4Month17Recently, Sanofi made a significant acquisition in one go.Earendil LabsTwo products“First-in-class bispecific antibody”Global Exclusive Rights:HXN-1002（α4β7AndTL1A) andHXN-1003（TL1AAndIL23），Earendil LabsWill Obtain1.25USD billion as an upfront payment, with a total amount up to17.2USD milestone payments, etc.

Self-immune, undoubtedly2025Hot words of the year!

As early as3Month21Day,BiGJointly organized with Shanghai Pudong Life Science Industry Development Co., Ltd.BiG Moment｜TL1A/FcRnCan the target become another one in the autoimmune market“Explosion Point”？This article will take you on an in-depth breakdownTL1A/FcRnThe Potential to Break the Deadlock!

RelevantReading：

TL1A Target: Can the Two-in-One Autoimmune Inflammation Pathway Amplifier Pass the Drug Development Test?

An Overview of Neonatal Fc Receptor (FcRn)

TL1A/FcRnWhether the target is available“Explosive Gene”？

TL1A（TNF-like ligand 1A) Like the inflammatory pathway"Intelligent Amplifier", through its unique ligand death receptor3（DR3) The combination activates a series of inflammatory signaling pathways, including regulationTh17Cell differentiation, upregulation of pro-inflammatory cytokines (such asIL-17A、IL-6) expression and affect the activity of fibroblasts.

From the perspective of clinical pathways,TL1ABoth an amplifier of inflammatory pathways and a solution for anti-fibrosis. In inflammatory bowel disease (IBD) in,TL1AIn ulcerative colitis (UC) and Crohn's disease (CD) is widely upregulated in the intestinal mucosa of patients, making it a key target for precision treatment. Moreover, studies show that neutralizingTL1ACan reverse the progression of colon fibrosis and limit pro-fibrotic factors such asTGF-β1The expression of waiting, which is crucial for early interventionIBDRelevance fibrosis provides a theoretical basis.

Figure1.TL1AAndDR3Role in the Immune Response

AndTL1ATargeting different inflammatory pathways,FcRn(NeonatalFcReceptor) plays a role in antibody metabolism"Smart管家". It can throughpHValue-dependent cycle mechanism, willIgGAntibodies are rescued from the lysosomal degradation pathway. However, in autoimmune diseases, this physiological mechanism instead prolongs the lifespan of pathogenic antibodies.By blockingFcRn(DevelopmentFcRninhibitor), it can achieve inhibition of a variety of autoantibodies"Indiscriminate Clearance", known as the field of autoimmune diseases"Master Key"。Wide application, covering myasthenia gravis (MG）、Idiopathic Thrombocytopenic Purpura (ITP) and other diseases.

Figure2.FcRnMechanism of Inhibitor Action

Clinical Needs: Pain Points and Opportunities in the Autoimmunity Track

Inflammatory Bowel Disease (IBD) is a disease that causes chronic inflammation of the digestive tract, mainly including ulcerative colitis (UC) and Crohn's disease (CD). Currently, existing anti-TNFDespite its remarkable efficacy, the drug has approximately40%TheIBDPatient ResistanceTNFBiological treatment presents primary or secondary loss of response. In addition, the problem of intestinal fibrosis caused by long-term inflammation is widespread, with over50%TheIBDPatients with a disease course of more than five years may develop fibrosis-related complications, and the effect of existing targeted therapies on fibrosis intervention is limited.

It has been mentioned earlier,TL1AIt is both an amplifier of inflammatory pathways and an anti-fibrotic solution. InhibitionTL1ANot only can it reduce the number of fibroblasts, but also reverse fibrosis-related indicators.

FcRnThe target reflects“One Drug, Multiple Treatments”The potential.Apart from inMGAndITPThe effective application in China, its further expansion to systemic lupus erythematosus (SLE), retinopathy and other diseases. Not only that, its combination therapy regimen with existing immunomodulators has also received significant attention in the industry.

Commercialization Path:

The Logic of Transformation from Target to Market

There is no targetedTL1ADrug Approved for Marketing, and all the candidate drugs targeting the same point in the clinical stage are developed by foreign pharmaceutical companies. Currently, there are at least a dozenTL1ATargeted drugs under research and development, including monoclonal antibodies and bispecific antibodies,6Clinical trials are underway,The fastest progress istulisokibart，3The indication is ulcerative colitis (UC), Crohn's disease (CD`) and interstitial lung disease associated with systemic sclerosis (`SSc-ILD）。

Table1.MNCExisting MainTL1APipeline Layout

With the first three pipelines (duvakitug、RG6631Andtulisokibart) Successively disclosed clinical data,TL1ATarget potential is further unleashed.

✔ TL1AThe target has better clinical therapeutic effects: inUCAmong the patients,duvakitug、RG6631AndtulisokibartThe clinical remission rates were respectively47.8%、29%、26.5%; InCDAmong the patients,duvakitug、RG6631AndtulisokibartThe endoscopic response rates were47.8%、26%、26%。 

✔ TL1AThe target has controllable safety and tolerability:duvakitug、RG6631AndtulisokibartBoth showed good tolerability and safety, with no serious adverse events reported.

Comparison of Three Pipelines in Terms of EfficacyduvakitugHas advantages, but who exactly isbest-in-classDrugs still need to be evaluated on a larger scale.3Performance of Phase Clinical Data.

As mentioned earlier,4Month17Day,Sanofi obtainedEarendil LabsTwo Self-Developed Potential First-in-Class Bispecific AntibodiesHXN-1002（α4β7AndTL1A) andHXN-1003（TL1AAndIL23) The global exclusive rights，Earendil LabsWill Obtain1.25USD billion as an upfront payment, with a total amount up to17.2USD billion in development and commercialization milestone payments, as well as tiered royalties on product sales.

Figure3.Earendil LabsEntered into an exclusive global licensing agreement with Sanofi

It is worth mentioning that 3SBio's recombinant anti-TL1AMonoclonal AntibodySSGJ-627Becoming the first in China to enterINDStageTL1AMonoclonal antibody,Preclinical studies have shown,SSGJ-627 WithTL1A With high affinity and specific binding, it has demonstrated significant efficacy in various animal models. Meanwhile,SSGJ-627 With good, acceptable safety.

Figure4.3SBioSSGJ-627EnterIND

BlockFcRnThe drugs in the pathway include targetedFcRnMonoclonal antibody drugs and in vitro recombinantFcFragment Protein, Related Field DrugsProducts include:FcRecombinant Protein DrugsEfgartigimod 、Monoclonal Antibody Rozanolixizumab、M281AndSYNT001etc. 

Figure5.FcRnInhibitor Research Layout

① Efgartigimod（Efgartigimod，ArgenxCompany), as the world's first approvedFcRnInhibitor, which has shown notable efficacy in patients with myasthenia gravis, with real-world evidence indicating a treatment response rate of70%The above. Its commercial potential has also been validated,2024Annual overseas sales have broken through20Billion US dollars, year-on-year growth84%。

EfgartigimodIs of human originIgG1TheFcRecombinant protein fragment in vitro. The product utilizesArgenxThe proprietary point mutation technology respectively in5Single-site PairFcThe sequence of the fragment has been mutated, and after the mutationFcProtein andFcRnThe binding ability has been significantly enhanced under neutral and acidic conditions.2020Year5End of the monthArgenxThe company announced,EfgartigimodIn the treatment of anti-acetylcholine receptor (AChR) Antibody-positive generalized myasthenia gravis (gMG) The Criticality of Patients3In the clinical trial, the primary endpoint was reached.2021Year12Month,EfgartigimodAs the world's firstFcRnAntagonist Receives Approval from the U.S. Food and Drug Administration(FDA)Approval.2021Year1Monthly Zaijing Pharmaceuticals &ArgenxReached an exclusive licensing cooperation, responsible forEfgartigimodDevelopment and commercialization efforts in Greater China.

Figure6.Efficacy After Completion of the First Cycle Infusion

② Nipocalimab(M281)Is a U.S. biopharmaceutical companyMomentaThe core product pipeline. Its molecular essence is deglycosylated fully humanIgG1Antibody, TargetedFcRn, the antibody was removedFcFunction.NipocalimabReceived orphan drug designation and rare pediatric disease designation for the prevention of fetal and neonatal hemolytic disease.Currently in clinical III Research phase.2020Year8 Month,Johnson & Johnson announced 65 Billion-dollar acquisitionMomenta，Thereby incorporating the product into its portfolio.

③ Rozanolixizumab(UCB-7665)Is from Brussels Biotech CompanyUCB BiopharmaA subcutaneous administration of a humanizedIgG4Antibody, capable of specifically binding to humansFcRn, BlockFcRnAndIgGInteraction, inhibiting circulationIgG`, Pathogenicity Induction`IgGClearance of autoantibodies.II The total in the clinical research phase showed thatIgGAnd Anti-AChRAverage reduction in antibody titer68%，Currently in the III In the research period.

④ Batoclimab(RVT1401)Is fromHarbour BioMedA complete human monoclonal antibody, andFcRnCombine, BlockFcRn-IgGInteract to accelerate the degradation of autoantibodies and treat various pathogenic factorsIgGMediated autoimmune diseases. The product was once included in the breakthrough therapy category in China,Clinical studies for various indications are currently underway.

MNCBusiness Layout and Competition

Multiple multinational companies (MNC) has been completed forTL1AOrFcRnThe Mega Deal:

● Merck & Co.2023Year108Billion-dollar acquisitionPrometheus Biosciences, willtulisokibartListed as a core pipeline.

● Roche in the same year71Billion-dollar acquisitionTelavant, focusing on developmentRG6631。

● Sanofi in the same year as Teva (Teva Pharmaceuticals) to reach a cooperation agreement, in15Billion USD InvestmentDuvakitugR&D.

● 2021Year1Month, Zai Lab andArgenxReached an exclusive licensing cooperation, responsible forEfgartigimodDevelopment and commercialization efforts in Greater China.

● 2020Year8 In the month, Johnson & Johnson announced that it would...65 Billion-dollar acquisitionMomenta, therebyNipocalimab(M281)Included under its umbrella.

FcRnProducts are already on the market in this track, including those from Johnson & Johnson,argenxMultiple large pharmaceutical companies, including Sanofi, Earendil Labs, etc., have made arrangements.TL1AThe field, due to the absence of globally approved products, presents a highly open market environment, with Merck, Roche, Sanofi, and others.MNCHave successively initiated research and development and achieved key progress; these transactions not only representMNCThe recognition of the mechanism of this target once again demonstrates its market potential of tens of billions of dollars.

TL1A/FcRnWhat are the trends for the next step in target development?

Multi-endpoint Design:TL1AInIBDTreatment can be combined with composite endpoints such as endoscopic improvement and dynamic changes in biomarkers to more comprehensively evaluate efficacy. This design can significantly increase the likelihood of new drug approval.IIIThe probability of the trial.

Layered Treatment:FcRnInhibitors can be based on circulationIgGHorizontal, biomarker characteristics formulate individualized dosing regimens to improve therapeutic stability.

Synergistic effects between new targets have become a hotspot for innovation. For example:TL1ATarget can be attempted withIL-23Inhibitor orJAKInhibitor Combination Composition“Dual Inflammatory Blockade”, and combined treatment with anti-fibrotic drugsIBDComplications;FcRnInhibitors can also be combined with immunosuppressants or tumor immunotherapy drugs to form a combined regimen.

WhenTL1AMeetFcRn, this is not only the convergence of two targets, but also the prelude to a revolutionary paradigm in immunotherapy. In this arena worth tens of billions of dollars, Chinese pharmaceutical companies are striving to catch up. Although the road ahead still has scientific uncertainties (such asTL1AExtraintestinal Effects、FcRnThe balance of immune homeostasis), but dare to"No Man's Land"The brave explorers will eventually reap the rewards of innovation. Let us look forward to these"Immunomodulator"How to Rewrite the Epic of Humanity's Battle Against Autoimmune Diseases!

References

[1] Earendil Labs Announces Worldwide Exclusive License Agreement with Sanofi for Next-Generation Bispecific Antibodies for Autoimmune and Inflammatory Bowel Diseases

[2] Center for Drug Evaluation, National Medical Products Administration, Information Disclosure

[3] TL1ATarget: Can the dual-perfect autoimmune-inflammatory pathway amplifier pass the drug feasibility test?BiGBiopharmaceutical Innovation Society

[4] An Article to Understand NewbornsFcReceptor (FcRn). Little Medicine Says Medicine