The role of molnupiravir in the treatment of cats with FIP in Australia

Richard Malik, Center for Veterinary Education, University of Sydney
Original article: A key role for molnupiravir in the management of cats with FIP in Australia, 10-2022

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

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 given when owners can no longer afford the high cost of treatment, at a time when the cat is doing well but probably not yet cured. The best dosage regimen for this repurposing drug is debated. The original paper suggested that ¼ tablet of Larium (62.5 mg) given twice weekly is adequate, while I prefer 20 to 25 mg per cat once daily. I often start giving this dose to cats near the end of GS-441524 treatment, and give the mefloquine for a few months to give the cat's immune system a little more time to "clear" all the FIP virus hiding in the cells of the mononuclear phagocytic system.

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.

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.

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 marginally, paxlovid is a combination of two drugs given at the same time, one used to inhibit the metabolism of the other drug; I can't find any precedent for its use in cats, which is a shame because in humans it is the more effective of the two available oral medications for COVID. It costs about the same as molnupiravir in Australia but is comparably more expensive than molnupiravir when bought from websites in India. It may fully prove to be a very useful drug for the treatment of FIP if it proves to be safe. In humans, one problematic side effect is a bad taste in the mouth, so-called "paxlovian mouth", which could prove disastrous if it were to occur in cats, as they have a tendency to foam their saliva.

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 use and that of their family members. This is because human patients who are prescribed expensive off-label drugs, ie drugs not covered by the PBS scheme, have to find their own way to get these drugs. It is not known how many Australians import the drugs, but it is legal under the personal importation scheme. Perhaps the best example is the "FixHepC Buyers Club" (https://fixhepc.com/), founded by Australian infectious disease doctors and general practitioners Dr 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.

“Each of them paid $1,000 to $2,000 to be cured, instead of the $84,000 that Gilead Sciences was charging in America. It's still expensive, but at least it's affordable for many."

However, it comes with some risk.
The online drug market is poorly regulated because it operates across jurisdictional boundaries and low-quality products are common. According to some data, up to 25 % drugs in circulation outside high-income countries are substandard. The biggest risk is an insufficient amount of the active substance, which can lead to unintentional undertreatment. For doctors, it is a complex space in which they have to navigate both from a clinical and medico-legal point of view. It is not clear how far the doctor's duty to provide care extends. The current code of conduct states that good medical practice includes "respecting the patient's right to access the necessary level of health care and, whenever possible, assisting him in doing so." There is no reason to believe that this would not also apply to helping patients import medicines that they could not otherwise afford, if it was clearly in their interests.

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?

1. 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
2. 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 –

The practical question is how to get molnupiravir in time. When purchasing from this website, it takes approximately 3 weeks for the medication to arrive in Australia and clear customs. So one option would be to start remdesivir and/or GS-441524 and switch to molnupiravir as soon as the drug arrives. An alternative is to form a "buyer's club", perhaps with the support of the Australian and New Zealand College of Veterinary Science Pharmacology chapter, and this will be the source of molnupiravir until the client can arrange to import its own stock. Another option would be for a compounding pharmacy to import the drug from a reliable manufacturer and reformulate it into a size suitable for cats and kittens, perhaps as a 60 mg metered tablet that could 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. Pathogens 2022, 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. Animals 2021, 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.)

5. https://www.smh.com.au/healthcare/fixhepc-the-buyers-club-for-hepatitis-c-drug-inundated-with-inquiries-20151002-gjzud9.html

6. https://insightplus.mja.com.au/2022/28/importing-medicines-from-overseas-guidance-needed/

7. https://www.tga.gov.au/products/unapproved-therapeutic-goods/personal-importation-scheme