RYSTIGGO Solution for injection Ref.[108735] Active ingredients: Rozanolixizumab

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies
ATC code: L04AG16

Mechanism of action

Rozanolixizumab is a humanised IgG4 monoclonal antibody that decreases serum IgG concentration by inhibiting the binding of IgG to FcRn, a receptor that under physiological conditions protects IgG from intracellular degradation and recycles IgG back to the cell surface.

By the same mechanism, rozanolixizumab decreases the concentration of pathogenic IgG autoantibodies associated with gMG. Clinical data with rozanolixizumab have not identified any clinically relevant impact on levels of albumin, which binds at a different site on FcRn.

Pharmacodynamic effects

In a double-blind placebo-controlled study in gMG patients, weekly subcutaneous administration of rozanolixizumab at the recommended dose (see section 4.2) resulted in a rapid and sustained reduction in total IgG serum concentrations, with significant lowering of IgG of 45% compared to baseline within 1 week, and a maximum decrease of 73% at about 3 weeks. After stopping administration, IgG concentrations recovered towards baseline levels within approximately 8 weeks. Similar changes were observed during the subsequent cycles of the study.

The reduction in total IgG by rozanolixizumab in neutralising antibody-positive patients was not different from patients who were antidrug antibody-negative (see section 4.4).

Clinical efficacy and safety

The safety and efficacy of rozanolixizumab was evaluated in patients with gMG in the pivotal phase 3 study MG0003. Long-term safety, tolerability and efficacy of rozanolixizumab were evaluated in 2 phase 3 open-label extension (OLE) studies, with 1 OLE (MG0007) administering rozanolixizumab as 6-week treatment cycles based on clinical needs.

Study MG0003

The study MG0003 evaluated 200 patients for up to 18 weeks where patients were randomised to receive weight-tiered doses of rozanolixizumab equivalent to approximately (≈) 7 mg/kg (corresponding to the recommended dose; see section 4.2) or a higher dose, or placebo. Treatment consisted of 1 dose per week for a period of 6 weeks followed by an 8-week observation period.

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

• at least 18 years of age, had a bodyweight of at least 35 kg
• diagnosis of gMG and had autoantibodies against AChR or MuSK
• a Myasthenia Gravis Foundation of America (MGFA) Class II to IVa,
• an MG-Activities of Daily Living (MG-ADL, a patient reported outcome [PRO] measure) score of at least 3 (with ≥3 points from non-ocular symptoms)
• a Quantitative Myasthenia Gravis (QMG) score of at least 11
• if on gMG therapy, to be kept stable prior to baseline and for the duration of the study (except for cholinesterase inhibitors)
• considered for additional treatment such as IVIg and/or PLEX

Patients were not permitted in the study if they had:

• a serum total IgG level ≤ 5.5 g/l or an absolute neutrophil count < 1 500 cells/mm³
• clinically relevant active infection or serious infections, mycobacterial infections, hepatitis B, hepatitis C, HIV infections
• been treated with PLEX, IVIg 1 month and monoclonal antibodies 3 to 6 months prior to starting treatment

The primary endpoint was the change from baseline to day 43 in the MG-ADL score. Secondary efficacy endpoints included a change from baseline to day 43 in MG-C (Myasthenia Gravis Composite) score and QMG score. Response in this study was defined as an at least 2.0-points improvement in MG-ADL at day 43 compared to the treatment cycle baseline.

In general, patient demographics and baseline disease characteristics were balanced across treatment groups. The majority of patients were female (60.5%), below 65 years of age (75.5%), were of predominantly White (68.0%) or Asian (10.5%) race, and presented with MGFA class II or III gMG (96.0%). The median age at MG diagnosis was 44.0 years, and the median time since diagnosis was 5.8 years. There was a lower proportion of male patients in the placebo group (29.9%) than in the rozanolixizumab ≈7 mg/kg dose group (40.9%). The autoantibody distribution among MG0003 patients were 10.5% anti-MuSK positive, 89.5% anti-AChR positive. Overall, 95.5% of patients received at least one MG baseline medication that continued during the study, including 85.5% receiving acetylcholinesterase inhibitors, as well as 64.0% receiving corticosteroids, 50.0% receiving immunosuppressants, and 35.5% receiving corticosteroids and immunosuppressants at stable doses.

In the rozanolixizumab and placebo groups, the median MG-ADL total score was 8.0, and the median QMG total score was 15.0.

Results for the primary and secondary efficacy endpoints are provided in Table 2 below. In total, 71.9% and 31.3% of patients in the rozanolixizumab and placebo groups, respectively, met MG-ADL responder criteria.

Table 2. Efficacy outcomes change from baseline to day 43:

^≈ =approximate dose; CI= confidence interval; N=total number of patients in treatment group; LS=least square; SE=standard error; MG-ADL=MG-Activities of Daily Living; MG-C=Myasthenia Gravis Composite score; QMG= Quantitative Myasthenia Gravis; MG=myasthenia gravis.

For the MuSK+ patients who received rozanolixizumab ≈7 mg/kg and had data available at day 43 (n=5), the results were consistent with the overall group.

No rozanolixizumab-treated patients and 3 placebo-treated patients received rescue therapy during the treatment period. During the course of the observation period, amongst the patients treated with ≈7 mg/kg, one patient received rescue therapy and 19 patients rolled over early to an open label extension study to receive treatment with rozanolixizumab.

Paediatric population

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