Today, a Chinese self-developed placebo-controlled small molecule drug, Zenotevir, is on the board. NEJM> . This study, published after the end of the COVID-19 pandemic and the epidemic has entered the new normal epidemic stage, reveals the tortuous clinical research process of the drug launched during the pandemic, and provides a good experience for the emergency approval of the subsequent outbreak of new infectious diseases.
The spectrum of illness caused by respiratory viral infection is broad, including asymptomatic infection, symptomatic infection (mild to moderate cases without hospitalization), severe (requiring hospitalization), and death. It would be nice if these clinical observation dimensions could be included in a clinical trial to evaluate the benefit of an antiviral drug, but for a strain that is becoming less virulent over the course of a pandemic, it is critical to select the primary clinical focus and objectively evaluate the efficacy of an antiviral drug.
The research purposes of antiviral drugs can be roughly divided into reducing mortality, promoting improvement of severe disease, reducing severe disease, shortening the duration of symptoms and preventing infection. At different stages of the epidemic, the clinical endpoints chosen often vary greatly. At present, no Covid-19 antiviral has been shown to be positive in reducing mortality and promoting severe remission.
For antiviral drugs for COVID-19 infection, Nematavir/Ritonavir conducted EPIC-HR (NCT04960202) , EPIC-SR (NCT05011513) and EPIC-PEP (NCT05047601) clinical trials, respectively. The three goals were to reduce severe disease, shorten the duration of symptoms and prevent infection. Nematavir/ritonavir was only demonstrated by EPIC-HR to reduce severe illness, and no positive results were obtained for the latter two endpoints.
With the transformation of the COVID-19 epidemic strain into omicron and the significant increase in the vaccination rate, the incidence of weight transfer in high-risk groups has significantly decreased, and it is difficult to obtain positive results by adopting the trial design similar to EPIC-HR with weight transfer as the endpoint. For example, NEJM has published a comparative study of VV116 versus Nematavir/Ritonavir  showing that the former is no worse than the latter in terms of time to sustained clinical recovery in adults with mild to moderate Covid-19 who are at risk of progression. However, the first clinical trial of VV116 used weight reversal as the study endpoint, and with the rapid evolution of the epidemic, it was difficult to observe the expected number of events. These studies suggest that how to evaluate the clinical efficacy of a new drug and what primary endpoint should be used as the criterion for efficacy evaluation have become important clinical research problems in the case of rapid disease evolution, especially the rapid reduction of weight conversion rate.
The Nematavir/Ritonavir EPIC-SR trial, which took 14 COVID-19 symptoms and used the time of symptom resolution as an endpoint, also yielded negative results. We can make three hypotheses: 1. The efficacy criteria are reliable, which means that nematavir is ineffective in improving the clinical symptoms of COVID-19; 2. The drugs are effective, but the standards of efficacy are unreliable; 3. The efficacy standard is not reliable, and the drug is also ineffective in this indication.
As China’s independently innovative Covid-19 antiviral drugs move from the laboratory to the clinical trial stage, we are faced with an important problem – the lack of clinical efficacy evaluation criteria. It is well known that every key aspect of clinical trial design is correct, and it is possible to prove the efficacy of a drug. How to think about these negative results determines whether China’s independent innovative drugs can be successful.
If the time of disappearance of Covid-19 symptoms is not a suitable endpoint for evaluating anti-SARS-CoV-2 drugs, it means that China’s independent innovative drugs can only continue to evaluate and reduce the weight to prove their efficacy, and this road of research and development will be completed after the pandemic rapidly completes global infection and herd immunity is gradually established. The window for achieving clinical research goals with light weight as the primary endpoint is closing.
On January 18, 2023, the phase 2-3 clinical trial of the treatment of mild-moderate novel coronavirus infection by Cenotevir carried out by Cao Bin et al. was published in the New England Journal of Medicine (NEJM) . Their research shows wisdom on how to overcome the lack of criteria for evaluating the efficacy of COVID-19 antiviral drugs in clinical trials.
This clinicaltrial, registered on clinicaltrials.gov on August 8, 2021 (NCT05506176), is the first placebo-controlled phase 3 clinicaltrial of a Chinese indigenous innovative anti-COVID-19 drug. In this phase 2-3 double-blind, randomized, placebo-controlled trial, patients with mild to moderate COVID-19 within 3 days of onset were randomly assigned 1:1 to either oral senotovir/ritonavir (750 mg/100 mg) twice daily or placebo for 5 days. The primary efficacy endpoint was the duration of sustained resolution of the 11 core symptoms, i.e. the recovery of symptoms lasted for 2 days without rebound.
From this article, we can find a new endpoint for the “11 core symptoms” of mild mild disease. The investigators did not use the 14 COVID-19 symptoms of the EPIC-SR clinical trial, nor did they use weight transfer as the primary endpoint.
A total of 1208 patients were enrolled, 603 of whom were assigned to the senotevir treatment group and 605 to the placebo treatment group. The results of the study showed that among MIT-1 patients who received drug treatment within 72 hours of onset, the duration of resolution of COVID-19 symptoms in the senotevir group was significantly shorter than that in the placebo group (180.1 hours [95% CI, 162.1-201.6] vs. 216.0 hours [95% CI, 203.4-228.1]; Median difference, −35.8 hours [95% CI, −60.1 to −12.4]; P=0.006). On day 5 of enrollment, viral load reduction from baseline was greater in the senotevir group than in the placebo group (mean difference [±SE], −1.51±0.14 log10 copies /ml; 95% CI, −1.79 to −1.24). In addition, the results of the study in all secondary endpoints and subgroup population analysis suggested that zenotevir could shorten the duration of symptoms in COVID-19 patients. These results fully indicate that Cenotevir has a significant benefit in this indication.
What is very valuable about this study is that it adopts a new criterion for evaluating efficacy. We can see from the attachment to the paper that the authors devoted a considerable amount of time to demonstrating the reliability of this efficacy endpoint, including the consistency of repeated measures of 11 core symptoms, and its association with 14 symptoms. Vulnerable populations, especially those with underlying medical conditions and those who are obese, benefit more from the study. This confirms the reliability of the study from many angles, and also indicates that Cenotevir has moved from research value to clinical value. The release of the results of this study allows us to see the success of Chinese researchers to creatively solve internationally recognized problems. With the development of innovative drugs in our country, we will inevitably face more similar clinical trial design problems that need to be broken through in the future.
Post time: Jan-20-2024