IMAAVY Concentrate for solution for infusion Ref.[116055] Active ingredients: Nipocalimab

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies
ATC code: L04AL03

Mechanism of action

Nipocalimab is a human IgG1 monoclonal antibody specifically targeting the IgG Fc binding site of FcRn with high specificity and high affinity at both neutral (extracellular) and acidic pH (intracellular) resulting in the reduction of circulating IgG, including IgG autoantibodies, without affecting other immunoglobulins (IgA, IgE or IgM). Nipocalimab did not demonstrate any clinically relevant impact on circulating levels of albumin, which binds at a different site on FcRn.

IgG autoantibodies are the underlying cause of the pathogenesis of MG. IgG autoantibodies impair neuromuscular transmission by binding to AChR, MuSK or LRP4.

Nipocalimab reduces the placental transfer of IgG from mother to foetus (see section 4.6).

Pharmacodynamic effects

In a double-blind placebo-controlled study in gMG patients, intravenous administration of nipocalimab at the recommended dose regimen (see section 4.2) resulted in a significant rapid reduction in total IgG serum concentrations of 75% compared to baseline within 2 weeks of treatment initiation, followed by a sustained reduction of approximately 70% compared to baseline from Week 4 through to Week 24. Similar dose-dependent reductions in all IgG subclasses (IgG1, IgG2, IgG3, and IgG4) were observed.

Immunisations (vaccinations)

The impact of nipocalimab on a T-cell dependent (Tdap) and a T-cell independent (PPSV23) vaccine response was assessed in a randomised, open-label study in healthy participants (n=15 for control, n=16 for nipocalimab). In the nipocalimab group, participants received nipocalimab at Week 0 (30 mg/kg IV), Week 2 (15 mg/kg IV) and Week 4 (15 mg/kg IV), and Tdap and PPSV23 were administered subcutaneously 3 days after the first nipocalimab dose.

Participants were able to mount a specific IgG response to these vaccines, but vaccine-specific IgG antibody levels were reduced during nipocalimab treatment with recovery to levels similar to the control group after treatment cessation.The anti-TT (tetanus toxoid) specific IgG levels are shown in Table 3. In participants who received nipocalimab, the anti-TT specific IgG levels achieved the peak response at Week 2, decreased at Week 4 and then increased through Week 16, 12 weeks after the last dose of nipocalimab at Week 4. Anti-PCP (pneumococcal capsular polysaccharide) specific IgG levels followed a similar pattern over time. See sections 4.4 and 4.5.

Table 3. Anti-TT IgG levels (mean±SE) over time:

Immunogenicity

Anti-drug antibodies (ADA) were very commonly detected at low titre. However, no evidence of ADA impact on pharmacokinetics, pharmacodynamics, efficacy or safety was observed.

Clinical efficacy and safety

Study MOM-M281-011 (adults)

The safety and efficacy of nipocalimab for the treatment of adults with gMG was studied in a 24-week, randomised, double-blind, placebo-controlled study. Patients participating in this study were subsequently allowed to enter an open-label extension phase during which all patients received nipocalimab.

The study enrolled patients who met the following main criteria at screening:

• Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV
• MG-Activities of Daily Living (MG-ADL) total score of ≥6
• On stable dose of standard of care (SoC) therapy prior to baseline, including acetylcholinesterase (AChE) inhibitors, steroids or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone.

A total of 196 patients (with or without autoantibodies) were randomised and received either nipocalimab plus SoC (n=98) or placebo plus SoC (n=98). Of these, 153 patients were antibody positive (n=77 for nipocalimab, n=76 for placebo). Patients were treated with nipocalimab at the recommended dose regimen (see section 4.2).

Of the 153 antibody positive patients, 88% were antibody positive for AChR, 10% were antibody positive for MuSK, and 2% were antibody positive for LRP4. Baseline characteristics were similar between treatment groups, including median age at screening (52 [20-81] years, 24% patients ≥65 years of age), median time since diagnosis (6 [0-38] years), gender (60% female), and race (63% white, 32% Asian). Mean MG-ADL total score was 9.2, and mean Quantitative Myasthenia Gravis total score was 15.4.

At baseline, over 97% in each treatment group were on stable background SoC therapy. During treatment, 85% were on AChE inhibitors, 66% were on steroids, and 54% were on non-steroidal immunosuppressive therapies (NSISTs) at stable doses.

The efficacy of nipocalimab was measured using the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) which assesses the impact of gMG on daily functions. A total score ranges from 0 to 24 with the higher scores indicating more impairment. In this study, an MG-ADL response was defined as a ≥2-point reduction in the total MG-ADL score compared to baseline. The efficacy of nipocalimab was also measured using the Quantitative Myasthenia Gravis (QMG) total score which measures muscle weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment. A QMG response was defined as a ≥3-point reduction in the total QMG score compared to baseline.

The key efficacy results for the primary and major secondary study endpoints are shown in Table 4. A statistically significant difference favouring nipocalimab was observed on MG-ADL and QMG changes from baseline.

Table 4. Summary of the primary and key secondary clinical responses:

¹ Mean change from baseline over Weeks 22, 23, and 24.
² Mean change from baseline over Weeks 22 and 24.
³ Average change over Weeks 22, 23, and 24 is at least a 2-point improvement from baseline.
⁴ At least 2-point improvement in MG-ADL total score at Week 4 and Week 24, and at least 2 point improvement at Week 6 through Week 23 with no more than 2 non-consecutive excursions (improvement less than 2 points) allowed.
⁵ Average change over Weeks 22, 23, and 24 is at least a 50% improvement from baseline.

Response over time (double-blind phase)

Improvements with nipocalimab compared to placebo were observed through Week 24.

The time course of response for the primary efficacy endpoint (MG-ADL) and key secondary efficacy endpoint (QMG) is shown in Figure 1.

Figure 1. Least Squares Mean Change from Baseline in MG-ADL Total Score (A) and QMG Total Score (B) Over 24 Weeks:

Over time, a higher proportion of patients achieved sustained MG-ADL (improvement >2 points from Week 2 through Week 24) and QMG (improvement >3 points from Week 2 through Week 24) responses in the nipocalimab group (45.5% and 33.8%, respectively) compared to the placebo group (21.1% and 7.9%, respectively).

Response over time (open-label extension phase)

Of the 153 antibody positive patients in the double-blind placebo-controlled phase, 137 entered into the open-label extension phase to receive nipocalimab. At the time of the analysis, in patients who initially received nipocalimab during the double-blind phase and continued to receive nipocalimab during the first 48 weeks (n=52) and 84 weeks (n=20) of the open-label extension phase, the mean improvements in MG-ADL and QMG total scores were maintained.

Paediatric population

Study 80202135MYG2001 (adolescent cohort)

The pharmacodynamics, pharmacokinetics, and efficacy of nipocalimab for the treatment of gMG in adolescent patients are evaluated at Week 24 in an ongoing open-label study.

Main study inclusion criteria are as follows:

• MGFA clinical classification class II to IV
• Positive for autoantibodies to AChR or MuSK
• On stable dose of SoC therapy prior to screening, including AChE inhibitors, steroids or NSISTs, either in combination or alone.

Eight patients had a median age of 13.5 years at screening (range 12 to 16 years) and a median time since diagnosis of 3.6 years (range 0.8 to 11.5). Seven patients were female; 5 were Asian, 1 was Black and 2 were of unknown race. Mean (SD) MG-ADL total score at baseline was 4.4 (2.26), and mean (SD) QMG total score was 13.3 (4.13). All patients were AChR antibody positive. At baseline, 4 patients were on AChE inhibitors, 6 were on steroids, and 7 were on NSISTs at stable doses.

Seven of the 8 adolescent patients were evaluated through Week 24 and received nipocalimab at the recommended dose regimen (see section 4.2). The primary endpoint was the effect of nipocalimab on total serum IgG. At Week 24, the median pre-dose percent reduction in total IgG from baseline (n=7) was 73.3%, consistent with the IgG reduction seen in the adult gMG study. The mean (SD) change at Week 24 in MG-ADL was -2.57 (0.535) and the mean change at Week 24 in QMG was -4.93 (3.81).

The European Medicines Agency has deferred the obligation to submit the results of studies with Imaavy in one or more subsets of the paediatric population in the treatment of myasthenia gravis (see section 4.2 for information on paediatric use).