"More than 200 percent, it really broke everyone's expectations."
The person who said this was Lin Qian (pseudonym), who was still in isolation. The WeChat chat page in her hand is also stuffed with "pioneering pharmaceuticals".
On April 6, Pioneering Pharmaceutical released the data results of the phase III global multi-center clinical trial of puklamide for non-hospitalized new crown patients with mild and moderate disease, compared with the interim data, the latest version of the data "corresponding protection rate is 100%", which changed the treatment effect of pkrutamine from "late poor students" to "full score". The opening of Hong Kong stocks on the day of the development of the pharmaceutical industry also rose by more than 200% at one point.
As a practitioner in the pharmaceutical industry, Lin Qian was not impressed by the enthusiasm of the investment market, "It is not easy for Chinese pharmaceutical companies to go overseas to do experiments. But 100% of the data is not so much a truth as a myth. Such data is of little value without specific breakout sessions. ”
01
Pkrutamine, crooked
Among the many "new crown special drugs", pkrutamine can be described as "crooked".
Check the official website of the development pharmaceutical industry to know that pkrutamine is an ACE2 and TMPRSS2 androgen antagonist (AR) that controls prostate cancer by inhibiting androgens. Pioneering early clinical trials in the pharmaceutical industry for patients with advanced castration-resistant prostate cancer.
However, in the phase III clinical data released by Pioneering Pharmaceuticals in 2020, the results of pkrutamine on patients with metastatic castration-resistant prostate cancer were not satisfactory. As a me-too drug that is "equivalent to existing drugs, but bypasses patent barriers", the performance of pkrutamine is clearly a failure.
(Pictured is pkrutamide)
Coincidentally, the emergence of the new crown epidemic has found a new outlet for pkrutamine.
In May 2020, a paper in the Journal of the American Society of Dermatology showed that most hospitalized patients with COVID-19 had male hair loss. Clinical data from three hospitals in Madrid also showed that 79% of the 122 male COVID-19 patients showed seborrheic alopecia. A study of 5,700 COVID-19 patients admitted to the hospital in New York, USA, found that men in all adult age groups had a higher mortality rate than women.
A retrospective study from the University of Ticino in Italy also pointed out that if a prostate cancer patient receives treatment with "androgen removal", the chance of contracting the new crown is only a quarter of that of other patients, and the hospitalization and mortality rates will also be significantly reduced.
Androgen expression is significantly related to the new crown epidemic. A paper published in cell by the Leibniz Primate Institute in Germany pointed out that androgens can promote cells to produce TMPRSS2 protease, which allows viruses to integrate into cell membranes and accelerate the spread of viruses.
(Mechanism of action of androgens)
By stopping androgens, you can control the COVID-19 pandemic. Pkrutamine, which happens to be an androgen antagonist.
Pioneering Pharmaceuticals quickly launched a study in Brazil, and out of 600 patients, pkrutamine reduced the mortality rate from 47.6% to 3.7%, and allowed 89% of patients to be discharged. Pioneering Pharmaceuticals also tripled its share price last year to a maximum of HK$85 per share.
Lin Qian pointed out that the experimental data in Brazil is very convincing. "In this clinic, the mortality rate of the control group actually reached 49.4%. Unless COVID-19 patients are left alone, such an exaggerated outcome is unlikely. And similar androgen antagonists do not achieve such an ideal effect. ”
The development of the pharmaceutical industry is speeding up and continuing to apply for larger-scale clinical trials in the United States. However, interim analysis data at the end of last year showed that 348 patients with COVID-19 did not reach statistical significance due to the small number of events. In other words, pkrutamine has not shown significant efficacy, and further trials are needed to develop the pharmaceutical industry.
The share price of pioneering pharmaceuticals also plunged 70.35% after the report was issued.
02
The vague "100%"
Compared with the previous performance, the new data of pioneering the pharmaceutical industry is an earth-shattering reversal.
A total of 733 cases of MILD-to-moderate COVID-19 infections were enrolled in the trial. One group took 200 mg of pkrutamine orally once a day for 14 days. The other group was placebo. It is evaluated in 28 days by measuring blood oxygen saturation, viral load and other indicators.
Data on the "protection rate of 100%" came from the experimental group of "taking the drug for more than 7 days". There were 693 patients in this group and 6 deaths in the control group. 0 people died in the pkrutamine group. In the experimental group of "taking the drug for more than 1 day", 8 people in the control group were hospitalized and 4 people in the pkrutamide group were hospitalized, and the protection rate reached 50%.
However, such glamorous data is more like a "victory" without front-line war reports.
"Only the last data is given, it is the result of the comparison, there is no processing process." Lin Qian said, "The specific number of participants in the elderly, hypertension, diabetes patients has not been announced. If there are many patients in the experimental group, these patients happen to have the disease again, and they will artificially 'set off' the propruamine, which is equivalent to pulling the bias frame. ”
Another issue that Lin Qian is concerned about is the basic situation of patients, "If you want to measure the load of the new crown virus, you need to consider whether the patient has preventive measures and whether there has been antiviral treatment before." The data on pkrutamide are not detailed, so it is unclear why patients recover. Because anyone can be effective, the effect of pkrutamine cannot be evaluated. ”
In addition, the number of clinical patients with pkrutamine is also difficult to support the current clinical scale of phase III of the new crown drug. For comparison, Pfizer's Paxlovid was in phase II/III clinical trials, with 774 patients in the first group and 1219 cases in the second group. Merck's Mmolnupiravir also enrolled 762 patients. If you want to give more convincing data, the development of the pharmaceutical industry requires thousands of patients, and the persuasiveness of 733 patients seems to be insufficient.
Although the clinical results of pkrutamide are debatable, the development of the pharmaceutical industry is ready to expand production. Relevant people in the company said that pukluamine can currently reach a production capacity of 1 million people / month, and reach 50 million copies / year production capacity at the end of the year. Tong Youzhi, CEO of Pioneering Pharmaceuticals, also pointed out in an interview that the synthesis of small molecules of pkrutamine is easier to put in volume and easy to control costs.
As for price and market issues, pkrutamine has not yet been approved due to indications and no accurate pricing has emerged. However, Tong Youzhi said that Kaikai Pharmaceutical is actively promoting the application for emergency drug authorization (EUA) from drug regulatory agencies in China, the United States and other places. Fosun Pharmaceutical also signed a cooperation agreement in July last year to commercialize in India and 28 African countries.
03
The final question of domestic new crown drugs: Who am I?
The surge in the development of the pharmaceutical industry has also made people refocus their attention on the "new crown special drug".
Up to now, 17 small molecule new crown drugs in the mainland have been carried out clinical research, of which Junshi Biology, Real Biology and Pioneering Pharmaceutical have entered the third phase of clinical stage.
Among domestic enterprises, Junshi Biotech's strategy is to "closely follow foreign giants and oralize remdesivir".
VV116 is the product of the transformation of the Shen Jingshan team of the Shanghai Pharmaceutical Institute based on remdesivir. Remdesivir is derived from Gilead, the core molecule is liver targeting, the metabolic process is complex, and the active ingredient in the human body "after the plane and the train", and even "forcibly slow down". Therefore, although remdesivir has antiviral activity, its efficacy is limited.
Therefore, VV116 will transform the active ingredient, through oral administration of the "car" process "one step in place", but also make the active ingredient in the plasma higher concentration, antiviral effect is better. Junshi's announcement in March showed that in three Phase I clinical studies of VV116, oral absorption was rapid and could be taken orally on an empty stomach or under ordinary dietary conditions.
After confirming the "oral, high safety", Junshi has also initiated an international multicenter, randomized, double-blind, controlled Phase III clinical study of VV116 in patients with moderate to severe COVID-19, and has completed the enrollment and administration of the first patient. VV116 is also approved in Uzbekistan for the treatment of patients with moderate to severe COVID-19. In addition, Junshi Bio is also developing VV993 based on 3CL protease, which is also closely following Pfizer's special drug program. In the long run, the goal of Junshi's new crown drug research and development is still "overtaking in curves".
Compared with Junshi Biology, the Azvedine of Real Organisms is more traditional, controlling viral replication from the source.
The drug was developed by the team of Zhengzhou University and is the first dual-target anti-HIV-1 drug in the world. In the treatment of covid-19, it can inhibit viral replication from the source and is drug-active at both the cellular and animal levels. At present, the drug has been tested in China, Brazil and Russia for three phases. A conference call of real biological experts showed that the drug would be blinded around April 10.
The cost of azifedine is better estimated: the drug is treated one week at a dose of 35 mg. Estimated at the cost of APIs, the price is about 50 yuan. Combined with the cost of external production and transportation, the price of the drug may be controlled below 300 yuan, and the price is much lower than Paxlovid's 2300 yuan. Real organisms are also considering actively joining the collection system in the future.
Compared with foreign giants, these three drugs have no problems in the phase III clinical process. However, domestic drugs as a whole are half a year slower than foreign drugs, because they miss the window period of drug trials, resulting in clinical research and development such as the father of the day, always failing to meet the standard.
The research and development of foreign new crown drugs has set a clear goal at the beginning: to reduce symptoms. If the new crown is compared to a fire, the new crown drug is a fire extinguisher, which can be used quickly to control the fire. Where fire extinguishers are needed, the fire risk is high and the fire brigade cannot be put in place quickly. The United States, where Pfizer and Merck conduct clinical trials, meet this requirement.
Both Pfizer and Merck conducted Phase III in July 2021, when the two-dose vaccination rate in the United States was just over 30 percent. If the effect of a COVID-19 drug is defined as "reducing symptoms", the trial can be better conducted and the results can be obtained. The assessment according to the criteria of "reducing mortality" and "reducing hospital stay" can also draw clear conclusions. As long as the new crown drug can avoid the patient's condition from "fire" to "fire", the goal has been achieved.
(The rapid advance of Pfizer and Merck drug trials also matches the Biden administration's strategy.)
China attaches great importance to prevention in the new crown epidemic, and the centralized treatment mode relies more on the system than on the individual: vaccinating is equivalent to a fire sprinkler, spontaneously controlling the fire; centralized epidemic prevention, dividing the area is like "digging a fireproof ditch and organizing a team to extinguish the mountain fire." The treatment model represented by the team has made it difficult for new crown drugs to become the "fire extinguisher" of the epidemic in China.
According to the "Clinical Guidelines for COVID-19 Drugs" issued by CDE in February 2022, the evaluation indicators of COVID-19 drugs in mainland China are still indicators such as "proportion of hospitalized or dead patients" and "recovery time". However, due to strict epidemic prevention measures, the current hospitalized patients of new crown may not be able to meet the scale of hundreds or thousands of patients. Judging from the situation that "the outbreak is fast and there are many diagnoses" in Omi Kerong, a lot of energy of medical personnel is still in the early screening, making it difficult for new crown drugs to obtain results according to clinical guidance.
It's like a fire extinguisher on the market, which requires fire extinguishing testing. However, the fire extinguisher developers found that the fires that can be extinguished are all flames. However, the extinguishing flames could not meet the required test standards, resulting in the delay in completing the approval of the fire extinguisher.
In a way, this means a repositioning of COVID-19 drugs. Its initial position is located in the "clinical" stage between "prevention-clinical-severe disease". But as the coronavirus evolves, the space left for "clinical" seems to be getting smaller and smaller, and vaccines have emerged in the "prevention" phase. Then the new crown drug needs to re-determine a set of evaluation criteria to complete the subsequent approval and promotion. In the "fire" of the new crown epidemic, the special drug may be fireproof clothing, fire hydrants, or even fire axes, but at present, it is certainly not a "fire extinguisher".
For Lin Qian, such a plot is very familiar:
"Like the COVID-19 vaccine track two years ago, it doesn't matter when it's lively, it can only be divided into highs and lows after the limelight."