Questions remain on DRDO’s COVID drug

A drug developed by the Defence Research and Development Organisation (DRDO) and approved by the Drug Controller General of India (DCGI) for “emergency use” in those with moderate to severe COVID may soon make its way to hospitals for treating moderate and severely ill patients, but independent experts say that from the information so far available, the drug’s utility in COVID care has not been established.

The lack of published data on its performance in human trials, opaqueness on whether the phase-3 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 — some of the concerns contributing to the uncertainty, experts told The Hindu.

2-Deoxy-D-Glucose drug has historically been extensively tested for treating cancer but is so far an unapproved drug.

The Institute of Nuclear Medicine and Allied Sciences (INMAS), a lab of the DRDO, in collaboration with Dr Reddy’s Laboratories (DRL), Hyderabad, too has been studying this drug, in the context of radiation therapy for cancer.

The drug had been tested in trials and was given to Dr Reddy’s Laboratories in 2014 as part of a collaboration, according to Dr. Sudhir Chandna, Additional Director, INMAS, DRDO. The basic mechanism of the drug involves inhibiting glycolysis, or one of the ways in which cells break down glucose for energy. This approach while used to starve and kill cancer cells, could in theory work in inhibiting virus cells too, that were almost entirely dependent on glycolysis for replication.

Tests at the Centre for Cellular and Molecular Biology, Hyderabad, last year indicated that the drug demonstrably killed virus cells after which it progressed to trials in people. Dr Reddy’s Labs approached a Subject Expert Committee (SEC) of the DCGI for permission to commercially market and furnishing data from a Phase-2 trial to evaluate the optimum dosage of the drug. The SEC, however, recommended a larger Phase-3 trial “with adequate sample size” and “clearly defined” criteria to evaluate if the drug demonstrably cured COVID.

Dr Reddy’s in its application to the SEC for Phase-2 trials in June 2020, noted that while the drug was yet unapproved, it had been tried in 218 clinical trials so far as an anti-cancer drug.

“Dr Reddy’s believes that this could potentially result in a preferential and disproportionately high accumulation of 2-DG in inflamed lung tissue of COVID-19 patients thereby leading to starvation in the lung cells, which in turn would lead to inhibition of viral replication,” their statement noted.

Annoucing the success of the drug, a press statement from from the DRDO said: “Clinical trial results have shown that this molecule helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence. Higher proportion of patients treated with 2-DG showed RT-PCR negative conversion in COVID patients.”

A “significantly higher proportion” of patients improved symptomatically, were free from supplemental oxygen dependence (42% vs 31% (in those who didn’t get the drug) by Day-3 in comparison to SoC, indicating an early relief from oxygen therapy/dependence, the statement noted.

“Cancer cells depend heavily on glucose for their survival and hence by tagging them with 2DG we can restrict cancer cell growth. Similarly, it can also affect high glucose utilising normal cells like brain cells (neurons) and could cause brain related side effects,” Dr. Cyriac Abby Philips, who specialised in Hepatology and Liver Transplant Medicine, at Rajagiri Hospital in Kerala said in an email.

He perused the available literature on the drug and observed that the safety profile of the drug was “still questionable” At a dose of 63 mg/kg/day, a clinical trial had observed cardiac side-effects and cast doubt on the feasibility of this drug for further clinical use in cancer patients. The sample size of 220 as mentioned in the CTRI (an ICMR website where all human trials must be registered) was inadequate for assessing safety profile along with efficacy, he noted.

Dr. Chandna told The Hindu that a detailed publication was due next month. The phase-3 trial having been conducted in 27 hospitals spanning several States, in the middle of a pandemic, meant that data “hadn’t been uploaded” from some sites. He, however, said the necessary data had been submitted to the DCGI, based on which the emergency use authorisation had been given. He added that in the set of patients who got the drug, there was “complete recovery” and there was “statistically significant improvement” in those who got the drug.

A properly conducted trial must be double blinded and the expected outcomes be clearly defined. This wasn’t apparent in the trial details, said Dr Sahaj Rathi, Assistant Professor, Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India, in an email. “The CTRI website has very limited information. For example, the primary outcome is listed as “efficacy of 2DG as adjunctive therapy”, which is not an outcome. Outcomes are supposed to be objective, and tangible, eg- survival, duration of hospitalisation, proportion of patients requiring mechanical ventilation.”

In the 1970’s, the drug had previously been tried as an antiviral against influenza, as a stimulator for gastric acid secretion and had been experimented with as a lone therapy or an add-on to cancer chemotherapy drugs, he noted. He said that he wouldn’t recommend the drug until peer-reviewed phase 2 and phase 3 data was published.

Rathi described the claimed result, of 42% of patients on the drug improving symptomatically and being free from supplemental oxygen within three days, against 31% who didn’t, as needing more substantiation

“Was this improvement sustained? Did it actually prevent patients from going onto the ventilator? Did it prevent deaths,” were crucial questions that so far lacked answers.