As one of the blue oceans in the field of autoimmune diseases , inflammatory bowel disease (IBD) treatment drugs are sought after and deployed by many multinational pharmaceutical companies.

Recently, Eli Lilly acquired Morphic for US$3.2 billion and obtained its core pipeline α4β7 integrin inhibitor MORF-057, further expanding its influence in the field of gastrointestinal diseases.

In addition to Eli Lilly, pharmaceutical giants including AbbVie, AstraZeneca, and Merck have laid out IBD treatment drugs and carried out related mergers and acquisitions.

Behind the frequent actions, why do multinational pharmaceutical companies favor IBD treatment drugs so much?

The dilemma of traditional treatment

IBD is a chronic inflammatory bowel disease that mainly affects the digestive system. Its symptoms include severe diarrhea, frequent abdominal pain, blood in the stool, weight loss, and severe cancer. IBD mainly includes two types: ulcerative colitis (UC) and Crohn's disease (CD). The two IBDs have both overlaps and differences in clinical and pathological characteristics: UC mainly affects the rectum and part of the colon, and the lesions are continuous, while CD mainly affects the ileum and colon, and the lesions are segmental.

At present, IBD is not common in China, but the number of patients is growing rapidly. According to statistics from the Chinese Center for Disease Control and Prevention in 2014, the cumulative number of IBD cases in China between 2005 and 2014 was approximately 350,000, but by 2025, it is estimated that the number of IBD patients in China will reach 1.5 million.

In the past, before the advent of targeted drugs, there was no good treatment for IBD. Traditional treatment drugs for IBD mainly include aminosalicylic acid preparations, glucocorticoids, immunosuppressants, etc. Although these drugs can bring a certain degree of relief to the condition of IBD patients, they all have limitations and it is difficult to meet the clinical treatment needs of IBD.
5-aminosalicylic acid preparations (5-ASA) represented by mesalamine have been the first-line treatment for IBD in the past because they hardly enter the bloodstream, are locally effective, and are safe. However, due to limited efficacy, they are generally only It is recommended for the treatment of patients with mild to moderate IBD in the active phase and remission phase.

Although glucocorticoids and immunosuppressants have a certain alleviation effect on moderate to severe IBD, they all have obvious and serious side effects. Therefore, they can only be used for short-term treatment of moderate to severe IBD in the active phase when 5-ASA treatment is ineffective. For long-term maintenance treatment.

Therefore, for a long time in the past, IBD treatment lacked effective but safe targeted drugs for moderate to severe patients, and there was a huge unmet clinical need.

Monoclonal antibodies and small molecules compete for prominence.

The development of targeted therapy for IBD must start with its pathogenesis. The essence of IBD is that the gastrointestinal tract exhibits abnormal immune responses. Although the pathogenesis is still not completely clear, the core of current targeted therapy for IBD is to suppress the immune response in the gastrointestinal tract, thereby inhibiting the occurrence of inflammation. The immune response with T cells as the core mainly includes the following key processes, which are also the focus of current new drug development:

1) T cells migrate from lymph nodes through the blood circulation to the intestinal parts that send out inflammatory signals. The targets in this direction Including integrin (α4β7) and its ligand MAdCAM-1 protein, as well as sphingosine-1-phosphate (S1P) receptors. Inhibiting or blocking these targets and their related signaling pathways can prevent T cells from traveling from lymph nodes to the intestine. 2 )

Pro-inflammatory factors activate downstream signaling pathways in T cells through T cell surface receptors, inducing T cell-mediated inflammatory responses (see Figure 2). Targets in this direction include the pro-inflammatory factor TNF-α , IL, TGF-β1, etc., as well as JAK enzymes, SMAD-7 molecules, etc. related to intracellular downstream signaling pathways. Inhibiting these targets and their signaling pathways can inhibit the occurrence of inflammation.

Starting from these two directions, many new IBD-targeted drugs with excellent efficacy have been born. Since infliximab and adalimumab were first approved for the treatment of IBD in 1998, IBD has entered a new era of targeted therapy, especially the development and marketing of biological agents, which has obviously entered the fast lane.

Nearly 10 monoclonal antibody drugs have been approved in the past 20 years, among which monoclonal antibody targeted agents targeting TNF-α and IL occupy the mainstream. However, these monoclonal antibody drugs have been approved for multiple indications. IBD may not be the focus of its market.

Therefore, the anti-α4β1 drug vedelizumab, which was approved for marketing in 2014, is extremely precious. It is the first targeted drug specifically designed for the treatment of IBD, and it is also the first and only intestinal-selective IBD targeted drug. drug. In 2023, global sales of vedelizumab will reach US$5.41 billion, becoming a super blockbuster and fully proving the superiority of its mechanism.

Entering 2018, the first IBD-targeted small molecule tofacitinib was approved for the treatment of IBD. This has since opened the era of small-molecule targeted therapy, and the development and marketing of new small-molecule targeted drugs have also begun.

Among them, JAK enzyme inhibitors and S1P receptor antagonists are outstanding representatives, especially JAK enzyme inhibitors, and its FIC drug tofacitinib has earned more than 2 billion in the field of autoimmune diseases including IBD. Its second-generation drug, Upadatinib, is even more impressive. In just a few years since its launch, its sales have almost exceeded 4 billion U.S. dollars, making it the “Ten Billion Drug King.” .
It is worth noting that the success of upadatinib is not accidental, nor is it just a commercialization factor; on the contrary, its success is entirely based on excellent clinical efficacy data. Of course, this article only uses the clinical data of IBD to provide some clues. Although there is currently no phase III head-to-head study of upadatinib and "big brother" tofacitinib in the treatment of IBD, judging from the phase III clinical data of UC indications that have been disclosed, the clinical performance of uppatinib The efficacy is amazing. The clinical remission rate in the acute phase reaches 26%-33%, with a difference of 22%-29% compared to placebo. The clinical remission rate in the maintenance phase reaches 42%, with a difference of 22%-29% compared to placebo. 31%. In contrast, the clinical remission rate of tofacitinib in the acute phase is only 17%-18%, and the difference compared with placebo is 10%-13%. The clinical remission rate in the maintenance phase is 34%, which is 34%. The difference compared with placebo was 23%; it can be seen that for the two primary endpoints, both the absolute value of the data and the difference compared with placebo, upadatinib is much greater than tofacitinib.

A similar conclusion also applies to vedelizumab, whose clinical remission rate in the acute phase of UC is 22% higher than that of placebo (47% vs 26%, P<0.001), which is also far superior to that of placebo. For the anti-TNF-α agent adalimumab, the clinical remission rate of the latter in the acute phase of UC was only 9.3% lower than that of placebo (18.5% vs 9.2%, P<0.05). It can be seen that vedelizumab is also a revolutionary drug in the treatment of IBD.

From adalimumab to vedelizumab, from tofacitinib to upadatinib, targeted treatments for IBD are making breakthroughs one after another. This is a victory for innovation and good news for patients.

The combination of targeted therapies may be a general trend.

In the past 20 years, a large number of advanced drugs have emerged in the treatment of IBD, which has continuously promoted new breakthroughs in the clinical remission rate of IBD. However, Silvio Danese et al. pointed out in a 2022 report that most advanced treatments now report 1-year clinical response rates between 30% and 50%, indicating that we may have reached the upper limit of treatment by using a single drug.

IBD is an immune-mediated inflammatory process driven by multiple pathways, and drugs that are effective for intestinal disease may not be effective for extraintestinal manifestations or concomitant immune-mediated diseases (IMID), necessitating the use of other drugs. With this in mind, the concept of advanced combination therapy (ACT), which is based on the use of at least two biologics, or both a biologic and a small molecule drug, may be an option for patients with refractory IBD who are at high risk for complications. A promising strategy for patients with or with uncontrolled IMID.

At present, this strategy has been applied in actual treatment and has achieved good results. A retrospective study in the United States reported on 50 patients with refractory IBD (10 of whom were complicated by IMID) who were not well treated with existing drugs and received ACT. The treatment regimen included vedelizumab + ustekinumab. (47%), tofacitinib + biological agents (40%), and vedelizumab + anti-TNF-α monoclonal antibody. The results showed that the clinical response rate of patients receiving ACT treatment (50% vs 14%, p =0.0018) and endoscopic response rate (34% vs 6%, p=0.0039) were significantly higher than the baseline values.

In addition, Waseem Ahmed et al. published a systematic review and meta-analysis on ACT treatment in 2022. This study included a total of 30 studies and 276 patients, including 81% of refractory IBD patients and 12% of patients. In patients with IBD complicated by extraintestinal manifestations or rheumatism, the most commonly used combinations include anti-integrin monoclonal antibody + anti-TNF-α monoclonal antibody (48%) and anti-integrin monoclonal antibody + ustekinumab (19%), clinical The response rate and endoscopic response rate were 59% and 34% respectively.

Finally, although scientific progress continues to bring hope to the treatment of IBD, due to the refractory and recurring nature of IBD, this undertaking is destined to have a long way to go. Looking to the future, I believe that more new drugs for targeted therapy will be developed for the treatment of IBD; at the same time, there is also reason to believe that combination therapy between targeted drugs will also shine in the treatment of IBD.

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