nipocalimab
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nipocalimab
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Nipocalimab - Clinical Use in Sjogren's Disease (SjD)
Last Updated: 01/06/2025
SUMMARY
- Nipocalimab is a fully human, aglycosylated, effectorless immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity to the IgG-binding site on the neonatal Fc receptor (FcRn). Nipocalimab is an investigational agent being studied for the treatment of adult patients with primary Sjogren’s disease (SjD).1
, 2 - By selectively blocking FcRn, nipocalimab interferes with IgG recycling and in turn reduces circulating IgG levels, including pathogenic IgG autoantibodies that may contribute to primary SjD (those that target Ro/La ribonuclear complexes, ie, antibodies to primary SjD-associated antigen A [anti-Ro/SSA] and primary SjD-associated antigen B [anti-La/SSB]).3
- By selectively blocking FcRn, nipocalimab interferes with IgG recycling and in turn reduces circulating IgG levels, including pathogenic IgG autoantibodies that may contribute to primary SjD (those that target Ro/La ribonuclear complexes, ie, antibodies to primary SjD-associated antigen A [anti-Ro/SSA] and primary SjD-associated antigen B [anti-La/SSB]).3
- A phase 2, multicenter, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of nipocalimab in adult patients with moderately to severely active primary SjD (NCT04968912).1,4
- Patients treated with nipocalimab 15 mg/kg demonstrated statistically significant (P=0.002) improvement in Clinical European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ClinESSDAI) score from baseline to 24 weeks versus placebo [least square mean change (LS) -6.40 vs -3.74, respectively] (primary endpoint).3
- Nipocalimab treatment was well tolerated with no new safety signals observed.
BACKGROUND
- SjD is a chronic, autoimmune, systemic, progressive disease that can be associated with significant morbidity and mortality.1
- SjD is characterized by lymphocytic infiltration of exocrine glands and B-cell dysfunction, resulting in sicca syndrome (dryness of the eye, oral cavity, pharynx, larynx, and/or vagina).5
,6 Ocular and oral dryness are the primary local manifestations, with >25% of patients also developing systemic symptoms.6,7 Commonly affected organs include cardiovascular (Raynaud phenomenon), digestive (dysphagia, chronic gastritis), pulmonary (pleuritis), ocular (uveitis), cutaneous, neurological, eyes/nose/throat, and urological systems.7 SjD also increases the risk of hematologic malignancies in patients.8 ,9 - SjD is classified into 2 categories5,10
- Primary SjD: Occurs by itself in an individual without underlying autoimmune disorder.
- Secondary SjD: Associated with other autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or systemic sclerosis.
- Primary SjD has a global incidence of 6.92 (95% confidence interval [CI], 4.98-8.86) per 100,000 person-years at risk and a global prevalence of 60.82 (95% CI, 43.69-77.94) cases per 100,000 people.11
It is more common in women than among men (incidence ratio, 9.15:1), with an onset typically between 50 and 60 years of age.11 - Primary SjD develops from the activation of both innate and adaptive immune systems, triggered initially by viral infection of the salivary epithelial cells.12
,13 This leads to B-lymphocyte hyperactivity, resulting in abnormally high levels of IgG and production of pathogenic IgG autoantibodies specifically targeting Ro/La ribonuclear complexes (ie, anti-Ro/SSA and anti-La/SSB).12,13 These pathogenic autoantibodies form immune complexes that activate inflammatory cascades, causing extraglandular tissue damage.12 Elevated B-cell activating factor levels are observed in the sera of patients with primary SjD and are upregulated in their salivary glands.14 Autoantibodies for rheumatoid factor, anti-Ro, and anti-La appear for a median of 4-6 years before symptom development.15 As the disease progresses, periductal infiltrate becomes more organized into ectopic lymphoid tissue, with an increase in the number of B-cells and formation of ectopic germinal centers.12 - Currently, there are no approved treatments to alter disease progression in SjD; thus, treatment strategies focus on symptomatic management.6 The Sjogren’s Syndrome Foundation has developed guidelines for assessing and managing dry eyes, dry mouth, and the systemic manifestations of SjD.16
- 18 First-line treatment typically involves hydroxychloroquine, followed by methotrexate, methotrexate plus hydroxychloroquine, corticosteroids, leflunomide, sulfasalazine, azathioprine, and cyclosporine for musculoskeletal pain. Rituximab may be considered for systemic manifestations.18 Tumor necrosis factor (TNF)- inhibitors are avoided unless patients have both primary SjD and RA.18
CLINICAL DATA
Phase 2 Study
A phase 2, multicenter, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of nipocalimab in adult patients with moderately to severely active primary SjD (NCT04968912).3
Study Design/Methods
- A total of 163 patients were randomized to receive intravenous (IV) nipocalimab 5 mg/kg or 15 mg/kg, or placebo every 2 weeks (Q2W) through week 22.1,3
- Patients were permitted to receive background standard-of-care therapies, including immunomodulators, antimalarial drugs, or glucocorticoids, as allowed by the protocol.1
- The study design is shown in Figure: Phase 2 Study Design (Primary SjD).
Abbreviations: ACR, American College of Rheumatology; anti-Ro/SSA, primary SjD-associated antigen A; clinESSDAI, Clinical European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index; COPD, chronic obstructive pulmonary disorder; CRESS, Composite of Relevant Endpoints for Sjogren’s Syndrome; ESSPRI, EULAR Sjogren’s Syndrome Patient Reported Index; EULAR, European League Against Rheumatism; IV, intravenously; R, randomized; SjD, Sjogren’s disease; STAR, Sjogren’s Tool for Assessing Response.
- Other key exploratory endpoints included pharmacokinetics and immunogenicity measures, clinical biomarkers, and pharmacodynamics.1
Results
A total of 163 patients were enrolled in the study. Baseline characteristics were comparable between groups. For complete baseline demographics, see Table: Baseline Demographic Characteristics (ITT Population).
Baseline Demographic Characteristics (ITT Population)3
| Characteristics | Placebo (n=56) | NIPO 5 mg/kg Q2W (n=53) | NIPO 15 mg/kg Q2W (n=54) | All Patients (N=163) |
|---|---|---|---|---|
| Age, years, median (range) | 46.5 (23-73) | 49.0 (20-72) | 48.5 (24-72) | 48.0 (20-73) |
| Female, % | 92.9 | 92.5 | 92.6 | 92.6 |
| White, % | 89.3 | 92.5 | 90.7 | 90.8 |
| Time since diagnosis, years, median (range) | 4.0 (0.6-34.0) | 3.7 (0.6-27.9) | 4.3 (0.6-18.2) | 4.0 (0.6-34.0) |
| ClinESSDAI score, mean (SD) | 10.0 (3.8) | 9.4 (3.1) | 10.2 (3.6) | 9.9 (3.5) |
| ESSPRI score, mean (SD) | 7.0 (1.3) | 7.0 (1.3) | 7.2 (1.2) | 7.1 (1.2) |
| Total IgG levels,a | 14.8 (7.7-40.5) | 14.8 (4.6-35.2) | 15.5 (7.6-49.6) | 14.9 (4.6-49.6) |
| Autoantibody positivity, N | 55 | 52 | 53 | 160 |
| Anti-Ro60, % | 98.2 | 98.1 | 98.1 | 98.1 |
| Anti-La, % | 74.5 | 76.9 | 64.2 | 71.9 |
| Anti-Ro52, % | 78.2 | 86.5 | 77.4 | 80.6 |
| RF, % | 78.6 | 71.7 | 63.0 | 71.2 |
| Abbreviations: ClinESSDAI, Clinical European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index; ESSPRI, European League Against Rheumatism Sjogren’s Syndrome Patient Reported Index; IgG, immunoglobulin G; ITT, intent-to-treat; NIPO, nipocalimab; Q2W, every 2 weeks, RF, rheumatoid factor; SD, standard deviation. aMeasured at a central laboratory. Reference range, 6.03-16.13 g/L. | ||||
Efficacy
- A statistically significant change in ClinESSDAI from baseline was observed at week 24 for nipocalimab 15 mg/kg compared to placebo (P=0.002).3
- Treatment with nipocalimab resulted in greater LS mean (90% CI) improvement from baseline to week 24 in the nipocalimab 5 mg/kg Q2W and 15 mg/kg Q2W groups when compared with placebo as illustrated in Figure: LS Mean (90% CI) Change in ClinESSDAI at Week 24.
Abbreviations: CI, confidence interval; ClinESSDAI, Clinical European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index; LS, least squares; NS, nonsignificant; Q2W, every 2 weeks.
- Mean changes in secondary and supportive endpoints are presented in Tables: Secondary Endpoints and Supportive Endpoints.
| LS Mean Difference (90% CI): Nipocalimab vs Placeboa | Nominal P-valueb | ||
|---|---|---|---|
| 5 mg/kg Q2W (N=53) | 15 mg/kg Q2W (N=54) | ||
| PhGA | -2.26 (-8.50 to 3.99) | -14.50 (-20.81 to -8.19) | <0.001 |
| ESSDAI | -0.52 (-1.67 to 0.63) | -1.79 (-2.94 to -0.63) | 0.012 |
| ESSPRI | 0.62 (0.01 to 1.23) | -0.41 (-1.03 to 0.20) | 0.268 |
| Abbreviations: CI, confidence interval; ESSDAI, European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index; ESSPRI, European League Against Rheumatism Sjogren’s Syndrome Patient Reported Index; LS, least squares; PhGA, Physician Global Assessment of Disease Activity; Q2W, every 2 weeks. aCompared with placebo group using a Mixed Effects Repeated Measures model with baseline score, study treatment, visit, region, baseline steroid use, baseline antimalarial use, and an interaction of treatment and visit as terms in the model. For continuous endpoints, participants with an intercurrent event per protocol were considered to have missing data thereafter. bThese endpoints were not adjusted for multiple comparisons. Therefore, the p-values displayed are nominal, and statistical significance has not been established. | |||
| Endpoint- Responder Rate at Week 24 | Difference in Proportions [% (90% CI)]: Nipocalimab vs Placeboa | Nominal P-valueb Nipocalimab 15 mg/kg Q2W vs Placebo | |
|---|---|---|---|
| 5 mg/kg Q2W (N=53) | 15 mg/kg Q2W (N=54) | ||
| ESSDAI-3 | 9.5 (-5.8 to 24.8) | 16.1 (0.8 to 31.4) | 0.172 |
| STAR | 11.7 (-3.9 to 27.2) | 23.7 (8.4 to 38.9) | 0.017 |
| CRESS | 25.5 (11.5 to 39.5) | 30.3 (16.3 to 44.3) | 0.001 |
| DALc | 18.9 (3.6 to 34.2) | 19.8 (4.5 to 35.0) | 0.046 |
| Abbreviations: CI, confidence interval; CRESS, Composite of Relevant Endpoints for Sjogren’s Syndrome; DAL, Disease Activity Level; ESSDAI, European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index; Q2W, every 2 weeks; STAR, Sjogren’s Tool for Assessing Response.aValues are percentages. Statistically compared with the placebo group using a Cochran-Mantel-Haenszel test with region, baseline steroid use, and baseline antimalarial use as stratification factors. For binary composite endpoints, participants with intercurrent events were considered nonresponders after the event. bThese endpoints were not adjusted for multiple comparisons. Therefore, the p-values displayed are nominal, and statistical significance has not been established. cDAL response is a reduction by at least 1 level from baseline in disease activity level in at least 1 ClinESSDAI domain (eg, articular, hematological, cutaneous, and constitutional). | |||
Safety
- Nipocalimab treatment was well-tolerated with no new safety signals observed.
- Overall, no cases of severe hypoalbuminemia (<20 g/L) or deaths were reported.
- Severe infections or infections requiring IV anti-infectives occurred in 3.8%, 1.9%, and 1.8% of participants in the nipocalimab 5 mg/kg, nipocalimab 15 mg/kg, and placebo groups, respectively, none of which were deemed related to the study treatment.
For safety results, see Table: Nipocalimab Safety and Tolerability.
| Participants with ≥1 AE, n (%) | Placebo (N=56) | Nipocalimab | ||
|---|---|---|---|---|
| 5 mg/kg Q2W (N=53) | 15 mg/kg Q2W (N=54) | Combined (N=107) | ||
| AEs | 35 (62.5) | 42 (79.2) | 43 (79.6) | 85 (79.4) |
| Serious AEs | 3 (5.4) | 4 (7.5) | 4 (7.4) | 8 (7.5) |
| Infections and infestations | 24 (42.9) | 32 (60.4) | 28 (51.9) | 38 (56.1) |
| Severe infectionsa | 1 (1.8) | 2 (3.8) | 1 (1.9) | 3 (2.8) |
| Opportunistic infections | 0 | 0 | 0 | 0 |
| Infusion reactions | 2 (3.6) | 6 (11.3) | 1 (1.9) | 7 (6.5) |
| Hypersensitivity reactions | 3 (5.4) | 6 (11.3) | 7 (13.0) | 13 (12.1) |
| MACEb | 2 (3.6) | 0 | 0 | 0 |
| Abbreviations: AE, adverse event; IV, intravenous; MACE, major adverse cardiovascular events; Q2W, every 2 weeks.aInfections that are severe or require IV anti-infective or operative/invasive intervention, as assessed by the investigator. bCardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. | ||||
Pharmacokinetic (PK)/ Pharmacodynamic (PD) Activity
- In a PK and PD simulation analysis, a 77% maximum reduction in total IgG was observed.
- Pre-dose (minimum) median reduction of 61% in total IgG was observed at week 24 in the nipocalimab 15 mg/kg group.
- Dose-dependent reductions from baseline in total IgG were observed with nipocalimab which returned to baseline levels by week 30.19
- Consistent reductions were observed in SjD-associated anti-Ro60, -Ro52, and -La IgG autoantibodies (see Table: Observed Predose (minimum) Percent Change from Baseline in Clinical Biomarkers at Week 24).
| Median (IQR) | Placebo (n=56) | Nipocalimab | |
|---|---|---|---|
| 5 mg/kg Q2W (n=53) | 15 mg/kg Q2W (n=54) | ||
| Total IgG | -0.5 (-6.8,-5.0) | –30.0 (–41.0, –22.2) | –60.9 (–66.0, –45.7) |
| IgG subclasses | |||
| IgG1 | –1.9 (–9.4, 3.8) | –29.7 (–49.1, –21.1) | –60.0 (–65.7, –44.9) |
| IgG2 | –1.6 (–10.2, 10.2) | –30.4 (–41.6, –19.1) | –54.7 (–64.0, –41.4) |
| IgG3 | 0 (–11.4, 5.2) | –31.7 (–42.2, –18.8) | –54.2 (–62.5, –47.1) |
| IgG4 | –2.6 (–11.1, 4.8) | –27.6 (–43.1, –17.5) | –50.0 (–58.6, 34.1) |
| IgG autoantibodiesb | |||
| Anti-Ro60 | 6.6 (–8.0, 20.3) | –29.5 (–43.4, –18.1) | –60.1 (–72.3, –42.4) |
| Anti-La | 8.5 (–9.3, 22.7) | –32.7 (–49.0, –18.1) | –53.5 (–62.7, –36.7) |
| Anti-Ro52 | 6.1 (–6.3, 18.8) | –23.0 (–39.3, –14.1) | –50.9 (–62.7, –37.0) |
| C3d-CIC | 5.7 (–21.7, 28.1) | –37.5 (–47.3, 0) | –55.3 (–67.5, –47.6) |
| IgM | 2.5 (–6.5, 10.0) | –5.0 (–11.6, 2.2) | –10.5 (–22.0, –4.1) |
| IgA | –1.2 (–6.2, 3.7) | 3.4 (–5.7, 11.4) | 6.0 (–1.0, 12.2) |
| RF | 0 (–3.4, 4.0) | –10.7 (–19.4, 0) | –15.3 (–29.0, 0) |
| ESR | –16.7 (–46.1, 14.0) | –17.1 (–34.8, 25.0) | –38.5 (–58.3, 0) |
| Abbreviations: C3d-CIC, C3d-bound circulating immune complex; ESR, erythrocyte sedimentation rate; Ig, immunoglobulin; IQR, interquartile range; Q2W, every 2 weeks; RF, rheumatoid factor.aIf a patient missed a planned dose of study intervention at any visit, their data were excluded from all subsequent visits after the first occurrence of a missed dose. Only data from patients with ≥1 valid postbaseline blood sample drawn for pharmacodynamic analysis were included.bOnly data from patients who were positive for anti-Ro60, anti-La, or anti-Ro52 at baseline were included in the anti-Ro60, anti-La, and anti-Ro52 analyses, respectively. | |||
Literature Search
A literature search of MEDLINE®
References
| 1 | Hubbard JJ, Campbell K, Sivils K, et al. Design of a phase 2, multicenter, randomized, placebo-controlled, double-blind study to assess the efficacy and safety of nipocalimab, an FcRn antagonist, in adults with primary Sjögren’s syndrome. Poster presented at: 15th International Symposium on Sjögren’s Syndrome; September 7-10, 2022; Rome, Italy. |
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