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In the development of modern medicine, drug research and development has always been a key force driving progress in disease treatment. Among them, the emergence of immune checkpoint inhibitors, especially PD-1 related drugs, is undoubtedly one of the most dazzling breakthroughs in the pharmaceutical field in recent years.
Since its emergence in the field of cancer treatment, PD-1 inhibitors have created many medical miracles and become the cornerstone therapy for cancer treatment. However, scientists' exploration has not stopped here. Nowadays, the research progress of PD-1 agonists in the field of autoimmune diseases is opening up new development space for this star target, showing promising prospects.
1 PD-1： Key regulatory proteins of the immune system
PD-1， Programmed cell death protein-1, as a key regulatory protein in the immune system, plays an important role in maintaining immune balance in the body. Under normal physiological conditions, the PD-1 pathway is an important pathway that affects the strength and weakness of T cell immunity. When PD-1 is activated, T cell immunity weakens. The specific mechanism is as follows: PD-L1 and PD-1 of APCs (antigen-presenting cells) bind, activating the PD-1 signaling pathway, and then the PD-1 pathway is transmitted downstream to activate the phosphatase SHP2 factor.
On the one hand, SHP2 factor can affect TCR (T cell receptor) by affecting ZAP70, thereby inhibiting the TCR pathway and suppressing the secretion of factors such as IL-2.
On the other hand, SHP2 affects CD28 by antagonizing its signaling pathway, thereby affecting the RAS → ERK pathway and inhibiting T cell activity, proliferation, survival, and secretion of various cytokines. As SHP2 continues to mediate deeper into the cell, it also involves the AKT pathway. Although this process is more complex, overall, the impact of SHP2 on the AKT pathway has a negative effect on T cell immunity.
In the field of cancer treatment, the mechanism of action of PD-1 inhibitors is to block the binding of PD-1 and its ligand PD-L1, thereby relieving tumor cells from inhibiting the immune system and activating T cells to recognize and attack tumor cells. This new treatment concept breaks the limitations of traditional cancer treatment methods and brings new hope to many cancer patients.
For example, Merck's "global drug king" K drug (pembrolizumab), as a PD-1 monoclonal antibody drug, has demonstrated excellent efficacy in the treatment of various cancers. The data disclosed in the 2024 financial report shows that K drug's annual sales reached 29.5 billion US dollars, which not only reflects its huge success in the market, but also highlights the important position of PD-1 inhibitors in the field of cancer treatment.
In China, more than ten PD-1 drugs have already been approved, such as Hengrui Pharmaceutical's Carilizumab, BeiGene's Trelizumab, Junshi Biological's Triprolizumab, etc. These drugs play an important role in the treatment of different types of cancer, and various pharmaceutical companies are fiercely competing around the indications for different types of cancer.
2、 PD-1 agonists: a new hope for the treatment of autoimmune diseases
However, as research on PD-1 continues to deepen, scientists have gradually discovered that the potential of this target is not limited to cancer treatment. The emergence of PD-1 agonists in the study of autoimmune diseases has brought new ideas for the treatment of this field. Autoimmune diseases are a type of disease caused by the body's immune system mistakenly attacking its own tissues and organs, such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, etc. The pathogenesis of these diseases is closely related to the overactivation of the immune system, and the mechanism of action of PD-1 agonists coincides with it.
In the context of autoimmune diseases, autoimmunity is due to the strong immune response, and PD-1 is preferentially expressed on activated Teff and Tfh/Tph cells that mediate autoimmune pathology. Teff, also known as effector T cells, is responsible for secreting inflammatory factors that cause tissue damage and inflammation to persist.
Tfh is a T follicular helper cell, and Tph is a T peripheral helper cell. Their main functions are to secrete CXCL13 and IL-21, recruit B cells and induce their activation into plasma cells, and then exert humoral immune processes. If PD-1 can activate T cells and suppress their immunity, then the self immune system's killing of body tissues can be alleviated.
Among the numerous studies on PD-1 agonists for the treatment of autoimmune diseases, AnaptysBio's Roslinimab is undoubtedly a highly anticipated drug. On February 12th local time, AnaptysBio announced that Rosnilimab achieved positive results in the phase 2b clinical trial RENOIR for the treatment of moderate to severe rheumatoid arthritis (RA) patients. This news was like a bombshell, instantly triggering strong reactions in the pharmaceutical industry. Affected by this news, AnaptysBio's US stock market rose more than 34% in intraday trading on the 12th, closing up 30%.
Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation, pain, swelling, and functional impairment of joints, which seriously affects the quality of life of patients. At present, although there are multiple treatment methods and drugs to choose from, there are still some patients who do not respond well to existing treatment plans and urgently need new treatment methods. In this context, the positive research results of Rosnilimab have brought new hope to patients with rheumatoid arthritis.
3、 Rosnilimab's outstanding performance and advantages
In this phase 2b clinical trial, Rosnilimab demonstrated good efficacy and safety. The trial recruited over 400 patients and divided them into four groups on average: 100mg subcutaneous injection of ranibizumab every four weeks (Q4W), 400mg subcutaneous injection every four weeks, 600mg subcutaneous injection every two weeks (Q2W), and placebo treatment.
On the baseline patient score, the average baseline DAS-28 CRP score was 5.64. From the efficacy data, the main clinical outcomes of different dose groups showed that the difference in score decline was not significant at 12 weeks, but gradually began to widen at 14 weeks. And the difference between the placebo group and different treatment groups was not significant at 12 weeks, mainly widening at 14 weeks.
For example, at week 12, the treatment group with 600mg Q2W decreased by 2.06 points, while the placebo group decreased by 1.69 points; At week 14, the 600mg group decreased by 2.65 points, while the placebo group only decreased by 1.39 points, resulting in a significant difference of 1.26 points in scores between the two groups. More importantly, the 600mg group has not yet reached the plateau period, and there is still significant room for score decline compared to the placebo group. This also makes people look forward to the changes in scores of the 600mg group at week 28.
In terms of security, Rosnilimab also performs well. Compared with other drugs currently available on the market for the treatment of rheumatoid arthritis, such as AbbVie's Rinvoq (Upatinib, JAK1 inhibitor), Roslinimab has a lower incidence of adverse reactions and infections. According to SELECT-NEXT data from the Phase III clinical trial of Upatinib in rheumatoid arthritis, 125 out of 221 patients (57%) receiving 15mg Upatinib reported adverse events, and 118 out of 219 patients (54%) receiving 30mg Upatinib reported adverse events.
In terms of infection rates with Upatinib, 64 out of 221 patients receiving 15 milligrams of treatment [29%] and 69 out of 219 patients receiving 30 milligrams of treatment [32%]. In the clinical trial of Rosnilimab, the incidence of adverse reactions in the 600mg group was 36%, and the incidence of infection was only 11%, resulting in a discontinuation rate of adverse reactions of only 2%. These data indicate that Rosnilimab has significant advantages in terms of security, which also lays a solid foundation for its future competition in the market.
Looking back at the development process of PD-1 agonists in the field of autoimmune diseases, it has not been smooth sailing. Previously, Peresolimab from Eli Lilly was also highly anticipated. In 2023, it achieved the primary clinical endpoint in Phase IIa clinical trials, also targeting indications for rheumatoid arthritis, and published relevant articles in the New England Journal of Medicine. In its design, there are three groups: placebo group, 300mg Peresolimab group, and 700mg Peresolimab group, with the number of people allocated in a 1:1:2 ratio.
The final results showed that for the 700mg group, at week 12, the DAS28-CRP changes in the 700mg peresolimab group decreased by 2.09 ± 0.18 points vs. -0.99 ± 0.26 points, indicating a significant therapeutic effect. However, this clinical trial did not show significant advantages in ACR50 (50% reduction compared to baseline) and ACR70 response, and a serious adverse reaction - hypothyroidism symptoms - occurred in the 700mg group, although according to evaluation, it was not related to drug intervention.
Unfortunately, the development of the drug was ultimately halted in the third quarter of last year, which had a certain impact on the entire PD-1 agonist field and raised doubts about its prospects.
Compared with Peresolimab from Eli Lilly, Roslinimab from AnaptysBio has more significant advantages in basic mechanisms. Rosnilimab targets the proximal epitope of the membrane, while the epitope bound by Lilly's Peresolimab is further away from the membrane, and Peresolimab has a weaker depletion effect on the target, resulting in a weaker excitatory effect of Peresolimab compared to Rosnilimab. It is these key differences that have made Rosnilimab stand out in clinical trials, injecting new vitality into the development of PD-1 agonists in the field of autoimmune diseases.
In China, although there are not many companies currently engaged in the research and development of PD-1 agonists and they are in the early stages, some companies have already taken exploratory steps. On February 10th, Jinsai Pharmaceutical announced that the National Medical Products Administration has approved the clinical trial of its self-developed humanized anti-PD-1 monoclonal antibody GenSci120 injection for rheumatoid arthritis.
As of now, the investigational product has been approved for clinical research on four autoimmune diseases: adult systemic lupus erythematosus, adult primary Sjogren's syndrome, inflammatory bowel disease, and rheumatoid arthritis. The company pipeline ILB-2110 of Yingnuohu Pharmaceutical in Hangzhou also belongs to PD-1 agonists and is still in the preclinical stage.
For domestic enterprises, the development of PD-1 agonists in the field of autoimmune diseases brings both opportunities and challenges. From the perspective of opportunities, with the continuous improvement of domestic pharmaceutical research and development level, more and more enterprises have the ability to carry out innovative drug research and development.
PD-1 agonists, as a promising field, provide opportunities for domestic enterprises to participate in international competition. If domestic enterprises can make breakthroughs in this field, it can not only meet the clinical needs of domestic patients, but also enhance their competitiveness in the international market. In addition, the government's support for pharmaceutical innovation is constantly increasing, and a series of encouraging policies have been introduced to provide a favorable policy environment for enterprise research and development innovation.
However, challenges cannot be ignored either. Firstly, the development of PD-1 agonists is difficult and requires companies to have strong research and development capabilities and professional technical teams. From target discovery, drug design to clinical trials, every step requires a significant investment of manpower, resources, and finances, and faces a high risk of failure.
Secondly, large international pharmaceutical companies have made certain progress in the research and development of PD-1 agonists, such as AnaptysBio's Roslinimab, which has achieved positive results in clinical trials of rheumatoid arthritis, which is a huge competitive pressure for domestic enterprises.
In this situation, domestic enterprises need to accelerate their research and development progress, improve research and development efficiency, and seek market opportunities through differentiated competition. In addition, the conduct of clinical trials is also a crucial step. Clinical trials need to strictly follow relevant regulations and standards to ensure the scientific and reliable nature of the trial. At the same time, it is necessary to address issues such as patient recruitment and trial costs, which place high demands on the organizational and coordination capabilities of enterprises.
Looking ahead, the development prospects of PD-1 agonists in the field of autoimmune diseases are highly anticipated. With the continuous deepening of research and advances in technology, we have reason to believe that more innovative drugs based on PD-1 targets will emerge, bringing more treatment options and better treatment outcomes to patients with autoimmune diseases. Meanwhile, the successful development of PD-1 agonists will also provide reference and inspiration for the research of other immune related targets, promoting the innovative development of the entire pharmaceutical industry.
The expansion of PD-1 agonists from cancer treatment to autoimmune diseases is an important breakthrough in the field of pharmaceutical research and development. It not only brings new hope to patients, but also opens up new development space for pharmaceutical companies.
In this field full of opportunities and challenges, both international giants and domestic enterprises are actively exploring and striving for innovation. I believe that in the near future, PD-1 agonists will write a new brilliant chapter in the field of autoimmune disease treatment and make greater contributions to human health.
Original link: https://www.xianjichina.com/special/detail_568286.html
Source: Xianji.com
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