SUMMARY

• The company cannot recommend any practices, procedures, or usage of IMAAVY that deviate from the approved labeling.
• IMAAVY 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) and is being studied for the treatment of rheumatoid arthritis (RA).¹
  • By selectively blocking the FcRn, IMAAVY prevents IgG recycling and in turn lowers IgG levels, potentially reducing the level of anticitrullinated protein autoantibodies (ACPAs) and other pathogenic antibodies.¹
• A phase 2a, multicenter, randomized, double-blinded, parallel, proofofconcept study evaluated the efficacy and safety of IMAAVY 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 (PBO) -controlled, proofofconcept study evaluated the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IMAAVY 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 IMAAVY vs PBO 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
  • IMAAVY 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

A phase 2a, multicenter, randomized, double-blinded, parallel, proof-of-concept study evaluated the efficacy and safety of IMAAVY 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 were 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 included:
  • IMAAVY intravenously (IV) plus certolizumab dose 1 subcutaneously (SC) at weeks 0, 2 and 4, followed by IMAAVY 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 PBO IV and certolizumab dose 2 SC at weeks 6 to 22
• The primary outcome was a change in DAS28-CRP from baseline to week 12.
• Secondary outcomes included:
  • 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 were being evaluated.²

Phase 2a Study: IRIS-RA

A phase 2a, randomized, multicenter, double-blinded, PBO-controlled, proofofconcept study evaluated the efficacy, safety, PK, and PD of IMAAVY 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 IMAAVY 15 mg/kg IV every 2 weeks (q2w) or PBO 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 IMAAVY (n=33) and PBO (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 IMAAVY vs PBO 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 IMAAVY vs PBO 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 IMAAVY achieved ACR20, ACR50, ACR70, and ACR90 at week 12 compared to PBO (see Table: Percentage of Patients Who Achieved ACR Responses at Week 12).¹

• Among patients with greater than median ACPA levels at baseline (IMAAVY, n=15; PBO, n=12), a higher proportion of patients treated with IMAAVY vs PBO 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 IMAAVY vs PBO 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 IMAAVY vs PBO group at week 12, respectively.¹

Safety

• IMAAVY 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 IMAAVY and PBO 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-aahu concentration ranged from 411 to 426 µg/mL across weeks 0, 2, and 8. Median preinfusion serum nipocalimab-aahu  concentrations were below the lower limit of quantitation across weeks 2 and 8.¹
• Antibodies to nipocalimab-aahu 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-aahu did not impact PK.¹
• Four patients who were positive for antibodies to nipocalimab-aahu 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 IMAAVY in patients from the IRIS study. There was a substantial and reversible reduction in IgG, ACPA, and CIC levels in IMAAVY-treated patients, consistent with the mechanism of action of IMAAVY.³
• Reductions in serum total IgG levels from week 4 through week 12 were observed in IMAAVY-treated patients, after which IgG levels returned to their baseline levels at week 18. Among patients treated with IMAAVY, 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 16 October 2025.