Why are domestic new crown oral drugs not approved?

Written by | Wang Chen

The source | Deep Blue View

As the epidemic continues to educate the domestic masses, every clinical trend of the new crown oral medicine involves the nerves of the entire industry, especially the secondary market.

On the evening of March 24, a securities company organized a clinical progress meeting on real biological new crown oral drugs, which directly set off a wave of Azvedine industrial chain on the next day. As if the drug is still in the laboratory, the profits of the relevant companies have all been obtained. In an outlet track, the crazy catch-up in the secondary market is so pure and certain.

In the investment community, many shareholders talk about the different virus suppression paths of 3CL and RdRp like talking about daily vocabulary; in various WeChat groups, some members have carefully dismantled the complex chemical synthesis path of new crown oral drugs; on various interactive platforms, analysts have calculated the profit contribution of each drug to upstream and downstream related companies... This secondary market frenzy stems from the fact that the approval of China's new crown oral drugs is increasingly put on the agenda of relevant departments.

As early as February 12, 2022, when there were only 101 new infections in China, and most of them were imported from abroad, the State Food and Drug Administration approved Pfizer's new coronavirus oral drug Paxlovid. At that time, people in the pharmaceutical industry were very surprised: there were so few infected people, who was it used for? Is it to open the door of the country? No one would have thought that a month and a half later, it would come in handy.

The fastest-spreading strain of the new crown, Olmikron, spread in China on a large scale in February and March 2022, breaking the calm situation in China that has lasted for months and only added a few dozen new confirmed cases per day.

In March, nearly 80,000 people were infected in China, and Jilin and Shanghai broke the defense.

When Omiqueron broke through the world where the vaccine barrier had been established, everyone realized that the new crown virus is not set in stone. In the face of the ever-changing new crown strains, there is no perfect vaccine that can stop the breakthrough infection of the virus, and the new crown treatment drugs that were originally considered dispensable will be hot at once, and perhaps in the future.

The most important weapon to prevent and control the new crown has become the new crown oral medicine.

At a price of 2300 yuan a box, Paxlovid began to be put into use in Jilin, Zhejiang, Guangdong and other places. 2300 yuan is already lower than the 530 US dollars in the United States, but in the context of domestic medical insurance "basic insurance", it is obviously not suitable, especially once there is a huge number of new crown patients brought about by large-scale infection. In this context, the importance of China's own ORAL COVID-19 drugs is also becoming increasingly prominent.

In fact, the domestic new crown treatment drugs are not too late to start - there are already 17 small molecule new crown drugs in emergency research and development, of which the oral drugs of Junshi Biology, Pioneering Pharmaceutical and Real Biology have entered the clinical phase III trial. However, most of the products currently under research have encountered a bottleneck, that is, the problem of clinical endpoints.

A number of enterprises and industry insiders involved in the research and development of new crown oral drugs said that the approval standards of the State Food and Drug Administration for the third phase of the new crown oral drug are still based on symptom improvement as the "clinical endpoint", especially "reducing the mortality rate of low-weight/critically ill patients", and when the virus strain changes, the infection of Aomi Kerong makes the infected population mostly asymptomatic and mild, and the proportion of severe patients and hospitalizations is very small - making the current clinical trials in China extremely difficult.

At one point, experts called for the indicator of "viral load reduction" as the main clinical endpoint, but this indicator is too simple, and sometimes the link between viral load and symptom reduction is not so absolute.

Wu Zunyou, a prevention and control expert, explicitly rejected this approach in a recent speech: "Viral load is not the main indicator of phase III clinical trials, and the choice of phase III clinical trial indicators should still depend on the observation of the severity of the disease." Cases are available at home and abroad, and it is necessary to contact and cooperate with hospitals and doctors. Clinical difficulties should not be a reason for the FDA to lower the evaluation standards. ”

How to find a balance between "reducing viral load" and "reducing symptoms" in the review of new crown treatment drugs, according to the characteristics of the latest strain, Semikron, the "keeping pace with the times" of drug review ideas, may be the key to the next step of China's new crown oral drug birth.

Where to find "inpatients"?

"Pfizer and Merck's COVID-19 oral medications are a good time." A scientist who is working with Pfizer overseas at about the same time as Pfizer on the development of COVID-19 therapeutic drugs said.

The NEW CROWN oral drugs approved by Pfizer and Merck at the end of last year were all conducted in Phase I clinical trials in March and April 2020, and phase III trials were carried out before and after July 2021.

For pharmaceutical people, this "good time" means that the new crown infected population is not affected by vaccines, virus mutations and other factors. In the process of clinical trials, whether it is selected from the population or the choice of clinical endpoints, it will be more "clear, brief, and easy".

Fortunately for Pfizer and Merck, when they conducted clinical trials of oral COVID-19 drugs, the COVID-19 vaccine had not been mass-vaccinated in the United States, and until July 2021, the two-dose vaccination rate in the United States was just over 30%.

At that time, the new crown virus had not yet produced a variant like the Oneon, and the original virus of the new crown and the Delta variant that began to conquer the United States in June 2021 caused higher hospitalization and severe illness rates in specific populations in the United States. Therefore, the FDA's approval of drugs for the treatment of new crown is also very strict with "efficacy" as the main endpoint in phase III clinical trials.

Specific to "efficacy," Pfizer's clinical measurement goals include the number of days inpatients stay in hospitals and intensive care units, and the proportion of patients who have died. The indicator of whether the "viral load" has decreased, although it is also included, is not an important indicator.

This means that when the new crown virus has not yet mutated into Omi kerong, the US FDA's evaluation criteria for new crown treatment drugs, and ultimately through the data of concern, still need to reduce the mortality rate of new crown patients and reduce the treatment time of hospitalized patients - this has a premise, there is a need for enough hospitalized patients.

But after July 2021, when about half of the people in the U.S. received their first dose of covid-19, the change came. In early July last year, even though an increase in the Delta mutation strain in the United States increased new cases by 19 percent, hospitalization rates and death rates fell by 6 percent and 29 percent, respectively.

This shows that the vaccination of mRNA vaccine has an amazing effect on reducing the infection rate and severe illness and mortality rate of the population, but it is "not too much like a vaccine", but partly assumes the role of new crown treatment drugs. "It doesn't block the infection 100 percent, but it reduces the symptoms of COVID-19 in vaccinated people." One scientist confessed.

The "intervention" of the new crown vaccine has once entered an optional embarrassment for the treatment of the new crown.

If the review criteria for reducing the number of days in hospitalizations and reducing deaths are followed, there will not be enough inpatients to recruit in countries with high vaccination rates after July 2021, especially the United States.

Pioneering Pharmaceuticals once fell into this embarrassment of "the timing is not right". Its new crown treatment drug pryukamide, after the brazilian research trial has obtained almost as good clinical trial data as Merck and Pfizer, but it has not progressed smoothly in the United States.

Proucamide was launched in a phase III clinical trial in the United States last March, when the first dose of vaccination in the United States had just begun. Unlike Pfizer, which began Phase III later, only chose not to be vaccinated, and had enough critically ill people to enroll, its clinical trial scope chose "the whole population".

At one point, the FDA asked whether it would exclude vaccinated people, and the pioneering team thought about it and refused. "We believe that the whole population is more reflective of the real-world demand for drug treatment in the future." A professional who was involved in the clinical trial at the time said.

The "whole population" trial design did not set restrictions on underlying diseases and unvaccinated, which greatly increased the difficulty of making significant differences between the treatment group and the control group. At the end of December, Pioneering Pharmaceuticals announced that the interim results of the third phase of the clinical phase of prukamide for non-hospitalized COVID-19 patients with mild and moderate diseases were not statistically significant.

Today, the Phase III clinical trial of proctamide in the United States has been completed, and the final results will be announced in April. "Judging from the available data, the results should be optimistic." A person who understands the progress revealed.

Because of the different epidemic prevention policies at home and abroad, Pfizer and Merck New Crown Oral Drugs can smoothly complete the phase III clinical, but the domestic related product research and development pharmaceutical companies, the clinical basic need to be pulled overseas to carry out, the cost of communication alone, it takes a lot of energy of local enterprises.

But in any case, Pfizer and Merck caught up with the window of increase in hospitalizations caused by the Delta variant without vaccines and vaccines, and finally made a new coronavirus treatment drug that passed the FDA review.

In addition, the size and strength of a large company like Pfizer has also contributed to its daring to complete experiments within the "window period". Pfizer has opened four or five hundred centers around the world, and one or two people can complete the trial at a center. At this point, it far surpasses the small companies that are conducting clinical trials at the same time as it.

"Dystocia" Chinese new crown oral medicine

All along, the NMPA's review of covid-19 drugs and the early US FDA review ideas have been consistent, with "symptom improvement" as the clinical endpoint. This almost makes the clinical trial of new crown drugs a fill-in-the-blank problem.

According to the "Clinical Guidelines for COVID-19 Drugs" released by the CDE on February 17, 2022, the design of the "effectiveness endpoint" is still based on the endpoint of symptom improvement, including "proportion of hospitalized or dead patients" and "recovery time". If the clinical endpoint is not done according to the indicator of "symptom improvement", it will basically not be approved for phase III clinical.

In China, the treatment drugs for COVID-19 that have entered the phase III clinical trial include pkrutamine (the first case of china's first enrollment in phase III was completed on February 10), VV116 of Junshi Bio (the first case of administration was completed in phase III on March 16), and Azfudine, which is recently considered to be the earliest real organism that may be approved.

Among them, Junshi Bio's VV116 is the main measurement target of the phase III clinical trial for patients with moderately severe covid-19, which is based on the efficacy of "the rate and mortality rate of progression to severe disease". And "viral load drop" is just one of several secondary measurement targets.

Many experts believe that if the number of patients with mild and moderate illness and more than 600 cases of moderate and severe patients is enrolled according to Junshi's claim of 1800-2000 cases, this is "difficult to achieve". Even in Jilin, where the epidemic is more severe, the number of hospitalizations is far from reaching this number (600).

The design of the phase III clinical endpoint of the pioneering pharmaceutical industry is also based on "symptom improvement". Therefore, they face the same dilemma: most of the patients infected with the Omiljun strain are mainly asymptomatic infections and mild diseases, and very few hospitalized patients, which directly increases the difficulty of clinical design with "number of days in hospital and mortality" as the main indicators.

An expert involved in the research and development of new crown oral drugs mentioned that he had communicated with relevant people from the State Food and Drug Administration and hoped to change the review idea according to the changes in the new crown strain. However, the other party expressed embarrassment: the review idea is formulated according to the "Clinical Guidelines for New Coronavirus Drugs" and cannot be changed arbitrarily.

But things seem to have taken a turn for the better.

Since late March, news of Azvdine's imminent approval has been coming. Its clinical practice in China (mild illness), Russia (moderately severe illness) and Brazil (moderately severe illness) is about to be blinded in April; some media even said that the Food and Drug Administration will conduct a listing review of it in the near future. This has also led to a sharp rise in the stock prices of some listed companies in Azfding's supply chain.

However, in a recently circulated "recording of the expert meeting of real biological COVID-19 drugs", the clinical endpoint of Azvedine's treatment of mild COVID-19 in China only mentioned "viral load", which caused doubts among experts in related fields.

After all, the Chinese CDE has not relaxed its approval endpoints for COVID-19 oral drugs, and if it is based on the relatively easy-to-measure "reduction of viral load", then there will be a batch of COVID-19 treatment drugs approved. However, relevant experts said: "Azvodine has not yet announced the specific situation of the phase III clinical, in addition to the "viral load", it is likely that there are indicators to improve symptoms. ”

However, since it emphasizes that the phase III clinical trial in China is mainly based on mild disease, how are the symptom improvement indicators set for mild disease? How much clinical room is there in mild patients? Are these clinical increment values worth the FDA's stamp? Industry insiders are waiting for its final results.

Up to now, the only approved treatment for COVID-19 in China is the combination therapy of the new coronavirus monoclonal neutralizing antibody ambavir monoclonal/romizumab (previously known as BRII-196/BRII-198 combination therapy). It was approved for marketing by the China Drug Administration (NMPA) on December 9.

The approval of Tengsheng Bo's new crown treatment drugs in China is accidental in the eyes of some industry insiders.

"Its approval is based on data from a Phase 3 clinical trial of ACTIV-2 supported by the National Institutes of Health (NIH). This is known in China as a 'scientific clinic' rather than a 'registered' clinic. Registered clinical trials are initiated by the company and approved by the drug regulatory authorities, and the evaluation of drugs in China requires a 'registered' clinical trial. ”

Some experts speculated that at that time, Tengsheng Bo Pharmaceutical's drug was approved because there were rumors that "it would pass the FDA's EUA review", which may have accelerated its approval process in China. In October 2021, Tengsheng Bo Pharmaceutical has completed the emergency use authorization application submitted to the FDA for the use of ambalizumab/romizumab combination therapy, but there are still no results.

Evaluation criteria: Is only "viral load" enough?

As the Olmikeron strain becomes the "main force" of the new crown strain, it seems to be becoming more and more difficult for clinical trial results to meet the original review standards for oral covid-19 drugs – this problem is not only happening in China, but also in the United States and Japan, but also encountering the same challenges, but the evaluation ideas of the United States and Japan are also changing.

On February 11, 2022, the US FDA announced the approval of the Eli Lilly COVID-19 neutralizing antibody Bebtelovimab Emergency Use Authorization (EUA), although Bebtelovimab designed a time for "symptom relief" on the criteria of the phase III clinical endpoint, but when it finally passed the review, it was in the case of not reaching a "statistically significant difference", in fact, it should be the FDA lowering the original standard and passing the review.

And Bebtelovimab only did a second phase of approval, the FDA on the basis of the already optional antibodies and small molecule drug therapy, a new approval of a monoclonal antibody therapy, it has to be said that there are some standard "reductions".

Coincidentally, S-217622 of Yoshino, Japan, which was rumored to be "100% eradication of the new coronavirus" in the previous paragraph, actually only published phase 2b clinical results for infected subjects with mild/moderate symptoms. Importantly, the primary endpoint was not met in terms of symptom improvement and there were no statistically different data outcomes. Although it has not yet received official production approvals, it has already signed a supply order in Japan, and industry insiders believe that it will soon be approved.

Although the current domestic covid-19 epidemic is in a state of local outbreak, it is impossible to predict in advance. The clinical layout of pharmaceutical companies needs to have a complete set of design and declaration processes, and in the emergency situation of this "band-type" outbreak in China, there are not too good conditions for new crown drug research and development enterprises to participate in the layout.

Zeng Haoyu, a pharmacologist and drug safety scientist who has worked at GSK and Merck for many years, believes that the indicator of "reducing viral load" is of great significance for the Omiljung strain with high infectivity, low hospitalization rate and severe disease rate.

"Reducing the viral load, an indicator, is important in interrupting community transmission," he said. Many people infected with the Omikejong strain are asymptomatic or mildly infected, and indicators of improved symptoms are of limited significance. However, reducing the viral load to a level that cannot be transmitted is very suitable for China's prevention and control ideas at this stage. ”

However, other experts mentioned that only "virus load reduction" was an indicator that the reviewers felt was too simplistic. "Everyone's individual situation is different, some people have a low viral load but severe symptoms; others have the opposite." Whether the reviewer would like to design indicators for symptom reduction in addition to reducing viral load.

The adjustment of the indicators of phase III clinical "symptom reduction" of new crown oral drugs has become a new challenge with the change of new crown strains.

When COVID-19 is no longer an infectious disease with a high fatality rate, then designing the indicators of "mortality and length of hospital stay" as the main goal of clinical endpoints will mean that it will be extremely difficult to obtain approval; how to select new indicators that can improve symptoms and meet the characteristics of the current new crown strain will become the key to the next step of China's new crown treatment drug approval.

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