Unlicensed molnupiravir is an effective rescue treatment after failure of unlicensed GS-441524 therapy in cats with suspected FIP

Meagan Roy 1, Nicole Jacque 2, Wendy Novicoff 3, Emma Li 1,Rosa Negash 1 , Samantha JM Evans 1 *

  1. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
  2. Independent Researcher, San Jose, CA 95123, USA
  3. Departments of Orthopedic Surgery and Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
  4. * 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)

Original article: Unlicensed Molnupiravir is an Effective Rescue Treatment Following Failure of Unlicensed GS-441524-like Therapy for Cats with Suspected Feline Infectious Peritonitis

Abstract

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 the FIP social media support group, and 37 questionnaire invitations were sent to those participants with available contact information. A total of 33 questionnaires were sent and follow-up emails were sent to 21 participants in order to obtain complete data from the questionnaires. Seventeen owners attached relevant documents to the sent questionnaires, and two other owners sent relevant documents to the study e-mail address, which included veterinary medical records, laboratory results and diagnostic images. These listed documents were used to document adverse reactions reported by one participant. One response was refusal to participate. Two cases were excluded because the cats did not have a veterinarian diagnosis of FIP (one was reportedly diagnosed based on the loss of a sibling to FIP, and the other was examined by a veterinarian who concluded that blood tests were not consistent with FIP). Thus, a total of 30 cats with suspected FIP were included in this study, 4 of which received no treatment prior to molnupiravir administration. These four cats were enrolled as a separate small cohort for first-line molnupiravir treatment. A block diagram 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 % non-neutered males. The average age at diagnosis was 9.7 months, with a range from 1 month to 6 years. Most cats were of mixed or unknown breed (70 %); among them were seven purebred cats and two special crossbred cats (eg, a cross between a Balinese and ragdoll cat and a Siamese cat). Responses identifying the cat as "American Shorthair" or "American Longhair" were instead categorized as mixed breed, given the commonly reported confusion among American owners regarding the breed's nomenclature.

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.

CatAge at diagnosis (months)Sex/castration status at diagnosisTribePrevious medical conditionsCountry of originFIP formDuration of initial treatment (weeks)Disease-free periodSecond therapyDuration of the second therapy (weeks)Disease-free periodThe third therapyDuration of the third therapy (weeks)Disease-free period
14catEuropean shorthairparasitic infections, URI at an early ageGermanyneurologicalinjectable oral GS-4415248noneinjectable and oral GS-44152415none
215neutered catBurmesenoneSwedeneffusive, non-effusive, neurologicalinjectable GS-44152412less than 4 weeksinjectable GS-4415241417 daysoral GS-4415245 weeksnone
39neutered catBritish ShorthairnonePolandeffusive, neurological, ocularinjectable GS-44152413less than 2 weeksinjectable GS-44152412more than 6 months, less than 1 year
45neutered catAbyssinianoneUSAeffusiveinjectable GS-44152412less than 2 weeksinjectable GS-44152414less than 4 weeks
54neutered catBalinese/Ragdol mixcalicivirus, conjunctivitis, giardiasis, tapeworm, URIUSAnon-effusiveinjectable GS-44152413less than 8 weeks
67neutered catSiamesenoneUSAneurologicalinjectable and oral GS-441524, injectable GC, injectable and oral molnupiravir12none
77neutered catAmerican ShorthairnoneUSAnon-effusiveinjectable and oral GS-4415245none
86neutered catAmerican Shorthair/Siamese mixtapeworm, FCoVUSAeffusive, neurologicalinjectable and oral GS-4415245none
94neutered catHomemade mixedbroken pelvisUSAeffusiveinjectable and oral GS-44152414less than 6 monthsoral GS-44152413less than 4 weeksoral GS-441524/injectable GC6 weeks in combination then 6 weeks of oral GSnone
104neutered catHomemade mixednoneUSAeffusiveinjectable GS-44152423less than 4 weeks
1172neutered catHomemade mixedFeLVUSAnon-effusiveoral GS-44152412less than 6 months
125catHomemade mixednoneUSAnon-effusive, neurological, ocularinjectable and oral GS-44152417none
1301.VcatSavannahnoneUSAeffusive, neurologicalinjectable and oral GS-44152424less than 6 monthsinjectable and oral GS-44152412less than 4 weeks
144neutered catHomemade mixedSkin and eye infections, fleasPolandnon-effusive, neurologicalinjectable GS-44152412less than 2 weeksinjectable GS-44152417less than 4 weeks
1512neutered catAmerican ShorthairnoneUSAeffusiveinjectable GS-441524/GC01.Vnone
165neutered catHomemade mixednoneUSAeffusive, neurologicalinjectable GS-44152412less than 4 weeks
174catAmerican longhairnoneUSAocularinjectable and oral GS-441524, GC37613none
186neutered catHomemade mixednoneUSAeffusiveinjectable GS-44152412none
1912neutered catHomemade mixednoneUSAnon-effusiveinjectable and oral GS-44152412less than 2 weeksinjectable GS-44152412none
206neutered catUnknownnoneUSAnon-effusive, neurologicalinjectable GS-4415244noneoral GS-4415243none
214neutered catNorwegian forestnoneUSAneurologicalinjectable GS-44152412less than 6 monthsinjectable GS-44152401.VnoneMolnupiravir, GS-441524, GC12 weeksnone
226neutered catHomemade mixednoneUSAneurological, ocularoral GS-4415243none
2312neutered catUnknownnoneGermanyneurologicalinjectable GS-44152416less than 6 months
243catHomemade mixednoneUSAneurologicalinjectable GS-44152412less than 6 months
256neutered catAmerican ShorthairnoneUSAeffusiveoral GS-44152413less than 1 week
261catUnknownnoneUSAnon-effusiveinjectable GS-44152412less than 1 week
277neutered catHomemade mixednoneUSAnon-effusive, neurologicalMolnupiravir12less than 1 week*Molnupiravir
2824neutered catHomemade mixednoneUSAeffusiveMolnupiravir
2912neutered catHomemade mixednoneUSAnon-effusive, ocularMolnupiravir
3024neutered catHomemade mixednoneUSAneurologicalMolnupiravir
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.

CatClinical symptoms at the beginning of treatmentBrand nameInitial dosage and frequencyFinal dosage and frequencyDuration of treatment (weeks)Time to improvePersistent clinical symptomsThe resultAdverse effects
1diarrhea, vomitingAura Plus11 mg/kg twice daily11 mg/kg twice daily12less than 1 weeknoneclinical remissionnone
2none reportedAura12 mg/kg twice a day12 mg/kg twice a day12uncertainnoneclinical remissionnone
3anisocoria, colored spots in the eye, polydipsia, pica, weight lossAura 280128 mg/kg twice daily14 mg/kg twice a day12within 2 weeksnoneclinical remissionnone
4anorexia, lethargy, weight lossEIDD7 mg/kg twice a day7 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
5colored spots in the eye, diarrhea, hiding and lack of socializationAura 28016 mg/kg once daily13 mg/kg once daily10within 2 weeksnoneclinical remissionnone
6anisocoria, constipation, anorexia, fecal and urinary incontinence, lethargy, paralysis, seizures, pale gums, weight lossAura 280120 mg/kg twice a day20 mg/kg twice a day11less than 1 weeknoneclinical remissionnone
7anorexia, difficulty walking, hiding, lack of socialization, jaundice, lethargyCapella EIDD9 mg/kg twice daily13 mg/kg twice a day10less than 1 weeknoneclinical remissionnone
8anorexia, difficulty walking, urinary incontinence, paralysisAura 280117 mg/kg twice a day17 mg/kg twice a day15less than 1 weekdifficulty walking persisted for 2 months, still not normal but has a normal lifeclinical remissionnone
9cough, anorexia, hiding, lack of socialization, polydipsia, weight lossAura 280112 mg/kg twice a day16 mg/kg twice a day13within 2 weekspolydipsia persisted for 1 weekclinical remissionnone
10anorexia, lethargy, weight lossAura 280112 mg/kg twice a day12 mg/kg twice a day16within 2 weeksnoneclinical remissionnone
11anorexia, lethargy, URI, weight lossAura 193112 mg/kg twice a day12 mg/kg twice a day12within 2 weeksnoneclinical remissionnone
12blindness, head bobbing, difficulty walkingAura 280110 mg/kg twice a day14 mg/kg twice a day12within 3 weeksnoneclinical remissionnone
13difficulty walking, hiding, lack of socialization, polyuria, lethargy, anorexia, paralysis, tremorsAura 280112 mg/kg twice a day12 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
14anorexia, heavy walking, hiding, lack of socialization, lethargy, unusual timidityAura 280111 mg/kg twice daily16 mg/kg twice a day18more than 4 weeksnothing physical but the MRI is still not normalclinical remissionnone
15blindness, constipation, anorexia, diarrhea, enlarged abdomen, hiding, lack of socialization, lethargy, pale gums, weight lossAura 280116 mg/kg twice a day16 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
16anorexia, difficulty walking, lethargy, seizures, tremors, weight lossAura 280114 mg/kg twice a day14 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
17cough, anorexia, difficulty breathing, hiding, lack of socialization, lethargy, vomiting, weight lossAura 2801 and Aura 193112 mg/kg twice a day17 mg/kg twice a day20within 3 weeksanorexiaclinical remissionnausea/vomiting, anorexia
18constipation, anorexia, difficulty walking, hiding, lack of socialization, weight lossAura 280112 mg/kg twice a day12 mg/kg twice a day8within 2 weeksnoneclinical remissionnone
19lethargy, anorexiaAura 280112 mg/kg twice a day12 mg/kg twice a day7within 2 weeksnoneclinical remissionnone
20trembling/shakingAura 280110 mg/kg twice a day23 mg/kg two to three times a day10less than 1 weekin remission about 1 1 weeks before the onset of seizureseuthanasiadecreased appetite when dosed three times a day, severe leukopenia, loss of beard, scaly skin on ears
21difficulty walking, fecal incontinenceAura 2801 and Aura 193113 mg/kg twice a day30 mg/kg twice a day14less than 1 weekdifficult walking, difficult jumping, fecal incontinence persisted during the study (1 week post treatment)relapse and euthanasiadrooping ear tips, muscle weakness
22colored spots in the eye, anorexia, difficulty walking, hiding, lack of socialization, lethargyAura 280116 mg/kg twice a day19 mg/kg twice a day9within 2 weeksnoneclinical remissionnone
23difficulty walking, anorexia, loss of balanceEIDD aura12 mg/kg twice a day15 mg/kg three times a day10within 2 weeksheavy walkingclinical remissionnone
24blindness, colored spots in the mouth, anorexia, difficulty breathing, difficulty walking, enlarged abdomen, urinary incontinence, jaundice, lethargy, paralysis, tremorsAura 280115 mg/kg twice a day15 mg/kg twice a day16less than 1 weeknoneclinical remissionnone
25difficulty breathing, difficulty walking, hiding, lack of socialization, lethargy, URIAura 28017 mg/kg twice a day7 mg/kg twice a day16within 2 weeksnoneclinical remissionnone
26lethargy, anorexiaAura 280114 mg/kg twice a day14 mg/kg twice a day15less than 1 weekneurological twitches, elevated liver enzymesclinical remissionnone
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.

CatClinical symptoms at the beginning of treatmentBrand nameInitial dosage and frequencyFinal dosage and frequencyDuration of treatment (weeks)Time to improvePersistent clinical symptomsConclusionAdverse effects
* 27Hiding, lack of socialization, lethargy, anorexia, URI, vomiting, weight lossAura 280119 mg/kg twice a day19 mg/kg twice a day10less than 1 weeknoneclinical remissionnone
28Anorexia, difficulty walking, distended abdomen, hiding, lack of socialization, lethargyAura 28018 mg/kg twice a day8 mg/kg twice a day13in two weeksnoneclinical remissionnone
29Anisocoria, blindness, eye color changes, anorexia, hiding, lack of socialization, urinary incontinence, lethargy,Aura 280110 mg/kg twice a day10 mg/kg twice a day13in two weeksnoneclinical remissionnone
30Hiding, lack of socialization, lethargy, pale gums, weight lossAura 280110 mg/kg twice a day12 mg/kg twice a day10in two weeksnoneclinical remissionnone
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 treatment, one cat was intolerant to the injectable form of GS and three owners were cost-restricted. Owners were not required to disclose the financial costs of treatment; this information was provided on a voluntary basis only. In addition, “0” responses that were reported were not included in the calculation of the following averages due to the inability to distinguish whether “0” means no cost or unknown cost. The mean reported cost of the first round of GS-441524-based treatment was $3448.83, and similarly the mean reported cost of the second round of GS-441524-based treatment was $3509.09. Only 4 owners reported paying for molnupiravir treatment, while 16 others reported “0” (or no cost/cost unknown). The overall mean for the 20 owners who responded to the financial cost survey question (including “0” responses) for molnupiravir was $209. The average cost of the four owners who did not answer “0” was $1045. While 90 % owners reported being "very" or "somewhat" satisfied with their cat's experience of treating their cat with molnupiravir, 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 producing 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 leaflet of HERO Plus 2801 also includes the preliminary results of the study "Effect of treatment with oral nutrition on survival time and quality of life in feline infectious peritonitis", which includes 286 cats with a diagnosis of 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 reporting [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, based on owner-reported data, unlicensed molnupiravir appears to be an effective treatment for suspected FIP as both first-line and salvage therapy. At a dosage of 12-15 mg/kg every twelve hours, minimal side effects are reported and it provides survival with clinical resolution of FIP symptoms. Although the experiences of these owners in treating and apparently curing cats from FIP are unconventional and potentially illegal, they are undeniably remarkable and we can learn a lot from the experiments these "citizen scientists" are conducting. By reporting these experiences, we aim to provide a starting point for investigating molnupiravir for use in cats with suspected FIP and to document a "herd health" phenomenon 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.

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