD-1931 (N4-hydroxycytidine), the active substance in Molnupiravir, has not received much attention in the treatment of FIP cats than Molnupiravir. EIDD-1931 has a 4-fold greater inhibitory effect against the virus than Molnupiravir (EC50 0.09 vs. 0.4 μM) and the percentage of cytotoxicity is slightly lower (2.3% vs. 3.8% at 100 μM) [15]. N4-hydroxycytidine is also efficiently absorbed orally [3], which was downplayed in the development of EIDD-2801 (Molnupiravir). This scenario is identical to the GS-441524 vs. Remdesivir, the second of which, Remdesivir, was chosen for commercialization, although current research suggests that GS-441524 would be the best candidate.[17].
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FIP Warriors CZ / SK - EIDD-2801 (Molnupiravir) https://www.fipwarriors.eu/en/eidd-2801-molnupiravir/
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