1. OBJECTIVES
The goal of this clinical study is to examine the safety and efficacy of Molnupiravir for the treatment of naturally acquired feline infectious peritonitis (FIP). In this report we will present our study method, real life clinical data from our study and our conclusion as to the efficacy of Molnupiravir via oral application for the treatment of feline infectious peritonitis (FIP).
2. INTRODUCTION
Resistance to GS-441524 in the treatment of feline infectious peritonitis (FIP) has been reportedly increasing in frequency across the world since 2019, especially among cats with neurological FIP.
Currently drug resistance can only be overcome in two manners: 1) by progressively increasing the dosage of GS-441524 to achieve drug levels in body fluids that exceed the level of resistance, or 2) by using another antiviral drug that utilize a different mechanism to overcome FIPV, either by itself or in combination with GS-441524. Until now, the first option has been the one most frequently chosen and has proven effective in a majority of cases. However, GS-441524 resistance can be total or so high that increasing the dosage is extremely costly for cat owners and unpleasant for the cats. In such cases, the second option has been increasingly explored by researchers. Molnupiravir is one of the most promising candidates that is commercially available as a potential alternative or supplement to GS-441524.
Molnupiravir is the isopropylester prodrug of N4-hydroxycytidine. It stops the replication of FIP virus by incorporating into the genome of RNA viruses. This leads to an accumulation of mutations known as viral error catastrophe which ultimately render the FIP virus strains harmless to cats. 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.
3. METHODOLOGY
The trial consists of 34 FIPV-infected cats ranging in age from 5 to 96 months. Out of the 34 cats, 21 cats (62%) are relapse cases and 12 cats are newly diagnosed with FIP. All the cats in the trial were diagnosed as having one of two forms of FIP: non-effusive (dry), effusive (wet), with 12 participants exhibiting ocular or neurological symptoms. Due to ethical factors, no placebo control group was formed.
The dosage of Molnupiravir for the clinical trial is as below:-Non neuro/ocular FIP: 10mg/kg PO SID [oral once per day]
Ocular and Neuro: 20mg/kg PO SID [oral once per day]The trial is divided into three phases of oral treatment. The duration of each phase is 30 days. A full panel blood test is carried out for the cats at the end of every phase (30 days) of treatment. This report will summarize the results and conclude the findings of the cats after their completion of the Molnupiravir treatment. Table 1 classified the information of the participating cats. The treatment was given at various dosages according to the weight of the cats. All cats were required to complete a pre-treatment blood test. All cats were required to carry out a blood test after 30 days of treatment to measure changes in key blood test markers.
| Cat's Age | Cat's Weight (Kg) | FIP Type | Status | Start of treatment |
MT001 | 4 | 3.7 | Neurological | Relapse | June 2022 |
MT002 | 2 | 3 | Neurological | Relapse | June 2022 |
MT003 | 2 | 0.74 | Wet | New FIP Case | July 2022 |
MT004 | 9 | 2.5 | Wet | New FIP Case | July 2022 |
MT005 | 1 | 4 | Ocular & Neurological | Relapse | July 2022 |
MT006 | 2 | 4.3 | Wet | Not responding/ Slow progress to GS treatment | July 2022 |
MT007 | 3 | 3.8 | Neurological | Not responding/ Slow progress to GS treatment | July 2022 |
MT008 | 4 | 1.6 | Dry | New FIP Case | July 2022 |
MT009 | 5 | 2.2 | Wet | New FIP Case | August 2022 |
MT010 | 11 | 5.8 | Wet | Not responding/ Slow progress to GS treatment | August 2022 |
MT011 | 2 | 4.1 | Neurological | Relapse | August 2022 |
MT012 | 10 | 1.8 | Neurological | New FIP Case | August 2022 |
MT013 | 2 | 3.8 | Wet | New FIP Case | August 2022 |
MT014 | 2 | 2.9 | Dry | New FIP Case | August 2022 |
MT015 | 3.5 | 2.9 | Ocular & Neurological | Relapse | August 2022 |
MT016 | 5 | 5.8 | Dry | Not responding/ Slow progress to GS treatment | August 2022 |
MT017 | 2 | 2.8 | Wet | Not responding/ Slow progress to GS treatment | August 2022 |
MT018 | 2 | 3.4 | Wet | Relapse | August 2022 |
MT019 | 2 | 4.1 | Dry | Relapse | August 2022 |
MT020 | 1 | 4.9 | Wet | New FIP Case | August 2022 |
MT021 | 2 | 4.2 | Neurological | Relapse | August 2022 |
MT022 | 3 | 3.2 | Wet | Relapse | August 2022 |
MT023 | 2.9 | 4.2 | Wet | New FIP Case | August 2022 |
MT024 | 4 | 5.8 | Wet | Not responding/ Slow progress to GS treatment | August 2022 |
MT025 | 1.5 | 3.4 | Neurological | Not responding/ Slow progress to GS treatment | August 2022 |
MT026 | 1 | 1.4 | Neurological | New FIP Case | August 2022 |
MT027 | 2 | 2 | Neurological | Relapse | August 2022 |
MT028 | 2 | 1.4 | Wet | Relapse | August 2022 |
MT029 | 4 | 0.5 | Dry | New FIP Case | August 2022 |
MT030 | 2 | 4.9 | Dry | Not responding/ Slow progress to GS treatment | August 2022 |
MT031 | 2 | 5 | Wet | Not responding/ Slow progress to GS treatment | September 2022 |
MT032 | 9 | 4 | Dry | New FIP Case | September 2022 |
MT033 | 9 | 5.4 | Wet | New FIP Case | September 2022 |
MT034 | 1 | 2.9 | Neurological | New FIP Case | September 2022 |
Tables 1-3: List of all cats participated in the Molnupiravir clinical trial.
4. RESULT & DISCUSSION
4.1 CATS EXITING THE TREATMENT
During the clinical trial, 16 cat owners have decided to stop the Molnupiravir treatment for their cat due to various reasons. 12 cat owners have decided to stop the treatment after receiving feedbacks from cat owners that the condition of their cat did not show improvement after starting Molnupiravir treatment (Figure A & B) and some that have lost their FIP cats that are undergoing Molnupiravir treatment (Figure C); 2 cat owners have decided to stopped the treatment in less than 2 weeks after starting the treatment as they do not see any observable improvements in their cats; 1 cat was advised to stop the treatment as the cat has kidney problems; and 1 cat owner have decided to stop the treatment without giving any reason.
4.2 TREATMENT OUTCOME
Out of the 18 cats that continued the trial, three cats died (MT001, MT007) or were euthanized (MT033) within the first week of treatment because of severe disease and other complications and fourth (MT005) died after 4 weeks of treatment due to presumably unrelated eye disease. The 14 remaining cats continued the treatment according to the planned phases. All of the 14 cats remain healthy at the time of this publication (December 2022) after at least 2 phases of treatment.
The clinical response of the 14 cats that completed the treatment was remarkable in the first few days, then the progress became stagnant as the treatment progressed. The cats regained activity level once the treatment started, but did not show marked improvement in appetite. This is believed to be due to the bitterness of Molnupiravir that has caused FIP cats under treatment to be inappetence. For cats with effusive FIP, abdominal effusions disappeared over a 1–2 week period. Cats that were dyspneic (MT018, MT022) responded rapidly to treatment and were no longer apparent after 5-7 days of treatment. Signs of ocular disease (MT015 and MT005) cleared in 3-6 days.
All 14 cats appeared outwardly normal or near normal in the estimation of the owners after about 4 weeks of treatment. The emphasis of treatment for a minimum of 6 weeks was on monitoring several blood test parameters including total white blood cells, total serum protein, serum globulin, serum albumin and A:G ratio.
4.3 Favorable treatment response indicators
4.3.1 Weight
The simplest long-term measure of treatment efficacy was body weight. In this trial, weight gains are observed in 11 out of the 14 cats (79%). The weight changes of the cats pre-treatment and post-treatment can be observed in table 2.
| Wetght (Pre-treatment) | Weight (Post-treatment) |
MT008 | 1.6 | 2.2 |
MT011 | 2 | 2.6 |
MT015 | 2.9 | 3.35 |
MT016 | 5.8 | 5.8 |
MT017 | 2.8 | 3.1 |
MT018 | 3.4 | 3.9 |
MT019 | 4.1 | 4.4 |
MT021 | 4.2 | 3.78 |
MT022 | 3.2 | 2.7 |
MT023 | 4.2 | 4.5 |
MT024 | 5.8 | 5.9 |
MT026 | 1.4 | 3 |
MT028 | 1.4 | 2.3 |
MT034 | 2.9 | 3 |
Table 2: The pre-treatment and post-treatment weight of cats that have completed the clinical trial for FIP treatment using Molnupiravir.
4.3.2 Serum protein
Cats with FIP frequently presented with higher than normal total serum protein concentration, high serum globulin, low serum albumin levels and a low A:G ratio. In this trial, 10 out of 14 cats that completed the treatment had completed the required blood test. Serum protein values of these cats have shown improvement and progressively reached normal levels after at least 2 phases (60 days) of treatment.
| a/g ratio pre-treatment | a/g ratio post-treatment | Globulin pre-treatment | Globulin post-treatment |
MT017 | 0.4 | 0.4 | 53 | 50 |
MT018 | 0.4 | 0.63 | 58 | 39 |
MT022 | 0.8 | 0.8 | 43 | 41 |
MT024 | 0.4 | 0.5 | 76 | 69 |
MT016 | 0.5 | 0.5 | 50 | 48 |
MT019 | 0.5 | 0.8 | 51 | 43 |
MT023 | 0.4 | 0.4 | 60 | 60 |
MT011 | 0.8 | 0.9 | 40 | 34 |
MT026 | 0.5 | 0.6 | 54 | 44 |
MT034 | 0.4 | 0.5 | 72 | 55 |
Table 3 shows the globulin and albumin/globulin readings for both pre-treatment and post-treatment of the 10 cats who successfully completed the clinical study
4.3.3 Side effects
observed during treatmentInappetenceAlmost 43% of cats in the trial (6 out of 14) have experienced a loss of appetite for food during the treatment. The effect is more significant if the content of the oral capsules are emptied and mixed with wet food for feeding. The bitterness of Molnupiravir may have caused the cat to lose appetite for food. Thus, cat owners are advised to directly feed the whole capsules to help cats regain their appetite during Molnupiravir treatment.
5. CONCLUSION
The clinical trial has demonstrated that Molnupiravir is a viable but inferior treatment option against effusive (wet) and non-effusive (dry) feline infectious peritonitis (FIP) for some populations of FIP cats. However, Molnupiravir is a valid alternative FIP treatment where GS-441524 fails to arrest FIPV replication. Molnupiravir can be used alone or in combination with GS-441524 to treat feline infectious peritonitis. A more in-depth study on the cytotoxicity of Molnupiravir should be carried out to establish the safety dosage guideline for the commercial use of Molnupiravir in the treatment of FIP in the future.
Reference:
Pedersen, NC., and Jacque, N. (2021). Alternative treatments for cats with FIP and natural or acquired resistance to GS-441524.
Pedersen, NC., Perron M., Bannasch, M., Montgomery, E., Murakami, E., Liepnieks, M., and Liu, H. (2019). Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. Journal of Feline Medicine and Surgery. 2019;21(4):271-281.
Appendix
Figure A
Figure B
Figure C
Published by: Research Team of basmifipthailnd.com for the advancement of FIP treatment. For questions regarding this study please us on our website, or call at at +1 (646) 653-2654, or email us at th@basmifip.com
Keywords: Feline infectious peritonitis, FIP, GS-441524, Molnupiravir, Remdisivir, FIP treatment, FIP cats.