What are the hopes of Remdesivir? When will it become a reality?

As Gilead Science published an unofficial announcement at NEJM that sympathetic use of some of the data of Ridesivir and another large uncontrolled trial, Remdesivir fermentation accelerated. Many people have great hopes for this product, including some very famous doctors, but some people are highly skeptical. No one can predict the success rate of new drugs with 100% accuracy, but there is still some scientific basis for how to predict. Today I will talk about how much hope people have from the perspective of new drug development.

Remdesivir was given high hopes first because similar SARS and MERS viruses showed certain in vitro and animal model therapies. Later, Wuhan virus proved that this drug had an inhibitory activity of EC50 = 1uM in cells infected with new crown. The recent NEJM sympathetic medication data and last week's Stat reported that most of the 113 critically ill patients were discharged within a week, and only two died. Later, monkey experiments showed that the drug can relieve the symptoms of new crown infection, but it has no effect on reducing the viral load. So how important are these data for predicting clinical efficacy, and what more important data have not been considered?

First of all, it is a good thing that SARS and SARS have animal activity. But after all, the new crown is a different virus, and these activities may not be transformed into the new crown. The 1uM of redcive in the new crown cell model is considered to be in range, but it is far from being active. Now more than 50 nM of old drugs have been screened out, but no one has reported much hope. Monkeys are the closest animals to humans, so the experimental improvement of symptoms is strong evidence, but the failure to reduce the viral load is obviously incompatible with the mechanism. There are many opportunities for errors in open-label, uncontrolled clinical trials, such as prematurely discharging patients and enrolling patients in milder conditions, so this is not enough evidence. The death rate of symptomatic patients of Diamond Princess, which is dominated by the elderly, is only 2.6%, although no one takes medication. The so-called serious illness in the Gilead test only needs oxygen inhalation, and it also eliminates the real serious patients who need a ventilator. In history, countless single-arm trials of drugs with very good efficacy have failed in controlled trials. There are no more cases than data. Only enough cases can be analyzed in a certain logical structure. Based on these facts, it can be said that Remdesivir has a certain chance of success, but it is definitely not a certainty.

In order to increase the success rate of new drugs, many companies have developed many evaluation criteria other than activities in the past 20 years, such as Pfizer's three pillars and AstraZeneca's 5R. Although these indicators are not efficacy data, they may be more reliable than non-controlled clinical trial results in judging the prospects of a drug. For example, Pfizer's three pillars say that drugs occupy the target in the body is very critical, which requires that the drugs have sufficient exposure concentration in diseased tissues and show mechanism-related pharmacological effects. For Remdesivir with EC50 = 1 uM, 1uM free drug concentration is required at any time point to inhibit 50% virus replication, but the concentration of Remdesivir in monkey experiments is not high, mainly accumulated in blood cells in. This not only affects the efficacy of the lungs, but also increases the systemic toxicity burden. According to the mechanism, this medicine should increase the amount of mutated RNA, but there is no data on this pharmacological effect. One of 5R is the correct target. There is no conclusion as to how important RNA polymerase is for the replication of the new crown, to what extent the inhibition can be seen, and at what stage the viral load is reduced. It is still unclear whether this is the correct target. Many data point to the need for cytokine storm control.

Another important factor is the historical success rate of this treatment strategy for similar virus infections, which indirectly reflects the efficiency of this treatment idea after highly optimized. Inhibition of viral replication has a very low success rate in the history of acute infections. Even antiviral drugs such as influenza, which are long-standing and in great demand, are generally effective. Remdesivir is not optimized for the new crown. It was first developed for the treatment of hepatitis C and later optimized for Ebola. The activity of the two virus-infected cells was higher than that of the new crown, but it was not successful in the clinic. Although cross-cutting things happen from time to time in the field of new drugs, waiting for the rabbits cannot be a strategy. Otherwise, anti-cancer drugs must start from the target of diabetes. To become a writer, you must read a medical school (Krauthamer language).

In summary, although Redcive's success may be there, it is definitely not as high as everyone expected. There are currently five clinical trials of Remdesivir, and two RCTs in China have ended because of patient recruitment problems, but because a considerable number of patients have been enrolled, it may generate some valuable data. Gilead has two single-arm phase III trials in progress, and because there is no control group, there is little possibility to show whether the drug is effective. There is only one NIH RCT in progress, but this trial has 8 primary endpoints and 30 secondary endpoints. Because the more endpoints you set, the greater the likelihood that at least one will be reached, so this trial will prove difficult to prove the efficacy of redisive unless it reaches more endpoints. In other words, these ongoing trials may not add up to whether Redisive is effective. The hope of the people may be just a hope in a short time, and no matter how great this hope is, it cannot be decided by voting.