Tofersen (1) – Qalsody®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted analyses of the Phase III VALOR trial. This is a multicentre, randomised, controlled, double-blind trial designed to investigate the safety and efficacy of tofersen compared with placebo.

Adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene

• Overall, there is a hint of a non-quantifiable additional benefit of tofersen for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene, as the scientific evidence does not allow for quantification.
• mortality
  • In the VALOR RCT, a total of one death (1.4%) occurred in the intervention arm.
  • Due to the minor number of events, the median time to death could not be determined.
  • There are no differences in the mortality category that are relevant for the benefit assessment.
• Morbidity – Motor function assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R)
  • For the subscores relating to gross motor function, fine motor function and respiratory function, there were no statistically significant differences between the treatment arms in terms of either improvement or deterioration.
  • With regard to improvement in the subscore for bulbar symptoms (impaired speech, swallowing or salivation), there was a statistically significant disadvantage for tofersen compared with placebo; however, no statistically significant difference was observed in terms of deterioration.
  • As a deterioration in motor function is to be expected in this therapeutic indication given the progressive nature of the disease, the analyses of deterioration are considered particularly relevant for this specific benefit assessment.
  • The disadvantage in the improvement in the subscore for bulbar symptoms is not taken into account in the assessment of additional benefit in this instance, given the comparison with placebo and the minor absolute number of events.
• Morbidity – time to death or to the need for permanent ventilation
  • In total, permanent ventilation occurred in 3 and 2 patients in the intervention and control arms, respectively.
  • For the combined endpoint ‘time to death or permanent ventilation’, 4 events occurred in the intervention arm and 2 events in the control arm.
  • Due to the minor number of events, the median times to the respective events could not be determined.
  • For the endpoints ‘time to permanent ventilation’ and ‘time to death or permanent ventilation’, there were no statistically significant differences between the treatment arms in either case.
• Quality of life – 36-Item Short Form Health Survey (SF-36)
  • No statistically significant differences were observed between the treatment arms for either a deterioration or an improvement of ≥ 15% of the scale range in the physical and mental total scores.
• Side effects
  • No statistically significant differences were observed between the treatment arms for the overall rates of severe adverse events, serious unwelcome events (SAE) or adverse events leading to discontinuation of study medication.
  • Adverse events of particular interest were not pre-specified.
• Overall assessment
  • For the benefit assessment of tofersen in the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene, results are available from the randomised, double-blind VALOR trial, in which tofersen was compared with placebo.
  • The results of the integrated analysis submitted by the pharmaceutical manufacturer, based on data from the VALOR RCT and the single-arm open-label extension study 233AS102, are not taken into account here, as they do not allow for a comparison of tofersen with placebo or another active ingredient (INN) and have methodological limitations.
  • During the VALOR study, one death occurred among patients treated with Tofersen. There are no differences relevant to the benefit assessment in the mortality category.
  • In the morbidity category, there are no statistically significant differences for the ALSFRS-R subscores relating to gross motor function, fine motor function and respiratory function in terms of an improvement or deterioration of 15% of the scale range. In the ALSFRS-R subscore for bulbar symptoms (impairment of speech, swallowing or salivation), there is a statistically significant disadvantage for Tofersen compared with placebo in terms of improvement, whereas no statistically significant difference is observed for deterioration. As a deterioration in motor function is to be expected in this therapeutic indication given the progressive nature of the disease, the analyses of deterioration are considered particularly relevant for this specific benefit assessment. The disadvantage on the improvement in the subscore for bulbar symptoms is not taken into account in the assessment of additional benefit in this instance, given the comparison with placebo and the minor absolute number of events.
  • For the endpoints of time to death or to permanent ventilation, fatigue, general health status and activities of daily living, no statistically significant differences were observed for either improvement or deterioration.
  • With regard to quality of life, the available data show no statistically significant differences in terms of improvement or deterioration in either the physical or mental health summary scores of the SF-36.
  • Similarly, in the area of side effects, there were no statistically significant differences in the overall rates of serious and severe adverse events, nor in the rates of therapy discontinuation due to adverse events. Adverse events of particular interest were not pre-specified.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn on the basis of the available data.
  • In its overall assessment of the available results regarding patient-relevant endpoints, the G-BA therefore classifies the extent of the additional benefit of tofersen for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene, as non-quantifiable, in accordance with the criteria set out in Section 5(8) in conjunction with Section 5(7), first sentence, points 1 to 4 of the AM-NutzenV, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.