BEIJING – China will kickstart a phase III trial Feb. 3 to determine whether patients with 2019-nCoV can be treated with Gilead Sciences Inc.’s NUC inhibitor, remdesivir, which was originally developed for Ebola, four days after a U.S. patient was said to have recovered by using the drug candidate.
The study, expected to be completed on April 27, is a phase III randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of remdesivir in hospitalized adult patients with mild and moderate 2019-nCoV infections. It will enroll 270 patients and be carried out in the China-Japan Friendship Hospital in Beijing.
Gilead said it is expediting the laboratory testing of remdesivir against 2019-nCoV samples and working with the Chinese authorities.
Remdesivir is being developed by the U.S. company as a monophosphoramidate prodrug of code GS-441524 that targets viral RNA-dependent RNA polymerase. It was intended to be an intravenous treatment for Ebola, but it also showed potential against coronavirus and Nipah virus infections.
Remdesivir is yet to be approved anywhere globally and has not been demonstrated to be safe or effective for any use. However, a paper in The New England Journal of Medicine published Jan. 31 suggested there was a possibility of using the drug candidate to help contain the deadly 2019-nCoV virus, which has killed 361 people so far.
On Jan 26, a 35-year-old patient in the U.S. with 2019-nCoV received remdesivir, a week after he was admitted to the hospital, according to reports. The following day, his fever went down from 39.4 degrees Celsius to 37.3 degrees Celsius, oxygen saturation values improved to 94% to 96%, and the previous bilateral lower-lobe rales were no longer present.
Five days after being treated with remdesivir, he was said to be afebrile, with all symptoms resolved except for his cough, which was getting better.
The encouraging result prompted Gilead and the Chinese authorities to move the phase III trial ahead and expand it to a lot more patients who need treatment desperately.
“Remdesivir is not a well-proven drug in either the U.S. or China,” He Gongxin, former chief representative of the Shanghai office at Gilead, told BioWorld. “Since 2019-nCoV is a new virus, we’ll just try it. There are good scientific reasons for us to believe it could be safe and efficacious.
“I believe this is the best chance we have for now,” He added.
In October 2015, a phase I study that evaluated the safety, tolerability and pharmacokinetics of remdesivir in healthy volunteers demonstrated promising results and supported further clinical studies.
The drug candidate has been evaluated in preclinical studies for the potential treatment of coronavirus infection.
“Remdesivir has demonstrated in vitro and in vivo activity in animal models against the viral pathogens MERS and SARS, which are coronaviruses that are structurally similar to 2019-nCoV,” said Gilead’s chief medical officer Merdad Parsey.
In mice, remdesivir significantly decreased Middle East respiratory syndrome (MERS)-coronavirus lung viral loads and improved respiratory function and disease outcomes, whereas lopinavir/ritonavir plus IFN-beta only improved respiratory function, according to the in vivo data presented at the 32nd International Conference on Antiviral Research in Baltimore in May 2019.
The in vitro data presented at the same conference in May 2017 showed that remdesivir was highly active against multiple coronaviruses, including severe acute respiratory syndrome (SARS), MERS and murine hepatitis with EC50 in the range of 0.02-0.07 mM, and exhibited selectivity indexes of 135 to 1,600 in human and murine cell lines.
As for now, it remains to be seen if there is antiviral data for remdesivir that show activity against 2019-nCoV.
“The U.S. patient’s conditions improved significantly, but that’s all we have,” He told BioWorld. “Once the clinical trial completes in April, the conclusion will be clear.”
He added the end of April would likely be the earliest point to tell if remdesivir works, as the clinical trial cannot go any faster. The treatment itself will take nine days, and the data analysis will also take time.
As of Feb 3., 17,242 people are confirmed to be infected and 361 have died. The numbers have skyrocketed over the past few weeks.
Due to the enormous pressure to curb the spread of 2019-nCoV, remdesivir could be the first drug used on Chinese patients under the compassionate use program, which was written into China’s Drug Administration Law in August 2019. The U.S. allowed remdesivir to be used on the 35-year-old patient on a compassionate basis.
Remdesivir had already been used on the same basis on a patient in the U.K. infected with Ebola in October 2015.
Currently, there are more than 40 drugs under development globally to fight the coronavirus infection, and efforts are concentrated on SARS and MERS. Among the drug candidates, 65% are against MERS and 25% against SARS.
The global pipeline will see two new drug candidates targeting the novel coronavirus 2019-nCoV, which will be developed by Moderna Therapeutics Inc. as an mRNA vaccine and Inovio Pharmaceutical Inc. as INO-4800.
Also joining the R&D efforts are Johnson & Johnson, Novavax Inc., Vir Biotechnology Inc., Regeneron Pharmaceuticals Inc., Wuxi Biologics Cayman Inc., Stemirna Therapeutics Co. Ltd., Bravovax Co. and Geovax Labs Inc. Ltd.
In academia, Hong Kong researchers led by microbiologist Yuen Kwok-yung have made progress in developing a vaccine for 2019-nCoV by modifying an influenza vaccine with a part of the surface antigen of the coronavirus. The University of Queensland (UQ) in Australia is also aiming to develop one.
HIV drugs also play a part.
Lopinavir/ritonavir, a HIV-1 protease inhibitor marketed by Abbvie in 2000, will be investigated in a clinical trial in China for 2019-nCoV. Ascletis Pharma Inc. has also filed with regulators to include its ritonavir and ASC09 fixed-dose combination for emergency use. The company said Feb. 3 it is in talks with medical researchers to assist them in initiating clinical trials.