SUMMARY

• Nipocalimab, a high-affinity, fully human, effectorless immunoglobulin G1 (IgG1) monoclonal antibody, is an investigational agent being studied for the treatment of adult patients with rheumatoid arthritis (RA).¹
  • By selectively blocking the neonatal FC receptor (FcRn), nipocalimab prevents IgG recycling and in turn lowers IgG levels, potentially reducing the level of anticitrullinated protein autoantibodies (ACPAs) and other pathogenic antibodies.¹
• An ongoing phase 2a, multicenter, randomized, double-blinded, parallel, proofofconcept study is evaluating the efficacy and safety of nipocalimab and certolizumab, an anti-tumor necrosis factor (TNF) agent, combination therapy in patients with active RA regardless of prior treatment with advanced therapies, including biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs; NCT06028438).²
• A phase 2a, randomized, multicenter, double-blinded, placebo-controlled, proofofconcept study evaluated the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of nipocalimab in patients with moderate to severe active RA (NCT04991753).^1,3,4
  • A greater least squares (LS) mean change in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) was observed in the nipocalimab vs placebo group at week 12 (-1.03 vs -0.58; LS mean difference, -0.45; 95% confidence interval [CI],   -1.17 to 0.28; P=0.224).¹
  • Nipocalimab was generally well-tolerated, without any new safety findings.¹

BACKGROUND

• RA is a chronic, systemic, autoimmune disorder with a complex pathogenesis characterized by symptoms of pain, stiffness, and inflammation of the joints, as well as symmetrical peripheral polyarthritis, often leading to progressive joint destruction and disability.^5,6
• Approximately, 50-90% of patients with RA are seropositive for ACPAs, which are largely of the IgG isotype, and are thought to contribute to increased joint damage and radiographic progression.^7-10
• Individuals with RA also have high levels of cytokines, including TNF-α, in the synovial fluid, which contribute to inflammation and joint destruction in RA.^11,12 Hyperplasia of the synovium from chronic inflammation results in formation of pannus, a thickened, hypertrophied synovial membrane that extends over and sometimes invades the adjacent cartilage and bone and contributes to cartilage destruction and bone erosion.¹³ The juxtaarticular cartilage degradation and bone erosion are characteristic features of RA that delineates it from other kinds of chronic arthritis.¹⁴
• Conventional synthetic DMARDs, bDMARDs, such as anti-TNF agents, and tsDMARDs are pharmacological agents commonly used in patients with RA to mitigate the disease activity.^15,16 Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GCs) are used as adjunctive therapy to reduce inflammation and pain.^17,18 The guidelines provided by the American College of Rheumatology (ACR) conditionally recommend a minimal initial treatment goal of low disease activity (LDA) over a goal of remission.¹⁵

CLINICAL DATA

Phase 2a Study: DAISY

An ongoing phase 2a, multicenter, randomized, double-blinded, parallel, proof-of-concept study is evaluating the efficacy and safety of nipocalimab and certolizumab combination therapy in patients with active RA regardless of prior treatment with advanced therapies (bDMARDs or tsDMARDs; NCT06028438).²

Study Design/Methodology

Adult patients are included in the study if they (a) had moderate to severe active RA for ≥3 months before screening, along with ≥6/66 swollen joints and 6/68 tender joints while undergoing screening and at baseline; (b) were positive for ACPA or rheumatoid factor and had C-reactive protein (CRP) levels ≥0.3 mg/dL during screening; (c) received prior bDMARDs (or biosimilars) other than anti-TNF agents for RA and demonstrated an inadequate response or intolerance to the therapy; or received prior anti-TNF agents (or biosimilars), and demonstrated an inadequate response to ≥1 anti-TNF agents (or biosimilars).²

The 2 treatment groups include:

• Nipocalimab intravenously (IV) plus certolizumab dose 1 subcutaneously (SC) at weeks 0, 2 and 4 followed by nipocalimab IV and certolizumab dose 2 SC at weeks 6 to 22
• Placebo IV plus certolizumab dose 1 SC at weeks 0, 2 and 4 followed by placebo IV and certolizumab dose 2 SC at weeks 6 to 22

The primary outcome is a change in DAS28-CRP from baseline to week 12. Secondary outcomes include change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Clinical Disease Activity Index (CDAI) scores at week 12, percentages of patients achieving ≥20% improvement in ACR response criteria (ACR20), ACR50, ACR70, ACR90, DAS28-CRP remission, and DAS28-CRP LDA at week 12. In addition, the number of patients with treatmentemergent adverse events (TEAEs), treatment-emergent serious adverse events (AEs), TEAEs leading to discontinuation of study intervention, and AEs of special interest up to week 30 are being evaluated.²

Phase 2a Study: IRIS-RA

A phase 2a, randomized, multicenter, double-blinded, placebo-controlled, proofofconcept study evaluated the efficacy, safety, PK, and PD of nipocalimab in patients with moderate to severe active RA and inadequate response or intolerance to ≥1 anti-TNF agents. (NCT04991753).^1,4

Study Design/Methodology

The study included a screening period (Weeks -6 to 0), a double-blind treatment period (Weeks 0-12), and a safety/PD follow-up period (Weeks 12-18). Patients were randomized (3:2) to receive nipocalimab 15 mg/kg IV every 2 weeks (q2w) or placebo IV from Weeks 0-10. Patients were allowed to be on stable doses of NSAIDS, oral corticosteroids or conventional synthetic DMARDs. Study endpoints were assessed at baseline and over time through week 12 (for efficacy and patient-reported outcomes) or week 18 (for safety, PK, PD and immunogenicity outcomes) of the follow-up period; see Figure: IRIS-RA Study Design).^1,4

Results

Baseline Characteristics

Patients (N=53) were randomized to receive nipocalimab (n=33) and placebo (n=20) and baseline characteristics were comparable between treatment groups (see Table: Baseline Characteristics).^1,19

Efficacy

Primary Endpoint

• A greater mean change in DAS28-CRP was observed in the nipocalimab vs placebo group at week 12 (-1.03 vs -0.58; LS mean difference, -0.45; 95% CI, -1.17 to 0.28; P=0.224).¹

Secondary and Exploratory Endpoints

• The P values presented for the secondary and exploratory endpoints were for descriptive purposes and do not represent statistical significance.^1,19
• A higher proportion of patients treated with nipocalimab vs placebo achieved DAS28-CRP remission and DAS28-CRP LDA at week 12 (for both, 21.2% vs 10%; treatment difference, 9.9%; 95% CI, -9.5 to 29.3; nominal P=0.456).^1,19
• A higher proportion of patients treated with nipocalimab achieved ACR20, ACR50, ACR70, and ACR90 at week 12 compared to placebo (see Table: Percentage of Patients Who Achieved ACR Responses at Week 12).¹

Among patients with greater than median ACPA levels at baseline (nipocalimab, n=15; placebo, n=12), a higher proportion of patients treated with nipocalimab vs placebo achieved DAS28-CRP remission (40% vs 16.7%) and ACR50 response (26.7% vs 0%) at week 12.¹

A greater reduction in ACR components (excluding CRP) was observed in the nipocalimab vs placebo group at week 12 (see Table: Mean Change from Baseline in ACR Components at Week 12).^1,19,20

A greater mean change in HAQ-DI (-0.42 vs -0.21; LS mean difference, -0.22; 95% CI,
-0.49 to 0.05; nominal P=0.108) and CDAI (-13.53 vs -6.01; LS mean difference, -7.52; 95% CI, -14.98 to -0.06; nominal P=0.048) scores was observed in the nipocalimab vs placebo group at week 12, respectively.¹

Safety

Nipocalimab was generally well-tolerated, without any new safety findings (see Table: Safety Results).^1,19

The percentage change in serum albumin and total cholesterol from baseline was -4.0% and 6.0% vs 3.6% and 9.1% in the nipocalimab and placebo group at week 12, respectively.¹

No TEAEs led to death or opportunistic infections, including pulmonary tuberculosis, anaphylactic reactions, major adverse cardiovascular events, or malignancies.¹

Pharmacokinetics and Immunogenicity

The median postinfusion serum nipocalimab concentration ranged from 411 to 426 µg/mL across weeks 0, 2, and 8. Median preinfusion serum nipocalimab concentrations were below the lower limit of quantitation across Weeks 2 and 8.¹

Antibodies to nipocalimab were detected in 21 (63.6%) patients, with most patients reporting low titer levels. Overall, 7/33 (21.2%) of patients were positive for neutralizing antibodies. The presence of antibodies to nipocalimab did not impact PK.¹

Four patients who were positive for antibodies to nipocalimab had an infusion-site reaction, of which 1 led to drug discontinuation.¹

Pharmacodynamics and Disease-Related Biomarkers

A separate analysis evaluated the pharmacodynamic effects of nipocalimab in patients from the IRIS study. There was a substantial and reversible reduction in IgG, ACPA, and CIC levels in nipocalimab-treated patients, consistent with the mechanism of action of nipocalimab.³

Reductions in serum total IgG levels from week 4 through week 12 were observed in nipocalimab-treated patients, after which IgG levels returned to their baseline levels at week 18. Among patients treated with nipocalimab, greater reductions in ACPA levels were shown by the responders who achieved DAS28-CRP remission or ACR50 at week 12 compared with the nonresponders.³

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 November 2024.