Iptacopan (1) – Fabhalta®

• Clinical trials
  • Alongside the APPOINT-PNH trial, the APPLY-PNH trial is one of two pivotal trials on iptacopan in this therapeutic indication. The APPLY-PNH trial is designed for previously treated adults with PNH who have haemolytic anaemia. It is a completed, multicentre, open-label, randomised controlled Phase III trial.

a) Treatment-naive adults with PNH who have haemolytic anaemia

• Overall, the G-BA classifies the extent of the additional benefit of iptacopan as monotherapy for the treatment of treatment-naïve adults with PNH who have haemolytic anaemia as non-quantifiable, as the scientific evidence does not permit quantification.
• The strength of the evidence is classified as ‘hint’.
• mortality
  • Overall survival was not assessed as an independent endpoint in the APPOINT-PNH study. Deaths were recorded as part of the adverse event monitoring. No deaths occurred throughout the entire study duration.
  • Due to the single-arm study design, a comparative assessment of overall survival is not possible.
• Morbidity – haemoglobin-associated endpoint
  • The primary endpoint of the study was an increase in the haemoglobin (Hb) level of ≥ 2 g/dl whilst remaining transfusion-free.
  • This endpoint represents a laboratory parameter with no direct relation to symptoms and is not, in itself, relevant to the patient. As this is the primary endpoint, it is presented here for the sake of completeness.
• Morbidity – absence of transfusions
  • The endpoint ‘transfusion-free status’ was defined as the proportion of participants who, between week 2 and week 24 or week 48, did not receive a transfusion of packed red blood cells (PRBC) and did not meet any of the following criteria for the need for a transfusion: [...]
  • Many patients in this therapeutic indication require regular transfusions. The long-term or sustained avoidance of transfusions (transfusion-free status or long-term transfusion avoidance) whilst maintaining a defined minimum haemoglobin level represents a relevant therapeutic goal in this therapeutic indication, enabling the control of anaemia and anaemia-related symptoms whilst avoiding the need for transfusions. Long-term freedom from transfusions may therefore constitute a patient-relevant endpoint in this therapeutic indication.
  • With regard to the operationalisation described above, there are uncertainties in that the reasons for the differing transfusion criteria for the Chinese population remain unclear, and it is not apparent why data collection only begins on day 14. The start on day 14 is viewed critically overall, as events occurring prior to this are not taken into account. Therefore, in this case, the analyses from Day 1 to Week 48 are based on patients who actually received a transfusion. This shows that 85 per cent of patients remained transfusion-free.
  • Due to the single-arm study design, a comparative analysis of the data is not possible.
• Morbidity – Breakthrough haemolysis
  • The endpoint ‘breakthrough haemolysis’ was defined in the APPOINT-PNH study as: a lactate dehydrogenase (LDH) level > 1.5 × ULN, as well as an increase in the LDH level compared with the last two measurements, AND the presence of at least one of the following clinical criteria: [...]
  • Breakthrough haemolysis could therefore be diagnosed solely on the basis of laboratory parameters (LDH and Hb) without the occurrence of clinically relevant symptoms. However, the two instances of breakthrough haemolysis observed in the APPOINT-PNH study involved exclusively symptomatic patients.
  • In principle, symptoms associated with breakthrough haemolysis are clinically relevant to patients. In the present case, the final assessment of whether breakthrough haemolysis was present was made by the investigators. In this regard, it remains unclear whether the operationalisation fully captured all individual symptoms that may occur in the context of breakthrough haemolysis.
  • Due to the uncertainties described, the endpoint of breakthrough haemolysis is not considered patient-relevant in this case and is presented only as supplementary information.
• Morbidity – Fatigue (FACIT-Fatigue and Patient Global Impression of Severity (PGIS))
  • In the APPOINT-PNH study, fatigue as perceived by patients was assessed using the FACIT-Fatigue and the PGIS.
  • The results are comparable in magnitude. An improvement in the FACIT-Fatigue score was achieved by 55% of patients, whilst the figure for the PGIS was 60%.
  • Due to the single-arm study design, a comparative analysis of the data is not possible.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • Data on symptoms were collected using the symptom scales of the EORTC QLQ-C30 questionnaire.
  • The EORTC QLQ-C30 is a generic measurement tool for assessing symptoms and quality of life in patients with oncological diseases. The relevance of individual items in the questionnaire to the symptoms in the present therapeutic indication is unclear. The symptom scales of the EORTC QLQ-C30 are therefore not used for this assessment.
• quality of life
  • Data on health-related quality of life from the APPOINT-PNH study are available based on the functional scales and the global health status scale of the EORTC QLQ-C30.
  • Improvements are evident across the individual scales in between 32.5% and 75% of patients.
  • Due to the single-arm study design, a comparative analysis of the data is not possible.
• Side effects (AEs) – total
  • AEs occurred in just over 90 per cent of patients. The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of iptacopan as monotherapy in the population of treatment-naïve adults with PNH who have haemolytic anaemia, results are available from the completed, multicentre, single-arm Phase III APPOINT-PNH trial regarding mortality, morbidity, quality of life and side effects.
  • In addition, the pharmaceutical manufacturer presents in the dossier an indirect comparison of these data with the retrospective APPEX comparison cohort.
  • The indirect comparison presented is deemed invalid due to the limited availability of data, the unclear structural equivalence and comparability of the APPOINT-PNH study with the external comparison cohort APPEX, as well as the inadequate adjustment for confounders using the propensity score methods employed, is assessed as invalid. The indirect comparison is therefore not taken into account for the present benefit assessment.
  • Due to the single-arm study design of the APPOINT-PNH study, no conclusion can be drawn from the study results regarding the extent of the additional benefit.

b) Previously treated adults with PNH who have haemolytic anaemia

• Overall, the G-BA classifies the extent of the additional benefit of iptacopan as monotherapy for the treatment of previously treated adults with PNH who have haemolytic anaemia as non-quantifiable, as the scientific evidence does not permit quantification.
• Particularly due to the open-label study design, the strength of the evidence is classified as ‘a hint’.
• mortality
  • Overall survival was not assessed as a standalone endpoint in the APPLY-PNH study. Deaths were recorded as part of the adverse event monitoring. No deaths occurred throughout the entire study duration.
• Morbidity – haemoglobin-associated endpoints
  • The co-primary endpoints of the study were an increase in Hb levels of ≥ 2 g/dl and to ≥ 12 g/dl whilst remaining transfusion-free.
  • These endpoints represent laboratory parameters with no direct relation to symptoms and are not, in themselves, relevant to patients. As these are co-primary endpoints, they are presented here for the sake of completeness.
• Morbidity – Freedom from transfusion
  • The endpoint ‘transfusion-free status’ was defined as the proportion of participants who, between week 2 and week 24 of the RCP, did not receive a red blood cell concentrate (RBC) transfusion or did not meet any of the following criteria for the need for a transfusion: [...]
  • Many patients in this therapeutic indication require regular transfusions. The long-term or sustained avoidance of transfusions (transfusion-free status or long-term transfusion avoidance) whilst maintaining a defined minimum haemoglobin level represents a relevant therapeutic goal in this therapeutic indication, enabling the control of anaemia and anaemia-related symptoms whilst avoiding transfusions. Long-term freedom from transfusions may therefore represent a patient-relevant endpoint in this therapeutic indication.
  • With regard to the operationalisation described above, there are uncertainties in that the start of data collection in week 2 is viewed critically overall, as events occurring prior to this are not taken into account. Furthermore, patients who met the criteria for a transfusion as defined in the study protocol were classified as having received a transfusion, regardless of whether a transfusion was actually administered. Consequently, individuals were classified as non-responders (‘transfused’) if they met the criteria for a transfusion but did not actually receive one.
  • In this regard, the pharmaceutical manufacturer has, in its written statement, submitted further analyses on the ‘transfusion-free’ endpoint; in the present case, the evaluations from Day 1 to Week 24 relating to patients who actually received a transfusion whilst experiencing symptoms are being used. This reveals a statistically significant advantage for Iptacopan.
• quality of life
  • Data on health-related quality of life from the APPLY-PNH study are available based on the functional scales and the global health status scale of the EORTC QLQ-C30.
  • Iptacopan shows statistically significant advantages on the scales for physical functioning, role functioning, social functioning and overall health status, which are collectively assessed as a marked improvement in quality of life.
• Side effects – Total adverse events (AEs)
  • AEs occurred in approximately 80% of patients in each study arm. The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of Iptacopan as monotherapy, with regard to the population of pre-treated adults with PNH who have haemolytic anaemia, results are available from the completed, multicentre, open-label, randomised controlled Phase III APPLY-PNH trial on mortality, morbidity, quality of life and side effects. In the study, iptacopan was compared with continued treatment with eculizumab or ravulizumab.
  • With regard to mortality, no deaths occurred in the APPLY-PNH study.
  • In the morbidity endpoint category, advantages were observed in terms of the transfusion-free endpoint, the symptom of fatigue and general health status, which are collectively assessed as a significant improvement in morbidity.
  • In terms of health-related quality of life, advantages were observed in physical functioning, role functioning, emotional functioning and overall health status, which are collectively assessed as a significant improvement in health-related quality of life.
  • With regard to side effects, no overall advantages or disadvantages of Iptacopan compared with Ravulizumab or Eculizumab can be identified.
  • In the overall assessment, when quantifying the extent of the additional benefit based on the significant advantages of Iptacopan compared with continued therapy with eculizumab or ravulizumab (C5 complement inhibitors), it is assumed that the results of the APPLY-PNH study are of limited applicability to the German healthcare context. This is based on the fact that, particularly in light of the statements made by clinical experts during the commenting procedure, in patients with clinically significant extravascular haemolysis—characterised in particular by persistent anaemia, reticulocytosis and the presence of symptoms, switching therapy to proximal complement inhibition (C3 complement inhibitors) rather than continuing terminal complement inhibition (C5 complement inhibitors) represents the current standard of care.
  • It can therefore be assumed that, for a large proportion of patients in the APPLY-PNH study, the continued use of ravulizumab or eculizumab without change does not reflect the current German standard of care. Due to this significant limitation, the extent of the additional benefit cannot be quantified with sufficient certainty in the overall assessment of the available results. However, the advantages of iptacopan compared with continuing treatment with eculizumab or ravulizumab in terms of improvements in morbidity and health-related quality of life are assessed as significant advantages.

Courtesy translation only, please refer to the German original.