Phase-3 clinical trials for 2-DG may continue till Aug: Registry data

With the government presenting DRDO-developed drug 2-DG as a potential game-changer in the fight against COVID-19, the clinical trial registry data suggests that the phase-3 trials for the medicine at over two dozen government and private hospitals and involving 220 patients may continue till August.

The third-phase trials began in January, while the phase-2 trials were conducted over a three-month period between June and September last year and involved 110 patients.

While 2-DG has been studied in more than 200 clinical trials for the treatment of various cancers globally, trials to use it as a COVID-19 drug are apparently being done in India only and incidentally, a strong case for its therapeutic use against the novel coronavirus was made in a study paper last year that had Patanjali Research Institute's Acharya Balkrishna as the lead author.

His co-authors included four others from Patanjali -- Pallavi Thakur, Shivam Singh, Swami Narsingh Dev, Anurag Varshney -- as also Viney Jain (Jain Vishwa Bharti Institute, Rajasthan) and Rakesh Kumar Sharma (Saveetha Institute of Medical and Technical Sciences, Chennai).

When contacted, Sharma said the paper was completed in October 2020 and it has been peer-reviewed as well.

He said the possibility of repurposing of 2-deoxy-D-glucose (2-DG), a radio-chemo-modifier drug used as an adjuvant to cancer therapy, and one of its derivative (1, 3, 4, 6-Tetra-O-acetyl-2- deoxy-D-glucopyranose), has been investigated by conducting ligand-receptor docking.

The paper was submitted to the Annals of National Academy of Medical Sciences on October 15, 2020. It was peer-reviewed and it was accepted on May 11, said Sharma, Dean of Saveetha Institute of Medical and Technical Sciences.

According to the paper, entry of SARS-CoV-2 is mediated through the viral spike glycoprotein (S2) and afterward, the virus gets hold of the host cell machinery by employing the use of viral main protease 3CLpro and NSP15 endoribonuclease.

It said that the possibility of repurposing of 2-deoxy-D-glucose (2-DG), a radiochemo-modifier drug used for optimizing cancer therapy, and one of its derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose, has been investigated by conducting ligand-receptor docking.

It said 2-DG can dock efficiently with viral main protease 3CLpro as well as NSP15 endoribonuclease, thus efficiently inactivating these viral receptors leading to incapacitation of the SARS-CoV-2 virus.

"The 2-DG derivative formed a hydrogen bond with the glutamine amino acid residues of the viral spike glycoprotein. The present in silico study supports the potential benefits of using 2-DG and its glucopyranose derivative as repurposed drugs/prodrugs for mitigating the novel COVID-19 infection.

"Since both these moieties present no signs of serious toxicity, further empirical studies on model systems and human clinical trials to ascertain effective dose-response are warranted and should be urgently initiated," it added.

An article in the January-February issue of the Indian Journal of Medical Research, a publication of the Indian Council of Medical Research, also cited this paper, while referring to the potential benefits of using 2-DG to mitigate COVID-19 infection.

The Drugs Controller General India (DCGI) had granted permission in May last year to Dr Reddy's Laboratories for conducting a clinical trial of 2-DG for "acute treatment of moderate to severe COVID-19 patients".

Interestingly, Dr Reddy's became the secondary sponsor after phase-2 trials and the DRDO's Institute of Nuclear Medicine and Allied Sciences became the primary sponsor and main source for material or monetary support during the phase-3 trial.

The phase II clinical trials were conducted at 12 sites across India, including at private and government hospitals. The trials were conducted over a three-month period between June-September 2020, for which a total of 110 COVID-19 patients aged 18-65 years were enrolled.

Those with COVID-19 symptoms like fever, cough, difficulty in breathing, fatigue, body ache, headache, diarrhoea, nasal congestion took part in phase-2 clinical trials. The drug was found to be safe in COVID-19 patients and showed significant improvement in their recovery.

Subsequently, phase-3 trials began in January 2021 on a sample size of 220 individuals aged between 18 and 90 years. According to the clinical trial registry data, the estimated duration of these trials are eight months and should therefore continue till August.

While more than 25 sites have been selected for the phase-3 trials, DRDO's Institute of Nuclear Medicine and Allied Sciences has been listed as the 'source of monetary or material support' as the primary sponsor in this stage, relegating Dr Reddy's to the position of 'secondary sponsor'.

As per the registry, "This is a prospective, interventional, multi-centre, phase III, randomised, open-label, two treatment group, parallel design trial to evaluate the efficacy, safety and tolerability of 2-DG administered as adjunctive (or add-on) therapy to standard of care, in comparison to standard of care alone, in the acute treatment of patients testing positive for SARS-CoV-2 and presenting with moderate or severe COVID-19."

An interim analysis will be planned for futility assessment and re-estimation of the sample size, it added.

Earlier, the phase-2-trial report had mentioned that "while 2-DG is not an approved drug, it has been studied in 218 clinical trials for the treatment of various cancers globally".

Noting at that time that 2-DG has not been evaluated in the acute treatment of moderate to severe COVID-19, the sponsors had stated the "mechanistic and in-vitro-evidence as well efficacy seen in the interventional clinical studies in malignancies and genital herpes" made them believe that 2-DG could be developed for the specific treatment of patients with COVID-19 disease in conjunction with other anti-viral therapies.

It credited INMAS, DRDO, Ministry of Defence for the genesis of this hypothesis and testing of the efficacy of 2-DG against SARS-CoV2.

The government recently launched 2-DG as an anti-COVID-19 therapeutic application of the drug 2-deoxy-D-glucose (2-DG).

The Health Ministry has said that clinical trial results have shown that this molecule helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence. A higher proportion of patients treated with 2-DG showed RT-PCR negative conversion in COVID patients. In the COVID infected cells, it inhibits virus synthesis and energy production for the process.

Health Minister Harsh Vardhan had said the drug has the potential to become a game-changer in the fight against the COVID-19 pandemic as it reduces the dependence of patients on oxygen administration and has the potential of getting absorbed differentially and in a selected manner.