In the field of autoimmune therapy, traditional biologics have long dominated the market. Although classic drugs represented by Humira have significant therapeutic effects, they have limitations such as the need for frequent injections and potential risks of infection, which lead to low patient compliance. In sharp contrast, oral autoimmune drugs are rising rapidly and becoming the next explosion point in the industry due to their multiple advantages such as convenient home administration, no need for cold chain transportation, and controllable production costs.

The next hot spot

Globally, there are approximately 100 different types of autoimmune diseases, which can affect almost any part of the body, from the skin to the joints to the digestive system. Epidemiological data show that the patient population covered by major indications such as psoriasis, atopic dermatitis, and asthma has exceeded 100 million, constituting the core treatment needs in the autoimmune field.

According to Frost & Sullivan, the global autoimmune disease drug market is growing rapidly, from US$113.7 billion in 2018 to US$132.3 billion in 2022, and will climb to US$176.7 billion in 2030.
For a long time, biologics have dominated the autoimmune drug market with the advantage of precise targeting, but such drugs have obvious limitations. For example, they rely on injections and require professional medical care to operate; they have high requirements for cold chain transportation, which increases the difficulty and cost of use; at the same time, there are potential risks of immunogenicity. These factors lead to generally low patient compliance.

Technological breakthroughs in small molecule targeted drugs have brought new opportunities in the field of autoimmune therapy.

Small molecule drugs in oral dosage form have many natural advantages, such as the convenience of not requiring professional medical care; their good penetrability enables them to break through the blood-brain barrier and achieve more precise targeted treatment; and they can be used in combination with biological drugs to exert synergistic potential. In addition, compared with the complex production process of biological drugs, the production cost of oral drugs is greatly reduced, further highlighting their advantages in market competition.

The list of "2024 Global Autoimmune Drug Sales TOP10" shows that AbbVie's JAK1 inhibitor upadacitinib, with its outstanding performance in the treatment of various autoimmune diseases such as rheumatoid arthritis, atopic dermatitis, and ulcerative colitis, will see its sales soar to US$5.971 billion in 2024, a year-on-year increase of 50.4%, ranking seventh on the list. Ruxolitinib, a small molecule JAK1/JAK2 inhibitor jointly developed by Incyte and Novartis, also successfully ranked ninth with sales of US$4.911 billion. The outstanding performance of these two small molecule oral drugs indicates that oral autoimmune drugs have entered the ranks of the world's top 10 autoimmune drugs, and will be more favored by the market in the future due to their advantages.

Competition among giants

Currently, international pharmaceutical giants are accelerating the filling of the next-generation oral autoimmune drug pipeline through high-frequency mergers and acquisitions and strategic cooperation capital actions, and building dual barriers of technology and products in differentiated competition.

Johnson & Johnson: Cyclic peptide technology reconstructs the oral administration of IL-23

IL-23 is a key node connecting innate immunity and adaptive immunity. Its abnormal activation is closely related to a variety of diseases such as psoriasis, ulcerative colitis (UC), Crohn's disease (CD), etc. Johnson & Johnson, AbbVie, Novartis and other companies have already shared the market in the field of injectable IL-23 inhibitors: Johnson & Johnson's Stelara (ustekinumab) sales in 2024 will reach US$10.36 billion, and AbbVie's Skyrizi (risankizumab) sales in 2024 will reach US$11.7 billion.

Johnson & Johnson is collaborating with Protagonist to develop the oral cyclic peptide IL-23 receptor antagonist Icotrokinra (JNJ-2113), the first targeted oral peptide that selectively blocks the IL-23 receptor and is suitable for adults and adolescents aged 12 years and older with moderate to severe plaque psoriasis.

The results of the ICONIC-LEAD study showed that the PASI 90 response rate reached 64.9% in patients with moderate to severe psoriasis after 24 weeks of treatment, which was significantly better than the 4.4% in the placebo group; 74.1% of JNJ-21133-treated patients achieved 0/1 points.

Eli Lilly: Betting on oral IL-17

In the field of psoriasis, the IL-17 target is the focus of research and development. Innovative drugs represented by injectable monoclonal antibodies, such as Novartis's Cosentyx and Eli Lilly's Taltz, have become core products for the treatment of psoriasis worldwide due to their good therapeutic effects. In 2024, Taltz will achieve sales of US$3.26 billion at a growth rate of 18%; and Taltz will achieve sales of US$6.141 billion at a growth rate of 25%, becoming Novartis' second-largest drug in terms of sales. The market performance of these drugs confirms the huge potential of the IL-17 target.

Eli Lilly is not satisfied with the current achievements of Ixezimab, but is actively exploring new growth points and turning its attention to the field of oral drugs.

In 2023, the company acquired DC-806 and DC-853 by acquiring DICE Therapeutics for $2.4 billion, officially entering the oral IL-17 small molecule drug track. DICE Therapeutics uses its core technology to convert the binding pocket of the IL-17 receptor into a structure that can be recognized by small molecules, allowing small molecule drugs to accurately bind to the IL-17 receptor and block signal transduction. Although DC-806 failed due to liver toxicity, the iterative molecule DC-853 is undergoing a Phase 2 clinical trial for psoriasis. It is more active than DC-806 and is expected to achieve a lower dosage.

Sanofi: Differentiated breakthrough of IRAK4 degrader

In the context of fierce competition for JAK inhibitors and crowded IL-23/IL-17 pathways, Sanofi has taken a different approach and placed its bets on IRAK4 degraders. In 2020, Sanofi and Kymera reached a research and development collaboration of up to US$2 billion to jointly develop KT-474 (SAR444656), a potential first-in-class candidate degrader for IRAK4.

IRAK4 is a core kinase in the TLR pathway, and its abnormal activation is associated with a variety of autoimmune diseases. Traditional IRAK4 inhibitors have an overly broad inhibition range, leading to an increased risk of infection. Degraders precisely degrade IRAK4 through E3 ubiquitin ligases. In a phase 1 atopic dermatitis clinical trial, the severity of itching was reduced by 63%, and the EASI score, which assesses the extent and severity of the patient's disease, decreased by 36%.

AbbVie: NLRX1 and IL-23 two-pronged approach

AbbVie acquired Landos Biopharma in 2024 and added its first-in-class oral NLRX1 agonist NX-13 to its pipeline. As a key immune regulatory protein located in mitochondria, NLRX1 inhibits excessive activation of the NF-κB pathway through a unique mechanism, blocking the cascade reaction of multiple pro-inflammatory factors from the source. Currently, NX-13 has entered Phase 2 clinical research for ulcerative colitis.

Based on the successful creation of Skyrizi (Lisenqizumab), a star product of IL-23 monoclonal antibody, AbbVie further strengthened its layout of this target. AbbVie acquired an oral IL-23 inhibitor in the preclinical stage through the acquisition of Nimbus, and simultaneously incorporated its proprietary peptide synthesis platform (Nimble technology). This layout aims to build a "biological drug + small molecule" synergistic product line: the former occupies the market of moderate to severe patients with high specificity, and the latter penetrates the mild to moderate population and maintenance treatment scenarios with the convenience of oral administration, forming a three-dimensional competitive advantage covering the entire course of disease.

Breaking through challenges

Despite the broad prospects, the road to research and development of oral autoimmune drugs is full of difficulties and obstacles, and many technical problems and practical difficulties need to be overcome.

The pathogenesis of autoimmune diseases is extremely complex and highly heterogeneous. Take the IL-23 pathway as an example. Although Skyrizi, a biological drug targeting this target, has become a billion-dollar product, oral small molecule inhibitors need to accurately inhibit IL-23 signals to avoid interfering with Th1 cell function by inhibiting homologous IL-12. In this regard, Johnson & Johnson's Icotrokinra has taken a different approach, achieving highly selective inhibition of IL-23 by targeting IL-23R rather than the p40 subunit, providing a new idea for the development of similar drugs.

The safety of small molecule drugs must be taken seriously. For example, oral JAK inhibitors have been issued a black box warning by the FDA due to the risk of thrombosis; the potential non-target toxicity of PROTAC molecules requires long-term systematic monitoring.

In addition, the centralized drug procurement policy in the Chinese market continues to advance, prompting clinical drug selection to lean towards cost-effective products. For innovative drugs (such as oral peptides and PROTACs) with R&D costs of up to US$1 billion, it is worth thinking deeply about how to quickly gain a foothold in this market.

Conclusion

With the entry of new-generation oral drugs such as AbbVie's NX-13 and Johnson & Johnson's JNJ-2113 into clinical trials, autoimmune therapy is shifting from being dominated by biological drugs to being coordinated by biological drugs and oral small molecules. This innovation, which began with the method of drug administration, not only brings convenience to hundreds of millions of patients around the world for home treatment, but also marks the reshaping of the commercial competitiveness of autoimmune therapy.

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