Momelotinib (1) – Omjjara®

• Clinical trials
  • The pharmaceutical manufacturer has submitted results from the multicentre, randomised, double-blind, Phase III SIMPLIFY-1 trial for the benefit assessment, in which momelotinib was compared with ruxolitinib.
  • The SIMPLIFY-2 trial is a multicentre, randomised, open-label, Phase III trial in which momelotinib was compared with best available therapy (BAT).
  • The MOMENTUM study is a multicentre, randomised, double-blind, Phase III study in which momelotinib was compared with danazol.

a) Adults with moderate or severe anaemia associated with primary myelofibrosis, post-polycaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, who have not been treated with Janus-associated kinase inhibitors (JAK inhibitors); for the treatment of disease-related splenomegaly or symptoms

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Overall, a non-quantifiable additional benefit is identified for momelotinib compared with ruxolitinib in the group of patients who have not been treated with JAK inhibitors, as the scientific evidence does not permit quantification.
• Overall, the certainty of the evidence for the identified additional benefit is classified as ‘hint’.
• mortality
  • In the SIMPLIFY-1 study, the endpoint of overall survival was defined as the time (in months) from the first dose in the blinded treatment phase until death, regardless of the cause of death.
  • No statistically significant difference was observed between the treatment arms.
• Morbidity – spleen response assessed by MRI/CT
  • In the SIMPLIFY-1 study, spleen response was the primary endpoint. The spleen response rate was defined as the proportion of patients with a ≥ 35 % reduction in spleen volume, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) at week 24 compared with baseline.
  • In this regard, there was no statistically significant difference between the treatment arms.
• Morbidity – Leukaemic transformation
  • In the SIMPLIFY-1 study, leukaemic transformation is defined as the time from randomisation to the occurrence of leukaemic transformation, defined as an increase in the blast count in the bone marrow of ≥ 20% or a blast count in peripheral blood of ≥ 20% in conjunction with an absolute blast count of ≥ 1 × 10/L, persisting for ≥ 2 weeks.
  • The results of the SIMPLIFY-1 study show no statistically significant difference between the treatment arms, with only one event observed in total.
• Morbidity – Transfusion-free survival
  • In the SIMPLIFY-1 study, the endpoint ‘transfusion-free status’ was defined as: the proportion of participants who did not receive any RBC transfusions for at least 24 weeks (transfusion-free status). Proportion of participants who did not receive any RBC transfusions for at least 24 weeks and did not have an Hb level < 8 g/dl. Proportion of participants who, by week 24, had achieved 12 weeks of transfusion independence with a haemoglobin (Hb) level that must not have fallen below 8 g/dl (cases associated with clinically manifest bleeding are excluded). Proportion of participants who, by week 24, had achieved 12-week transfusion independence with a haemoglobin level that must not have fallen below 8 g/dl during this period, and who were transfusion-dependent at baseline (cases associated with clinically manifest bleeding are excluded).
  • Due to the relevant uncertainties mentioned above, the results of SIMPLIFY-1 are assessed as not sufficiently robust to derive any additional benefit from them.
• Morbidity – Transfusion dependency
  • The transfusion dependency rate is defined as the proportion of individuals who are transfusion-dependent after 24 weeks. In the SIMPLIFY-1 study, the transfusion dependency rate is defined as meeting one of the following criteria: at least 4 units of RBC transfusions in the preceding 8 weeks or a haemoglobin level < 8 g/dl in the preceding 8 weeks.
  • Against this background, the endpoint is not considered clinically relevant and is not used for the benefit assessment.
• Morbidity – Symptoms assessed using the MPN-SAF
  • Symptoms were assessed in the SIMPLIFY-1 study using the MPN-SAF at baseline and subsequently at 4-week intervals.
  • No statistically significant difference was observed between the treatment arms.
• Morbidity – Brief Fatigue Inventory
  • The pharmaceutical manufacturer provides analyses for improvements and deteriorations in the BFI total score, as well as in the two subdomains (fatigue score and interference score) of ≥ 15 % of the scale range at week 24 (≥ 1.5 points).
  • No differences were observed between the treatment arms.
• Morbidity – PGIC
  • The pharmaceutical manufacturer provides responder analyses at week 24. In this context, positive responders are defined as individuals showing any improvement in symptoms, i.e. ‘major improvement’, ‘much improvement’ or ‘slightly improved’.
  • There is no statistically significant difference between the treatment arms.
• Morbidity – EQ-5D-VAS
  • Health status was assessed in the SIMPLIFY-1 study using the EuroQoL 5-Dimensions (EQ 5D) visual analogue scale (VAS).
  • There is no statistically significant difference between the two treatment arms.
• quality of life
  • Quality of life is assessed in the SIMPLIFY-1 study using the SF-36. For the benefit assessment, responder analyses with a 15% response criterion at week 24 are presented.
  • No difference in quality of life was observed between the treatment arms.
• Side effects – Total adverse events (AEs)
  • AE occurred in almost all study participants. The results are presented for supplementary information only.
• Side effects – Serious AEs (SAEs) and severe AEs (CTCAE grade ≥ 3)
  • There were no statistically significant differences between the treatment arms for SAE and severe AEs (CTCAE grade ≥ 3).
• Conclusion on side effects
  • Overall, with regard to the ‘side effects’ endpoint category, momelotinib shows a disadvantage in terms of the endpoint ‘therapy discontinuations due to AEs’. In detail, among the specific AEs, there is a single relevant difference in the PT ‘anaemia’, with an effect in favour of momelotinib compared with ruxolitinib.
• Overall assessment
  • For the benefit assessment of momelotinib in the treatment of disease-related splenomegaly or symptoms in adults with moderate or severe anaemia due to primary myelofibrosis, post-polycaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, who were not being treated with Janus-associated kinase inhibitors (JAK inhibitors), the SIMPLIFY-1 study provides results on mortality, morbidity, quality of life and adverse events.
  • Overall, for momelotinib compared with ruxolitinib in the group of patients who have not been treated with JAK inhibitors, a non-quantifiable additional benefit is identified, as the scientific evidence does not permit quantification.

b) Adults with moderate or severe anaemia associated with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis who have been treated with ruxolitinib; for the treatment of disease-related splenomegaly or symptoms

• Hint of a minor additional benefit.
• Overall, a minor additional benefit is identified for the group of patients treated with ruxolitinib, based on the positive effects of momelotinib on splenic response, combined with an improvement in symptoms and a reduction in symptom severity.
• Due to relevant uncertainties arising, amongst other things, from the definition of the mITT population relevant for the benefit assessment and imbalances in baseline characteristics, the strength of the evidence is classified as ‘hint’.
• mortality
  • In the SIMPLIFY-2 and MOMENTUM studies, no statistically significant difference was observed between the treatment arms.
• Morbidity – spleen response assessed by CT/MRI
  • In both studies, the spleen response rate was defined as the proportion of participants with a ≥ 35 % reduction in spleen volume, as measured by MRI or CT at week 24 compared with baseline.
  • In this regard, the SIMPLIFY-2 study showed no statistically significant difference between the treatment arms.
  • In the MOMENTUM study, a statistically significant advantage was observed for momelotinib compared with danazol. This advantage, in conjunction with the advantage in symptom response (MFSAF), is considered a patient-relevant effect representing a clinically relevant improvement.
• Morbidity – Leukaemic transformation
  • In the SIMPLIFY-2 study, leukaemic transformation is defined as the time from randomisation to the occurrence of leukaemic transformation, defined as an increase in the blast count in the bone marrow of ≥ 20% or a blast count in peripheral blood of ≥ 20% in conjunction with an absolute blast count of ≥ 1 × 10/L, persisting for ≥ 2 weeks.
  • The results of the SIMPLIFY-2 study show no statistically significant difference between the treatment arms, with only 3 events observed in total.
• Morbidity – Transfusion-free survival
  • In the SIMPLIFY-2 study, the endpoint ‘transfusion-free status’ was defined as: the proportion of participants who had not received any RBC transfusions for at least 24 weeks (transfusion-free status). Proportion of participants who did not receive any RBC transfusions for at least 24 weeks and did not have an Hb level < 8 g/dl. Proportion of participants who, by week 24, had achieved 12 weeks of transfusion independence with a haemoglobin level that must not have fallen below 8 g/dl (cases associated with clinically manifest bleeding are excluded). Proportion of participants who, by week 24, had achieved 12-week transfusion independence with a haemoglobin level that must not have fallen below 8 g/dl during this period and who were transfusion-dependent at baseline (cases associated with clinically manifest bleeding are excluded).
  • Due to the relevant uncertainties mentioned above, the results of the MOMENTUM study are assessed as not sufficiently robust to infer any additional benefit.
• Morbidity – Transfusion dependence
  • The transfusion dependency rate is defined as the proportion of individuals who are transfusion-dependent after 24 weeks. In the SIMPLIFY-2 study, these endpoints are defined as meeting one of the following criteria: at least 4 units of RBC transfusions in the preceding 8 weeks, or a haemoglobin level < 8 g/dl in the preceding 8 weeks.
  • Against this background, the endpoint is not considered relevant to patients and is not used for the benefit assessment.
• Morbidity – MFSAF
  • Symptoms were assessed in the MOMENTUM study using the MFSAF v.4.0.
  • There is a statistically significant advantage for momelotinib compared with danazol.
• Morbidity – Brief Fatigue Inventory
  • Due to minor response rates, which were already evident by week 4 (momelotinib 68.2% and BAT: 66.6%) and continued to deteriorate up to week 24, particularly in the intervention arm (momelotinib: 40.9%; BAT: 58.9%), no data suitable for analysis in the SIMPLIFY-2 study are available.
• Morbidity – Patient Global Impression of Severity (PGIS)
  • Momelotinib showed positive effects for the items ‘severity of symptoms’ and ‘severity of fatigue’. Based on Hedges’ g, it cannot be concluded that a clinically relevant effect is present.
• Morbidity – Patient Global Impression of Change (PGIC)
  • The SIMPLIFY-2 study shows a statistically significant advantage for momelotinib compared with BAT.
• Morbidity – EQ-5D-VAS
  • Health status was assessed in the SIMPLIFY-2 study using the EuroQoL 5-Dimensions (EQ 5D) visual analogue scale (VAS).
  • No statistically significant difference was observed between the treatment arms.
• Quality of life – SF-36
  • Quality of life was assessed in the SIMPLIFY-2 study using the SF-36. For the benefit assessment, responder analyses with a 15% response criterion at week 24 are presented.
  • Due to minor response rates, which were already evident at week 4 (momelotinib and BAT: 66.7% each) and continued to deteriorate up to week 24, particularly in the intervention arm (momelotinib: 39.4%; BAT: 59.0%), no usable data are available for the SF-36.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all participants in the SIMPLIFY-2 and MOMENTUM studies. The results are presented here for supplementary information only.
• Conclusion on side effects
  • Overall, with regard to the ‘side effects’ endpoint category, momelotinib showed a disadvantage compared with BAT in terms of the endpoint ‘therapy discontinuations due to AEs’ in the SIMPLIFY-2 study. In detail, there were advantages for individual specific AEs.
• Overall assessment
  • For the benefit assessment of momelotinib for the treatment of disease-related splenomegaly or symptoms in adults with moderate or severe anaemia due to primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who have been treated with ruxolitinib, the randomised Phase III trials SIMPLIFY-2 and MOMENTUM form the basis of the assessment.
  • Overall, a minor additional benefit is observed for the group of patients treated with ruxolitinib, based on the positive effects of momelotinib on splenic response, combined with an improvement in symptoms and a reduction in symptom severity.

Courtesy translation only, please refer to the German original.