Trial Outcomes & Findings for Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) (NCT NCT04266301)

This study randomized participants in 149 centers in 36 participating countries.

Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

OS is the time from randomization until death due to any cause.

OS is the time from randomization until death due to any cause.

FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer participants. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. Time to definitive deterioration of fatigue is defined as time from randomization to at least 3 points worsening from baseline in FACIT-fatigue scores with no subsequently observed improvement above this threshold, or death due to any cause, whichever occurred first.

Annualized transfusion free rate is defined as the average number of days in RBC transfusion-free intervals in a year (i.e., the total number of days in RBC transfusion-free intervals divided by the total days in the study multiplied by 365.25), where RBC transfusion-free intervals correspond to cumulative times of intervals with no evidence of RBC transfusion for at least 8 weeks at any point after randomization until death due to any cause.

FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer participants. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. The responder is defined as having 3 points improvement from baseline confirmed by a second improvement of 3 points at any time, regardless of preceding worsening. A participant who could not improve was considered as a non-responder.

EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer participants. Participants' responses to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. The responder is defined as having 10 points improvement from baseline confirmed by a second improvement of 10 points at any time, regardless of preceding worsening. A participant who could not improve was considered as a non-responder.

EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer participants. Participants' responses to 4 questions about their emotional functioning (Items 21-24) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. The responder is defined as having 10 points improvement from baseline confirmed by a second improvement of 10 points at any time, regardless of preceding worsening. A participant who could not improve was considered as a non-responder.

Response rate of participants with complete remission (CR), or marrow remission (mCR), or partial remission (PR), or hematologic improvement (HI). CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100\*109/L AND Neutrophils ≥ 1.0\*109/L AND Peripheral blasts 0%. mCR: Bone marrow: ≤ 5% blasts and blast count decrease by ≥ 50% compared to baseline; Peripheralblood/transfusion: Marrow CR may be achieved with or without improved blood counts or with or without transfusions PR: All CR criteria except bone marrow: ≥50% decrease from baseline in blasts in bone marrow AND blast count in bone marrow \>5%. HI: restoration or enhancement of the function of the body's blood cell-producing system that must last as least 8 weeks.

Response rate of participants with stable disease. SD is the failure to achieve at least partial response (PR), but no evidence of progression for \>8 weeks.

PFS is defined as the time from randomization to disease progression (including transformation to acute leukemia per WHO 2016), relapse from CR (IWG-MDS), or death. Disease progression: bone marrow blasts increase ≥ 50% over baseline, to \> 5% if initially \< 5%, \> 10% if 5%-\<10%, or \> 20% if 10%-\<20%. Includes a peripheral blood count decrease ≥ 50% from maximum remission/response levels: neutrophils \< 1.0x109/L, platelets \< 100x109/L, or hemoglobin drop ≥ 2 g/dL to \< 10 g/dL, becoming transfusion-dependent. Relapse from CR: baseline bone marrow blast % return, neutrophils decrease ≥ 50% to \< 1.0x109/L, platelets decrease ≥ 50% to \< 100x109/L, or hemoglobin drop ≥ 1.5 g/dL to \< 10 g/dL, becoming transfusion-dependent. Leukemia transformation: \> 20% blasts per WHO 2016 (Arber et al 2016).

LFS is defined as the time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia, or death due to any cause

Improvement in RBC transfusion independence as per International Working Group for MDS (IWG-MDS) criteria. RBC transfusion independence was defined as having received 0 units of RBC transfusions during at least 8 consecutive weeks after randomization. The number of participants was shown in only those with transfusion dependence at baseline (BL).

Improvement in Platelets transfusion independence as per International Working Group for MDS (IWG-MDS) criteria. Platelets transfusion independence was defined as having received 0 units of Platelets transfusions during at least 8 consecutive weeks after randomization. The number of participants was shown in only those with transfusion dependence at baseline (BL).

Cmax is the maximum (peak) observed drug concentration after single dose administration (mass x volume-1).

AUCinf is the AUC from time zero to infinity (mass x time x volume-1).

Anti-drug Antibody (ADA) prevalence is the number of participants with at least one sample meeting the criteria at baseline. ADA-positive participants were calculated as the number of participants with at least one on-treatment ADA-positive sample divided by the number of participants with a determinant baseline IG sample and at least one determinant post-baseline IG sample.

The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. For each of the 5 dimensions, subject's responses are scored on a 5-point scale (1=no problem to 5=extreme problems). Change from baseline is being presented for EQ Index score. Index score is defined as a weighted combination of the levels of the 5-dimention scales, ranging from 0 to 1 (perfect health), with higher scores indicating better health-related quality of life. The United States value set from Pickard et al 2019 was used.

The EQ-5D-5L VAS records the participant's self-rated health on a visual analogue scale numbered from 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". Change from baseline was presented.

EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer participants. Participant's responses to 2 questions (Items 29+30: "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. Change from baseline to Cycle 12 Day 1 as presented.

Deaths were collected from randomization until the end of the trial, approx. 52 months, including post-treatment survival follow up period.