VYVGART Concentrate for solution for infusion Ref.[50188] Active ingredients: Efgartigimod alfa

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA58

Mechanism of action

Efgartigimod alfa is a human IgG1 antibody fragment engineered for increased affinity to the neonatal Fc Receptor (FcRn). Efgartigimod alfa binds to FcRn, resulting in a reduction in the levels of circulating IgG including pathogenic IgG autoantibodies. Efgartigimod alfa does not affect the levels of other immunoglobulins (IgA, IgD, IgE or IgM), or those of albumin.

IgG autoantibodies are the underlying cause of the pathogenesis of MG. They impair neuromuscular transmission by binding to acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4).

Pharmacodynamic effects

In a double-blind placebo-controlled study in gMG patients, efgartigimod alfa decreased serum IgG levels and AChR autoantibody levels at the recommended dose and schedule (see section 4.2). Maximum mean percentage decrease in total IgG levels compared to baseline reached 61% one week after the last infusion of the initial treatment cycle and returned to baseline levels 9 weeks after the last infusion. Similar effects were also observed for all subtypes of IgG. Decrease in AChR autoantibody levels followed a similar time course with maximum mean percentage decrease of 58% one week after the last infusion and return to baseline levels 7 weeks after the last infusion. Similar changes were observed during the second cycle of the study.

Clinical efficacy and safety

Efficacy of efgartigimod alfa for the treatment of adults with generalised Myasthenia Gravis (gMG) was studied in a 26-week, multicentre randomised double-blind placebo-controlled trial.

In this study, patients had to meet the following main criteria at screening:

• Myasthenia Gravis Foundation of America (MGFA) clinical classification class II, III or IV;
• Patients with either positive or negative serologic tests for antibodies to AChR;
• MG-Activities of Daily Living (MG-ADL) total score of ≥5;
• On stable doses of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids or non-steroidal immunosuppressive therapy (NSIST), either in combination or alone [NSISTs included but were not limited to azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, and cyclophosphamide];
• IgG levels of at least 6 g/l.

Patients with MGFA Class V gMG; patients with documented lack of clinical response to PLEX; patients treated with PLEX, IVIg one month and monoclonal antibodies six months prior to starting treatment; and patients with active (acute or chronic) hepatitis B infection, hepatitis C seropositivity, and diagnosis of AIDS, were excluded from the trials.

A total of 167 patients were enrolled in the study and were randomised to either efgartigimod alfa (n=84) or placebo (n=83). Baseline characteristics were similar between treatment groups, including median age at diagnosis [45 (19-81) years], gender [most were female; 75% (efgartigimod alfa) versus 66% (placebo)], race [most patients were white; 84.4%] and median time since diagnosis [8.2 years (efgartigimod alfa) and 6.9 years (placebo)].

The majority of patients (77% in each group) tested positive for antibodies to AChR (AChR-Ab) and 23% of patients tested negative for AChR-Ab.

During the study, over 80% of patients in each group received AChE inhibitors, over 70% in each treatment group received steroids, and approximately 60% in each treatment group received NSISTs, at stable doses. At study entry, approximately 30% of patients in each treatment group had no previous exposure to NSISTs.

Median MG-ADL total score was 9.0 in both treatment groups, and median Quantitative Myasthenia Gravis (QMG) total score was 17 and 16 in the efgartigimod alfa and placebo groups, respectively.

Patients were treated with efgartigimod alfa at the recommended dose regimen and received a maximum of 3 treatment cycles (see section 4.2).

The efficacy of efgartigimod alfa was measured using the Myasthenia Gravis-Specific 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 responder was a patient with ≥ 2-point reduction in the total MG-ADL score compared to the treatment cycle baseline, for at least 4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of the cycle.

The efficacy of efgartigimod alfa was also measured using the QMG total score which is a grading system that assesses muscle weakness with a total possible score of 0 to 39 where higher scores indicate more severe impairment. In this study, a QMG responder was a patient who had a ≥3-point reduction in the total QMG score compared to the treatment cycle baseline, for at least 4 consecutive weeks with the first reduction occurring no later than 1 week after last infusion of the cycle.

The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders during the first treatment cycle (C1) between treatment groups in the AChR-Ab seropositive population.

A key secondary endpoint was the comparison of the percentage of QMG responders during C1 between both treatment groups in the AChR-Ab seropositive patients.

Table 2. MG-ADL and QMG responders during cycle 1 in AChR-Ab seropositive population (mITT analysis set):

AChR-Ab = acetylcholine receptor-antibody; MG-ADL = Myasthenia Gravis Activities of Daily Living; QMG = Quantitative Myasthenia Gravis; mITT = modified intent-to-treat; n = number of patients for whom the observation was reported; N = number of patients in the analysis set; CI = confidence interval; Logistic regression stratified for AChR-Ab status (if applicable), Japanese/Non-Japanese and standard of care, with baseline MG-ADL as covariate / QMG as covariates
Two-sided exact p-value

Analyses show that during the second treatment cycle MG ADL responder rates were similar to those during the first treatment cycle (see Table 3).

Table 3. MG-ADL and QMG responders during cycle 2 in AChR-Ab seropositive population (mITT analysis set):

AChR-Ab = acetylcholine receptor-antibody; MG-ADL = Myasthenia Gravis Activities of Daily Living; QMG = Quantitative Myasthenia Gravis; mITT = modified intent-to-treat; n = number of patients for whom the observation was reported; N = number of patients in the analysis set.

Exploratory data shows that onset of response was observed within 2 weeks of initial infusion in 37/44 (84%) patients treated with efgartigimod alfa in the AChR-Ab seropositive MG-ADL responders.

In the double-blind placebo-controlled study, the earliest possible time to initiating the subsequent treatment cycle was 8 weeks after the initial infusion of the first treatment cycle. In the overall population the mean time to the second treatment cycle in the efgartigimod alfa group was 13 weeks (SD 5.5 weeks) and the median time was 10 weeks (8-26 weeks) from the initial infusion of the first treatment cycle. In the ongoing open-label extension study the earliest possible time of initiation of the subsequent treatment cycles was 7 weeks.

In patients that responded to treatment, the duration of clinical improvement was 5 weeks in 5/44 (11%) patients, 6-7 weeks in 14/44 (32%) of patients, 8-11 weeks in 10/44 (23%) patients and 12 weeks or more in 15/44 (34%) patients.