The other co-primary endpoint, overall survival (OS) analysis, is immature and will need to complete the next phase to complete the analysis.
This also means that this trial of TIGIT immunotherapy combined with PD-L1 first-line treatment of non-small cell therapy has failed in stages.
From: Genentech official website
And just 2 months ago, the therapy failed a phase 3 trial in extensive-stage small cell lung cancer – the phase 3 trial failed to meet the co-primary endpoint of PFS; in the interim analysis, it did not meet the co-primary endpoint of OS, and The company believes that the final analysis results are also unlikely to reach statistical significance.
In the past few decades, Genentech has been the goal of many new drug start-ups, not only creating a myth of wealth, but also creating an era of biotechnology; Roche’s annual R&D funds have exceeded 10 billion US dollars, and it has been three consecutive years. No. 1 in the world. Their powerful combination is almost the “ceiling” of global new drug research and development, and the previous test performance of the new therapy has also been amazing.
This result surprised many people, and Roche’s stock price fell 7.87% that day.
“The probability of failure in Phase III clinical trials is now around 40%.” Dr. Zheng Weiyi, chairman of Nanjing Yingnuo Pharmaceutical Technology Co., Ltd. told Huxiu that the probability of failure in the tumor field is even higher, reaching more than 52%.
That is to say, in the research and development of innovative drugs, it is not common for a new drug to fail at the last moment after undergoing various preclinical studies and clinical phase I, II and III safety and efficacy trials, but it is not surprising at all. .
but,It is worth noting that there is an increasing trend in the failure rate of Phase III clinical trials.A study by BMT, part of the Informa database, and BIO, one of the world’s largest biotech industry organizations, shows that from 2004 to 2014, the overall failure rate of phase III clinical trials was only about 33%. Among them, in 2013, the phase III clinical failure rate of non-tumor drugs was 29%, and that of tumor drugs was 48%.
Judging from the information released by various companies, there have been more and more cases of “rollovers” in the third phase of the test in recent years, and many of them are multinational giants. It can be seen that since 2022 alone, in addition to Roche’s two consecutive losses, many multinational giants such as Novartis and Pfizer have also fallen.
What’s the hidden secret behind it? How has the field of innovative drugs changed?
“Unexpected” failure
According to public information on Genentech’s official website, Skyscraper-01 is a global phase III, randomized, double-blind study involving 534 patients with locally advanced, unresectable or metastatic non-small cell lung cancer with high PD-L1 expression.
Participants were divided into two groups and randomized 1:1 to receive Tiragolumab + Tecentriq or placebo + Tecentriq. According to the trial design, patients in both groups were treated until disease progression, loss of clinical benefit, or unacceptable toxicity. The co-primary endpoints were overall survival and progression-free survival.
According to the registration information on the Global Clinical Trials Registry website, the trial is expected to be completed on August 25, 2022, with a maximum duration of 59 months. According to the company’s public information, the research will continue, and the final results will be announced at an upcoming medical meeting.
The good news is that the therapy saw numerical improvements in both co-primary endpoints. The data showed that the new therapy was well tolerated by patients, and no new safety signals were identified with the addition of tiragolumab to the T drug. In other words, the safety of this therapy is still good.
Both Tiragolumab and Tecentriq are important products in tumor immunotherapy.
Among them, Tecentriq is a hot PD-L1 inhibitor, also known as T drug. It is a checkpoint inhibitor and has been approved for the indication of lung cancer treatment alone.
Tiragolumab, a rising star that selectively binds to TIGIT targets, is a new inhibitory immune checkpoint inhibitor that the FDA has previously granted breakthrough therapy designation based on phase II trial data for PD-L1 hypermetastatic disease Initial treatment of non-small cell lung cancer.
The principle of action of immune checkpoint inhibitors is simply to “kick off” the immune suppression and restore the immune response.
The most successful example of this type of drug is PD-1/PD-L1. Among them, Merck’s Keytruda (also known as “K drug”) has global sales of more than 17.1 billion US dollars in 2021. In the first quarter of 2022, it is even more 4.809 billion US dollars, more than the “King of Medicine” Humira.TIGIT is regarded by the industry as one of the most potential tracks after PD-1/PD-L1.
Combining two checkpoint inhibitors is to “siege” from different targets to form a double block to achieve the effect of “1+1>2”.
In the original mouse colon cancer experiments, TIGIT alone inhibited tumor growth; PD-L1 alone caused tumor regression but recurrence; combined, the tumor disappeared completely.
By December 2021, the results of the Phase II clinical trial announced by Roche were even more stunning:Compared with PD-L1 monotherapy, this therapy reduced the risk of death by 71%, and the median progression-free survival (mPFS) increased from 4.1 months to 16.6 months.In the Phase II data first announced by Roche at the 2020 ASCO Annual Meeting,67% lower risk of disease progression or death in people with high PD-L1 expression.
The results of this series of studies are encouraging, and this therapy has been hailed as the “king-fried” combination for the treatment of non-small cell lung cancer, and has always been high hopes. From the global clinical trial registration website, there are 12 combined trials of the two registered by the Roche family.
In addition, many domestic pharmaceutical companies such as BMS (Bristol-Myers Squibb), Merck, Gilead, BeiGene, Innovent, and Kangfang are following up on PD-1/PD-L1, and many have already caught up with them. In the phase III clinical trial stage, the progress is very tight.
In this sense, as a “leader”, whether the failure of this clinical trial is a “dark light” for the industry or a surprise for the latecomers, I am afraid we will soon find out.
Phase 3 trials frequently fail
Looking at the public information, it can be seen that since 2021, many giants have failed and have been planted in Phase III clinical trials.
Just before Roche’s new treatment for widespread small cell lung cancer failed Phase III clinical trials, on March 14, the IL-2 receptor agonist NKTR-214 jointly developed by BMS and Nektar combined with Opdivo (Odivo, also known as “O drug”, In the phase III clinical trial of the treatment of unresectable or metastatic melanoma, PFS (progression-free survival) and ORR (overall response rate) did not reach the endpoint, and OS (overall survival) was not statistically learning difference.
Nektar’s stock price plummeted 60% directly, and the $3.6 billion that BMS spent on purchasing part of NKTR-214 was also lost.
In February, a pivotal Phase III trial of Pfizer’s Clostridium difficile vaccine candidate PF-06425090 failed to meet the primary endpoint of preventing infection! Pfizer had optimistically estimated that the drug could reach peak sales of $300 million when it hits the market.
Earlier, the Phase III trial of Takeda’s pevonedistat combined with the chemotherapy drug azacitidine in the initial treatment of rare bone marrow cancer, and the Phase III trial of Biogen’s gene therapy timrepigene emparvovec for the rare hereditary eye disease choroideremia, both failed.
Similar plots have also been used in AstraZeneca’s diabetes drug, Roche’s Genentech rheumatoid arthritis drug combined with Remdesivir in the treatment of new coronary pneumonia, Roche’s MDM2 inhibitor in the treatment of acute myeloid leukemia, and Novartis’ Canakinumab in combination with chemotherapy drugs. staged in studies such as non-small cell lung cancer.
At the beginning of last year, China’s Kanghong Pharmaceutical also stopped the global multi-center Phase III clinical trial of Conbercept ophthalmic injection, because the mid-term review did not reach the expected goal.
Such intensive failures have been rare before. The most direct reason is “too much haste”.
“They’re all rushing for time.” Zheng Weiyi also told Huxiu.
In fact, after Roche Genentech released the Phase II clinical trial of Tiragolumab + Tecentriq combination therapy, some investors were already concerned about the reliability of its Phase II clinical trial results, including whether the sample size was too small, whether the grouping was reasonable, and whether it was under fierce competition Next, whether the Phase III clinical trial was carried out too hastily, etc.
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 basic research in the early stage is insufficient, the phase III clinical trial is indeed very easy to fail, especially in the increasingly popular “combination drug”. Multiple drugs interact in the human body, and the situation is more complicated. If the preliminary basic research is not solid enough, various problems will occur.
“Phase II clinical trials have to be solid before we can start Phase III.”Zheng Weiyi emphasized to Huxiu.
Behind this phenomenon, the global pharmaceutical market is in the midst of new changes.
What’s the hurry?
“It is too difficult to develop new drugs now, especially antibody drugs.” An industry insider confirmed to Huxiu that new targets are becoming more and more difficult to find, and drug development with known targets is often deployed by many people and the competition is fierce. All of these put enormous pressure on clinical trials.
The reality faced by the giants is that, on the one hand, the growth of mature varieties is weak, and on the other hand, the competition for new drug research and development is intensifying.
Take Roche, for example. The 2021 annual report shows that the “troika” that drove the rapid growth of Roche’s performance in the past – Rituxan (rituximab), Avastin (bevacizumab), Herceptin (trastuzumab), Under the impact of generic drugs, sales decreased by 35% compared with 2020.
And new drugs are still difficult to offset the impact of the weak market of these “explosions”, and its oncology business revenue fell by 11% overall. Although the sales of T drugs have increased by more than 20%, as PD-1/PD-L1 is in the most crowded track, the competitive pressure is self-evident.
Even Pfizer, the “big pharmaceutical company in the universe”, has experienced sluggish growth after the market for mature drugs such as Lipitor and Norvox has shrunk sharply. In the 2021 financial report, excluding the income of the new crown vaccine and small molecule drugs, the remaining business will only increase by 2%.
Under the belly and back of the enemy,The giants desperately need to find new “cash cows”.
However, there are objective laws that cannot be violated in the research and development of new drugs, and being too impatient is often counterproductive.
“Trial design is critical.” The aforementioned industry insiders told Huxiu that effective populations can be found through reasonable trial design, so that such populations can be effectively treated, while unreasonable design and blind expansion of the population may dilute the effective population, and then Failure to reach the primary endpoint resulted in failure.
In addition, the standards for drug review and approval in various countries are also improving. “It’s because the competition is too fierce.”
This can also be seen in the actions of pharmaceutical companies.
Just last October, Agenus announced that it had withdrawn the marketing application of balstilimab (a PD-1 monoclonal antibody) for the treatment of recurrent or metastatic cervical cancer with disease progression after chemotherapy. According to incomplete statistics from the industry, at least 6 new indications of PD-1/PD-L1 drugs will be withdrawn from the FDA’s fast-track approval from 2021 to 2022 due to improved standards.
Such fierce competition also poses challenges to the traditional new drug R&D model.
Not long ago, gene sequencing giant Illumina announced its entry into the field of AI pharmaceuticals. 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 crystal forms and discover advantageous crystal forms. The cycle is long, the cost is high, and the accuracy is also a problem. The risk of failure remains high, and it is no longer suitable for new market demands.
Emerging artificial intelligence (AI) and digital technologies can assist drug design, realize high-throughput screening, analyze the relationship between compounds and drug activities, and simulate the interaction between targets and drugs, which has the potential to improve efficiency and reduce costs. Advantages have been increasingly valued by capital and pharmaceutical companies.
However, in fact, these new technologies are still in their infancy, and are far from being a “life-saving straw” for pharmaceutical companies.
Some people in the industry pointed out that these technologies can only be auxiliary, and even make mistakes. The completion of the task is still inseparable from the cooperation and supervision of people. The discovered targets and compounds also need to be further verified, and they are limited by the particularity of medical treatment. , data acquisition is also a problem.
Perhaps as a health industry fund investor said at a public meeting,Now that you have chosen to make innovative drugs, don’t be too hasty. Making medicine is inherently slow and needs to go through many hurdles.
“These results are not what we hoped to see in our first analysis,” said Dr. Levi Garraway, chief medical officer and head of Roche, in an announcement announcing the results of the “Skyscraper-01″ interim analysis. 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.
