DRUG WAR INTENSIFIES

The pandemic has entered yet another phase, with the Omicron variant wreaking havoc across the globe. The high infection rate of this new cause for concern, in India, has also triggered a ‘war of medical opinions’ between the Indian Council of Medical Research (ICMR) and the Drugs Controller General of India (DCGI). Pharma majors are churning out viable treatment options at a feverish pace, in a bid to become the most widely accepted drug listed in COVID-19 treatment protocols. Merck’s Molnupiravir is one such drug that is embroiled in a ‘safety vs efficacy’ contest. Let’s investigate further.

Molnupiravir, the oral antiviral drug developed by Merck and its partner Ridgeback Biotherapeutics, that received DCGI approval for the treatment of mild to moderate COVID-19 in India, is being opposed by the Indian Council of Medical Research (ICMR) due to safety concerns. Priced at Rs 1,399 for the full five-day course, the drug is claimed to be one of the cheapest antiviral coronavirus therapies during the pandemic. A repurposed COVID-19 drug, originally developed to treat influenza, it is meant for mild or moderately ill COVID-19 patients who are at risk of developing a serious illness. The pill, if administered during the first five days after contracting the infection, has the potential to prevent serious illnesses.

A host of pharma companies including Hetero, Sun Pharma, Natco and Dr. Reddy’s Laboratories have rolled out the oral therapy. Approved by the UK’s drug regulator and recently by the US Food and Drug Administration, the pills are projected to be

a game-changer in COVID-19 treatment. Even the Drugs Controller General of India (DCGI) granted permission for restricted use of molnupiravir for treatment of adult patients with SpO2 93 per cent, and who have a high risk of progression of the disease.

However, ICMR has come up with a word of caution and has flagged certain side effects. The question remains - are these drugs required for the Indian market when on the one hand a sizable population has been vaccinated while on the other, the new variants are losing steam, according to the latest trends.

The ICMR gave a thumbs down to Merck’s Molnupiravir, the antiviral drug that received approval for emergency use by the DCGI. Prof. Balram Bhargava, ICMR Director General, has been voicing safety concerns of Molnupiravir. The drug, according to Dr Bhargava, could trigger abnormalities in foetus development apart from other side effects such as damage to muscles and cartilages.

All for the drug

Leading health experts treating coronavirus patients across the country believe that the COVID antiviral drug molnupiravir is reducing hospitalisation by 30-50 per cent, as well as the severity of the disease. Countering what Dr Bhargava said, some sections of the experts said the benefits of the drug outweigh potential risks.

According to Dr Deepak Talwar, Senior Consultant & Chairman, Metro Respiratory Centre, Pulmonology & Sleep Medicine, physicians have to keep in mind the patient profiles while prescribing any drug. He says, “We have to use the available therapy rather than counting its side-effects, that too which are potential, but not known.”

Agreeing with Dr Talwar, Dr Dhruva Chaudhry, President-Elect ISCCM, Editor in Chief, Critical Care Communications, a Nodal Officer for COVID-19 at PGIMS Rohtak and Head of the Pulmonary and Critical Care Medicine opines, “While approving, the FDA, as well as DCGI, have gone through the safety data of the drug. Only once satisfied this drug has been approved. Even in the phase-3 clinical trials Molnupiravir, which demonstrated a significant reduction in the risk of hospitalisation or death with no observed safety concerns when compared to the placebo group.”

Dr Vasant Nagvekar, an infectious diseases consultant at Lilavati Hospital and member of the COVID task force, has prescribed it to 30 patients since its availability in the market. Molnupiravir, according to him, should be administered as soon as possible after a diagnosis of COVID-19 has been made within five days of symptom onset.

Dr S K Jindal, Medical Director and Sr Consultant Pulmonology at Jindal Clinics Chandigarh; Former HOD, Pulmonology Medicine, PGIMER, Chandigarh opines, “Side-effects of mutagenicity does not matter, if the drug is indicated for certain patient profiles, for a treatment course of five days.

As new variants of the virus continue to emerge, it is crucial to expand the country’s arsenal of COVID-19 therapies using emergency use authorisation, while continuing to generate additional data on their safety and effectiveness. According to Patrizia Cavazzoni, Director of the FDA’s Centre for Drug Evaluation and Research, Molnupiravir is restricted to situations where other FDA-authorised treatments for COVID-19 are inaccessible or aren’t clinically appropriate and will be a useful treatment option for some patients with COVID-19 at high risk of hospitalisation or death.

Biophore India Pharmaceuticals has developed and started manufacturing the key intermediates of Nirmatrelvir, one of the active ingredients of Paxlovid, the latest anti-COVID therapy, approved by the US FDA through the emergency use authorisation route. The manufacturing is being done in collaboration with Rakshit Group. This is expected to greatly reduce the dependence on imports, mainly from China, from where these intermediates are being procured currently. Biophore is also

‘‘We have to use the available therapy rather than counting its side-effects, that too which are potential, but not known.’’

- Dr Deepak Talwar, Senior Consultant & Chairman - Metro Respiratory Centre, Pulmonology & Sleep Medicine

‘‘While approving, the FDA, as well as the DCGI, have gone through the safety data of the drug. Only once satisfied this drug has been approved.’’

- Dr Dhruva Chaudhry, President-Elect ISCCM, Editor in Chief, Critical Care Communications, a Nodal Officer for COVID-19, PGIMS Rohtak

‘‘Molnupiravir is restricted to situations where other FDAauthorised treatments for COVID-19 are inaccessible or aren’t clinically appropriate and will be a useful treatment option for some patients.’’

- Patrizia Cavazzoni, Director of the FDA’s Centre for Drug Evaluation and Research

Side-effects of mutagenicity does not matter if the drug is indicated for certain patient profiles.

- Dr SK Jindal, Medical Director and Sr Consultant Pulmonology at Jindal Clinics Chandigarh; Former HOD, Pulmonology Medicine, PGIMER, Chandigarh

‘‘The present set of antivirals will not prove to be a gamechanger; rather they may play a supporting role in pandemic management.’’

- Dr Anup R Warrier, Head - Infectious Diseases and Infection Control, Aster DM Healthcare - India Units

‘‘There would be a demand for these drugs as no other drugs in the antiviral group are approved for COVID-19 treatment.’’ - Akshay Daftary, Director, SIRO Clinpharm

manufacturing Nirmatrelvir in a US FDA compliant facility and has announced that they will be filing for approval with DCGI soon.

Paxlovid’s breakthrough approval was given by the US FDA in December 2021 and is indicated for the treatment of mild-to-moderate COVID-19 in adults and paediatric patients.

Dr Jagadeesh Babu Rangisetty, CEO, Biophore, says, “The development and manufacturing of these intermediates is extremely complex and is significantly more challenging than earlier antivirals that have been indicated for COVID.”

Natco Pharma has signed a non-exclusive license agreement with the Medicines Patent Pool (MPP), Switzerland to manufacture and sell Molnupiravir capsules 200 mg for treatment of COVID-19. MPP had taken a licence from Merck Sharp & Dohme Corp (MSD), USA for the same, the company said in a statement. Natco said with this licence agreement it can manufacture and sell Molnupiravir capsules 200 mg for the Indian market, which will be sold under brand name MOLNUNAT for treatment of COVID-19 infection in patients who have high risk of progression of the disease including hospitalisation or death.

In another development, Central Drug Research Institute (CDRI) scientists in Lucknow are in the process of developing a drug for COVID treatment without any side-effects. A team led by chief scientist Ravi Shankar, is working on two combinations to provide the safest medication to coronavirus patients. Scientists are working on two combinations - Umifenovir with Molnupiravir (an antiviral) and Umifenovir with Niclosamide (antiparasitic). A safe and efficacious combination of Umifenovir with Niclosamide is being researched for the exact dosage in the combination that can give positive results.

Marketing strategy

Vaccines are proven to be efficient against the latest variant of COVID so why is there a need for oral drugs when patients are bound to have side effects. The medical fraternity is also confused a lot where DCGI has given a go-ahead on one hand and the

other ICMR has come out with safety concerns.

Says Dr Anup R Warrier, Head - Infectious Diseases and Infection Control, Aster DM Healthcare - India Units, “The present set of antivirals will not prove to be a game-changer; rather they may play a supporting role in pandemic management. The volume of use typically depends on the marketing strategy and the inherent fear of ‘not doing enough’ while facing this new disease that drives prescriptions from the doctors.”

Upendra Nath Sharma, Partner, J Sagar Associates (JSA), says “Marketing of COVID pills being launched in the Indian market is going to be an uphill task. With great difficulty, the efficacy of vaccines like Covishield and Covaxin had started sinking into the minds of the masses in India. Hence, to be able to provide a meaningful alternative, the effectiveness of such pills would have to be very well established in the market and advertised well across various media platforms.”

Some experts have also opined that there is rampant and irrational use of pills which can set a dangerous precedent.

Akshay Daftary, Director, SIRO Clinpharm mentions, “There would be a demand for these drugs as no other drugs with the antiviral group are approved for COVID-19 treatment. In later phase studies, these drugs have proven efficacy in preventing severe disease in the at-risk population and this will be a factor propelling the demand.”

Pricing

Going by the estimate of drugmakers, the pill has been launched in 200 mg strength. The recommended dose of Molnupiravir is 800 mg twice a day for five days, which means, the entire treatment would require 40 tablets and the total cost would stand between Rs 1,600 and Rs 3,000.

A majority of Indians are particular about where and how much they are spending. The government may have to underwrite part of the costs, to ensure it is attractive enough for the common man. If pricing is reasonable and effectiveness established against various mutations of the virus and adequate education provided to the masses, people would certainly find it easier to buy a pill off the shelf and consume it.

Says Sharma, “Initially there would be a lukewarm response and bulk orders may follow in due course, depending upon how the above-mentioned conditions are addressed.”

Daftary opines, “Regarding cost; traditionally India has been a generic market and cost is one of the major factors in deciding the use by the medical fraternity or by the population. Looking at this, there would be a significant response to these drugs if launched at a subsidised cost.”

Agree to disagree?

It is too premature to come to a conclusion mentioning that the drug can do more harm. Also, the ICMR, DCGI, and the Central Drugs Standard Control Organisation (CDSCO) should work together to come out with a conclusive report before coming out with individual reports and creating confusion among doctors and patients alike. It needs to be seen how these departments can work towards a conclusive goal and help save precious lives amidst various variants of covid.

‘‘Marketing of covid pills being launched in the Indian market is going to be an uphill task.’’

- Upendra Nath Sharma, Partner, J Sagar Associates (JSA)

‘‘Molnupiravir, according to him, should be administered as soon as possible after a diagnosis of COVID-19.’’

- Dr Vasant Nagvekar, Infectious Diseases Consultant, Lilavati Hospital