The curtain call of ＂medicine king＂! Trillion drug-free track opens a new competition

The year 2023 is of great significance to the drugs for autoimmune diseases and even to the global innovative drug market. With the expiration of patents in key markets, Hummel (adalimumab) will officially hand over the title of global sales champion for 11 years, and the first generation of "drug king" will officially end.

Due to the complex pathogenesis, the number of patients with autoimmune diseases is large and it is difficult to cure. The long-term or even lifelong demand for drugs has spawned a huge market for autoimmune drugs, which has become a hotbed for the growth of heavy drugs.

Under the demonstration effect of "drug king", major pharmaceutical companies around the world have been scrambling for layout in recent years. At present, breakthroughs have been made in the development of new drugs for potential targets such as JAK and interleukin, and the free drug track is expected to usher in a new round of competition. Local innovative drug companies try to gain a place in the domestic free drug market through differentiated distribution of indications and continuous optimization of safety.

The market for self-exempted drugs continues to grow steadily.

Autoimmune system diseases refer to diseases caused by immune response to autoantigens and self-tissue damage. Genetic defects and environmental factors are all important links in inducing autoimmune diseases. The complex disease mechanism leads to a wide variety of autoimmune diseases and a large patient base. At present, there are more than 100 known main disease types, including psoriasis, atopic dermatitis, compulsory spondylitis, rheumatoid arthritis and systemic lupus erythematosus.

As a chronic disease, autoimmune diseases usually do not directly kill people, but it is also difficult to cure them. Such as compulsory spondylitis, systemic lupus erythematosus, etc., once suffering from it, it will be difficult to reverse, which is called "undead cancer". Patients need long-term or even lifelong medication, thus giving birth to the long-term and stable growth of market demand for self-immune drugs.

Based on the financial report data of major pharmaceutical companies, in 2022, there were 22 self-disease-free drugs in the list of TOP100 drugs with global sales scale, of which 10 drugs exceeded $3 billion and the total sales exceeded $70 billion.

According to the statistics of AARDA, patients with autoimmune diseases account for 7.6%-9.4% of the global population in recent years. Jost Sullivan’s statistics show that there are nearly 500 million patients with various kinds of self-immune diseases in the world, and the global self-immune drug market will reach about 132.3 billion US dollars in 2022, which has become the second largest disease market after cancer.

Jost Sullivan predicted that by 2030, the global self-exempted drug market is expected to reach US$ 176 billion, with a compound annual growth rate of 3.6% from 2022 to 2030. Among them, the self-exempted drug market in China is expected to reach nearly US$ 25 billion in 2030, a tenfold increase compared with 2020, which is an important incremental source of global self-exempted drugs.

The "King of Medicine" made a curtain call, and new drugs rose one after another.

Treatment strategies for autoimmune diseases include inflammation alleviation and immunosuppression. Although non-steroidal anti-inflammatory drugs, corticosteroids and anti-rheumatic drugs have good anti-inflammatory effects, they are difficult to fundamentally stop the development of the disease, and they are easy to relapse after stopping taking drugs. However, traditional non-selective immunosuppressants such as cyclosporine and methotrexate are not only slow to take effect, but also lead to a higher risk of cancer. As new immunosuppressants, bio-targeted drugs can selectively suppress the immune system, ensuring the safety while improving the curative effect, which is the most promising.

Hummel is a fully humanized monoclonal antibody against TNF-α developed by AbbVie Company, which was approved by FDA in 2002 for the treatment of rheumatoid arthritis. Because of its remarkable efficacy and safety in the treatment of self-immune diseases, Hummel’s indications have been expanding since its listing, and it has gradually become the highest-selling self-immune drug, and ranked first in global drug sales in 2012. Since then, through a series of marketing and patent strategies, AbbVie has made great efforts to extend the life cycle of Hummel, and promoted the drug to become the "drug king" in the world for ten consecutive years, with accumulated sales exceeding 200 billion US dollars since its listing.

With the official expiration of the patent in the United States in 2023, the market share of self-exempted drugs controlled by Hummel was quickly robbed by many similar biological drugs. According to AbbVie’s third quarterly report in 2023, nearly 10 biologically similar drugs have entered the market. As a result, the cumulative sales of Humele in the first three quarters of 2023 was only $11.1 billion, a sharp drop of 29.1% year-on-year. Nature Reviews Drug Discovery, a well-known medical journal, predicts that the annual sales of Hummel in 2023 will be about $13.6 billion, less than 60% of Keytruda of Top1, and the first generation of drug kings will soon "abdicate".

Corresponding to the curtain call of "King of Medicine", many innovative drugs with potential targets have risen rapidly, and a new generation of heavy drugs is coming out.

According to the global sales forecast of innovative drugs in 2023 recently released by Nature Review of Drug Discovery, the sales of self-immune biological agents Dupixent and Stelara, which target IL-4/IL-13 and IL-12/IL-23 respectively, have increased rapidly, and it is estimated that they will rank among the Top10 with sales of more than 10.6 billion US dollars.

Abbey, the owner of Hummel, is also actively looking for the next generation of self-free drugs. The sales amount of oral JAK1 inhibitor Rinvoq (upatinib) and IL-23 monoclonal antibody Skyrizi (risazhuzumab) under the company has increased rapidly in recent years. In 2022, the total sales revenue has exceeded 7 billion US dollars, and the growth rate is higher than 50%. Abbway predicts that by 2027, the combined sales revenue of these two drugs is expected to exceed the sales peak of Hummel’s $20 billion.

Domestic pharmaceutical companies compete for the next potential target.

Compared with the highly competitive innovative cancer drugs, the number of participants and innovative drugs in the self-exempt drug market is still relatively limited, and the overall market competition pattern is good. However, the huge unmet clinical needs and the continuous improvement of the diagnosis rate in China have also attracted more and more domestic innovative pharmaceutical companies to enter the drug-free track, and tried to gain a competitive advantage by virtue of differentiated layout potential targets and occupy a place in the domestic market.

So far, the targets of self-immune targeted drugs mainly focus on TNF-α, JAK, interleukin and BlyS, and the main indications are common rheumatoid arthritis, psoriasis, systemic lupus erythematosus and so on. Among them, targeted TNF-α drugs are the most classic targeted drugs for autoimmune diseases because of their early market time, mature targets and the widest range of indications. However, this track has basically been controlled by foreign-funded enterprises, and the development space of local manufacturers that follow is relatively limited. Domestic innovative drug companies have turned their research direction to JAK, interleukin and other targets.

Interleukin and its receptors are important target families in human immune regulation, and play an important role in various immune and inflammatory reactions. Psoriasis is the main indication of interleukin targeted drugs at present, and some targeted drugs have been proved to be safer than TNF-α antagonists in certain circumstances.

At present, the effective interleukin-targeting drugs listed in the world include tosilizumab targeting IL-6, ulinuzumab targeting IL-12/23, skukiyuzumab targeting IL-17A and gusechizumab targeting IL-23. Among domestic enterprises, Hengrui Pharma (600276.SH), Zhixiang Jintai (688443.SH) and Kangfang Bio (09926.HK) all have approved the listing of interleukin-targeted biological agents, and Quanxin Bio (01883.HK), Livzon Group (000513.SZ), Junshi Bio (688180.SH) and Cinda Bio.

JAK signaling pathway plays a very important role in autoimmune, tumor, hematological and other diseases, and it is one of the promising potential targets. Because the first generation of JAK inhibitors showed great toxic and side effects in the treatment process, the main research and development direction of major pharmaceutical companies is the second generation of JAK inhibitors targeting JAK1, JAK3, TYK2 and other targets with high specificity.

In clinical trials, the second generation JAK inhibitors have shown good data in terms of safety and efficacy. Among them, Upatinib, a JAK1 inhibitor listed by AbbVie, showed a better key remission index under the same safety in the head-to-head experiment of treating rheumatoid arthritis and adalimumab. In the first three quarters of 2023, the sales amount of Upatinib has reached US$ 2.71 billion, exceeding the annual performance in 2022. AbbVie expects that the drug is expected to achieve sales of more than $7.5 billion in 2025.

In view of the good performance of this target, the research on JAK-specific subunits has become one of the important directions of global innovative drug companies. Among domestic enterprises, Hengrui Pharma, Dizhe Medicine (688192.SH) and Nuocheng Jianhua (688428.SH) are in the top of the research and development progress. Among them, Nuocheng Jianhua recently disclosed that its TYK2 inhibitor ICP-488 under research has completed the first clinical administration for psoriasis patients in Phase II. ICP-332, another self-immune drug with the same target, disclosed the second phase clinical data of moderate and severe atopic dermatitis indications in December 2023. Orient securities believes that domestic JAK-targeted self-immune drugs are expected to achieve rapid volume increase after marketing through differentiated distribution of indications and optimized breakthrough in safety.

BlyS is one of the key factors in the differentiation and maturation of B lymphocytes, which is the most important effector cell of autoimmune diseases. By inhibiting BlyS, many autoimmune diseases can be treated. At present, there are two BlyS inhibitors on the market, namely, GlaxoSmithKline’s Beliyuzumab and Rongchang Bio (688331.SH)’ s Tatasip. The main indications are systemic lupus erythematosus, and the market structure is good.

Tetasip is an innovative drug of BLyS/APRIL dual-target fusion protein independently developed by Rongchang Bio. Clinical data show that the drug has the same level of efficacy and safety as Belizumab. In 2021, National Medical Products Administration conditionally approved Tatasip for the treatment of adult patients with systemic lupus erythematosus, and included it in the 2022 edition of the National Medical Insurance Catalogue; In November, 2023, the treatment of Tatasip in this indication was fully approved.

Rongchang Bio is also continuing to promote the clinical research on other indications of Tatasip, and the research on many indications such as rheumatoid arthritis, Sjogren’s syndrome and multiple sclerosis has entered the final clinical stage. In August, 2023, Tatasip was used to treat patients with rheumatoid arthritis in Phase III, and submitted an application for domestic marketing. On December 20th, the global multicenter Phase III clinical IND of Tatasip in the treatment of active primary Sjogren’s syndrome in adults was approved by the FDA of the United States, and clinical research will be carried out in many countries and regions around the world. The continuous enrichment of the clinical pipeline of Tetasip is expected to consolidate the innovative product matrix of the company and promote the continuous growth of the company’s income.