Recently, Astellas announced that Japan’s MHLW has approved its ADC drug ennozumab PADCEV and Merck’s K drug as a first-line combination therapy for adult patients with fundamentally unresectable urothelial cancer.

With excellent data, this combination treatment regimen was approved by the Japanese MHLW in such a short time after Merck announced on September 4 that it had been approved by the European Commission (EC) as a first-line therapy. However, sporadic victories cannot conceal the plight of K-drugs.

For the pharmaceutical industry, the biggest hot spot in the past two weeks is definitely the announcement by Kangfang Biologics on September 8 that ivocilimab has become the world's first and only single-drug head-to-head phase III clinical study to prove that its efficacy is significantly better than that of pabrolib. The drug Zizumab. On the day the results were announced, Merck's stock price fell in response, and the dilemma was obvious. Under the predicament of core patent cliffs and new drugs facing tough competition in 2028, how can K-drugs cope with the situation so that it can stand out from the encirclement of challengers?

K Drug Becomes the King: From Double Fight to Big Melee The "OK" battle witnessed the development of the PD-1 drug market, and also achieved the position of K drug as the "King of Drugs".

In June 2014, nivolumab (Opdivo, also known as O drug), jointly developed by Bristol-Myers Squibb and Japan's Ono Company, was the "First in class" PD-1 inhibitor and was the first to be launched in Japan. In September of the same year, K drug passed FDA certification and was approved for marketing in the United States.

Since its launch in 2014, drug K has been competing with drug O in the depth and breadth of indications. After two key nodes, 1) in 2016, drug K defeated drug O in the first-line treatment of non-small cell cancer (NSCLC); 2) in 2018, the number of FDA indications surpassed it. Subsequently, K drug began to dominate the PD-1 market and firmly established itself as the drug king.

Until 2023, K-drug will surpass Humira and become the new global "drug king" with sales of US$25 billion. The great success of K drugs has also led to a swarm of competitors. Since 2017, the number of PD-1/PD-L1 target clinical trials has surged.

According to a report in Nature Reviews Drug Discovery, by the end of 2021, 5,683 clinical trials worldwide are evaluating PD-1/PD-L1 monoclonal antibodies as monotherapy or in combination with other therapies, an increase of 278% from 2017.

As of July 31, 2024, my country's NMPA/US FDA has approved a total of 190 indications for 20 cancer types and 26 immune checkpoint inhibitors. Among them, K drug can participate in the treatment of 16 cancer types, totaling about 40 indications, and its market total and share have also increased over time to 25 billion US dollars and 55% share.

This shows that in the first half, K drug’s strategy of leveraging its first-mover advantage to rapidly expand its indications and thereby enjoy the economic benefits brought by blockbuster drug patents was very correct. The data trend is bright, but the patent cliff in 2028 still hangs over K-drugs like a sword of Dalmos. Moreover, it seems that the possibility of focusing on single-drug indications has also been lost after Kangfang Biotech’s ivocilimab overturned K-drug’s lung cancer stronghold.

But is this really the case? In fact, K Medicine has already planned the second half. Second half: The road to organizing K drugs. Data disclosed by Nature Reviews Drug Discovery show that in 2022, the number of global PD-1/PD-L1 immunotherapy clinical trials declined for the first time after continuous growth, and research and development cooled down. The cooling of clinical trials shows that pharmaceutical companies' expectations for the future market size of PD-1 drugs will tend to be stable, and the number of players entering the market will also tend to stabilize.

This shows that the second half will be a competition between existing players in the predictable existing market. American management scientist Michael Porter mentioned three effective competitive strategies in his book "Competitive Strategy", which are total cost leadership strategy, differentiation strategy and specialization strategy. If you don’t want to compete with prices, you must differentiate yourself from your competitors.

According to statistics, K-drug biosimilars from nearly 10 pharmaceutical companies, including Amgen, Sandoz, Samsung Bioepis, and Qilu Pharmaceuticals, have entered the clinical trial stage, and the fastest has entered Phase III clinical trials.

For K-drug, after the patent cliff expires in 2028, falling into a price war with me too companies is definitely a nightmare that it does not want to face.

To break through, it must find a differentiated advantage from its competitors. For K drugs, combination therapy is its differentiated advantage. According to statistics from the FDA official website, the author found that K drug currently has 16 combination treatments (pemetrexed, platinum chemotherapy, paclitaxel, etc.) among the 42 indications approved by the FDA.

According to Merck’s official website, the company has led more than 1,600 K-drug studies involving “various cancers and treatment settings.” There are more than 15 clinical trials of K drug combined with lenvatinib alone .
Under such a layout, the difficulties faced by K-drug will be significantly reduced than most people expected. Why? Because the combination therapy layout of K drug has three major benefits for maintaining its market share after its patent expires and is challenged by other innovative drugs:

First, drug efficacy determines everything. For the drug king, the way to avoid the patent cliff is actually very simple. , do your own me better. K-drug has deployed a large number of combination therapies to improve its efficacy, which will greatly reduce the impact of the efficacy of K-drug single-drug generics on its combination therapies in the future.

Second, current innovative drugs such as Kangfang Biotech’s ivocilimab have only successfully challenged the single-drug effect of K-drug. Whether it can defeat the combined therapy of K-drug remains to be studied. The deployment of combination therapy will greatly increase the difficulty of the challenge and make the challenge more difficult. Delay the progress of his challenge.

Third, the combination therapy of K drug with other drugs will establish K drug as a cornerstone drug, and the share of K drug will be greatly increased through "bundled sales" with other drugs.

Under such a strategic layout, K-drug successfully dragged the second half into a team battle. Challengers who challenge K-drug alone will appear to be weak. Therefore, for other challengers, it may be the best solution to seize the opportunity to also combine other highly effective drugs, work together to quickly challenge the core indication field of the drug king, and defeat its combination therapy.

It is worth noting that at the 2024 European Society for Medical Oncology (ESMO) annual meeting, Kangfang Biotech released for the first time its independently developed PD-1/VEGF bispecific antibody Ivosi combined with or without a new generation of CD47 monoclonal antibody. Excellent Phase II clinical research results of anti-refalib as first-line treatment of PD-L1-positive (CPS ≥ 1) recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In addition, the phase III study of Kangfang Biotech's Ivosi combined with Lefali versus pembrolizumab regimen for the first-line treatment of PD-L1-positive R/M HNSCC has been launched.

In addition, Evosi is about to launch three new phase III clinical studies, including Evosi combined with AK117 (CD47) combination regimen for the first-line treatment of PD-L1-positive head and neck squamous cell carcinoma (vs. pembrolizumab), Evosi combination regimen First-line treatment of biliary tract cancer (vs. durvalumab combination regimen), and Ivosib combination regimen for first-line treatment of pancreatic cancer.

Therefore, in the second half of the battle for drug kings, the victory of a single drug may no longer be critical, but the power of drug synergy will play a decisive role. It remains to be seen what the future of K drugs will be.

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