Patisiran (1) – Onpattro®

• 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, blinded, controlled APOLLO trial, which investigated the efficacy and safety of patisiran 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)

• Patisiran offers considerable additional benefit for the treatment of hereditary transthyretin amyloidosis (hATTR amyloidosis) in adult patients with stage 1 or 2 polyneuropathy.
• mortality
  • Mortality was recorded as part of the adverse event data. Seven (4.7%) patients in the patisiran arm and six (7.8%) patients in the control arm died. The results do not show a statistically significant difference between the treatment groups.
  • Based on the data presented, no conclusion regarding additional benefit can be drawn for the endpoint category of mortality.
• Morbidity – Polyneuropathic symptoms (mNIS+7)
  • The change in polyneuropathic symptoms (assessed using the mNIS+7, modified Neuropathy Impairment Score + 7) was recorded as the primary endpoint.
  • In the APOLLO study, the mean mNIS+7 score at baseline was 81 in the patisiran arm and 75 in the control arm. After the 18-month treatment period, the mean mNIS+7 score was 75 points in the patisiran arm and 101 points in the control arm. The difference between the treatment groups is statistically significant in favour of patisiran.
  • A full validation of the mNIS+7 was not carried out. Furthermore, no conclusive validation studies for the scales underlying the mNIS+7 were presented in the dossier. In addition, the criteria for weighting the individual domains are not sufficiently explained.
  • In light of the existing uncertainties, the mNIS+7 is presented here as supplementary information for the benefit assessment.
• Interim conclusion on morbidity
  • For the morbidity endpoint, the APOLLO study presents statistically significant and clinically relevant results regarding mean walking speed (measured using the 10-MWT) health status (as measured by the EQ-5D VAS) and limitations in activities of daily living (as measured by the R-ODS) in favour of patisiran.
  • For all morbidity endpoints, the number of patients who could be included in the control arm was significantly lower than in the patisiran arm (70–73% vs. 93%). This imbalance in terms of missing values leads to an increased potential for bias across all morbidity endpoints.
  • Taking an overall view of the positive results for the morbidity endpoints of mean walking speed, health status and limitations in activities of daily living, a considerable additional benefit for Patisiran can be inferred.
• quality of life
  • In the APOLLO study, disease-specific quality of life was assessed using the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire, which was developed to measure health-related quality of life in patients with neuropathy.
  • After the 18-month treatment period, the mean Norfolk QoL-DN score was 55.4 points in the patisiran arm and 71.7 points in the control arm. The results show a statistically significant difference between the treatment arms (95% CI [-27.2; -15.0]; p < 0.001). As there is no valid MID (Minimum Important Difference) for the Norfolk QoL-DN, Hedges’ g was calculated to assess clinical relevance, and it was found that the observed effect is clinically relevant (Hedges’ g −1.05, 95% CI [–1.39; –0.70]).
  • As with the morbidity endpoints, the number of patients who could be included in the control arm was significantly lower (62%) than in the patisiran arm (91%) for the Norfolk QoL-DN quality of life questionnaire. This imbalance in terms of missing values leads to an increased potential for bias in this endpoint. Notwithstanding this, based on the results of the Norfolk QoL-DN, an additional benefit for patisiran can be inferred for the quality of life endpoint; however, the extent of this benefit is non-quantifiable.
• Side effects
  • The recording of adverse events (AEs) in the APOLLO study was standardised in accordance with the Medical Dictionary for Regulatory Activities (MedDRA), using the System Organ Class (SOC) and Preferred Terms (PT).
  • In both treatment groups, the most common AEs were diarrhoea and peripheral oedema. Peripheral oedema and infusion-related reactions occurred significantly more frequently in the patisiran arm than in the control arm (peripheral oedema 30% vs. 22%, infusion-related reactions 19% vs. 9%). Falls and muscle weakness were recorded more frequently in the control arm than in the patisiran arm (falls 29% vs. 17%, muscle weakness 14% vs. 3%); anaemia and syncope were also more common in the control arm (14% vs. 3% in each case).
• Overall assessment
  • For the endpoint category of mortality, no conclusion regarding additional benefit can be drawn from the data presented.
  • For the morbidity endpoint, the APOLLO study showed statistically significant and clinically relevant advantages in terms of mean walking speed (as measured by the 10-MWT), health status (as measured by the EQ-5D VAS) and limitations in activities of daily living (as measured by the R-ODS) in favour of patisiran.
  • With regard to disease-specific quality of life, there are also statistically significant results from the Norfolk-QoL-DN questionnaire in favour of patisiran.
  • However, whilst the overall results regarding morbidity and quality of life are positive, it must be noted that there was an imbalance in terms of missing values, as the number of patients who could be included in the control arm was significantly lower than in the patisiran arm (morbidity 70–73% vs. 93 per cent, and quality of life 62 per cent vs. 91 per cent). This leads to an increased potential for bias in these endpoints.
  • In the side effects category, the APOLLO study shows that patisiran was associated with minor adverse events leading to treatment discontinuation. Furthermore, as the mean duration of treatment and the proportion of patients with a treatment duration of at least 15 months were higher in the Patisiran arm than in the control arm, it cannot be ruled out that the safety results are biased against Patisiran. The potential for bias is assessed as high overall.
  • Despite the high potential for bias in the endpoints, the G-BA considers the extent of the additional benefit of Patisiran, when viewed in the overall context of the positive results of the APOLLO study and 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, as considerable.

Courtesy translation only, please refer to the German original.