Image source @ Visual China
Text | Amino Finance
The most fascinating thing about research and development is that you can never draw conclusions about a drug until the last minute.
Pioneering the pharmaceutical industry's new crown oral drug pukrutamine is typical.
Early last year, in a Phase III clinical trial in Brazil, pkrutamine reduced the risk of death in severe COVID-19 patients by 92 percent, and was once seen as "the people's hope."
However, the good times were not long, on December 27, 2021, Pioneering Pharmaceutical announced that the phase III clinical interim trial did not reach statistical significance, and the next day, the opening stock price of Pioneering Pharmaceutical flashed 85% within one minute, reaching a minimum of 6.91 Hong Kong dollars per share.
More than three months later, on April 6, things reversed again, and pioneering pharmaceuticals released key data for the clinical phase III trial.
In particular, the protection rate of pkrutamine reached 100% in patients who took the drug for more than seven days and in middle- and high-age COVID-19 patients with high-risk factors.
The figure of 100% greatly stimulates the sensitive nerves of investors, and the capital market is also excited. At the opening of the market on April 6, the stock price of Pioneering Pharmaceutical rose by more than 200% at one point, and as of the close, Pioneering Pharmaceutical reported closing at HK$28.85 per share, a surge of 106.37%.
At the same time, however, there is still some controversy surrounding its clinical data, such as the lack of clarity about whether the primary endpoint results are statistically significant, the clinical sample size, and the long preset dosing time. Everything needs to be validated by more clinical data.
In the second half of the new crown, oral medicine is becoming the protagonist, and domestic pharmaceutical companies, including pioneering pharmaceuticals, are also running at full speed. Undoubtedly, in the future, domestic pharmaceutical companies and domestic new crown oral drugs will bring fundamental changes to the treatment of new crown. Of course, in the end, who can stand out depends on strength.
01 Pkrutamine that flips against the wind
If the new crown oral medicine is a race, then pkrutamine is definitely the most concerned player.
Proclamide has been slowly moving forward in controversy.
As early as March 12, 2021, pkrutamine published the results of a Phase 3 clinical trial in Brazil for the treatment of severe COVID-19 patients, which can reduce the risk of death in severe COVID-19 patients by 92% and shorten the average length of hospital stay by 9 days.
This result has led many people to shout "good and unbelievable". However, because the data is too eye-catching, and pkrutamine is only an androgen receptor antagonist, the efficacy of treating the new crown is questionable, so the market has more doubts about Pkrutamine.
In the face of doubts, pkrutamine is still opening phase III clinical trials in the United States to try to prove itself. Unfortunately, Pkrutamine did not make the last laugh.
On December 27, 2021, Pioneering Pharmaceuticals issued an announcement that pkrutamine did not reach statistical significance due to the small number of events. The next day, the company's stock price fell sharply, and the opening minute flashed 85%.
In general, the story of the drug in this situation ends here. The phase III clinical mid-term trial is the mid-term examination of the drug, and the mid-term test results are too bad, and the pharmaceutical company usually chooses to stop or abandon the clinical trial.
Even if the pharmaceutical companies do not give up, the final result will not be too good. Typically like Merck's oral drug molnupiravir, it showed a 50% protection rate in the medium-term clinical trial, but only 30% after the final clinical results were released.
Obviously, pkrutamide is an exception. Just when people had almost given up hope of treating COVID-19 with puclutamide, the reversal came again.
On April 6, Pioneering Pharmaceuticals announced that the key data results of the phase III clinical trial of puclutamide for non-hospitalized COVID-19 patients with mild and moderate diseases can provide 50%, 71% and 100% protection rates for subjects who have been taking the drug for 1 day, more than 1 day and more than 7 days, respectively.
From clinical failure to 100% effective, why is Pkrumiramine headwinds flipping?
02 At present, it is only the success of the subgroup
Strictly speaking, pkrutamine cannot yet be said to have succeeded. This turnaround, in the final analysis, is still a victory for subgroup analysis.
The so-called subgroup analysis is that in addition to the statistical analysis of all the research objects, some of the research objects (subgroups) will also be analyzed.
Specifically, subgroup analyses include two categories:
One is definitive subgroup analysis that has a clear plan at the beginning of a clinical trial; the other is exploratory subgroup analysis after the clinical trial is completed.
In general, the results of the confirmatory subgroup analysis are more reliable than those of the exploratory subgroup analysis. The subgroup analysis of pkrutamine falls into the latter category.
Overall, the primary endpoint of the phase III clinical endpoint of pkrutamine was the proportion of no hospitalizations or deaths occurred within 28 days.
That is, the primary endpoint was to include all subjects, and only the set of data (N=730) who took the drug randomly for at least 1 day represented the primary endpoint.
Unfortunately, the protection rate of this group is only 50%, and the P-value is not published, which may mean that pkrutamine does not reach a statistically significant gap in the eyes of many people.
P-values are often used to measure statistical significance to rule out whether differences in efficacy between study and control groups are due to efficacy of control measures or to sampling errors.
The larger the p-value, the greater the probability of being caused by the sampling error, and conversely the smaller the P-value, the smaller the probability of causing the error. A P-value of 0.05 is generally considered an acceptable wrong boundary level.
Looking back at the performance of pkrutamine, the P< 0.02 in the subgroup that took the drug for more than 7 days did not exceed 0.05, so it can be said that this subgroup is statistically significant. However, although this P-value is statistically significant, it is > P-value of Pfizer Paxlovid
According to this result, without subgroup analysis, pkrutamine is likely to fail again.
Fortunately, it is not too late to make amends. After the end of the clinic, the results of the clinical trial of pkrutamine were divided into three groups, that is, the three groups we are currently seeing.
In this way, at least one of these groups can achieve a 100% protection rate and achieve statistical significance. With the success of the subgroup, pkrutamine may be able to be successfully approved.
But it's hard to say whether the FDA will pay for it. After all, if this is the case, it only proves that pkrutamine can only be effective in certain cases for a certain type of patient, not all patients.
03 "Variables" on a small clinical scale
In addition, it is also important to note that the enrollment scale of the phase III clinical trial of Pkrutamide is relatively small.
Specifically, the three treatment groups announced by pkrutamine: subjects who completed taking the drug for at least 1 day (N=730), more than 1 day (N=721), and more than 7 days (N=693), were all about 700.
Divided into experimental group and control group, there were only more than 300 people respectively. As a result, the number of cases was relatively small, with 8 cases vs 4, 7 VS 2 and 6 vs0 (P<0.02) in the control group and pkrutamide group, respectively, and the final conclusion was that the corresponding protection rates were 50%, 71% and 100%, respectively.
Laterally compared with Pfizer's Paxlovid, a clinical trial of Paxlovid for high-risk non-hospitalized adults with Covid-19, a total of 2246 patients were randomized.
In patients receiving Paxlovid, within 3 days of the onset of symptoms, Paxlovid reduced the risk of HOSPITALization or death associated with COVID-19 by 89% compared with placebo;
By day 28, 0.7% (5/697) of patients in the Paxlovid group were hospitalized, compared with 6.5% (44/682) of patients in the placebo group. Of these, no one died in the Paxlovid group and 9 people died in the placebo group. The P > of this experiment
It is not difficult to see that compared with the two, the patient size of Pkrutamine is small, only 1/3 of the number of Pfizer clinical trials. Still, there is no denying that some subgroups of pkrutamine are still statistically significant, but there appear to be larger "variables" than Pfizer's clinical trials.
In addition, the new crown patients recruited by prumlamide in the United States did not exclude patients who had been vaccinated against the new crown, nor did they exclude patients without risk factors. The patients enrolled in the oral covid-19 drugs of Merck and Pfizer excluded patients who had previously received the new crown vaccine, because the new crown vaccination rate in the United States was higher, the mRNA vaccine improved the high critical illness protection rate for the population, and the hospitalization rate of patients was reduced.
Specifically, in July 2021, when about half of the people in the United States received their first dose of the COVID-19 vaccine, even though the increase in the Delta mutation strain increased new cases by 19%, hospitalization rates and mortality rates fell by 6% and 29%, respectively.
After the mid-term clinical failure, Pioneering Pharmaceuticals has talked about revising the clinical trial protocol in coordination with the FDA and plans to continue to recruit subjects with only underlying disease/no COVID-19 vaccination.
However, in the complete phase III clinical trial, the pioneering pharmaceutical disclosed that the enrolled patients still did not exclude patients who had been vaccinated against COVID-19 and those with no risk factors.
However, since pkrutamine does not disclose baseline status in enrolled patients, it remains uncertain whether the increase in protection rates is due to enrollment of high-risk patients.
Therefore, in the absence of a clear risk population, the quality of its clinical data is also debatable.
04 Why is the treatment time so long?
In addition to the protection rate, another important indicator of ORAL COVID-19 is viral load. The so-called viral load, simply put, is to show the number of viruses in each milliliter of blood by measurement.
The load of the new crown virus affects its ability to spread and affects the effectiveness of testing. In general, the higher the viral load, the easier it is to spread the virus.
Delta, for example, produces more viruses in the human body, with a viral load more than 1,000 times that of the original strain of infection.
And here in Aumechon, the viral load has increased to 8 to 16 times that of Delta. The higher viral load makes it easier to spread, which is also an important reason why the Aumechjong mutant strain has been able to spread rapidly and break through the mainland's epidemic prevention front.
Therefore, reducing viral load is regarded as an important indicator of COVID-19 drugs.
In terms of viral load reduction, the pkrutamide treatment group significantly and consistently reduced the viral load from day 3 to day 28 (days 3 and 28, p<0.01) relative to the control group.
Looking at Pfizer's Paxlovid, taking Paxlovid within 5 days of illness compared to placebo reduced viral load by about 10 times.
However, because pkrutamine does not specify the extent to which the viral load is reduced, it is not possible to judge how well pkrutamine reduces viral load.
However, in terms of medication time, pkrutamine has a longer medication time than Pfizer.
According to a clinical trial on Nature Medicine, patients had the highest viral load after 5-6 days, followed by a gradual decrease in viral load, with a small percentage of patients testing positive after 28 days.
In other words, even if the drug is not used, the body's new crown virus load will gradually decrease within 28 days.
Therefore, the evaluation of pkrutamine for a treatment period of 28 days has led many people to question whether the decline in viral load is the credit for pkrutamine.
Although some of the data released by pkrutamine is optimistic, we need more data to support the overall performance of pkrutamine.
05 Who can become the first domestic COVID-19 oral drug?
Pkrutamine, which has completed the global international multi-center clinical trial, may be followed by breaking through the FDA and communicating with domestic regulators to discuss approval for listing.
Regardless of the outcome, whether pkrutamine can grab the crown of the first domestic new crown oral drug, its efforts are undeniable.
A true warrior who dares to face a bleak life and face the dripping blood. The same is true for drug research and development, and truly innovative pharmaceutical companies should have the courage to go to the global market to accept global standards.
Although pkrutamine has been questioned since it was used in the new crown, in the face of doubt, pkrutamine has also been proving itself through clinical trials around the world. This point is worth learning from all domestic pharmaceutical companies.
Back to the competition for COVID-19 oral medicines. With the arrival of Aomi Kerong, the domestic epidemic prevention and control is also encountering tremendous pressure. Relying only on the new crown vaccine has been unable to resist the increasingly arrogant virus, and the only approved new crown oral drug in China is Pfizer's Paxlovid, priced at 2300 yuan / box.
As an important part of the epidemic prevention puzzle, Paxlovid has been included in medicare, but from a practical point of view, the large-scale supply of the drug is obviously a problem, and the high price of Paxlovid is not a small test for the payer. In this case, we urgently need our own oral COVID-19 drug.
In addition to pkrutamine, there are also many new crown oral drugs in China that have entered the clinical stage. The fastest progress is the oral nucleoside anti-SARS-CoV-2 drug VV116, developed by Junshi Bio in cooperation with Wangshan Wangshui, and azfedine of real organisms.
Among them, VV116 has been approved in Uzbekistan at the end of 2021 for the treatment of patients with moderate to severe COVID-19; in the country it is in the phase III clinical stage.
The real-life Azfudine is the first dual-target anti-HIV-1 drug and is being tested in Phase III in China, Brazil and Russia. The Company expects to complete a Phase III trial in Brazil for patients with moderate to severe COVID-19 in April 2022 and a trial in mild cases in July 2022.
Not surprisingly, the first domestic new crown oral drug will appear in VV116, azifdine, and pkrutamine. Who will be the first to go ashore, we will wait and see.