SUMMARY

• Nipocalimab, a fully human, aglycosylated, effectorless immunoglobulin G1 (IgG1) anti-neonatal fragment crystallizable receptor (FcRn) monoclonal antibody, is an investigational agent being studied for the treatment of adult and pediatric patients with generalized myasthenia gravis (gMG).^1-3
  • By interfering with the binding of IgG to FcRn, nipocalimab increases the lysosomal degradation of IgG, which reduces serum levels of total IgG and pathogenic IgG autoantibodies that cause myasthenia gravis (MG).
• A phase 2, multicenter, randomized, double-blind (DB), placebo-controlled clinical trial evaluated the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of nipocalimab in 68 adult patients with gMG who had an insufficient response to ongoing, stable standard of care (SOC) therapy.²
  • The proportion of patients with treatment-emergent adverse events (TEAEs) was comparable in the nipocalimab vs placebo groups. No clinically significant safety signals were identified.
  • Greater mean improvements in Myasthenia Gravis Activities of Daily Living (MG-ADL) total scores from baseline to day 57 were observed in all continuous nipocalimab dosing groups vs placebo.

BACKGROUND

• MG is a rare, heterogeneous, neuromuscular, autoimmune disease characterized by fluctuating, fatigable muscle weakness. The symptoms may range from purely ocular to severe weakness of the limb, bulbar, or respiratory muscles. Majority of the patients develop ocular motor disturbances, including diplopia and/or ptosis, during the course of their disease. The disease course of MG is described as variable but progressive, with most patients having progressive weakness during the first 2 years that involves oropharyngeal and limb muscles. Up to 80% of patients with ocular onset develop gMG.^4,5
• The highest incidence rates of MG in men are observed between ages 60 and 89 and in women around ages 30 and 50 (bimodal distribution). Pediatric patients (onset before age 18) constitute approximately 10% of cases.⁴
• MG is an antibody-mediated autoimmune disease of the neuromuscular juncture, with autoantibodies against acetylcholine receptors (AChRs) found in about 80% of patients. Antibodies against muscle-specific kinase occur in approximately 7-10% of all MG patients and up to 40% of patients with gMG who are seronegative for anti-AChR antibodies. Low-density lipoprotein receptor-related protein 4 (LRP4) antibodies are seen in 2%-50% of the patients who are double seronegative.^4,6
• The mortality rate is 5%-9% and is slightly higher in males vs females.⁴

CLINICAL DATA

Phase 2 Clinical Trial

Antozzi et al (2023)² conducted a phase 2, multicenter, randomized, DB, placebo-controlled clinical trial to evaluate the safety, efficacy, PK, and PD of nipocalimab in adult patients with gMG who had an insufficient response to ongoing, stable SOC therapy.

Study Design/Methods

The study included a 4-week screening period, followed by an 8-week treatment period. Posttreatment follow-up assessment was performed for a period of 8 weeks. For study design/methods, see Figure: Phase 2 VIVACITY-MG Study Design.

Although patients were eligible to enter the open-label extension (OLE) trial (NCT03896295), due to the coronavirus disease 2019 (COVID-19) pandemic, the OLE trial was terminated.⁷

Exploratory endpoints included: proportion of patients with durable response (MG-ADL of ≥2 points for ≥4 consecutive weeks), PD activity of nipocalimab (changes in total IgG, IgG subclasses, IgA, IgM, IgE concentrations), autoantibodies (anti-AChR and anti-muscle-specific kinase [MuSK]), and the incidence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs) to nipocalimab.

Results

Of the 68 randomized patients, 57 completed the treatment period. Treatment discontinuation occurred in 8 patients in the combined nipocalimab group (COVID-19, n=7; violation of exclusion criteria, n=1) and 3 patients in the placebo group (AEs, n=2; withdrawal of consent, n=1). For baseline demographics, see Table: Baseline Demographic Characteristics (ITT Population).

Safety

The proportion of combined nipocalimab-treated patients with TEAEs (83.3%) was comparable to that of placebo-treated patients (78.6%). No correlation was found in the overall incidence of TEAEs among the 4 nipocalimab dose regimens or for any individually reported preferred terms. See Table: Incidence of TEAEs in the NIPO vs Placebo Group. All TEAEs in the nipocalimab-treated group were mild or moderate (grade 1 or 2). The most frequent TEAEs reported across all groups were headache, nasopharyngitis, and diarrhea (11.1% each). One patient in the 5 mg/kg every 4 weeks (Q4W) group (7.1%) reported a TEAE of MG worsening/exacerbation and did not require rescue treatment or discontinue treatment.

No grade 3 adverse events of special interest (AESIs) related to infection were reported. The proportion of infections was comparable between the nipocalimab-treated (33.3%) and placebo-treated (21.4%) groups, with nasopharyngitis being the most common.

No grade 3 AESIs related to hypoalbuminemia were reported. Mean serum albumin concentrations were within the normal limits of 3.5-5.5 g/dL throughout the treatment and follow-up periods for all tested doses. In the 60 mg/kg every 2 weeks (Q2W) group, mean albumin reduction was -0.83 g/dL at day 57 (baseline mean, 4.34 g/dL; day 57 mean, 3.5 g/dL), and albumin levels returned to baseline by the end of posttreatment follow-up (day 113, 4.8 g/dL).

Efficacy

A statistically significant linear trend, indicating a positive dose-response, was observed for the primary efficacy endpoint at day 57 in the MG-ADL score (P=0.03) across the placebo, nipocalimab 5 mg/kg Q4W, 30 mg/kg Q4W, and 60 mg/kg Q2W groups.

Treatment with nipocalimab resulted in greater mean improvement from baseline to day 57 in the nipocalimab 5 mg/kg Q4W, 30 mg/kg Q4W, and 60 mg/kg Q2W arms compared to placebo as illustrated in Figure: MG-ADL Improvement from Baseline to Day 57.

Mean changes in efficacy measures are presented in Table: Improvement in MG-ADL, QMG, MG-QoL-15r, and MGFA Classification from Baseline to Day 57 (ITT Population).

Patients with a greater decrease in IgG levels tended to exhibit greater reductions in the MG-ADL total scores. Single dose administration of nipocalimab 60 mg/kg, which assessed durability of effect with maximal IgG reduction, showed large reductions in MG-ADL total scores through day 29 (mean [standard deviation; SD] change from baseline: -3.9 [1.32]); the magnitude of reduction decreased thereafter (mean [SD] change from baseline at day 57: -1.5 [2.82]).

Through day 57, the proportion of patients with a durable response ranged from 42.9% to 64.3% in the nipocalimab groups, compared to 14.3% in the placebo group.

PK/PD Activity

Posttreatment serum samples from 54 nipocalimab-treated patients were evaluable for ADAs. The incidence of ADA through day 113 (16 weeks) in the nipocalimab- and placebo-treated groups was reported in 22 (40.7%) patients and 1 (7.1%) patient, respectively. Notably, 35.8% of samples from the nipocalimab-treated group tested positive for ADA on day 15; however, the ADA-positive rates significantly decreased at subsequent visits (from 12.2% on day 29 to 8.7% on day 113). The ADA-positive rates at day 29 and beyond in the nipocalimab- and placebo-treated groups were similar, ranging from 7.7% on day 29 to 10.0% on day 113. ADA titers were generally low (≤1:480).

Overall, 8 (14.8%) patients in the nipocalimab group were positive for NAbs. Comparisons of median serum nipocalimab or IgG concentrations between ADA-positive and ADA-negative patients over time showed that the presence of ADA did not affect the PK or IgG lowering of nipocalimab and was not associated with reduced clinical efficacy (MG-ADL change from baseline over time) or AEs. The incidence of NAb was too low to assess its effect on PK or PD.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 12 June 2024.