There is a need for aggregation and analysis of the vast data that will be generated from the use of repurposed drugs such as Remdesivir, Favipiravir and Dexamethasone in the coming times to understand their true potential for COVID treatment
Repurposing broad-spectrum antiviral agents have been deemed ‘safe-in-man’ through testing on early phase clinical trials for COVID-19. In April 2020, an international collaborative research team conducted a large-scale drug repurposing survey to identify existing drugs that prevent the COVID-19 virus from replicating. The team consisted of scientists from the Sanford Burnham Prebys Medical Discovery Institute, Scripps Research Institute, University of California San Diego, University of California Los Angeles (all CA, USA), The University of Hong Kong (China), University of Vienna (Austria), Texas Biomedical Research Institute (TX, USA) and Icahn School of Medicine at Mount Sinai (NY, USA). The team discovered 300 drugs that could stop the virus from replicating. Utilising molecular tools such as PCR and immunofluorescence microscopy, the researchers were then able to determine 30 most effective candidates. A few are already under evaluation for use in COVID 19 around the world.
Back home, after extensive use of hydroxychloroquine, repurposed drugs Remdesivir, Favipiravir and Dexamethasone have been touted to show a lot of promise in early trials for the treatment of COVID-19. These drugs have been approved for treatment by the ICMR under emergency use authorisation conditions. There is an informed consent form which the prescribing doctor first explains to a patient before the patient starts the course. All patients will be observed and patient data will be analysed and submitted for review to the regulatory body in India. Now, each of these drugs responds differently and are utilised at different stages of the illness. For instance, as part of the FAITH trial, a combination of Umifenovir and Favipiravir has been used for ‘mild and moderate’ COVID-19 cases. Whereas, Remdesivir is for patients with more severe symptoms of the infection. Dexamethasone, a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects has been utilised to reduce the risk of death among severely ill patient. While all these drugs have shown some good outcomes in the initial trials some of these are termed as a wonder drug or miracle cure for COVID.
Express Healthcare in this article aims to understand the existing safety evidence on Indian patients from the clinician’s perspective.
So let’s begin with first understanding the advantages of repurposing drugs and then gain clarity on the original purpose of said repurposed drugs used for COVID treatment and why and how these drugs show promise for COVID treatment and what is the caveat emptor associated with these drugs.
The advantages of repurposed drugs
According to various scientific publications, repurposed drugs are an immediate response to the pandemic which has accelerated beyond the containment strategies. It is a strategy often used in the oncology space. A pharma technology review paper mention that borrowing drugs from other indications is a time saver because these drugs have proven themselves to be safe in pre-clinical and early clinical testing. They can be fast-tracked straight into the final stage of clinical development, Phase III and can be easily evaluated for their safety and efficacy as COVID-19 treatment. The expediency of this strategy has captured the imagination of pharma companies and university researchers committed to quickly resolving the COVID-19 pandemic. Some publications indicate the following benefits.
Creating access to patients sooner: Ensuring access to some treatment that can block or prevents a mechanism of action that a virus might use to replicate is very critical. This is where repurposed drugs come into the picture. Hospitals remain overwhelmed with patients who have contracted a virus for which no reliable treatments exist. Repurposed drugs could substantially accelerate the delivery of treatment and elevate the suffering of afflicted patients.
Relying on safety information from the existing drug: The primary reason that repurposed drugs have shorter development programmes is that sponsors can rely on existing drug safety data for a New Drug Application (NDA). Because the safety of the drug product has already been proven, typically fewer studies are required. Additionally, clinical trials to determine if a repurposed drug can halt disease progression can be relatively short-term and inexpensive since researchers generally know the safety profile and have a good idea of the proper dose and duration. Regulators can approve such drugs if several studies show consistent benefit when weighed against the observed side effects. Progress can be made with several candidates in consideration.
Reduced cost of drug development programmes: These shorter development timelines and streamlined studies lead to significant cost savings for sponsors. Moving rapidly to the clinic with so many unanswered questions about efficacy carries considerable risk, and the scale of manufacturing needed for COVID-19 therapies is enormous. Especially in an uncertain funding environment, having a cost-optimised strategy for a well-understood active ingredient could enable a programme to progress to approval or authorisation.
Repurposed drugs and one big human trial…
We are all aware that the safety evidence of these 3 drugs is not originally licensed for Covid-19. They are part of clinical trials and have been authorised for emergency use under clinician supervision. Therefore, experts also provide a word of caution on the use of these drugs.
According to Dr Balasubramanian Mahadevan, Ex-Medical Director at PD Hinduja, Saifee, Bhatia, Shushrusha and Lilavati Hospitals in Mumbai, drug repurposing is an emerging strategy where existing medicines, having already been tested safe in humans, are redeployed to combat difficult-to-treat diseases.
While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, as was for HIV in the 1990s. In the absence of any vaccines to prevent COVID-19, there are many clinical trials (CT) taking place to find a treatment. These CTs are mainly focusing on either repurposing or repositioning the existing molecules. WHO has published a landscape of therapeutics which could be used for treating COVID-19, and some of them are undergoing CTs as well. Generally speaking, patents are not a concern when it comes to old molecules under CTs because these molecules are already out of patent protection. However, a few of these molecules are still under patent protection in many countries. Two in particular – Remdesivir and Favipiravir – are under patent protection in India. The generic availability of these medicines can facilitate compassionate use and CTs in India without depending on supply from the patent holders. Therefore, the Government of India should use the compulsory license or government use license to facilitate the generic production of these medicines.”
Dr Mahadevan further elaborates on the different drugs on clinical trials in India in an article Drug repurposing and its impact (https://www.expresshealthcare.in/blogs/guest-blogs-healthcare/drug-repurposing-and-its-impact/422780/)
The clinical response so far…
To understand the current clinical response of these drugs and its actual utilisation in the Indian market, we spoke to some clinical experts who have been prescribing these drugs to their patients and are constantly monitoring the efficacies of the same.
“All three drugs are beneficial when started at an early stage for the treatment. Once the patient is critical and on ventilatory support, their utility is limited. Having said that, Dexamethasone can be given to all patients, even the ones with mild changes on the chest CT scan. Favipiravir and Remdesivir are started to patients who require oxygen support and who we feel are likely to have a clinical deterioration,” says Dr Chinmay Godbole, Chief of Intensive Care, KJ Somaiya Hospital, Superspecialty Centre.
Dr Manisha Mendiratta, Senior Consultant – Respiratory Disease & Sleep Disorder, Sarvodaya Healthcare, Faridabad who has been prescribing Fabiflu (Favipiravir) for the COVID 19 patients since last 2 weeks urges healthcare providers to be more judicious while prescribing these drugs.
She warns, “The manufacturer of Faviflu (Favipiravir) says that it is effective in 82-88 per cent of cases which sometimes we assume that the recovery has happened normally. There is a lack of strong evidence proving the efficacy of this drug on COVID 19, and no comparative studies have happened to prove its advantage over any other parallel drug in the same condition. This drug was used in Japan 2014 for H1N1 influenza and is just repurposed for COVID 19 mostly to manage this pandemic situation without concrete evidence. We get accustomed to thinking that such drugs are all antiviral, which may not be the case. Doctors using Favipiravir in the trials for COVID 19 observed that the drug suppresses the symptoms in people suffering from mild attacks of the coronavirus. However, the drug does not offer total safety and there can be grave side-effects too. So, the drug should be used judicially and only after the recommendation of an expert physician.”
Dr Samrat Shah, Consultant Internist, Bhatia Hospital< Mumbai states that the main treatment in COVID-19 revolves around three main drugs-antivirals, anti-inflammatory and anticoagulation.
He further explains the antivirals first
FACTS of Favipiravir
- Favipiravir, Remdesivir contains the viral replication and it’s not viricidal (doesn’t destroy the virus directly).
- It doesn’t have any major role in saving you from mortality but it can reduce the days of your suffering from COVID-19.
Antivirals like Remdesivir and Favipiravir are falsely hyped as lifesaving drugs.
Advantages of Favipiravir are:
- Favipiravir is effective in mild /moderate stages
- It is easily administered orally
Disadvantages of Favipiravir include the following:
- There is pill load because of a high dose of 18 tablets given on day one and followed by eight tablets per days for 7-14 days.
- It causes Hepatotoxic which is damaging or destructive to liver cells.
FACTS of Remdesivir
- Remdesivir is claimed to be effective in the severe and critical stage but its disadvantage lies in IV administration.
- It is also hepatotoxic and damaging or destructive to liver cells.
- Practically speaking viral replication ends in first 1-7 days, complications which occur in critical and severe COVID 19 post 7-8 days is due to an inflammatory response (SIRS). So this drug ideally should be used in the early stages when viral replication is happening to reduce the viral load in the body.
Similarly, Dr Shah updates us on anti-inflammatory Steroids- Dexamethasone/MPS saying, “Lifesaving as always, its key role is in severe and critical COVID 19 pneumonia and ARDS. This medicine should be used with extreme caution in early stages when viral replication is going on, early judicious use can boost the viral replication and lead to viremia.”
Dr Kedar Toraskar, Chief of Critical Care, Wockhardt Hospitals, Mumbai Central, informs, “Favipiravir is an oral antiviral used for resistant influenza in 2014. It has been repurposed in the view of this pandemic. There were trials in Japan, China and there are ongoing trials in India. It is a relatively safe drug but the only problem is the dose is high. The patients have to take nine pills on day one and 4 pills, twice a day, on subsequent days for at least 6-14 days. The total course is 7-14 days, and that’s the problem. Also, if the patient has underline gout, he/she needs to be careful, and the patient will have to be monitored for their liver function before taking it. The cost of Favipiravir is around Rs 100, so the cost comes to be around Rs 7,000 Rs for a full course of seven days, and it can be unaffordable for a common man. Also, the pill burden is high. It is not a wonder drug; we are still waiting for the trial reports. It has to be used in initial stages (first seven to eight days). It is used for mild to moderate symptoms. It helps or doesn’t help is still not known.”
He further explains the clinical efficacy of Remdesivir. “This drug is intravenous right now. It is also a repurposed drug and an antiviral. Right now, it has been licensed for moderate to severe patients. It has to be administered early (between six to 12 days). If it is used late then efficacy is not good. Again, clinical trials are ongoing and it is not a proven benefit. Recovery time from this drug is less but whether mortality is low, is not known yet. But, Remdesivir seems to be promising. On the first day, 200 milligrams are given and the second day, subsequent 100 milligrams, and the cost of this drug is Rs 5,000. For administering it, liver and renal function tests have to be monitored. It can’t be given to those patients having renal failure. One will have to use antivirals in an early stage. They won’t work after 10-12 days. Dexamethasone is a steroid. It was found useful in the recovery trial done in the UK. It is for patients who have hypoxia (oxygenation problems). It is not to be used in the early phase as it can harm the patient than doing good. It has to be started after 10 days. It is used for patients with respiratory failure. If it is used too late then also it will not benefit. It is a steroid and can also cause secondary infections also. Use it with caution and in the patients, who have high sugar.”
Dr Deepesh G Aggarwal, Consultant and HoD Critical Care Medicine, Saifee Hospital speaking about how these repurposed drugs have given us a fighting chance in combating COVID 19 when used appropriately, states, “Steroids and Remdesivir have been quite effective. Our experience with favipiravir is relatively lesser as it has been recently introduced. Injection Tocilizumab has been a lifesaver in patients with Cytokine storm.”
Further sharing his observation Dr Toraskar expounds, “We will have to see the trial results. Dexamethasone and steroids are helpful for us. In some patient so. Remdesivir seems promising but we have to keep a close watch on it. It is like an option that wasn’t available before. The timing of the drugs and patient selection is important. Antivirals like favipiravir and Remdesivir have to be used early on in the viremia phase in the first 10 days of symptom onset. Remdesivir is to be used for moderate to severe cases between fifth to 12th day. Steroids will be harmful in the viremia phase if used early. They have only shown proven benefit in patients who have respiratory failure requiring supplemental oxygen and ventilation. Start using it when available on compassionate grounds after discussing the pros and cons with the patient and their relatives. Steroids in low dose seem to work as proven by the recent recovery trial results and that has been our experience in the last two months too.”
More data required and stringent rules against black marketing
Just as clinical experts point out that these drugs certainly bring hope to healthcare providers and patients alike, their application should be strictly monitored. Most doctors clearly indicate that the high dose of these drugs can be detrimental to patients. Moreover, there is a need for aggregation and analysis of the vast data that will be generated in the coming times. Only then can the true potential of these repurposed drugs be judged. Another issue that healthcare providers are currently facing is the shortage of drugs such as Remdesivir.
Dr Godbole raises his concerns on the shortage of drugs. “We should have some way to procure these drugs easily as currently procuring them is a challenge. More importantly, since these are observed to be life-saving drugs, it should be made available easily. Further, the awareness of the indications of these drugs is important. We do not want hoarding of these essential drugs by anyone,” he notifies.
Likewise, an industry source informed Express Healthcare that in many places, especially in Mumbai, Remdesivir is not available easily and is sold in black. The cost of which varies between Rs 50,000 to Rs 85,000 per vial. In order to tackle this menace, drug company Hetero, which has obtained a license to supply Remdesivir (COVIFOR 100 mg vial) has been directly contacting hospital pharmacies to ensure the drug is available at the right price. However, when Express Healthcare contacted the Pharma company, the company informed that the stocks for Remdesivir will be available only after July 10, 2020.