Professor Zhang Fengchun: Inventory of targeted B cell therapy programs for lupus, why did you choose the "Chinese program"?

*For medical professionals to read for reference Lupus new drug development is in full swing, how do we get out of the "Chinese road"? For a long time, many scientific researchers have been devoted to solving the shortage of medicines in the field of systemic lupus erythematosus (SLE)
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At present, the discovery of drug targets and the development of new drugs are in full swing.
There are countless new drugs under development in the SLE field, and the competition is fierce
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How domestic new drugs can stand out among many "challengers", come up with a "Chinese plan", and walk out of a "Chinese road" is a question we are eager to seek
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In this issue, the medical community is honored to invite Professor Zhang Fengchun of Peking Union Medical College Hospital to discuss with us the latest progress in the development of new drugs in the field of SLE, and answer questions for readers
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Interview with Professor Zhang Fengchun Video SLE is an autoimmune disease.
What key immunological factors play a role in the pathogenesis of SLE? Prof.
Fengchun Zhang: SLE is a representative of autoimmune diseases
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It is mainly characterized by multiple system or organ damage and elevated levels of various autoantibodies
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The etiology of SLE is complex, involving both congenital genetic factors and acquired environmental factors
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Among the immunological factors, SLE involves a wide range of innate and adaptive immunity
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Therefore, both T cells and B cells play an important role in the pathogenesis of SLE, and their interaction can strengthen autoimmunity, leading to the recurrence and exacerbation of the disease: T cells recognize and bind pathogenic antigens (eg.
self-antigens) After that, it can produce a variety of cytokines and activate autoreactive B cells.
After the B cells differentiate and mature, the formed plasma cells can secrete a large number of pathogenic autoantibodies, which are important pathogenic factors of SLE
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Conversely, B cells can also act as antigen-presenting cells, presenting internalized soluble antigens to T cells, thereby activating T cells and forming a cycle [1]
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If we map the causative factors of SLE into a map, each pathway is densely woven into an intricate "signaling network", and we can see that B cell-related pathways occupy a large part of the plate
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Therefore, in terms of the current research findings, the B cell pathway plays a key role in the pathogenesis of SLE, and inhibition of B cells can prevent SLE disease progression to a certain extent
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Figure 1: The roles of various immune cells in the pathogenesis of SLE According to our current research findings, what are the targeted drugs that can be used in the clinical treatment of SLE? What is their mechanism of action and how effective is the treatment? Professor Zhang Fengchun: Although there are many studies focusing on the development of SLE-targeted drugs, it was not until 2011 that we had the first SLE-targeted therapy drug approved by the U.
S.
Food and Drug Administration (FDA), which is now on the market in China
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The study of this drug in Northeast Asian (China, Korea, Japan) populations was led by me, and the results proved its definite effect on SLE [2]
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The targeted therapy drug mainly acts on B lymphocyte stimulating factor (BLyS), thereby inhibiting the development and maturation of B cells and exerting curative effect through the B cell pathway
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In March 2021, China's self-developed new SLE drug, tetacept, passed the priority approval process and was approved for domestic marketing by the China National Medical Products Administration (NMPA)
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This is the second biologic approved for SLE indication in the world and the first new lupus drug in China
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Its mechanism of action is similar to that of BLyS inhibitors, and it also acts on the B cell pathway
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In contrast, tetacept is a dual-target biological agent, which not only inhibits BLyS, but also inhibits proliferation-inducing ligand (APRIL), preventing the activation of mature B cells and the secretion of antibodies from plasma cells, providing a more comprehensive coverage The process of B cells from development to maturity and then to antibody secretion is more complete, and the B cell pathway is more completely inhibited
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Therefore, by targeting B cells, tetacept can play a good role in controlling the progression of SLE disease
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I also led the clinical research of tacitabine.
We have completed its Phase I and Phase II clinical trials since 2011 and are currently conducting Phase III clinical trials
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Combined with the results of its Phase II clinical study and some Phase III study data, the National Center for Drug Evaluation (CDE) approved the application of tetacept for the clinical treatment of SLE
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According to the results of previous clinical studies and the clinical application data after its listing, tetacept has a good curative effect and is better than the previous treatment in the improvement of some clinical indicators [3]
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Figure 2: The primary endpoint of the phase II clinical study of tetacept The third class of drugs is type I interferon (IFN) targeted therapy drugs, and the activation of type I IFN pathway is also an important pathogenic factor for SLE
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However, this type of drug is currently only available in the United States and has not yet been approved for use in China
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Moreover, in terms of current clinical data, its efficacy is relatively weak.
The SLE remission index (SRI-4) response rate in the phase III clinical study (TULIP-1) was only 46.
9% [4], and it was not comparable to the placebo group.
significant difference
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After 48 weeks of tetacept treatment, the SRI-4 response rate can reach 70% or more [2-3]
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In addition to the above approved drugs, other biologics targeting B cells, such as anti-CD20 monoclonal antibody rituximab, may also have good effects in some areas of SLE treatment, but the efficacy is not yet clear and there are no approved indications
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Table 1: Summary of information on B cell-targeted treatment regimens[2-3,5-6] What are the new research progress of the above-mentioned targeted drugs after they are marketed? Professor Zhang Fengchun: Any drug will continue to carry out follow-up studies after it is marketed, such as phase IV studies to expand the sample population to further monitor drug efficacy and adverse reactions
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At the same time, according to the mechanism of action of the drug and the pathogenic mechanism of the disease, researchers will continue to explore and expand new indications
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For example, a LN-related study (BLISS-LN) has been carried out for BLyS inhibitor certificate to prove its efficacy in LN [5]; Taitacept has also carried out a number of off-indication exploratory trials at home and abroad, such as Preliminary research results have been obtained in some fields such as rheumatoid arthritis (RA), IgA nephropathy, multiple sclerosis, Sjögren's syndrome,
etc.

Tips: In addition to SLE, clinical trials of tatarcept in China are also underway for other six types of B cell-mediated autoimmune diseases, including two for neuromyelitis optica spectrum diseases and rheumatoid joints.
Registration clinical study of inflammation, two phase II clinical studies for IgA nephritis and Sjögren's syndrome, two phase II clinical studies for multiple sclerosis (MS) and myasthenia gravis (MG) and other intractable rare diseases.
research
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Figure 3: The current research progress of tetacept The advent of tetacept is of great significance and has been widely praised
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Many reports claim that it is a "Chinese solution" for Chinese SLE patients
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What do you think of this statement? Professor Zhang Fengchun: The advent of Taitahip is indeed the pride of our Chinese people
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In the past, these landmark innovative drugs often came from Western countries, while China's drug research and pharmaceutical industry were dominated by imitations, and innovative drugs were very rare
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The research and development of new drugs in the SLE field is even more difficult, and successful cases are few and far between
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Taitacept, independently developed by China, is the world's first dual-target biological new drug in the field of SLE, reflecting China's outstanding contributions and major achievements in the field of innovative drugs
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Figure 4: The results of the Phase IIb clinical study of tacitacept were presented at the American College of Rheumatology (ACR/ARP) in 2019.
The clinical study of tacitacept was carried out in multiple centers in China, and the results reflected its effectiveness in the Chinese population.
data
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After being launched in China, it will continue to accumulate data on the Chinese population in clinical practice, which can indeed be called a "Chinese solution" for SLE treatment
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Of course, the "Chinese solution" does not mean that it is only applicable to the Chinese patient population, which is by no means the ultimate goal of our research and development
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I hope that our innovative drugs will set sail from this, go abroad, go to the world, and bring benefits to more patients
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At present, the international clinical research of tacitabine is also under preparation, which has received extensive attention
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How do you see the application of B cell-targeted therapeutics in the field of SLE? What are your expectations for the future development of Tetracept? Prof.
Fengchun Zhang: Since B cells play a central role in the pathogenesis of SLE, therapeutic regimens targeting B cells can play an active and effective role in the treatment of SLE
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But we know that SLE is a systemic, systemic autoimmune disease that can affect many organs and systems
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Its pathogenic mechanism is not limited to the B cell pathway.
We also need to explore more potential therapeutic targets, which may achieve better results with the cooperation of multiple parties
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In the course of our study of tetacept, we have obtained its effect on overall disease activity control
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In future studies, we may pay more attention to its improving effect on various organs and systems, such as the kidneys
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Renal involvement is a very common phenomenon in SLE patients, and it is also an important factor causing poor prognosis of patients
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In a phase II clinical trial, we found that tetacept can effectively improve the renal involvement of SLE patients, but what about other organ damage? This is for us to explore further
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The above research directions provide imagination space for the follow-up research work.
Combined with the clinical use, we will further refine its applicable scenarios and give full play to its positive role
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For us, the research and application of Taitacept has just started, and the future prospects are very broad, which requires continuous efforts and exploration
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Expert Profile Professor Zhang Fengchun Chief Physician, Professor, Doctoral/Postdoctoral Supervisor Chairman of the National Internal Medicine Resident Training Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences Chairman of the Rheumatology and Immunology Branch of the China Association for the Promotion of International Exchanges in Healthcare, and the Internal Medicine Branch of the Chinese Medical Doctor Association Executive Vice President Chinese Physician Training College Vice President Member of National Pharmacopoeia Committee References: [1].
Justiz Vaillant AA, et al.
Systemic Lupus Erythematosus.
2020 Aug 10.
In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2020 Jan–.
[2].
Zhang F, et al.
Ann Rheum Dis 2018;77:355-63.
[3].
Zhang Fengchun.
Results of a pivotal clinical trial of RC18 in the treatment of systemic lupus erythematosus.
[4].
Tanaka Y, et al.
Mod Rheumatol.
2021, 31(1):1-12.
[5].
Furie R, et al.
N Engl J Med.
2020, 383(12):1117-1128.
[6].
Lee WS, et al.
Immunol Med.
2020, 43(1): 16-35.
*This article is for the purpose of providing scientific information to healthcare professionals only and does not represent the platform's position
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