In recent days, the news of Roche's clinical trial failure has become a hot topic in the pharmaceutical industry. On May 10 local time, Genentech, a subsidiary of Roche, released the interim results of the phase III clinical trial "skyscraper-01" - the evaluation found that the trial of tiragolumab plus tecentriq (atilizumab, also known as "t drug") for the treatment of non-small cell lung cancer did not reach the common primary endpoint of progression free survival (PFS).
Another common primary endpoint overall survival (OS) analysis is still immature, and the next stage needs to be completed before the analysis can be completed.
This also means that the trial of tigit immunotherapy combined with PD-L1 first-line treatment for non-small cell therapy has failed in stages.
From: Genentech official website
Just two months ago, the phase III trial of the treatment for extensive small cell lung cancer just failed - the phase III trial failed to reach the common primary endpoint of PFS; In the interim analysis, the common primary endpoint of OS was not reached, and the company believes that the final analysis result is unlikely to reach statistical significance.
In the past few decades, Genentech has been the goal of many new drug start-ups. It has not only created the myth of wealth, but also created an era of biotechnology; Roche has spent more than 10 billion US dollars on R & D every year, ranking first in the world for three consecutive years. Their strong combination is almost the "ceiling" of global new drug research and development, and the previous experimental performance of new therapies can be called amazing.
This result surprised many people. Roche's share price fell 7.87% on the same day.
"Now the probability of clinical phase III failure is about 40% Dr. Zheng Weiyi, chairman of Nanjing yingnuo Pharmaceutical Technology Co., Ltd., told Hu olfactory that the probability of failure in the field of cancer is still higher, reaching more than 52%.
In other words, in the research and development of innovative drugs, it is not common for a new drug to "fail" at the last minute after undergoing various preclinical studies and clinical phase I, II and III Safety and efficacy trials, but it is not surprising.
However, it is worth noting that the phase III clinical failure rate tends to increase** A study by BMT under informa database and bio, one of the largest biotechnology industry organizations in the world, shows that the overall failure rate of phase III clinical trials was only about 33% from 2004 to 2014. Among them, in 2013, the phase III clinical failure rate of non-tumor drugs was 29%, and that of tumor drugs was 48%.
According to the data released by various companies, there are indeed more and more cases of "rollover" in phase III in recent years, including multinational giants. It can be seen that since 2022 alone, in addition to Roche's two consecutive failures, many multinational giants such as Novartis and Pfizer have also stumbled.
What is the secret behind it? What changes have taken place in the field of innovative drugs?
Unexpected failure
According to the public information on Genentech's official website, skyscraper-01 is a global phase III, randomized, double-blind study involving 534 patients with first-line PD-L1 overexpression, locally advanced, unresectable or metastatic non-small cell lung cancer.
Participants were divided into two groups and randomly received tiragolumab + tecentriq or placebo + tecentriq in a ratio of 1:1. According to the trial design, both groups of patients will continue to receive treatment until the disease progresses, the clinical benefits are lost or unacceptable toxicity occurs. The common primary end points were overall survival and progression free survival.
According to the registration information on the global clinical trial registration website, the trial is expected to be completed on August 25, 2022, with a maximum time of 59 months. According to the public information of enterprises, the research will continue, and the final results will be announced at the upcoming medical conference.
The good news is that the treatment observed numerical improvements in both common primary endpoints. The data showed that the patients had good tolerance to the new therapy, and the addition of tiragolumab on the basis of T drug did not find a new safety signal. In other words, the safety of this therapy is good.
Tiragolumab and tecentriq are important products of tumor immunotherapy.
Among them, tecentriq is a popular PD-L1 inhibitor, also known as drug T. it is a checkpoint inhibitor. The indication for lung cancer treatment alone has been approved.
Tiragolumab is a rising star, which can selectively combine with tigit targets. It is a new inhibitory immune checkpoint inhibitor. Previously, FDA has granted it a breakthrough treatment designation according to the phase II trial data for the initial treatment of PD-L1 highly metastatic non-small cell lung cancer.
The action principle of immune checkpoint inhibitor is simply to "kick away" immunosuppression and restore immune response
The most successful model of this kind of drugs is PD-1 / PD-L1. Among them, keytruda (also known as "K drug") of MSD had global sales of more than US $17.1 billion in 2021 and US $4.809 billion in the first quarter of 2022, surpassing xiumeile, the "king of medicine" Tigit is regarded by the industry as one of the most potential tracks after PD-1 / PD-L1
The combination of two checkpoint inhibitors is to "siege" from different targets to form double blocking, so as to achieve the effect of "1 + 1 > 2".
In the initial mouse colon cancer experiment, tigit alone can inhibit tumor growth; PD-L1 alone can make the tumor subside but relapse; Combined with the two, the tumor disappeared completely.
By December 2021, Roche's phase II clinical trial results were even more amazing: compared with PD-L1 monotherapy, this treatment reduced the risk of death by 71% and extended the median progression free survival (MPFs) from 4.1 months to 16.6 months* In the phase II data first released by Roche at the 2020 ASCO annual meeting, among people with high expression of PD-L1, the risk of disease deterioration or death was reduced by 67% .
This series of research results are exciting. This therapy is also known as the "King fried" combination for the treatment of non-small cell lung cancer, and has been highly expected. From the global clinical trial registration website, Roche has registered 12 combined trials.
In addition, BMS (Bristol Myers Squibb), MSD, Gilead, domestic Baiji Shenzhou, Xinda biology, kangfang biology and other pharmaceutical enterprises are following up on PD-1 / PD-L1, and many of them have reached the phase III clinical trial stage, and the progress is very tight.
In this sense, as a "leader", I'm afraid it will soon be known whether the failure of this clinical trial is the "dark lamp" of the industry or the unexpected joy of the latecomers.
Phase III tests failed frequently
It can be seen from the public information that since 2021, many giants have been on the verge of success and have been planted in phase III clinical trials.
Just before the phase III clinical failure of Roche's new therapy for extensive small cell lung cancer, on March 14, in the phase III clinical trial of IL-2 receptor agonist nktr-214 jointly developed by BMS and nektar combined with opdivo (odivo, also known as "drug o", which is also PD-1 monoclonal antibody) in the treatment of unresectable or metastatic melanoma, PFS (progression free survival) and orr (overall remission rate) did not reach the end point, and there was no statistical difference in OS (overall survival).
Nektar's share price plummeted by 60% after BMS spent $3.6 billion to buy part of nktr-214.
Pfizer failed to reach the key endpoint of phase I vaccine for Clostridium difficile infection in March! Pfizer had optimistically estimated that the peak sales of the drug could reach $300 million after it went on the market.
Earlier, the phase III trial of pevonedistat combined with azacitidine in the initial treatment of rare bone marrow cancer and the phase III trial of timrepigene emparvovec gene therapy for rare hereditary eye disease without choroidal blood indication of Takeda pharmaceutical failed.
Similar stories have also been performed in the studies of AstraZeneca's diabetes drugs, Roche Genentech rheumatoid arthritis drugs combined with redcivir in the treatment of COVID-19, Roche MDM2 inhibitors in the treatment of acute myeloid leukemia, and Novartis' canakinumab combined with chemotherapy drugs in the treatment of non-small cell lung cancer.
At the beginning of last year, China's Kanghong pharmaceutical industry also stopped the global multicenter phase III clinical trial of CommScope ophthalmic injection because the mid-term review did not reach the expected goal.
Such intensive failures were rare before. The most direct reason is "being too hasty".
"They are all rushing for time." Zheng Weiyi also told Hu sniff
In fact, after Roche Genentech released the phase II clinical trial of tiragolumab + tecentriq combination therapy, some investors have been worried about the reliability of the results of the phase II clinical trial, including whether the sample size is too small, whether the grouping is reasonable, and whether the phase III clinical trial is carried out too hastily under the fierce competition.
In this regard, many people who have been engaged in the research and development of innovative drugs for a long time also tend to believe that if the preliminary basic research is not sufficient, the phase III clinical trials are indeed easy to fail, especially in the increasingly popular "combination drugs". The interaction of multiple drugs in the human body is more complex. If the preliminary basic research is not solid enough, a variety of problems will appear.
"Phase II clinical trials should be done very solidly before phase III can be started." Zheng Weiyi emphasized to Hu olfactory.
Behind this phenomenon, the global pharmaceutical market is in a new situation.
What's the hurry
"Now it's too difficult to develop new drugs, especially antibody drugs." A person in the industry confirmed to Hu olfactory that new targets are becoming more and more difficult to find, and drug R & D with known targets often has a large number of layout and fierce competition. All these have brought great pressure to clinical trials.
The reality faced by the giants is that, on the one hand, the growth of mature varieties is weak, on the other hand, the competition for new drug research and development is intensifying
Take Roche as an example. According to the annual report of 2021, the sales of the "troika" - rituximab, bevacizumab and trastuzumab, which used to drive the rapid growth of Roche's performance, decreased by 35% compared with 2020 under the impact of generic drugs.
New drugs are still difficult to offset the impact of these "hot money" market weakness, and its tumor business revenue fell by 11% as a whole. Although the sales of T drugs have increased by more than 20%, as PD-1 / PD-L1 are in the most crowded track, the competitive pressure is also self-evident.
Even Pfizer, the "Cosmos pharmaceutical company", experienced sluggish growth after the sharp contraction of mature drug markets such as Lipitor and loxoxi. In the financial report of 2021, excluding the income of Xinguan vaccine and small molecule drugs, the remaining business only increased by 2%.
Under the enemy, the giants urgently need to find a new "cash cow"**
However, new drug research and development has its objective laws that cannot be violated. Being too anxious is often counterproductive.
"Experimental design is critical." The aforementioned insiders told Hu olfactory that effective people can be found through reasonable experimental design, so that such people can receive effective treatment, while unreasonable design and blind expansion of the population may dilute the effective population, and then fail to reach the main end point, resulting in failure.
In addition, the standards of drug review and approval in various countries are also improving. "It's still because the competition is too fierce."
This can also be seen from the actions of pharmaceutical enterprises.
In October last year, agenus announced that it had withdrawn the listing application of balstilimab (a PD-1 monoclonal antibody) for the treatment of recurrent or metastatic cervical cancer with disease progression after chemotherapy, which is related to the improvement of FDA standards. In addition, according to incomplete industry statistics, due to the improvement of standards, at least six new indications of PD-1 / PD-L1 drugs withdrew from FDA rapid approval from 2021 to 2022.
Such a fierce competitive situation also poses a challenge to the traditional new drug R & D model
Not long ago, gene sequencing giant Illumina announced its entry into the field of AI pharmacy. In addition to its own development bottleneck, it is also a pain point in the pharmaceutical field. The traditional model uses experimental trial and error to explore the crystal form and find the dominant crystal form. It has long cycle, high cost and accuracy. The risk of failure remains high and no longer meets the new market demand.
Emerging artificial intelligence (AI) and digital technology can assist drug design, realize high-throughput screening, analyze the relationship between compounds and drug activity, and simulate the interaction between targets and drugs. They have the advantages of improving efficiency and reducing cost, and have been paid more and more attention by capital and pharmaceutical enterprises.
However, in fact, these new technologies are still in their infancy and are far from becoming the "life-saving straw" of pharmaceutical enterprises.
Some industry insiders pointed out that these technologies can only play an auxiliary role, and even make mistakes. The completion of the task is still inseparable from human cooperation and supervision. The targets and compounds found need to be further verified. Moreover, due to the particularity of medical treatment, data acquisition is still a difficult problem.
Perhaps as a health industry fund investor said at a public meeting, since you choose to be an innovative drug, don't be too hasty. It's slow to make medicine. It needs to cross many hurdles**
"These results are not what we want to see in the first analysis." In the announcement of the interim analysis results of "skyscraper-01", Dr. Levi Garraway, Roche's chief medical officer and head, said, "we still believe that tigit may play a role in cancer treatment."
The global competition around PD-1 / PD-L1 and tigit is far from over. The competition in the field of innovative drug research and development has just begun.