Rozanolixizumab (1) – Rystiggo®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the MG0003 trial in the dossier. This is a three-arm, double-blind, randomised, multicentre Phase IIItrial in which rozanolixizumab was compared with placebo, in addition to standard therapy, in adults with anti-AChR- and anti-MuSK-antibody-positive generalised myasthenia gravis (gMG) over one treatment cycle.

a) Adults with anti-AChR-antibody-positive generalised myasthenia gravis who are eligible for adjunctive treatment to standard therapy

• For a) adults with anti-AChR-antibody-positive generalised myasthenia gravis who are eligible for add-on treatment to standard therapy, there is a hint of considerable additional benefit for rozanolixizumab.
• mortality
  • The number of patients who died was recorded as part of the safety monitoring. No deaths occurred during the course of the study.
• Morbidity – Disease-specific symptoms assessed using the Myasthenia Gravis – Activities of Daily Living (MG-ADL)
  • In the post-hoc responder analysis, with a responder threshold of 15 per cent (improvement of ≥ 4 points), a statistically significant difference was observed in favour of rozanolixizumab compared with placebo at the end of the 6-week treatment cycle.
  • However, the regression model failed to converge when the continuously scaled baseline values were included; consequently, the baseline values could not be fully incorporated into the present analysis.
• Morbidity – Disease-specific symptoms assessed using the Quantitative Myasthenia Gravis (QMG)
  • The pharmaceutical manufacturer considers the QMG to be irrelevant for the assessment and does not present any post hoc responder analyses with a responder threshold of 15 per cent. Although the available results from the continuous QMG analyses show a statistically significant difference in favour of rozanolixizumab, the clinical relevance cannot be assessed on the basis of the available data.
  • Even taking into account that further, more meaningful analyses of disease-specific symptoms are available, the endpoints are not considered in the overall assessment for the purposes of this benefit assessment.
• Morbidity – Disease-specific symptoms assessed using the Myasthenia Gravis Symptoms Patient-Reported Outcome (MG Symptoms PRO)
  • In the post-hoc responder analyses submitted as part of the commenting procedure, with a responder threshold of 15% (improvement of ≥ 15 points for the respective domain) and taking baseline values into account, a statistically significant advantage in favour of rozanolixizumab over placebo was observed in the domains ‘muscle weakness/muscle fatigue’, ‘ocular symptoms’ and ‘bulbar symptoms’ at the end of the 6-week treatment cycle.
  • In the ‘Physical fatigue’ domain, there was no statistically significant difference.
  • In the MG Symptoms PRO domain ‘Respiratory symptoms’, the regression model (both dichotomous and continuously scaled) could not converge when baseline values were included as a variable.
  • The regression model used to calculate the responder analysis for the ‘Muscle Weakness/Muscle Fatigue’ domain failed to converge when using the continuously scaled baseline values; consequently, the baseline values were not fully incorporated into the present analysis.
• Morbidity – General health status (EQ-5D VAS)
  • In the post-hoc responder analyses conducted by the pharmaceutical manufacturer, using a clinical relevance threshold of 15 per cent, no statistically significant difference was observed for this endpoint between rozanolixizumab and placebo at the end of the 6-week treatment phase.
  • However, the regression model failed to converge when the continuously scaled baseline values were included; consequently, the baseline values could not be fully incorporated into this analysis.
• Analyses at the end of the follow-up period (Day 99)
  • For the study data collected at the end of the follow-up phase (Day 99), no analyses were submitted as part of the commenting procedure in which the baseline values of the respective instrument were taken into account as variables in the (stratified) logistic regression.
  • The analyses that did not include baseline values as a variable show no significant differences between the treatment arms for the MG-ADL and the various domains of the MG Symptoms PRO at the end of treatment.
• quality of life
  • In the post hoc responder analysis, conducted with a responder threshold of 15 per cent (improvement of ≥ 5 points), a statistically significant difference was observed in favour of rozanolixizumab compared with placebo at the end of the 6-week treatment cycle.
  • At the end of the follow-up period (day 99), in line with the analysis excluding baseline values, there was no significant difference between the treatment arms.
• Side effects
  • For the analysis of endpoints in the ‘side effects’ category, adverse events (AEs) that occurred from the first dose of the study medication until the end of the follow-up period (Day 99) were taken into account.
  • No statistically significant differences were observed between the treatment arms for the overall rates of serious AEs, severe AEs, or AEs leading to discontinuation of the study medication.
• Overall assessment
  • No deaths occurred in the mortality endpoint category.
  • In the morbidity category, rozanolixizumab showed advantages over placebo in disease-specific symptoms, namely in the MG-ADL and in the ‘muscle weakness/muscle fatigue’, ‘ocular symptoms’ and ‘bulbar symptoms’ of the MG Symptoms PRO in the responder analyses at Day 43. No advantages or disadvantages of rozanolixizumab over placebo at the end of treatment on Day 43 can be inferred from the ‘Physical fatigue’ domain or the EQ-5D VAS. No evaluable data are available for the ‘Respiratory symptoms’ domain of the MG Symptoms PRO.
  • With regard to health-related quality of life, the MG-QoL15r indicates an advantage for rozanolixizumab compared with placebo at the end of the treatment cycle.
  • With regard to side effects, neither an advantage nor a disadvantage of rozanolixizumab compared with placebo, in each case in combination with standard therapy, can be identified.
  • Taking the results as a whole, an additional benefit can be inferred for rozanolixizumab, based on the positive effects observed in morbidity endpoints – i.e. disease-specific symptoms (MG-ADL, the ‘Muscle weakness/muscle fatigue’, ‘ocular symptoms’ and ‘bulbar symptoms’ of the MG Symptoms PRO) – and health-related quality of life, an additional benefit can be inferred, the extent of which is assessed as considerable.

b) Adults with anti-MuSK antibody-positive generalised myasthenia gravis who are eligible for add-on treatment to standard therapy

• For b) adults with anti-MuSK antibody-positive generalised myasthenia gravis who are eligible for add-on treatment to standard therapy, there is a hint of a non-quantifiable additional benefit for rozanolixizumab, as the scientific evidence does not permit quantification.
• mortality
  • No deaths occurred.
• morbidity
  • For general information on the various measurement tools, please refer to the details provided for patient group a).
• Morbidity – MG-ADL
  • At the end of the 6-week period, the responder threshold was statistically significant
• Morbidity – MG Symptoms PRO
  • In the post hoc analysis (improvement in ≥ 1 domain of the MG Rozanolixizumab and
• Morbidity – QMG
  • For patients in the pharmaceutical arm as well, the responder threshold showed a continuous, statistically significant effect; the effect is therefore also
• quality of life
  • At the end of the 6-week period, the responder threshold showed a significant reduction
• Overall assessment
  • No deaths occurred in the MG0003 study. Similarly, within the anti-MuSK antibody-positive patient group, there were no serious or severe AEs or AEs that led to discontinuation of the study. Consequently, no conclusions regarding the extent of the additional benefit can be drawn from the data on mortality and side effects.
  • Neither for the endpoints relating to disease-specific symptoms (MG-ADL, MG Symptoms PRO) and health status, as well as for health-related quality of life (MG-QoL15r), there were neither advantages nor disadvantages with rozanolixizumab compared with placebo at the end of the 6-week treatment cycle. It is therefore not possible to quantify the additional benefit on the basis of the data on the endpoint categories of morbidity and quality of life.
  • In its overall assessment of the available results for the patient-relevant endpoints, the G-BA classifies the extent of the additional benefit of rozanolixizumab for the treatment of adults with gMG, who are anti-MuSK antibody-positive, as non-quantifiable on the basis of the criteria set out in Section 5(8), first sentence, 2 in conjunction with Section 5(7), first sentence, number 4 of the AM-NutzenV, as non-quantifiable, because the scientific evidence does not permit quantification.
• Validity of the evidence
  • The potential for bias in the MG0003 study is considered high for the patient population with MuSK-positive antibody status. This assessment is based primarily on the very minor number of cases.
  • Furthermore, the various evaluation strategies regarding the classification of antibody status lack transparency. Consequently, result-biased reporting cannot be ruled out entirely.
  • Furthermore, due to the short duration of treatment and follow-up – even taking into account the fluctuating course of the disease – no conclusions can be drawn regarding longer-term effects.
  • Taken as a whole, the uncertainties mentioned regarding the validity of the evidence suggest a hint of additional benefit.

Courtesy translation only, please refer to the German original.