Development of the pharmaceutical industry pkrutamine new crown test progress telephone exchange meeting

2021.12.28

Management: Tong Youzhi, Lu Yan, Ma Liandong

Interpretation of the data of the interim clinical analysis of MRCT mild and moderate disease phase III in the United States:

The design of the trial is based on the results of two Phase 3 clinical trials in Brazil, one for men with mild disease from September to November 2020 and one for women from November 2020 to January 2021. We did clinical trial design for MRCT based on these data, with multi-center, seven or eight countries participating in the world. In Brazil, the results were good, with hospitalization rates of 27% vs 2% for men and 18% vs 2% for women, protection rates of more than 92%, patients without any vaccination background at the time, and no testing for viral variants in this trial. In terms of virus cleanup, after seven days of treatment, 82-83% of patients had the virus turned positive and negative, compared with 30% in the control group.

Approved in the United States in March this year, the phase 3 clinical trial was approved, the trial design was based on the global hospitalization rate at that time and the historical data of our drugs, the design assumption at that time was 9:3 (9% of the people in the control group had the number of hospitalization events, and 3% of the treatment group had the number of hospitalization events), according to this hypothesis, 667 people were included in the clinical trial, there should be 70-80 events, the hospitalization rate in the United States at that time was 7-8%, and more than 15% in other countries. The trial was originally planned to enroll 30% of patients in the United States and 70% of other countries to meet the REQUIREMENTS of the FDA. However, there was a serious deviation in the results in the medium term, mainly because: 1) The vaccine entered the vaccination stage of a wide range of people in the United States from April to May last year, and the vaccine protection rate against severe diseases was very good, especially the MRNA vaccine in the United States did a good job in this regard; 2) In more than a year, the doctor's treatment experience is increasing, and the new crown mild disease to severe disease is changing; 3) As the epidemic progresses, the infected population changes, with the older people in the early stages and more young people in the back (the average age of the early Brazilian trials was 55 years old, and the average age of the later US trials was 38 years old); Based on these factors, the number of events throughout the trial was very small, in single-digit proportions. On the other hand, based on the considerations at the time, the results in Brazil were very good, so this MRCT design was for the whole population, and Merck and Pfizer's clinical classification of high-risk (unvaccinated, high risk of disease progression), standard-risk (unvaccinated, or vaccinated and at high risk of disease progression) patients, in this group, usually have a higher hospitalization rate. More than 90 percent of Merck's trials were foreign patients, 7 percent were in the United States, and half of Pfizer's trials were enrolled in the United States. The hospitalization rate in the Pfizer control group was 6.8% and Merck was 9.7%. In this kind of people, the possibility of drugs being able to make a statistical gap is high, of course, Pfizer's results are much better than Merck's. At that time, considering the label of the drug, we did not realize the changes after vaccination, and our trial included high-risk people, people who had been vaccinated with risk factors, and people who had not been vaccinated. We enrolled a total of 728 patients, of whom 6-7 patients were enrolled in Brazil and South Africa, and about 720 were from the United States. Numerically, there is no statistical difference. The trial also gives a better hint to verify the authenticity of clinical trials in Brazil, and we have also seen the trend of drug efficacy and have a clearer understanding of the future clinical and commercial layout.

In terms of enrollment, more than 300 patients were enrolled in six or seven months, more than 100 patients were enrolled every week in the last two weeks of December, a total of 728 patients, and all patients who completed the original protocol were enrolled. By the beginning of February, the 42-day observation period for all patients will be over, and we will follow closely to observe the number of events in the last two hundred or so patients. At the same time, we will communicate with the FDA and other regulatory authorities to decide whether to increase the inclusion of high-risk groups (perhaps 600-1000 people), there are more than 50 clinical centers in the United States in operation, more than 20 centers in other regions, the enrollment base of the entire high-risk patient in the future is much better, and it is possible to enroll suitable patients in a relatively fast time.

We also have two Phase III clinical trials ongoing. One is MI3001, for mild patients, this is china, Brazil, Malaysia, the Philippines and other countries to participate, and now it is also gradually joining the group. The trial is also preparing to include more high-risk groups and will also communicate with regulators; At the same time, in some countries with serious epidemics and rapid approval of clinical trials, registered clinical trials in separate countries are carried out to obtain more evidence, and the specific content is also under discussion. Another phase III clinical trial was a severe case trial, conducted in 14-15 countries, with participation from China, the United States and other countries. There is no good treatment for severe diseases, and merck and Pfizer's drugs are used for mild cases. Serious illnesses with death threats are a matter of great importance to all countries, and we will make every effort to promote research on severe diseases. Researchers from Brazil and the United States once conducted a small intensive case trial in southern Brazil, and the clinical results were just published two days ago. Previously this paper was not published in the New England journal because of the lack of raw data, and the journal now published is not a high impact factor journal, but it contains a lot of raw data, the quality of the magazine itself and the real situation that can reflect the data. We are also doing our own collation and analysis of the raw data from our more than 600 clinical trials in Brazil.

The unsatisfactory analysis in the medium term will cause a delay in the commercialization plan, and we will make commercial adjustments. At the same time, another conclusion reached by the clinical trial is that the safety of the drug is not a problem. We are willing to provide free medicines for empathy.

Q&A

Q: When the number of events is observed in the blind state, but the library is still locked, can it be judged that the data and expected deviation are relatively large at that time?

A: Many of the events I see occur in August-September, and very few occur in October. We should have adjusted our plans early to include more high-risk patients. Our mid-term locking was in early October, when we were expecting more events to happen, and the locking was delayed for two weeks, and locking the library or not having little significance for the change in results.

Q: Is it common to complete the enrollment of all patients and then adjust the protocol, and do I need to reopen the clinic? A: We have also discussed whether to increase the sample size or reopen the clinic, and we should communicate with the regulatory authorities. We have more than seventy clinical centers, and it takes a lot of energy to reopen the clinic, and if the regulatory authorities agree to increase the sample size, the time will be much faster.

Q: How much did global MRCT cost on cash reserves?

A: There are about 1.2 billion yuan in hand. By the end of November, three MRCT had cost $24 million. There will be some additional costs for the 3001 outpatient trial to increase the sample size, as will clinical trials in some individual countries. In addition to the funds in hand, our bank credit facilities, funded by the Ministry of Science and Technology of the People's Republic of China, funded by the local government of Suzhou, BD expansion, EUA commercial orders, etc., can provide sufficient financial support in the future. We are confident that we will support 3 MRCT trials, hair loss trials, macromolecules, and other preclinical studies over the next 12 months, with sufficient funding.

Q: Recent hospitalization/mortality rate of 5% + in the US. According to the original design, if it was 3:5 (5% of the control group would be hospitalized, and 3% of the treatment group would be hospitalized), would the original sample size be enough?

A: It should not be enough, the sample size needs to be expanded. To do a trial in all populations, it may require thousands of sample sizes. If narrow becomes high-risk patients, things will change, and hospitalization rates may now be well below 5%, compared to 6.8% for control groups of Pfizer high-risk patients. Merck is in a country of more than 20 people, of which the United States of America treated 41 people, 4 people hospitalized, placebo group 45 people, 5 people hospitalized, so the hospitalization rate is 9.8% vs 11.1%, almost no gap; Merck admitted 34 people in the Brazilian treatment group, 1 hospitalization, and 9 out of 40 people in the placebo group, with a hospitalization rate of 2.9% vs 22.5%, which is close to our data in Brazil at that time. It was proved that hospitalization rates varied greatly from country to country, and overall, the hospitalization rate in the placebo group had to be significantly increased to show the results of drug treatment.

Q: Is the next control group to use Pfizer?

A: Communication with the FDA is required. As for whether it is head-to-head, Pfizer is only EUA, not full approval. But in the past, when there were neutralizing antibodies, the US FDA also agreed to use our drug to control placebo. If the FDA requires head-to-head, it may also be a good opportunity for us to enroll more patients outside the United States.

Q: In the absence of significant differences, what is the specific content of the good trend seen? What is the Primary Secondary Endpoint Value? Is continuing recruitment a recommendation given by IDMC or an idea of your own? Will patients who continue to recruit do one trial or another alone? Progression of severe illness? A: In the medium-term analysis, we are still blind, and we know that the trend of drug efficacy exists in the communication with idMC. The recommendation to continue experimenting was given by idMC. We have also measured the pros and cons of continuing to recruit or starting a new trial, and after a month we may have a clearer understanding of what the status is, mainly time and speed. Severe illness is still in the group, the time of the mid-term data readout can not be given, the enrollment is related to the new crown epidemic, and there is uncertainty at the time point. In terms of critical illness centers, there are now 5 in the United States, 6 in Ukraine, including the Philippines and other countries, a total of about 20 intensive care centers, all of which are recruiting.

Q: At the beginning of the month, a phase 2 clinical trial of Enzaluamine severe disease was announced for more than 40 people, and the results of the trial group were worse than those in the drug group, and the conclusion was that Enzaluamine could not be used for severe disease. Can you explain the mechanism of pkrutamine again?

A: The mechanism of action of prunamide and enzaluamine is not the same, in addition to the AR antagonism mechanism, prunamide can also reduce proteins, enzaluamine has no degradation mechanism. In the viral infection test, enzaluamine is not as effective as puklamide. In terms of inhibiting inflammation, pkrutamine is also more effective than enzaluamine. In summary, the mechanism is different, and the activity of pkrutamide is higher. According to brazilian data, treatment effects were also shown for patients enrolled in our trial after the use of enzaluamine. In terms of biomarkers of the inflammatory response, it has been observed that pkrutamine has a good control of the acute inflammatory response in patients with new crown.

Q: What are the difficulties in designing and statistically modifying the clinical protocol on the basis of the existing one? A: The key problem is that there must be a very accurate judgment on the hospitalization rate of the subject population placebo, so that it is possible to have a more accurate judgment on the test design and assumptions. The available data will not be available until the specific information is revealed.

Q: Now that we have seen the trend of efficacy and the availability of drugs and vaccines is relatively full, will we choose global partners to promote clinical practice? A: I've talked to a lot of companies. Because the mechanism of the drug is relatively novel, the Brazilian results give us a good starting point, and probably a lot of big companies want to see more evidence chains. In the presence of medium-term data, we will also actively seek out partnership partners.

Q: What is the next definitive readout time of clinical data? A: The changes in the epidemic have brought many uncertainties, which are different from tumor drugs. Accurate guidance cannot be given, but the company will maintain full and transparent communication with the market.

Q: Is there any data for Omicron? A: Researchers at the University of Michigan School of Medicine are being commissioned to test in vitro infection data, and the results can be obtained in January.

Q: Admission to severe illness?

A: After more than two months, the specific data is not convenient to disclose. More than 20 centers are accelerating enrollment, and more than 20 more will open next month. If Omicron causes the outbreak to worsen, enrollment accelerates. Guidance may be given in January.

Q: What are the possible EUA applications in other countries?

A: EuAs in many small and medium-sized countries are for patients with severe illnesses, which are life-threatening. The EUA applied for in Paraguay and European countries is based on the results of Brazil. For many countries, we are willing to provide medicines to help reduce mortality. Our strategy is to start with EUA severe care and then advance clinical trials in mild cases.

Q: What are the specific assumptions of severe clinical practice? A: Length of hospital stay.

Q: Most of the Omicron-infected population has been vaccinated, and if it is limited to high-risk patients, will the recruitment rate be accelerated?

Affected? A: There is still a large proportion of people in the United States who have not been vaccinated, and there are many in other countries. The situation in each country is different, and it is necessary to consider the specific situation.

Q: If you adjust the plan, will both high-risk and medium-risk be included? A: The program is adjusted for high-risk groups, and the whole population will not be considered after the high-risk population is considered. #投资 #