Efgartigimod alfa (1) – Vyvgart®

• Clinical trials
  • The ADAPT study was a multicentre, double-blind, randomised controlled trial in which the efficacy and safety of efgartigimod alfa (hereinafter referred to as efgartigimod) were compared with placebo – in each case in combination with standard therapy.

Adults with generalised myasthenia gravis who are anti-acetylcholine receptor antibody-positive

• For adults with generalised myasthenia gravis who are positive for anti-acetylcholine receptor antibodies, there is a hint of considerable additional benefit for efgartigimod alfa.
• Overall, there is a hint of considerable additional benefit for efgartigimod alfa in addition to standard therapy.
• 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)
  • The primary endpoint of the ADAPT study was the percentage of AChR-AK-positive individuals who showed an improvement in the total MG-ADL score of ≥ 2 points over a period of at least 4 consecutive weeks, with the first improvement occurring no later than one week after the last dose of the study medication in treatment cycle 1, compared with the baseline value.
  • For this endpoint, the study demonstrated a statistically significant advantage for efgartigimod.
  • Furthermore, the pharmaceutical manufacturer provided analyses of the area under the curve (AUC) in the dossier to better capture the fluctuating course of the response. Due to the significantly reduced response rates (< 40 %) after week 20, the results are only considered up to and including week 20. Based on the p-value, a statistically significant difference in favour of efgartigimod can be inferred.
• Morbidity – Disease-specific symptoms assessed using the Quantitative Myasthenia Gravis (QMG) scale
  • In the post hoc responder analysis, with a responder threshold of 15 per cent (≥ 6 points) in the first treatment cycle, a statistically significant difference in favour of efgartigimod compared with placebo was observed.
  • Overall, the results on disease-specific symptoms (QMG and MG-ADL) suggest an advantage of efgartigimod over placebo.
• Morbidity – Health Status (EQ-5D VAS)
  • Health status was assessed in the ADAPT study using the visual analogue scale of the European Quality of Life-5-Dimensions (EQ-5D-VAS). In the post-hoc responder analyses conducted by the pharmaceutical manufacturer, using a clinical relevance threshold of 15%, a significant advantage of efgartigimod over placebo was observed for this endpoint in treatment cycle 1.
• Quality of life – Myasthenia Gravis Quality of Life 15 (MG-QoL15r)
  • The results on health-related quality of life, assessed using the MG-QoL15r, show a statistically significant difference in favour of efgartigimod compared with placebo in the post hoc responder analysis with a responder threshold of 15% in the first treatment cycle.
• 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 final visit (over a period of up to 26 weeks) were taken into account.
  • No statistically significant differences were observed between the treatment arms for the overall rates of serious AEs, severe AEs and AEs leading to discontinuation of the study medication, as well as AEs of particular interest.
  • However, the results are subject to uncertainty, as the pharmaceutical manufacturer did not provide analyses excluding disease-related events or events related to the underlying condition, and the AEs and SAEs observed may also include events from the ‘morbidity’ category.
  • Furthermore, the potential for bias is increased due to the patient-specific treatment regimen and the study design, which may involve early transition to the ADAPT+ study. Overall, the potential for bias in the ‘side effects’ category is therefore assessed as high.
• Overall assessment
  • No deaths occurred in the mortality endpoint category.
  • In the morbidity category, the responder analyses show statistically significant advantages in favour of efgartigimod over placebo for both disease-specific symptoms (MG-ADL and QMG) and general health status (EQ-5D VAS) for the first treatment cycle. Furthermore, there is a statistically significant, clinically relevant advantage for the morbidity endpoint ‘MG-ADL AUC’, which takes into account the chronically fluctuating course of the disease over 20 weeks.
  • With regard to health-related quality of life, the MG-QoL15r indicates an advantage for efgartigimod alfa.
  • With regard to side effects, no advantage or disadvantage of efgartigimod 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 efgartigimod, based on the positive effects observed across all available patient-relevant endpoints for morbidity – i.e. disease-specific symptoms (MG-ADL, QMG) and general health status – and health-related quality of life, an additional benefit can be inferred for efgartigimod, the extent of which is assessed as considerable.
• Validity of the evidence
  • For the pivotal double-blind, randomised controlled trial ADAPT, on which this benefit assessment is based, the potential for bias at the study level is assessed as minor.
  • Uncertainties arise primarily from the short follow-up period of the data used. With the exception of the ‘MG-ADL AUC’ endpoint, which shows an advantage in myasthenic symptoms over 20 weeks, the endpoints relating to morbidity and quality of life refer to the first treatment cycle, i.e. an observation period of 8 weeks. To assess the sustainability of the effects, evaluable data over a longer observation period would have been necessary.
  • Furthermore, there are uncertainties as to whether, and to what extent, treatment-refractory patients are included in the study population. Consequently, it is unclear whether the effects observed in the ADAPT study are fully transferable to this patient group.
  • Overall, the uncertainties mentioned regarding the validity of the evidence provide a hint of additional benefit.

Courtesy translation only, please refer to the German original.