Treatment of FIP in cats with Remdesivir

Original article: Treatment of FIP in cats with Remdesivir
Richard Malik DVSc PhD FACVSc FASM

Until recently, the diagnosis of FIP for a feline patient was a death sentence. Although omega-interferon and polyprenyl immunostimulant had some effects in some cases, most cats and kittens diagnosed with FIP died or euthanasia was required due to poor condition.

Figure 1. (A) BOVA Remdesivir reconstituted and ready for treatment. (B) The pathway that Remdesivir takes intracellularly to activate as GS-441524

That all changed a few years ago when the lifelong research of FIP Professor Niels C. Pedersen of UC Davis culminated. Niels first managed to save the lives of several cats with FIP with the protease inhibitor GC-376, and soon after showed that the nucleoside analog GS-441524 is even more effective in treating FIP, although the required dose depended on whether there was ocular or CNS involvement. . GS-441524 was a drug developed by the American company Gilead, which unfortunately did not show interest in further research into the molecule for veterinary use in the treatment of FIP. To fill the gap for effective FIP therapy, various companies have begun to manufacture GS-441524 and sell it on the black market. Although it was very expensive, the availability of quality GS-441524 provided determined cat owners with a way to save cats with wet or dry FIP, although obtaining this drug was complicated, usually associated with the help of a Facebook group. Unfortunately for cat lovers, APVMA and the Australian Veterinary Practitioner Board eventually made the import of GS-441524 and its use for veterinary purposes significantly more difficult, with repressive measures for veterinarians who wanted to help cats with FIP.

It is ironic that the COVID 19 pandemic has solved this problem. Gilead has developed remdesivir (GS-5734) for the treatment of human coronavirus disease. The drug received a temporary TGA marketing authorization in June 2020 for the treatment of SARS-Cov-2 infections in human patients. This process would normally take several years, but COVID accelerated it. Remdesivir is essentially GS-441524 with the addition of several additional phosphate groups to improve intracellular penetration (Figure 1B). Because remdesivir is an approved human drug, it can also be used off-label in veterinary practice, such as the treatment of FIP in cats. This circumvented problems with the use of an unlicensed medicine purchased on the black market and related problems with unproven efficacy, purity and consistency.

Figure 2. Dry FIP with pyogranulomatous inflammation of the intra-abdominal lymph nodes. Instead of exploratory laparotomy, lymph node biopsy, histology and immunohistology, it could be more cost-effective to try a 3-day intravenous Remdesivir treatment.

BOVA Aus was able to provide a reliable source of remdesivir. Studies in Australia have determined shelf life and confirmed in vitro efficacy against coronaviruses. We have been using it in clinical practice for the treatment of FIP for the last 6 weeks. Some of these cases were newly diagnosed cats, while others were cats that had already improved with GS-441524 obtained from the black market, which subsequently became unavailable. Several cases of wet and dry FIP have been treated. Even with the small number of cats, remdesivir appears to be very effective in treating FIP infections. Its subcutaneous administration is slightly easier compared to GS-441524, and it appears to be slightly less painful. It is supplied in a 100 mg vial, which is diluted with 9 ml of sterile water for injections to give a solution with a concentration of 10 mg / ml (10 ml vial after dilution).

In newly diagnosed cats with severe disease, we opted for the intravenous administration of remdesivir at a high starting dose (10 mg / kg dissolved in 10 ml saline and administered over 10 minutes) during the first 3 days of treatment, thus achieving a rapid onset of antiviral activity; The clinical signs of cats improved significantly during the initial therapy within 2-3 days. Cats then switch to subcutaneous treatment, usually at a lower dose. For common cases of FIP, we used 5-6 mg / kg once daily (SIUD) because remdesivir is thought to be approximately as effective as GS-441524 (Niels Pedersen, personal communication). In case of overt eye disease, a dose of 8 mg / kg SID is recommended and cats with neurological FIP with CNS symptoms are given 10 mg / kg SID. Treatment is then continued by daily subcutaneous injections for another 2-3 months. In cats for which SC injections were painful, we used gabapentin and / or buprenorphine for sedation / analgesia, and in some cases we introduced a new cephalic catheter every 5 days, which allowed the owners intravenous administration. In situations where owners could not afford the entire treatment, or when the injections were too painful, we used mefloquine (62.5 mg 2-3 times a week; obtained from BOVA or a local pharmacy) for initial work-based antiviral treatment after initial treatment with Remdesivir. Jacqui Norrisa and colleagues from the University of Sydney.

Figure 3. Which cat has FIP and is being treated with remdesivir?

The main advantage of FIP Remdesivir treatment is that the active substance we use is present in an approved medicine for human use. It is just a matter of writing a prescription with the name and address of the client, the name of the patient and the dose to be administered. BOVA can usually prepare and deliver vials to any veterinarian in Australia within 24-48 hours. At present, the cost per 100mg vial is $ 250 plus GST and postage, although it is possible that the price will decrease over time due to larger orders. We believe that most owners will feel much better if they get the product from a well-known Australian company than to send money abroad and hope that black market drugs will get safely from China to Australia.

Veterinarians who want to know more about this treatment option or have general questions about FIP can contact me by email (richard.malik@sydney.edu.au). The diagnosis of FIP is beyond the scope of this newsletter, but effusive cats are most easily diagnosed by cytology and effusion analysis, followed by immunohistochemistry at VPDS, University of Sydney (easily arranged via Vetnostics, QML, ASAP, VetPath, Gribbles or IDEXX). Dry FIP is more problematic because it usually requires an accurate aspiration biopsy of pyogranulomatous lesions in the liver, kidneys, or abdominal lymph nodes. We found that 3 days of intravenous Remdesivir therapy could be used as a cost-effective therapeutic test in cats with dry FIP as an alternative to biopsy of intra-abdominal structures in exploratory laparotomy, as FIP cases rapidly improve most clinical symptoms. If veterinarians do not want to start treatment with Remdesivir themselves, we can recommend veterinarians interested in FIP treatment who would like to accept such cases.

Resources

Kim, Y .; Liu, H .; Galasiti Kankanamalage, AC; Weerasekara, S .; Hua, DH; Groutas, WC; Chang, KO; Pedersen, NC Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathog. 2016, 12, e1005531.

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, 378–392.

Murphy, BG; Perron, M .; Murakami, E .; Bauer, K .; Park, Y .; Eckstrand, C .; Liepnieks, M .; Pedersen, NC 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 .; Montgomery, E .; Murakami, E .; Liepnieks, M .; Liu, H. 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

Dickinson PJ, Bannasch M, Thomasy SM, et al. Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis. Journal of Veterinary Internal Medicine. 2020. doi: 10.1111 / jvim.15780.

McDonagh, P .; Sheehy, PA; Norris, JM Identification and characterization of small molecule inhibitors of feline coronavirus replication. Vet. Microbiol. 2014, 174, 438–447. Read "FIP remdesivirus treatment"

Thanks to COVID, veterinarians can now legally treat FIP in cats

Original article published on walkervillevet.com.au, 24.11.2020.

The nightmare is almost over. Until recently, there was a diagnosis infectious peritonitis in cats death sentence. Either a slow, persistent decline, or a decision to euthanize and end suffering. This happened to about 1% cats, mostly still kittens.

It was later found that certain antiviral drugs they can not only improve the symptoms, but can even lead to cure. But there was still a problem.

These antivirals were not licensed in Australia and therefore their import and use were illegal. The only cats that survived were therefore those whose owners and veterinarians were willing to take risks. My own veterinary association despite evidence of treatment effectiveness strongly warned against using them.

All the problems are over today.

Remdesivir: A new hope for the FIP

You must have heard of remdesivir. It was promptly approved by the TGA and the FDA due to promising results in the treatment of COVID-19. Importantly for remdesivire is that it is almost identical to black market drugs such as GS-441524.

It is now freely available with a valid prescription and meets all the strict criteria we expect from licensed drugs. Veterinarians still need to warn you that this is an off-label treatment, but it is the same as other cases where we use a human drug for treatment (which is often the case!).

Preliminary testing in Sydney has yielded excellent results. So now we have a cure for everyone. I estimate that fewer than 5% cats with FIP are currently undergoing treatment. Now all cat owners are offered a chance for treatment and most will seize it, although the cost problem still exists.

The cost of using remdesivir in cats

As you can imagine, it is an expensive medicine. I estimate that the 80-day treatment will cost around $ 4,800.

Is a however, this is very similar to the prices people currently pay for GS-441524 from the black market with unproven purity or efficiency. This time, if the cat is insured, it is likely that the treatment will even be covered by the insurance company.

Based on our previous observations, 84-day treatment should cure most affected cats. It is given as a subcutaneous injection once a day, but don't be put off. Everyone can do it and we will be happy to show you how.

Advice on the use of remdesivir for veterinarians

Australian veterinarians reading this article can contact me about a document that contains the recommended dosage, protocols based on the symptoms of the disease and how to obtain the drug itself. See the comments section below for some dosing notes. (translator's note - click on the link leading to the original article).

We are all committed to the work of Dr. Richard Malik DVSc PhD FACVSc FASM and the Feline Diseases Research Team at my alma mater The University Of Sydney.

We also thank the volunteer groups that helped many cats regain their health by taking risks. Their work is complete and we are grateful.

Andrew Spanner BVSc (Hons) MVetStud, a veterinarian in Adelaide, Australia. These blogs come from a series of regularly published e-mails and  Twitter.
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The Russian company is trying to produce the drug remdesivir for COVID-19 without a patent

Original article: Russian firm seeks to produce COVID-19 drug remdesivir without patent; 2.11.2020
Translation: 17.1.2021

MOSCOW (Reuters) - Russian drugmaker Pharmasyntez has asked the Kremlin to allow it to produce a generic version of the US drug COVID-19 remdesivir, which is used to treat US President Donald Trump, despite not having a patent, the company director said on Monday.

Remdesivir is not available in Russia, said Pharmasyntez CEO Vikram Punia, but the generic version cannot be produced and distributed without the consent of the patent holder, the American company Gilead Sciences GILD.O.

In July, Pharmasyntez asked the American company for approval in the form of a voluntary license, but did not receive any response, Punia said.

The Siberian drugmaker is now asking the Kremlin to activate a compulsory licensing process based on national security concerns, giving it the right to produce a generic Remdeform without the consent of Gilead.

"This medicine could save many lives." The longer this drug is unavailable, the more people we lose, ”said Punia.

The law has never been applied to a pharmaceutical product in Russia, Punia said after the daily Vedomosti reported on a letter from his company to the Kremlin on Monday.

It was not possible to contact Gilead on Monday outside normal business hours to comment on the situation. It has already granted voluntary licenses to manufacturers in 127 countries, mainly in low-income countries or in countries that have other significant barriers to accessing healthcare.

Russia recorded a record high 18,665 new cases of coronavirus on Sunday, bringing the total number since the start of the pandemic to 1,655,038.

Remdesivir was granted emergency use by the US Food and Drug Administration in May after government-initiated tests have shown that it shortens hospital stays for patients with COVID-19. He was one of the drugs Trump received during his treatment for this disease.

The FDA officially approved the drug this month, despite the recent results of a study sponsored by the World Health Organization, which showed that remdesivir did not improve patients.

According to a record in the registry, Pharmasyntez has completed clinical trials of a generic drug on 300 patients with COVID-19 in 23 Russian hospitals.

Punia said the company could sell its drug at a significantly lower price of around 540$ for 6 vials. Five days of remedivirus treatment from Gilead, sold under the Veklury brand, was priced at 3120$. Read "Russian company is trying to produce the drug remdesivir on COVID-19 without a patent"

Dr. Pedersen on the relationship between Remdesivir and GS441524

Original article: SOCKFIP

Dear veterinarians, cat owners and the public,

I am still asked about the relationship between GS-441524 and the very promising treatment for Covid-19 - Remdesivir. GS-441524 is a biologically active ingredient in Remdesivir and has been commonly used worldwide for the safe and effective treatment of feline infectious peritonitis (FIP) for over 18 months. FIP is a common and fatal coronary heart disease in cats. GS-441424 and Remdesivir are almost identical drugs. Remdesivir is a form of GS-441424 that Gilead Sciences has decided to use in humans to treat COVID-19, and clinical trials are currently underway in China, the United States, and several other countries. Remdesivir is called product. The prodrug is transformed by infected cells into the active ingredient, which in this case is GS-441524 with the addition of one phosphate group (i.e. GS-5734). Gilead researchers slightly modified GS-5734 to protect the added phosphate group and allow absorption into the cells. This form of GS-441524 is known as Remdesivir. Upon entering the cell, its enzymes remove protection to give GS-5734. GS-5734 is further activated in the cells by the addition of two additional phosphates to form the triphosphate form GS-441524. This is a molecule that inhibits the production of viral RNA. We decided to use GS-441524 to treat FIP because it had the same antiviral properties as Remdesivir and at that time Gilead Sciences did not anticipate its use in humans. GS-441524 is also much cheaper than Remdesivir. Therefore, there was no apparent conflict between the use of one form for cats and another form for humans. However, Gilead believed that our research on cats would affect the approval of Remdesivir for use in human medicine and refused to allow GS-441524 for the treatment of animals. This refusal, coupled with the desperate need for FIP treatment worldwide, led to the Chinese black market with GS-441524. FIP is a major problem for domestic cats in China, and Chinese cat owners have demanded FIP treatment even more desperately than owners in other countries. The first papers describing the treatment of FIP with GS-441524 were published in 2018 and 2019, and thousands of cats have since been treated. Despite this experience, the medical community, including researchers, was apparently unaware of the use of GS-441524 to treat FIP and its relationship to Remdesivir. Veterinarians have considerable but underappreciated experience with coronaviruses, coronavirus diseases and vaccines in pigs, calves and poultry. Ferrets also suffer from a serious FIP-like disease caused by their own coronavirus species. What happens to GS-441524 for cats if Remdesivir is shown to be safe and effective in treating Covid-19? GS-441524 is the first critical step in the production of Remdesivir and it is logical to assume that it will lead to the existence of competition in its use for cats and humans. On the positive side, the worldwide approval of Remdesivir may also help to change the opposition to the granting of rights to use GS-441524 in animals. If Remdesivir were approved for human use (although not approved by GS-441524 itself), it could also become legally available for use in veterinary medicine. However, the safety and efficacy of Remdesivir for the treatment of FIP have not been established.

-Niels C. Pedersen, DVM, PhD, School of Veterinary Medicine, UC Davis .. Read “Dr. Pedersen on the relationship between Remdesivir and GS441524 ”

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