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      Phase 2 Nipocalimab Data Establish Proof of Mechanism in Adults Living with Moderate to Severe Rheumatoid Arthritis, Supporting its Progression into a Combination Study

      This first-ever clinical study of an FcRn inhibitor in RA showed nipocalimab reduced levels of circulating IgG antibodies, including ACPAs, indicating they may play a key role in driving RA disease activity.

      Nipocalimab demonstrated improvements in primary and secondary endpoints and participants with higher baseline ACPAs had more than twice the placebo adjusted DAS28-CRP remission compared to the overall study population

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      SPRING HOUSE, PENNSYLVANIA, NOVEMBER 7, 2023 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced data from the Phase 2a IRIS-RA clinical study for the treatment of adults living with moderate to severe active rheumatoid arthritis (RA) who have tested positive for anti-citrullinated protein antibodies (ACPAs)a and/or rheumatoid factor (RF), and who have had an inadequate response or intolerance to at least one anti-tumor necrosis factor (anti-TNF) therapy. The data from this study establish proof of mechanism for nipocalimab in RA and support its progression into a combination study.1 IRIS-RA is the first clinical study to assess the efficacy and safety of the anti-neonatal Fc (FcRn)-driven MOA for the treatment of RA.2 The study findings, along with an acceptable benefit-risk profile, support the further investigation of nipocalimab in this refractory population.1 A trial investigating the efficacy and safety of nipocalimab in combination with an anti-TNFα treatment in patients living with RA has recently been initiated.3

      Treatment with nipocalimab, an anti-FcRn receptor therapy, resulted in numerically greater improvements at Week 12 across primary and secondary efficacy endpoints including Disease Activity Score 28 using C-reactive protein (DAS28-CRP),b American College of Rheumatology (ACR) responses,c DAS28-CRP remission and Health Assessment Questionnaire – Disability Index (HAQ-DI).1,d A numerically greater number of patients in the nipocalimab group achieved ACR50 (n=5/33 nipocalimab versus n=1/20 placebo) and DAS28-CRP remission (n=7/33 nipocalimab versus n=2/20 placebo) compared with the placebo group.1

      By selectively blocking the FcRn receptor, nipocalimab reduced levels of circulating immunoglobin G (IgG) antibodies, including ACPAs, indicating they may play a key role in driving RA disease activity.4 The placebo adjusted DAS28-CRP remission rate of a subpopulation of study participants with higher mean baseline levelse of ACPAs was more than double the overall study population (23.3 percent difference from placebo [n=27]; versus 11.2 percent difference from placebo [n=53] respectively).1,4

      These data will be presented for the first time as an oral presentation at ACR Convergence 2023, taking place in San Diego, California on November 12, 2023.1 In addition, a poster (#2144) on the pharmacodynamic effects of nipocalimab in the IRIS-RA study will be presented at ACR.1,4

      “There is an urgent need for new therapeutic avenues capable of reducing the impact of rheumatoid arthritis for more patients,” said Dr. Peter C. Taylor, MA, Ph.D., FRCP, FRCPE, Norman Collisson Professor of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford.f “Even with the use of the current targeted therapies, up to half of those living with rheumatoid arthritis do not reach remission or still have low disease activity. We believe autoantibodies are major contributors to this disease activity and current rheumatoid arthritis treatments like TNF inhibitors generally don’t effectively reduce autoantibodies. These encouraging results are the first time that the selective reduction of IgG autoantibodies has shown evidence of efficacy in a clinical study and are the first ever from a clinical study of an FcRn inhibitor in rheumatoid arthritis indicating nipocalimab has the potential to improve disease activity through a novel mechanism of action.”

      IRIS-RA clinical trial results at Week 12:

      At Week 12, the IRIS-RA data show that treatment with nipocalimab resulted in consistent and numerically higher improvements across change from baseline in DAS28-CRP score (Table 1) and HAQ-DI (Supplement, Table 1) as well as ACR responses (Supplement, Table 2), compared to placebo.1 The data also highlighted the differential response to treatment with nipocalimab for patients with higher baseline levels of ACPAs (Table 2).1,4

      PK/PD simulation based on data from previous nipocalimab studies predicted median total IgG reduction of 64 percent at the trough (the timepoint at which the concentration of nipocalimab is at its lowest) and 76 percent at the peak with 15mg/kg IV nipocalimab.4 IRIS-RA study data are consistent with the model predictions and showed 62 percent reduction (median) in total IgG at the trough.4

      Table 1: Mean Change from Baseline Scores for Patients at Week 121


      Nipocalimab, n=33 (95 percent Confidence Interval [CI])

      Placebo, n=20

      (95 percent CI)

      Least squares mean difference (95 percent CI)P value
      DAS28-CRP score-1.03 (-1.66; -0.40)-0.58 (-1.24; 0.07)-0.45 (-1.17; 0.28)0.224

      Table 2: Difference of Nipocalimab and Placebo Response in Patients with Higher Mean Baseline Levels of ACPA (ACPAHigh) at Week 121

      All patients, n=53

      (nipocalimab vs. placebo)

      ACPAHigh patients, n=27

      (nipocalimab vs. placebo)

      DAS28-CRP remission11.2 percent (21.2 vs. 10.0)23.3 percent (40.0 vs. 16.7)
      ACR5010.2 percent (15.2 vs. 5.0)26.7 percent (26.7 vs. 0.0)

      Nipocalimab demonstrated an acceptable benefit-risk profile:

      • The proportion of patients with treatment-emergent adverse events was 27 out of 33 (81.8 percent) in the nipocalimab group versus 12 out of 20 (60 percent) in the placebo group.1
      • In the nipocalimab group, three serious treatment-emergent adverse events were reported, including burn infection, infusion-related reaction and deep-vein thrombosis.1 There were no deaths.1No serious adverse events were reported in the placebo group.1
      • Nipocalimab did not have a clinically meaningful impact on albumin (-1.83 percent in nipocalimab versus 1.54 percent in placebo mean change from baseline to Week 18)5 or total cholesterol (-2.34 percent in nipocalimab versus 3.13 percent in placebo mean change from baseline to Week 18).6

      “Significant patient need remains for those suffering from rheumatoid arthritis and our research shows autoantibodies like ACPAs may contribute to the development and activity of rheumatoid arthritis,” said Terence Rooney, M.D., Vice President, Rheumatology Disease Area Leader, Janssen. “Current treatments, like TNF-inhibitors, may not markedly reduce autoantibodies when used alone so these results are promising for patients who have had inadequate responses to other advanced therapies. The combination of nipocalimab with therapies that have a complementary MOA, such as anti-TNFs, will be of interest as we explore alternative avenues of treatment for patients with rheumatoid arthritis, and we are excited to have initiated the Phase 2a DAISY-RA trial to explore this combination. We are also encouraged by the efficacy of nipocalimab in the autoantibody high subpopulation, providing a potential precision-medicine approach to treating patients.”

      Janssen recently initiated a Phase 2a proof-of-concept trial, DAISY-RA (NCT06028438), investigating the efficacy and safety of nipocalimab in combination with an anti-TNFα treatment in patients living with RA who have had an inadequate response or intolerance to at least one advanced disease-modifying antirheumatic drug therapy.3 The DAISY-RA trial is currently ongoing and is recruiting patients in the study.3

      Nipocalimab is the only anti-FcRn currently being studied across three key disease segments: maternal fetal immune, rare autoantibody and prevalent rheumatic diseases and is the only anti-FcRn being studied in pregnant individuals at high risk of hemolytic disease of the fetus and newborn.2,22,23,24,25,26,27,28,29

      Editor’s Notes

      a. ACPAs are autoantibodies against citrullinated proteins and may be reliable markers for the early diagnosis of RA.7 Up to 80 percent of patients living with RA are seropositive for ACPAs and/or RF.8

      b. DAS28-CRP is a tool used to assess RA disease activity, calculated based on the tender joint count and swollen joint count (both out of 28 evaluated joints), patient’s global assessment of disease activity, and CRP.9 Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement.10 CRP is a type of protein that increases during inflammatory conditions, such as RA.11,12

      c. ACR20/50/70/90 response is defined as at least 20/50/70/90 percent improvement from baseline in the number of tender and swollen joints, and at least 20/50/70/90 percent improvement from baseline in three of the following five criteria: patient’s assessment of pain by visual analog scale, patient’s global assessment of disease activity, physician’s global assessment of disease activity, patient’s assessment of physical function measured by HAQ-DId and CRP.2,13

      d. HAQ-DI is a 20-question instrument assessing eight functional areas, range: 0-3, 0=no difficulty, 3=inability to perform a task in that area.14

      e. Higher baseline levels are defined as ACPAa values above the median of the study population.1

      f. Dr. Peter C. Taylor is a paid consultant for Janssen. He has not been compensated for any media work.

      Supplement

      Supplement Table 1: Mean Change from Baseline Scores for Patients at Week 121,15

      Nipocalimab, n=33 (95 percent Confidence Interval [CI])

      Placebo, n=20

      (95 percent CI)

      Least squares mean difference (95 percent CI)P value
      HAQ-DI
      -0.42 (-0.66; -0.19) -0.21 (-0.45; 0.04) -0.22 (-0.49- 0.05) 0.108

      Supplement Table 2: Percentage of Patients Who Achieved A Response at Week 121

      Nipocalimab, n=33Placebo, n=20Treatment Difference (95 percent CI)P value
      ACR2045.5 percent20.0 percent27.0 percent (3.2-50.9)0.055
      ACR50
      15.2 percent5.0 percent8.6 percent (-6.7-23.8)0.390*
      ACR7012.1 percent0 percent11.6 percent (0.9-22.3)0.285*
      ACR906.1 percent0 percent5.8 percent (-2.0-13.6)0.521*
      DAS28-CRP remission21.2 percent10.0 percent9.9 percent (-9.5-29.3)0.456*
      *The p value was based on the Cochran-Mantel-Haenszel chi-square test, stratified by random stratification factor: baseline methotrexate use. The Mantel Fleiss criterion was not satisfied with the indicated p values and was therefore based on the Fisher’s exact test.1

      About IRIS-RA
      The IRIS-RA study (NCT04991753) is a Phase 2a multicenter, randomized, double-blind, parallel-group, placebo-controlled, proof-of-concept clinical trial that is designed to evaluate the efficacy and safety of nipocalimab in adults living with moderate to severe active RA.2 Nipocalimab is being studied with the aim to reduce the severity and progression of RA by lowering concentrations of IgG isotype antibodies, including ACPAs and their immune complexes to reduce disease activity.1 The Phase 2a IRIS-RA study is the first in RA to assess the efficacy and safety of anti-FcRn mechanism of action that specifically targets IgG isotype antibodies, including ACPAs.2 The trial enrolled adult patients with moderate to severe active RA (≥6 swollen/tender joints), positive for ACPAs or RF, and who have had an inadequate response or intolerance to at least one anti-TNF therapy.2 Fifty-three patients were enrolled, 33 of whom received nipocalimab and 20 received placebo.1 Participants were randomized 3:2 to receive intravenous 15 mg/kg nipocalimab or placebo every other week for 10 weeks.1 Demographic and baseline disease characteristics were generally comparable between groups.1 The primary endpoint was the change from baseline in DAS28-CRP at Week 12.1 Secondary endpoints included the proportion of patients who achieved ACR20, ACR50, ACR70, and ACR90 responses, DAS28-CRP remission, and change from HAQ-DI at Week 12.1

      About Rheumatoid Arthritis
      Rheumatoid arthritis (RA) is a chronic, symmetric, inflammatory disease involving the synovial joints.16 RA occurs when the immune system loses its normal state of balanced control and activates sustained inflammation in the soft inner lining of joints, called synovial tissue.17 This inflammation produces joint pain, swelling, and stiffness, and can lead to permanent damage and deformity in structural joint elements like cartilage and bone.17 Significantly reduced physical function and health-related quality of life typically accompany these features.18 Antibody systems, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are associated with RA, having been identified based on the antigens these antibodies bind to.8 RA is the most common inflammatory arthritis and affects an estimated 13 million people worldwide.19 It is estimated that 1.5 million people in the United States are affected by RA.17,20

      About Nipocalimab
      Nipocalimab is an investigational, high-affinity, fully human, aglycosylated, effectorless, monoclonal antibody that is IgG-specific and designed to selectively block FcRn to reduce levels of circulating IgG antibodies, including autoantibodies and alloantibodies that underlie multiple conditions.21 Nipocalimab is the only anti-FcRn being studied across three key segments in the antibody-driven space: prevalent rheumatological diseases (e.g., rheumatoid arthritis, Sjögren’s disease, and systemic lupus erythematosus), maternal-fetal diseases mediated by maternal alloantibodies (e.g., Hemolytic Disease of the Fetus and Newborn [HDFN]); and rare autoantibody diseases (e.g., generalized myasthenia gravis in adults and children, chronic inflammatory demyelinating polyneuropathy, warm autoimmune hemolytic anemia, and idiopathic inflammatory myopathies).2,22,23,24,25,26,27,28,29 Blockade of FcRn by nipocalimab has the potential to reduce overall allo-/autoantibody levels while potentially maintaining immune function. FcRn blockade is also believed to prevent placental transfer of maternal alloantibodies to the fetus.22,30

      About Janssen

      At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension.

      Learn more at www.janssen.com. Follow us at https://twitter.com/JNJInnovMed.

      Janssen Research & Development, LLC is a Johnson & Johnson company.

      Cautions Concerning Forward-Looking Statements

      This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of nipocalimab. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 1, 2023, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither of Janssen Research & Development, LLC nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

      References

      1Taylor PC, Schett G, Fowzia I, et al. Efficacy and Safety of Nipocalimab in Patients with Moderate to Severe Active Rheumatoid Arthritis (RA): the Multicenter, Randomized, Double-blinded, Placebo-controlled Phase 2a IRIS-RA Study. Data presentation at American College of Rheumatology Convergence 2023, November 10-15.

      2ClinicalTrials.gov Identifier: NCT04991753. Available at: https://clinicaltrials.gov/study/NCT04991753. Last accessed: November 2023.

      3ClinicalTrials.gov Identifier: NCT06028438. Available at https://clinicaltrials.gov/study/NCT06028438. Last accessed: November 2023.

      4Panchakshari RA, Loza MJ, Huizinga TWJ, et al. Pharmacodynamic Effects of Nipocalimab in Patients with Moderate to Severe Active Rheumatoid Arthritis (RA): Results From The Multicenter, Randomized, Double-Blinded, Placebo-Controlled Phase 2a IRIS-RA Study. Data poster presentation at American College of Rheumatology Convergence 2023, 10-15 November.

      5Janssen data on file. Summary of Albumin Laboratory Values and Percent Change From Baseline Over Time Through Week 18; Safety Analysis Set. TSFLABALB02. Prepared: November 2023.

      6Janssen data on file. Summary of Total Cholesterol Laboratory Values and Percent Change From Baseline Over Time Through Week 18; RF-284947. Prepared: November 2023.

      7Liu J, Gao J, Wu Z, Mi L, Li N, Wang Y, Peng X, Xu K, Wu F, Zhang L. Anti-citrullinated Protein Antibody Generation, Pathogenesis, Clinical Application, and Prospects. Front Med (Lausanne). 2022 Jan 12;8:802934. doi: 10.3389/fmed.2021.802934. PMID: 35096892; PMCID: PMC8791387.

      8Myrthe A.M. van Delft, Tom W.J. Huizinga, An overview of autoantibodies in rheumatoid arthritis, Journal of Autoimmunity, Volume 110, 2020, 102392, ISSN 0896-8411, https://doi.org/10.1016/j.jaut.2019.102392.

      9Nielung L, et al. Validity and Agreement between the 28-Joint Disease Activity Score Based on C-Reactive Protein and Erythrocyte Sedimentation Rate in Patients with Rheumatoid Arthritis. Arthritis. 2015; 401690. doi: 10.1155/2015/401690

      10Janssen Research and Development. Statistical analysis plan. A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Guselkumab Administered Subcutaneously in Subjects with Active Psoriatic Arthritis including those Previously Treated with Biologic Anti-TNFα

      Agent(s). March 2019. Available at: https://classic.clinicaltrials.gov/ProvidedDocs/96/NCT03162796/SAP_001.pdf. Accessed: November 2023.

      11Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018 Apr 13;9:754. doi: 10.3389/fimmu.2018.00754. PMID: 29706967; PMCID: PMC5908901.

      12Nielsen SF, et al. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ 2012;345:e5244. Available at: doi: 10.1136/bmj.e5244.

      13Medicine Matters. At a glance: Common scores used in rheumatology. 2018. Available at: https://rheumatology.medicinematters.com/treatment/patient-reported-outcomes-/at-a-glance-rheumatology-scores/16077860. Accessed: November 2023.

      14Bruce B, Fries JF. The health assessment questionnaire (HAQ). Clin Exp Rheumatol 2005; 23 (Suppl. 39): S14-S18.

      15Janssen data on file. Secondary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from Baseline in HAQ-DI Score at Week 12 Using an ANCOVA Model; RF-284926. Prepared November 2023.

      16Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA. 2018 Oct 2;320(13):1360-1372. doi: 10.1001/jama.2018.13103. PMID: 30285183.

      17Arthritis Foundation. Rheumatoid Arthritis: Causes, Symptoms, Treatments and More. Accessed November 2023. Available at https://www.arthritis.org/diseases/rheumatoid-arthritis.

      18Malm K, Bergman S, Andersson ML, Bremander A, Larsson I. Quality of life in patients with established rheumatoid arthritis: A phenomenographic study. SAGE Open Med. 2017 Jun 7;5:2050312117713647. doi: 10.1177/2050312117713647. PMID: 28611920; PMCID: PMC5466281.

      19Cieza A, et al. “Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019.” The Lancet 396, no. 10267 (2020): 2006-2017. doi: https://doi.org/10.1016/S0140-6736(20)32340-0.

      20World Health Organization. The global burden of disease: 2004 update. Geneva: WHO Press, 2008. Accessed November 2023. Available at https://apps.who.int/iris/bitstream/handle/10665/43942/9789241563710_eng.pdf?sequence=1&isAllowed=y.

      21Roy S, Nanovskaya T, Patrikeeva S, et al. M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model. Am J Obstet Gynecol. 2019;220(5):498 e491-498 e499.

      22ClinicalTrials.gov Identifier: NCT03842189. Available at: https://clinicaltrials.gov/ct2/show/NCT03842189. Last accessed: November 2023.

      23ClinicalTrials.gov Identifier: NCT05265273. Available at: https://clinicaltrials.gov/ct2/show/NCT05265273. Last accessed: November 2023.

      24ClinicalTrials.gov Identifier: NCT04951622. Available at: https://clinicaltrials.gov/ct2/show/NCT04951622. Last accessed: November 2023.

      25ClinicalTrials.gov Identifier: NCT05327114. Available at: https://clinicaltrials.gov/ct2/show/NCT05327114. Last accessed: November 2023.

      26ClinicalTrials.gov Identifier: NCT04119050. Available at: https://clinicaltrials.gov/ct2/show/NCT04119050. Last accessed: November 2023.

      27ClinicalTrials.gov Identifier: NCT04968912. Available at: https://clinicaltrials.gov/ct2/show/NCT04968912. Last accessed: November 2023.

      28ClinicalTrials.gov Identifier: NCT04882878. Available at: https://clinicaltrials.gov/ct2/show/NCT04882878. Last accessed: November 2023.

      29ClinicalTrials.gov Identifier: NCT05379634. Available at: https://clinicaltrials.gov/ct2/show/NCT05379634. Last accessed: November 2023.

      30Roy S, Nanovskaya T, Patrikeeva S, et al. M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model. Am J Obstet Gynecol. 2019;220(5):498 e491-498 e499.

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