Some experts question 2-DG, but DRDO defends its Covid wonder drug

The pandemic has birthed many antidotes—some bordering on outright quackery—as a desperate, stressed market scramble for life savers. Into this scrum, the purported anti-COVID drug developed by the Defence Research and Development Organization (DRDO) made its foray recently.

DRDO is charged with the military's research and development in India and its foray into medicine is extremely rare, to say the least.

Named 2-DG—short for 2-Deoxy-D-Glucose—it has been developed by the Institute of Nuclear Medicine and Allied Sciences or INMAS. INMAS is a lab of the DRDO, which has worked in collaboration with Dr. Reddy’s Laboratories in Hyderabad to develop this medicine.

The drug was developed at a frenetic pace. During the first wave of COVID in April 2020, DRDO scientists in INMAS conducted some lab experiments in collaboration with the Centre for Cellular and Molecular Biology (CCMB) of Hyderabad. By May, in a matter of a few weeks, the Drugs Controller General of India (DCGI) gave it permission to begin Phase II trials in clinics on corona patients.

These trials were conducted between May and October 2020. In this period, ``the scientists found that this DRDO anti-corona drug is safe for corona patients and had shown noticeable recovery,” according to an official note issued by the DRDO.

The DRDO 2-DG medicine Phase II and Phase IIB trials were conducted in six and 100 hospitals across the nation, respectively.

Bingo! On to the next stage. After receiving positive responses in Phase II and Phase IIB trials, the DGCI permitted Phase III trials in November 2020, which included 220 patients!

These were conducted between December 2020 to March 2021. A majority of these 220 belonging to 10 states—UP, West Bengal, Gujarat, Delhi, Maharashtra, Telangana, Rajasthan, Tamil Nadu, and Karnataka—showed ``improvements and became independent from supplemental oxygen by Day 3,’’ the DRDO release said.

Dr Reddy’s has fixed its price at ₹990 per sachet – no less - but the pharma company has let it be known that it would provide the drug to government hospitals, central and state governments at a discounted price.

The drug comes in a powder sachet and can be taken orally by dissolving it in water. Union Defence minister Rajnath Singh released the first batch of the 2-DG on May 17.

The drug, according to officials, showed efficacy in trial stages to reduce oxygen dependence of hospitalised COVID-19 patients and enable their faster recovery, including quicker RT-PCR-negative conversion.

Clearly then, approved by the DCGI for 'emergency use’ in those with moderate to severe COVID, 2-DG has made its way to hospitals for treating moderate and severely ill patients.

Experts are, however, raising question marks on its efficacy.

``I will not use this so-called anti-COVID drug nor recommend that someone else use it,” says Vineeta Bal from the Indian Institute of Science Education and Research (IISER), Pune.

IISER is an autonomous public research university established in 2006, established by the Government of India’s Ministry of Education.

``There is no clinical data for this so-called anti-COVID drug; at least it is not in the public domain. How it has been categorized as a medicine to counter coronavirus, can only be answered by DRDO scientists,” Bal told Moneycontrol.

According to her, there are ethical concerns for the use of drugs, devices, vaccines, etc., and they need to be followed.

``Otherwise we are losing out on what we have achieved as a civilised society over the years. Experimenting on Jews, on prisoners, on blacks without consent was practised then and is not acceptable now. Providing a vaccine to a healthy person without knowing the statistical probability of protection is unethical,” she points out.

Bal is convinced that while anti-COVID drugs are urgently needed, it does not mean that anything and everything goes because vital human lives are involved.

The lack of published data on 2-DG’s performance in human trials, opaqueness on whether the Phase-III trial objectively evaluated the benefit from, or lack of it, of the drug and the drug's history — of being an unapproved anti-cancer drug and therefore potentially able to harm healthy cells, are yet to be established.

Specialists say that they would not recommend the drug until peer-reviewed Phase 11 and Phase 111 data was published.

``A properly conducted trial must be double blinded and the expected outcomes be clearly defined. This wasn't apparent in the trial details,” Dr Sahaj Rathi, Assistant Professor, Hepatology, Institute of Liver and Biliary Sciences, New Delhi, told The Hindu.

“The Clinicals Trial Registry (CTRI) website has very limited information. For example, the primary outcome is listed as “efficacy of 2-DG as adjunctive therapy”, which is not an outcome. Outcomes are supposed to be objective, and tangible, e.g.- survival, duration of hospitalisation, proportion of patients requiring mechanical ventilation,” he told the newspaper.

Rakesh Mishra, Director for the Centre for Cellular and Molecular Biology (CCMB), who had earlier helped DRDO scientists in INMAS conduct some lab experiments for this drug, called 2-DG an `analogy of glucose'.

Asked why the drug, in the absence of peer-reviewed data or its tiny human trial number, could be certified as a medicine of mass consumption, Mishra told Moneycontrol ``that the DRDO scientists must be about to put all such information in the public domain.”

When Moneycontrol asked the DRDO how 2-DG had been categorized as a medicine to counter coronavirus, given that there is total lack of any clinical data to describe it as such, a spokesperson for the organization said that ``DCGI has given the Emergency Use Approval (EUA) after reviewing the extensive and complete data of Phase-II and Interim data of Phase-III clinical trial.”

When told that uncomfortable questions were being asked about the lack of published data on 2-DG’s performance in human trials and opaqueness on whether the Phase-III trial objectively evaluated the benefit from, or lack of it, the DRDO said: ``Soon the manuscripts will be published in a peer reviewed journal.”

When informed of the view of some specialists that 2-DG should not be recommended for public use until peer-reviewed Phase II and Phase III data is published, the DRDO replied: ``The expert’s committee of DCGI/CDSCO has given the approval by evaluating both the safety and efficacy data, similarly as other emergency use drugs. Under emergency use approval, it is permitted to be given in a hospitalized setting under the supervision of doctors. Approval for emergency use is given to the drug for saving lives in such a pandemic situation, which cannot wait the lengthy peer review process. Moreover, the expert committee members are also peers.”

The DRDO also played down the pace at which they had developed this anti-COVID drug. Between April 2020 to about May 2021, an entire drug formulation was declared fit for public use, fast tracking all procedures, without adequate safeguards.

Said the DRDO in its response to Moneycontrol: ``The Phase-I to Phase-III clinical trial of this molecule in brain tumour patients was already conducted by INMAS-DRDO in more than 300 patients, earlier. Therefore, formulation of this drug was already standardized. Same formulation was re-purposed, and dose was standardized in COVID patients in Phase-II study. During this pandemic situation, one-year time to complete Phase-II and Phase-III is optimum. Other antiviral drugs have completed their trials in a few months and brought to the market by July 2020. We should understand that the development was done in an emergency pandemic situation.”

When told about the observations of some experts that a properly conducted trial must be double blinded and expected outcomes clearly defined, the DRDO stated that ``Double blinded trials take longer time. Due to the emergency, the majority of COVID drug trials of other antivirals have also been conducted as open label trials, with a purpose to bring rapid relief in pandemic.”

The World Health Organization’s manual, `How are vaccines developed?’ talks of pretty elaborate procedures - presumably in normal, non-pandemic times.

``Each vaccine under development must first undergo screenings and evaluations to determine which antigen should be used to invoke an immune response…If the vaccine triggers an immune response, it is then tested in human clinical trials in three phases,” it points out.

In Phase I, the vaccine is given to a small number of volunteers to assess its safety, confirm it generates an immune response, and determine the right dosage, while in Phase II, it is given to several hundred volunteers to further assess its safety and ability to generate an immune response, WHO says.

In Phase III, the vaccine is ``next given to thousands of volunteers – and compared to a similar group of people who didn’t get the vaccine, but received a comparator product – to determine if the vaccine is effective against the disease it is designed to protect against and to study its safety in a much larger group of people. Most of the time, Phase III trials are conducted across multiple countries and multiple sites within a country to assure the findings of the vaccine performance apply to many different populations.’’

Experts agree that there is no specific medicine for COVID-19 currently available in India. Experimental or repurposed drugs are being used to treat the patients and these include Remdevisir, Ivermectin, Tocilizumab, steroids, and plasma therapy, all of which are part of treatment protocols.

The situation is open for experimentation, but it is the quality of this experimentation that is weighing heavy on the minds of those following the complex drug trials in these challenging times.