Multiple Phase III Clinical Trial Results of Remdesivir for COVID-19 Released Amid Global Anticipation

By Xiang Dong

On April 29, Gilead’s official website finally released the highly anticipated Phase III (open-label) clinical trial data for remdesivir in the treatment of COVID-19. These data were primarily derived from Gilead’s own Phase III SIMPLE trial, which mainly enrolled patients with severe COVID-19. Gilead did not explicitly state whether the study results were successful or unsuccessful [1].

However, the second news item on its official website, “Gilead Sciences Statement on Positive Data Emerging From National Institute of Allergy and Infectious Diseases’ Study of Investigational Antiviral Remdesivir for COVID-19,” revealed that another clinical trial of remdesivir for COVID-19 conducted by the U.S. National Institute of Allergy and Infectious Diseases (NIAID)—a randomized, double-blind, placebo-controlled trial—had yielded “Positive Data” [1].

Figure 1. Information disclosed by Gilead Sciences, image sourced from reference [1]

The aforementioned news revealed that the study conducted by the National Institute of Allergy and Infectious Diseases (NIAID) had reached its primary endpoint, with detailed data to be disclosed in an upcoming briefing. Subsequently, NIAID published partial data from its randomized controlled trial involving 1,063 patients on its official website [2]. According to the released data, patients treated with remdesivir recovered 31% faster than those receiving placebo (p < 0.001). Specifically, the median time to recovery was 11 days for patients in the remdesivir group, compared to 15 days for those in the placebo group. The results also indicated that remdesivir improved patient survival rates; the mortality rate was 8.0% in the remdesivir group versus 11.6% in the placebo group (p = 0.059).

Furthermore, The Lancet also published on the 29th relevant data from a clinical trial of remdesivir conducted in China [3]. However, these data indicated that the use of remdesivir was not associated with time to clinical improvement (hazard ratio 1.23 [95% CI 0.87–1.75]).

Preliminary Results of the SIMPLE Clinical Trial

This trial evaluated the safety and efficacy of 5-day versus 10-day remdesivir treatment in hospitalized patients with severe COVID-19. The results showed that improvements in clinical status were similar between patients receiving 5 days of remdesivir and those receiving 10 days (Odds Ratio: 0.75 [95% CI 0.51–1.12] on Day 14). No new safety signals were identified in either treatment group.

In this study, the time to clinical improvement for 50% of patients was 10 days in the 5-day treatment group and 11 days in the 10-day treatment group. More than half of the patients in both treatment groups were discharged by day 14 (5-day: 60.0%, n=120/200 vs. 10-day: 52.3%, n=103/197; p=0.14). By day 14, clinical recovery was achieved in 64.5% (n=129/200) of patients in the 5-day treatment group and 53.8% (n=106/197) of patients in the 10-day treatment group.

Figure 2. Clinical Efficacy and Safety Data of Remdesivir, Image Source: Reference [1]

Meanwhile, the study indicated that remdesivir was generally well tolerated in both the 5-day and 10-day treatment groups. The most common adverse events (AEs) occurring in more than 10% of patients in either group were nausea (5-day: 10.0%, n=20/200 vs. 10-day: 8.6%, n=17/197) and acute respiratory failure (5-day: 6.0%, n=12/200 vs. 10-day: 10.7%, n=21/197). Grade 3 or higher elevations in liver enzymes (ALT) occurred in 7.3% (n=28/385) of patients, and 3.0% (n=12/397) of patients discontinued remdesivir treatment due to elevated liver function tests.

In response to the aforementioned study, Gilead Sciences merely provided an objective description of the data obtained, without further analyzing its clinical success or failure. Data released by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) indicated that another remdesivir clinical trial for COVID-19 conducted by the institute—a randomized, double-blind, placebo-controlled trial—yielded “positive data.” This suggests that the clinical trials of remdesivir for COVID-19 are highly likely to succeed. The next challenges will be whether it can obtain FDA approval as soon as possible and whether supply will be sufficient.

Will Remdesivir be approved as soon as possible?

Based on data from the aforementioned studies, and in light of the severe epidemic situation currently prevailing in the United States and globally (excluding China), there are two possible scenarios for the FDA’s approval of remdesivir for the indication of treating COVID-19.

1. Proceed directly with the formal approval process to approve remdesivir for marketing with an indication for the treatment of COVID-19. However, this approach may present two issues. First, even with the fastest possible review, the cumbersome drug approval process would still require considerable time to complete. Second, as the study in question is not a double-blind controlled trial, questions remain regarding the validity of its data. The double-blind controlled trials conducted in China have been terminated or suspended, and the multicenter, randomized, double-blind, placebo-controlled clinical trial (NCT04280705) conducted by the National Institute of Allergy and Infectious Diseases (NIAID) is expected to release its results in late May. Therefore, formal approval may need to await the publication of the results from the NIAID’s double-blind clinical trial.

2. Grant Emergency Use Authorization (EUA) for remdesivir directly, while continuing to advance clinical trials of remdesivir in the United States and globally. This approach would allow a broad population of patients with COVID-19 to access remdesivir as quickly as possible, without having to go through compassionate use programs or expanded access protocols. EUA refers to the authorization by the U.S. FDA for unapproved medical products or unapproved uses of approved medical products during actual or potential emergency situations. During the 2009 H1N1 influenza pandemic, the FDA granted EUA for intravenous peramivir, which was not yet approved at the time, for the clinical prevention and treatment of severe influenza. More recently, the FDA authorized chloroquine phosphate and hydroxychloroquine sulfate under EUA for the treatment of COVID-19 [4].

Relatively speaking, given the severity of the pandemic situation, remdesivir is more likely to be authorized for emergency use. The New York Times also reported that the FDA plans to announce the Emergency Use Authorization (EUA) for remdesivir as early as Wednesday.

Can the Supply of Remdesivir Meet Demand?

As of April 29, there were over 3.08 million confirmed cases worldwide, with 1.01 million confirmed cases in the United States. According to data disclosed by Gilead Sciences on April 5 [3], its existing supply totaled 1.5 million doses, including finished products available for distribution and investigational drugs in the final stages of production. Based on the optimal treatment duration under investigation in its clinical trials, this supply is sufficient to treat more than 140,000 patients.

Given the impact of the pandemic, many intermediate manufacturers have suspended production due to COVID-19. Furthermore, as remdesivir is an injectable agent, the quality standards for its active pharmaceutical ingredient (API) are significantly more stringent than those for oral formulations. Consequently, securing a supply of API that meets these quality standards in the short term is challenging. Additionally, the finished product requires manufacturing facilities with sterile production capabilities. Therefore, whether the production capacity for remdesivir is sufficient has become a widespread concern.

Figure 3. Remdesivir production line, image sourced from reference [5]

Following the launch of clinical trials for remdesivir in February, Chinese pharmaceutical companies Borui Medicine and Hainan Haiyao successively announced that they had begun mass production of remdesivir’s active pharmaceutical ingredient (API). Hainan Haiyao further announced that it had completed the first batch of remdesivir formulation production and had established large-scale manufacturing capacity with an annual output of 3.5 million vials. Subsequently, stocks associated with the “remdesivir concept,” including Borui Medicine (stock code: 688166), Hainan Haiyao (stock code: 000566), Porton Pharma (stock code: 300363), Yongtai Technology (stock code: 002362), and Jiuzhou Pharmaceutical (stock code: 603456), experienced sustained increases. This upward momentum subsided only in early March, when Borui Medicine and Hainan Haiyao received regulatory censure.

However, according to previous announcements by relevant companies, firms such as BrightGene Bio-Medical Technology and Hainan Haiyao Pharmaceutical have already achieved batch production of remdesivir active pharmaceutical ingredients (API). Porton Pharma Solutions has long provided Gilead Sciences with services for the production of remdesivir intermediates, and Zhejiang Yongtai Technology has also secured orders for Gilead’s intermediates. With the domestic epidemic in China basically contained and factories having resumed operations for an extended period, these enterprises possess sufficient production capacity. Given the currently severe global pandemic situation, it is highly likely that Gilead Sciences has entered into collaborations with more than one company to supply intermediates, API, and even finished injectable formulations.

According to previously announced information from Gilead Sciences, the company aims to produce enough medication for over 500,000 treatment courses by October, with supply capacity exceeding 1 million treatment courses by the end of this year. However, if Gilead’s own production capacity cannot meet the global demand for COVID-19 patients in the short term, under pressure from compulsory patent licensing by various governments, it is highly likely that Gilead will proactively grant production licenses for remdesivir to pharmaceutical companies in relevant countries, consistent with its corporate approach. Similarly, China, where the epidemic has been largely brought under control, will serve as a reliable supplier of drug intermediates and active pharmaceutical ingredients (APIs) for these manufacturers.

Therefore, the supply of remdesivir is expected to be tight initially; however, as production capacity from relevant partners ramps up fully, and considering other therapeutic options and spontaneous patient recovery, remdesivir should soon meet the needs of the remaining patients.

Conclusion

The data released by Gilead Sciences, Inc., along with the National Institute of Allergy and Infectious Diseases’ (NIAID) announcement of “positive data” from the clinical trial of remdesivir for COVID-19, serve as a much-needed boost amid the currently severe global epidemic situation. Patients under the shadow of the SARS-CoV-2 virus no longer need to rely solely on their own physical resilience; instead, they can directly combat the virus with remdesivir. It is believed that, with remdesivir treatment and the dedicated efforts of healthcare workers, the global pandemic will soon be effectively controlled, and the sluggish economy will gradually recover.

References

[1] Gilead Sciences Official Website:

Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19.

Gilead Sciences Statement on Positive Data Emerging From National Institute of Allergy and Infectious Diseases’ Study of Investigational Antiviral Remdesivir for COVID-19.

[2] NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19

[3] Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.

[4] Emergency Use Authorization：https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization

[5] Gilead WeChat Official Account: An Open Letter from Daniel O’Day, Chairman and CEO of Gilead Sciences, on the Supply and Donation of Remdesivir