Inotersen (1) – Tegsedi®

• Clinical trials
  • For the benefit assessment pursuant to Section 35a of the German Social Code, Book V (SGB V), the pharmaceutical manufacturer has submitted the multicentre, randomised, double-blind, controlled NEURO-TTR trial (Phase II/III).
  • This trial investigated the efficacy and safety of inotersen compared with placebo in patients with hereditary transthyretin amyloidosis (hATTR amyloidosis).

Adult patients with stage 1 or 2 polyneuropathy associated with hereditary transthyretin amyloidosis (hATTR)

• Against this background, the G-BA classifies the extent of the additional benefit of inotersen as non-quantifiable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing.
• mortality
  • Mortality was recorded as part of the adverse event data.
  • Five (4.5%) patients died in the inotersen arm and no patients in the control arm.
  • Notwithstanding the fact that a 2:1 randomisation was carried out in the study – meaning twice as many patients were treated with Inotersen compared with placebo – there is a numerical imbalance in terms of deaths to the detriment of Inotersen.
  • A definitive assessment of the results is not possible, as it cannot be determined overall whether the deaths that occurred can be attributed to the administration of Inotersen.
• Morbidity – Polyneuropathic symptoms (mNIS+7)
  • The change in polyneuropathic symptoms (assessed using the mNIS+7, modified Neuropathy Impairment Score + 7) was recorded as a co-primary endpoint.
  • In the NEURO-TTR study, the mean mNIS+7 score at the start of the study was 79.3 in the inotersen arm and 74.1 in the control arm.
  • After 66 weeks of treatment, the mean mNIS+7 score was 84.5 points in the inotersen arm and 98.5 points in the control arm.
  • The difference between the treatment groups is statistically significant in favour of inotersen.
  • A full validation of the mNIS+7 was not carried out.
• Morbidity – Walking ability (PND score)
  • Changes in the patient’s mobility and neuropathy stage were assessed via the PND score by an independent evaluator.
  • Walking ability, as measured by the PND score, is considered to be relevant to patients.
  • At week 65, an improvement in the PND score was observed in a higher proportion of patients in the intervention arm (10.5%) compared with those in the control arm (3.8%).
  • As the proportions of patients in PND score I differed by approximately 10 % between the treatment groups, uncertainties remain regarding the comparability of the patient groups.
  • Furthermore, as the results on walking ability were presented only descriptively, no conclusions can be drawn regarding the statistical significance and clinical relevance of these results.
• Health-related quality of life – Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN)
  • In the NEURO-TTR study, disease-specific quality of life was assessed using the Norfolk QoL-DN as the second primary endpoint.
  • The mean total score on the Norfolk QoL-DN was 48.6 points in both study arms at the start of the study.
  • After 66 weeks of treatment, patients in the inotersen arm showed an average decrease of 0.08 points, whereas those in the control arm showed an increase of 10.77 points.
  • These changes from baseline in the Norfolk QoL-DN total score show a statistically significant difference in favour of inotersen at week 66.
  • As there is no valid MID (Minimum Important Difference) for the Norfolk QoL-DN, Hedges’ g was calculated to assess the clinical relevance of the change during the treatment phase.
  • The 95% confidence interval for Hedges’ g does not lie entirely outside the irrelevance range of –0.2 to 0.2; consequently, it cannot be concluded that the effect observed in the mean differences is clinically relevant.
• Side effects
  • Adverse events (AEs) in the NEURO-TTR study were recorded in a standardised manner in accordance with the Medical Dictionary for Regulatory Activities (MedDRA), using the System Organ Class (SOC) and Preferred Terms (PT).
  • The most common AEs were nausea, fatigue and headache in both treatment groups.
  • Injection-site erythema occurred in 31% of patients exclusively in the inotersen arm.
  • Severe AEs occurred in 27.7% of patients in the inotersen arm and in 21.7% of patients in the control arm.
  • No statistically significant differences were observed between the treatment groups in terms of serious adverse events (SAEs) (32.1% in the Inotersen arm vs. 21.7% in the control arm).
  • The SOC ‘Renal and urinary tract disorders’ was recorded as a common serious adverse event (incidence ≥ 5% and ≥ 5% difference between the treatment groups) exclusively in the inotersen arm (in 6 (5.4%) patients).
• Overall assessment
  • With regard to mortality, five deaths occurred in the NEURO-TTR study in the inotersen group and none in the placebo group.
  • A definitive assessment of the results is not possible, as it cannot be determined overall whether the deaths that occurred can be attributed to the administration of inotersen.
  • No meaningful data are available for the morbidity endpoint that can be used for benefit assessment of inotersen.
  • In the area of health-related quality of life, a statistically significant and clinically relevant advantage in favour of inotersen is evident for the‘Physical Functioning’domain of the generic SF-36 questionnaire; however, methodological uncertainties remain regarding a possible overestimation of the positive effect.
  • With regard to side effects, the NEURO-TTR study shows a higher incidence of adverse events leading to treatment discontinuation with Inotersen.
  • Taking the results of the NEURO-TTR study as a whole, Inotersen appears to have a positive effect on quality of life, although there are uncertainties regarding a possible overestimation of this effect.
  • This is offset by statistically significant disadvantages in terms of side effects.
  • Against this background, the G-BA classifies the extent of the additional benefit of inotersen as non-quantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing.

Courtesy translation only, please refer to the German original.