Drug repurposing is considered as a rapid strategy for COVID-19 drug discovery [1] and many drugs have been tried. Tocilizumab, a recombinant humanized anti-IL-6 receptor monoclonal antibody FDA approved drug for diseases other than COVID-19, was initially shown to shorten the median time to COVID-19 clinical improvement [2] and it also showed non-statistically significant lower mortality in patients with severe to critical COVID-19[3]. Interestingly, though several studies have even showed tocilizumab to significantly improve the clinical outcomes in severe cases of COVID-19 pneumonia [4-8], yet phase III double blind, placebo-controlled clinical trials have recently declared that tocilizumab did not improve the clinical status in patients with COVID-19 associated pneumonia, and didn’t prevent intubation or death in moderately ill hospitalized patients with Covid-19, though potential benefit/harm could not be entirely excluded [9, 10]. In comparison, some preliminary results anticipated the success of remdesivir, a nucleotide analogue prodrug, to treat COVID-19 [11, 12]. However, other studies have suggested that remdesivir is unexpected to possess significant clinical benefits based on its released results and safety profile [13-17]. Moreover, even open label phase III trial results showed no significant difference between a 10-day remdesivir course (median length of treatment, 6 days) compared with standard care while claiming a benefit for the 5-day course[18], yet the drug continues to be marketed globally and priced at 3,120 USD for the typical patient with private insurance in USA. Moreover, a black market has developed in India [19] and perhaps other developing countries. Notably, the WHO Solidarity Trial Consortium has recently announced the results of randomized trials performed in 405 hospitals located in 30 countries where 2750 patients received remdesivir and it was shown to have little or no effect on hospitalized COVID-19 patients, as indicated by overall mortality, initiation of ventilation and duration of hospital stay[20] and despite all criticism and warnings, the FDA has recently approved remdesivir to be used for COVID-19[21] after an unprecedented consultation of a diverse group of experts outside the FDA [22]. Fortunately, the WHO has declined to acknowledge remdesivir and recommended against its use in COVID-19 regardless of disease severity[23]. Unfortunately, many countries all over the world continue to use it, including the author’s; Egypt.
Similar to remdesivir paradox, favipiravir (T-705) was approved in Japan in 2014 as a treatment for novel or re-emerging influenza viruses, yet its local approval was heavily restricted as its clinical use needed governmental authorization, which was only permitted for potentially lethal diseases and a similar cautious attitude was also adopted in China[24]. Furthermore, the Japanese drug safety bureau, possibly due to limited safety data, recommended favipiravir to be avoided where alternative drugs could be used and adverse effects such as hyperuricemia and teratogenicity/embryotoxicity were reported from favipiravir human and four different animal species studies, respectively and QTc prolongation potential was recommended to be further investigated [24, 25]. Hepatitis was also reported in 4 out of 63 COVID-19 patients who received favipiravir[26]. Notably, >85% of favipiravir completed clinical trials in registries or in published papers are unavailable which led to failure of conducting meta-analysis to generate conclusive evidence to support recommendation of favipiravir use in COVID-19 or know about its safety and efficacy profile [27], and a Japanese study showed no significant efficacy of favipiravir in SARS CoV-2 elimination. This study also shows the cautious attitude of a Japanese health authority, Fujita Health University, which conducted the study as out of 47 facilities across Japan that took part; only 88 patients were enrolled and completed the study[28]. Most importantly, favipiravir is a nucleoside analogue that acts as a mutagen with a distinct bias to induce transitions in influenza virus RNAs by incorporating into both positive and negative stranded RNA and being aberrantly copied as multiple bases[29] and favipriavir-induced lethal mutagenesis of influenza virus may be the reason for the difficulty in isolating favipiravir-resistant influenza viruses in laboratories or to evolve resistance against clinically[24, 29].
In conclusion, we would like to join the WHO in its recommendation against the use of remdesivir for COVID-19. Furthermore, a teratogenic, embryotoxic and virally mutagenic favipiravir should undergo extensive studies to assess its potential gene mutation and/or chromosomal damage effects as well as to evaluate its potential human carcinogenicity before allowing wide scale global trialing. On the other hand, we would like to recommend considering tocilizumab for selected critical cases of COVID-19 after considering the risk benefit ratio because of an overwhelming evidence coming from several independent and well-designed clinical trials showing a remaining potential benefit, until the results of other studies fill the missing gaps as regards to its COVID-19 efficacy.
Conflict of interests:
None
Funding/Financial disclosure:
None
Acknowledgement
This main bulk of this manuscript has been denied, for months, an opportunity to be properly peer reviewed by several journals, however a draft has been sent by one of them to the WHO before its historic decision regarding remdesivir.
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