Economic Observer reporter Zhang Ying

A pharmaceutical company called "Revolution" has developed a drug that may change the fate of pancreatic cancer patients worldwide. Pancreatic cancer, known as the "king of cancer", is extremely difficult to treat, and many celebrities, such as Jobs, Shen Dianxia, Wu Zunyou, have been killed by it.

On April 13, the phase III clinical trial data released by the American pharmaceutical company Revolution Medicine (hereinafter referred to as RevMed) showed that this drug, called daraxonrasib, extended the median total survival period of previously treated patients with metastatic pancreatic cancer from 6.7 months to 13.2 months. The survival period almost doubled, which was unprecedented in the history of pancreatic cancer treatment.

Although the drug has not undergone clinical trials in China, this result has inspired many Chinese doctors. We should know that the median survival period of all patients with pancreatic cancer, including early, middle and late stages, is only more than one year.

This data has also greatly boosted the confidence of investors and companies in the same industry.

On the first trading day after the data was released, RevMed's stock price rose by over 40%, with a current market value of $29.5 billion (approximately RMB 200 billion), which is extremely rare for pharmaceutical companies that have not yet launched new drugs. This market value has surpassed top Chinese innovative pharmaceutical companies such as Xinda Biotechnology (01801. HK) and Kangfang Biotechnology (09926. HK). At the same time, the stock prices of two Chinese pharmaceutical companies with similar drug layouts also surged, with Jinfang Pharmaceutical (02595. HK) rising more than 17% and Jiakesi (01167. HK) rising more than 8%.

The data is very good, exceeding the overall industry expectations. "Lu Qiang, Chairman of Jinfang Pharmaceutical, defined RevMed as a phenomenal product. He told the Economic Observer that in fact, the industry had high expectations for the drug before, but the overall survival period was generally expected to be around 10 months.

RevMed has planned to submit clinical trial data to the US Food and Drug Administration and will use the granted priority review voucher. Lv Qiang expects that daraxonrasib is expected to be approved in 2026, while similar drugs in China may be launched in 2028.

In addition to the second-line treatment of metastatic pancreatic cancer, RevMed is also carrying out a phase III clinical trial of first-line treatment of metastatic pancreatic cancer (that is, directly using daraxonrasib without chemotherapy first). There are also multiple clinical trials targeting non-small cell lung cancer and colorectal cancer.

Previously, multiple institutions predicted that the annual sales peak of Daraxonrasib would be between 5 billion and 10 billion US dollars. After the latest clinical data is released, some optimistic institutions such as Bank of America Securities predict that the annual sales peak of Daraxonrasib may exceed $12 billion.

Revolutionary Breakthrough

Whether for physicians or surgeons, pancreatic cancer is a thorny disease. Pancreatic cancer starts insidiously and is not easy to be found by routine physical examination. When obvious symptoms appear, it is basically late and the survival period is very short.

Yang Liu, director of the Department of Oncology of Zhejiang Provincial People's Hospital, said that patients with pancreatic cancer are generally divided into resectable, borderline resectable and unresectable. Early patients who can be resected can undergo surgery first; For patients with resectable borders, conversion therapy (such as chemotherapy) should be performed first, and the tumor should be reduced before surgery; For unresectable late stage patients, chemotherapy is the only option.

Li Zhao, director of hepatobiliary surgery at Peking University People's Hospital, said that pancreatic cancer surgery is the most complicated surgery in hepatobiliary pancreatic surgery. Even if a mature surgeon uses a robot to perform surgery, it will take four or five hours, and even seven or eight hours for complex cases. But what made him even more regretful was that most of the pancreatic cancer patients who came to him for consultation were advanced and could not be operated on.

Yang Liu said that in first-line treatment, the median time for late stage patients to have no tumor progression after chemotherapy is only about 6-10 months. After first-line treatment progresses, second-line treatment continues with chemotherapy, and the median survival time is about 4-6 months.

This means that for a long time, it is difficult for a large number of patients with pancreatic cancer to survive more than 1.5 years after diagnosis.

People have been trying to find better treatment options beyond surgery and chemotherapy for a long time. In the 1980s, through the analysis of a large number of pancreatic cancer samples, the scientific community found that more than 90% of pancreatic cancer carried the KRAS mutation gene. Unfortunately, the surface of KRAS protein is extremely smooth and there is no "pocket" for drugs to settle in, making it extremely difficult to develop this target into a drug.

In 2018, RevMed acquired a company founded by Harvard professor Gregory Verdine and obtained a molecular gel technology that effectively solved the problem of difficult binding between KRAS targets and drug molecules, giving birth to daraxonrasib.

Daraxonrasib not only inhibits mutated KRAS genes, but also suppresses NRAS and HRAS, making it a pan RAS inhibitor.

The RAS gene is an important signaling molecule in human cells, which opens and closes like a valve to control cell growth. If the valve remains open and downstream signals continue to activate, cell proliferation will be uncontrolled until a tumor appears.

Li Zhao made a vivid metaphor: "It's like a traffic signal that remains green all the time, and vehicles continue to pass in all directions, which can easily cause traffic congestion

During an interview with industry media, Wang Yinxiang, Chairman of Jiakesi, said that among all targeted anti-cancer drugs currently available, RAS targets cover the largest number of patients. The first human RAS gene was discovered in 1982, and it has been almost half a century since then. Several generations of scientists have been working on it, but it has always been one of the most difficult targets to break through in the field of targeted anti-cancer drugs. Previous attempts have mostly ended in failure.

He believes that it took nearly 50 years for humans to prove that inhibiting RAS can treat cancer, and in terms of time span, the difficulty is no less than landing on the moon.

After the release of Daraxonrasib Phase III data, both doctors and patients have seen new hope. Yang Liu's department has done a series of clinical studies on pancreatic cancer and advocated precise diagnosis and treatment of pancreatic cancer. She believes that this drug may become a pillar drug in the field of pancreatic cancer in the future, which will greatly change the treatment pattern of pancreatic cancer.

It's a super track, but different from PD-1

This is not the first time that humans have proven that RAS targets can be used as drugs. Prior to this, six RAS inhibitors (four domestically produced) were approved for market worldwide, but they were all single targets of KRAS G12C (note: RAS genes include KRAS, NRAS, HRAS, and KRAS includes G12C, G12D, G12V, etc.).

The world's first approved KRAS G12C inhibitor was developed by American pharmaceutical company Amgen. Subsequently, same target drugs from Bristol Myers Squibb, Jinfang Pharmaceutical, Yifang Biotechnology (688382. SH), Gakos, and Jiminxin were also launched, but their sales were not impressive, with the highest annual sales not exceeding 500 million US dollars.

The reason why KRAS G12C inhibitors are unsatisfactory is that single target inhibitors tend to make patients resistant to drugs. In addition, G12C mutations account for a relatively low proportion of cancers, for example, only 1% -2% of pancreatic cancer, and only a few patients can benefit from related drugs.

As a pan RAS inhibitor, the success of daraxonrasibde has brought new imaginative space to the RAS inhibitor race. According to Evaluate Pharma's prediction, the global market size of RAS inhibitors will exceed $20 billion by 2030.

The market's expectations for RAS inhibitors have led many people to associate them with PD-1. PD-1 has rewritten the history of cancer treatment, pioneering immunotherapy as a new and revolutionary pillar therapy that has enabled many advanced cancer patients to achieve long-term survival. In 2024, the global sales of PD-1 monoclonal antibodies have exceeded 50 billion US dollars, with Merck's K drug winning the global "drug king" title with 29.48 billion US dollars.

In Lv Qiang's view, the global RAS mutation rate among cancer patients is 30%, and it is expected that about 6.5 million cancer patients will carry RAS mutations by 2025. RAS inhibitors may indeed become a super race track, but due to differences in their mechanisms of action, the applicable population is still difficult to match PD-1. PD-1 is the cornerstone of immunotherapy and can be widely used in combination, covering a large number of indications; RAS inhibitors are the backbone of the RAS pathway field, with their influence limited to the pathway, making it difficult to become a top-level track like PD-1. ?

However, in terms of the pace of commercialization, Lv Qiang believes that the dosage of RAS pan inhibitor will be faster, because the indications focus on three major types of cancer: pancreatic cancer, colorectal cancer, and non-small cell lung cancer. The patient population is clear, and once approved, it can quickly penetrate. The dozens of indications for PD-1 have been gradually validated, and the sales volume has gone through a process of gradual increase, with a relatively longer peak time.

Currently, there are over 20 pan RAS/pan KRAS inhibitor pipelines entering clinical trials worldwide. In the field of pan RAS inhibitors, in addition to RevMed, companies such as Erasca, Jinfang Pharmaceutical, and Hengrui Pharmaceutical (600276. SH/01276. HK) have advanced research and development progress; In the field of pan KRAS inhibitors, products from domestic companies such as Jiakesi, BeiGene (688235. SH/06160. HK/ONC. US), and Zhengda Tianqing have also entered the clinical stage.

Will there be a foam in the PD-1 field when the RAS track is hot? In Lv Qiang's opinion, the answer is no.

Before founding Jinfang Pharmaceutical, Lv Qiang participated in the research and development of two PD-1/L1 drugs, both of which were approved for market. He believed that the success rate of PD-1/L1 monoclonal antibody research and development was very high, almost one by one, and the foam was punctured in the commercialization stage; The RAS track is exactly the opposite - although there are many clinical players, the success rate of research and development is extremely low.

Lv Qiang said that currently available KRAS G12C inhibitors are relatively easy to produce, but in the broader field of KRAS G12D and pan RAS, a large number of pipelines are limited to early clinical trials. Currently, no more than four companies have provided effective clinical data for pan RAS/pan KRAS inhibitors. This is a natural law of R&D elimination - there are many participating companies in the early stage, but high-quality players will be screened out by technical and regulatory barriers in the later stage, and the degree of competition in this track will be much lower than that of PD-1 in the future.

Lv Qiang believes that in order to achieve the expected sales of Daraxonrasib in the market, which can reach tens or billions of dollars, two challenges still need to be overcome. One is that single RAS inhibitor is almost ineffective in colorectal cancer at present, and the other is to verify the efficacy and safety of RAS inhibitor in first-line treatment of pancreatic cancer. And both of these challenges require drug combination strategies.

How to find the best joint partner and avoid the accumulation of side effects is a threshold that all players must cross, and it is also the focus of differentiated competition for companies within the track.