Blood and Lymph Conditions

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Iron Deficiencies

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Polycythemia

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N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide

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Participants will receive momelotinib plus placebo to match danazol

Participants will receive danazol plus placebo to match momelotinib

Momelotinib tablets will be self-administered orally once daily

Momelotinib

Danazol placebo capsules will be self-administered orally twice daily

Placebo to match danazol

Danazol capsules will be self-administered orally twice daily

Momelotinib placebo tablets will be self-administered orally once daily

Placebo to match momelotinib

Srdan Verstovsek, M.D., Ph.D.

Ruben Mesa

MOMENTUM is a randomized, double-blind, active control Phase 3 trial intended to confirm the differentiated clinical benefits of the investigational drug momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic participants who have previously received an approved Janus kinase inhibitor (JAKi) therapy for myelofibrosis (MF). The purpose of this clinical study is to compare the effectiveness and safety of MMB to DAN in treating and reducing: 1) disease related symptoms, 2) the need for blood transfusions and 3) splenomegaly, in adults with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The study is planned in countries including, but not limited to: Australia, Austria, Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Romania, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom (UK) and United States (US).

Participants must be symptomatic with a Myelofibrosis Symptom Assessment Form (MFSAF) version (v) 4.0 Total Symptom Score of \>= 10 at screening, and be anemic with hemoglobin (Hgb) \< 10 gram/deciliter (g/dL). For participants with ongoing JAKi therapy at screening, JAKi therapy must be tapered over a period of at least 1 week, followed by a 2-week non-treatment washout interval prior to randomization.

Participants will be randomized 2:1 to orally self-administer blinded treatment: MMB plus placebo or DAN plus placebo. Participants randomized to receive MMB who complete the randomized treatment period to the end of Week 24 may continue to receive MMB in the open-label extended treatment period to the end of Week 204 (a total period of treatment of approximately 4 years) if the participants tolerates and continues to benefit from MMB.

Participants randomized to receive DAN may cross-over to MMB open-label treatment in the following circumstances: at the end of Week 24 if they complete the randomized treatment period; or at the end of Week 24 if they discontinue treatment with DAN but continue study assessments and do not receive prohibited medications including alternative active anti-MF therapy; or at any time during the randomized treatment period if they meet the protocol-defined criteria for radiographically confirmed symptomatic splenic progression. Participants randomized to receive DAN who are receiving clinical benefit at the end of Week 24 may choose to continue DAN therapy up to Week 48. The comparator treatment, DAN, is an approved medication in the US and in some other countries and is recommended by national guidelines as a treatment for anemia in MF.

MOMENTUM Contact Email: GSKClinicalSupportHD@gsk.com

During the 24 week randomized treatment phase of the study, participants, investigators and sponsor and relevant vendor personnel (with the exception of specified unblinded personnel, for example clinical supply) will remain blinded to the participant's treatment assignment and to aggregate data that may lead to inadvertent unblinding. Participants who continue treatment with momelotinib or danazol after Week 24 in the extended treatment phase will receive unblinded treatment.

A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Participants (MOMENTUM)

A Randomized, Double-blind, Phase 3 Study to Evaluate the Activity of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic, Anemic Subjects With Primary Myelofibrosis (PMF), Post-polycythemia Vera (PV) Myelofibrosis, or Post-essential Thrombocythemia (ET) Myelofibrosis Who Were Previously Treated With JAK Inhibitor Therapy

Myelofibrosis Symptom Assessment Form (MFSAF) TSS version (v) 4.0 response rate was defined as percentage of participants with a \>= 50 percent (%) reduction from Baseline in mean MFSAF TSS over consecutive 28-day period immediately before end of Week 24. TSS response rate was measured using MFSAF v4.0. MFSAF v4.0 comprises 7 domains representing 7 most relevant symptoms of myelofibrosis (MF) identified through existing participant and clinician-based evidence: fatigue,night sweats,pruritus,abdominal discomfort,pain under left ribs,early satietyand bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0(absent) to 10(worst imaginable). The MFSAF TSS was calculated as sum of scores of 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date.

TI status was defined as not receiving red blood cell (RBC) or whole blood transfusion for \>=12 weeks, with no hemoglobin (Hgb) level \< 8 grams per deciliter (g/dL) during the same interval. Percentage of participants with TI have been presented.

Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of \>=25% from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date.

TSS was measured using the MFSAF v4.0. The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF TSS was calculated as the sum of scores of the 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.

Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of \>=35 % from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date.

Percentage of participants with zero RBC units transfused over 24-weeks were reported.

Percentage of participants with \<=4 RBC units transfused over 24-weeks were reported.

Duration of MFSAF TSS response is defined as the number of days from the start of the initial 28-day period in which a participant had a \>= 50% reduction from Baseline TSS to the first day of the 7-day assessment that determines the mean TSS for the 28-day period during which the participants TSS equals or exceeds their Baseline value.

Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level \< 8 g/dL (except in the case of clinically overt bleeding).

Cumulative transfusion risk was calculated as the estimated mean cumulative number of whole blood units transfused during the study.

TD status at Week 24 is defined as requirement of \>=4 RBC units in an 8-week period immediately prior to the end of Week 24.

Hemoglobin responses are defined as increases of \>= 1, \>= 1.5, or \>= 2 g/dL from Baseline in Hgb, as measured over a (rolling) period of at least 12 consecutive weeks falling entirely before the end of Week 24. Baseline was the last assessment done before or on the day of first dose date. Data has been reported for percentage of participants who had \>= 1, \>= 1.5, or \>= 2 g/dL increase from Baseline in hemoglobin.

Participants were defined as having TD if they met both of the following requirements in the 8 weeks immediately before the end of Week 24: \>= 4 red blood cell or whole blood units were transfused (except in the case of clinically overt bleeding), each in response to a hemoglobin assessment of \<= 9.5 g/dL; and there were \>= 2 hemoglobin assessments with \>= 28 days between the earliest and latest hemoglobin assessments. TI status was defined as not requiring red blood cell transfusion (except in the case of clinically overt bleeding) for \>= 12 weeks immediately prior to the end of Week 24, with hemoglobin levels \>= 8 g/dL.

An adverse event (AE) is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.

An AE is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.

Overall survival is defined as the interval from the first study drug dosing date (or randomization date for participants who did not receive treatment) to death from any cause.

LFS is defined as the interval from first study drug dosing date (or randomization date for participants who did not receive treatment) to any evidence of leukemic transformation and/or death (from any cause).

The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). Data has been reported for Disease-related Fatigue domain measured using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable), higher score indicates worst outcome. An increase in score from Baseline indicated a worsening of fatigue and a decrease in score from Baseline indicated an improvement in fatigue. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.

The EORTC QLQ-C30 is comprised of 5 functional scales (physical, role, emotional, social, cognitive), eight single item symptom scales (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea), as well as sub-scales assessing global health/quality of life and financial impact. Most items use a 4-point Likert scale from "not at all" to "very much" and a one-week recall period with the exception of the final two items which use a 7 point scale response from "very poor" to "excellent". Scores were averaged and transformed to a 0-100 scale, with higher scores representing better functioning/quality of life. An increase in scores from Baseline indicated an improved functioning/quality of life, and a decrease in scores from Baseline indicated a worsened functioning/quality of life. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.

PROMIS Physical Function Short Form 10b consists of 14 questions; each with a 5-point response. PROMIS short form assesses self-reported capability of a participant rather than actual performance of physical activities. This includes functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back) as well as instrumental activities of daily living, such as running errands. Participants scored each response on a scale from 1 (unable to do) to 5 (without any difficulty, or not at all). Total possible range of scores was 14 to 70, with higher scores corresponding to a greater physical function ability. An increase in score from Baseline indicated an improvement in physical function ability and a decrease in score from Baseline indicated a reduction in physical function ability. Baseline was last assessment done before or on the day of first dose date. Change from Baseline was defined as post-Baseline value minus Baseline value.

Sierra Oncology LLC - a GSK company

Serious adverse events (SAEs) and non-SAEs were measured in the Safety analysis set, which included all participants in the ITT analysis set who received at least one dose of study drug. All-cause mortality was measured in the ITT analysis set, which included all randomized participants. Data are presented per treatment received.

Participants were randomized to receive 200 mg of MMB orally QD and a DAN-placebo orally BID during the randomized 24-week double-blind treatment period.

MMB 200 mg QD + Placebo- Randomized Double-Blind Treatment Period

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period.

DAN 300 mg BID + Placebo- Randomized Double-Blind Treatment Period

Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period.

MMB 200 mg QD- Open-Label Extended Treatment Period

Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants who received DAN 300 mg BID during randomized period switched to receive 200 mg of MMB orally QD during open-label extended treatment period.

DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended Treatment Period

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

MMB 200 mg QD + Placebo

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants who received DAN 300 mg BID during randomized period switched to receive 200 mg of MMB orally QD during open-label extended treatment period.

DAN 300 mg BID + Placebo

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.

GSK Response Center

Measured in the Intent-To-Treat (ITT) Analysis Set, which included all randomized participants.

Total Symptom Score (TSS) Response Rate at Week 24

Percentage of Participants With Transfusion Independence (TI) at Week 24

Splenic Response Rate (SRR) of >=25% at Week 24

ITT Analysis Set. Only those participants with data available at specified time points were analyzed.

Change From Baseline in MFSAF TSS at Week 24

Splenic Response Rate (SRR) of >= 35% at Week 24

Percentage of Participants With Zero RBC Units Transfused Over 24-Weeks

Percentage of Participants With <=4 RBC Units Transfused Over 24-weeks

ITT Analysis Set. Only those participants with data available at specified time point were analyzed.

Duration of MFSAF TSS Response

Duration of TI Response

Mean Cumulative Number of Whole Blood Units Transfused Over 24 Weeks

Percentage of Participants With Transfusion Dependence (TD) Status at Week 24

>=1g/dL Increase

>=1.5g/dL Increase

>=2g/dL Increase

Percentage of Participants With a Hemoglobin Response

Number of Baseline TD Participants With TI Status at Week 24

Duration of TI in Baseline TD Participants

Any non-SAEs

Any SAEs

Safety analysis set included all participants in the ITT Analysis set who received at least one dose of study drug.

Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24

Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks

ITT Analysis Set. Values are presented based on the Kaplan-Meier analysis. All participants (overall population) were included in analysis.

Overall Survival (OS)

Leukemia-free Survival (LFS)

Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24

Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24

Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24

MMB 200 mg Once Daily (QD) + Placebo

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 enrolled in an open-label extended treatment period. Participants switched to receive 200 mg of MMB orally QD during open-label extended treatment period. All participants elected to receive MMB as open-label treatment during the open-label extended treatment period.

Spots Global Cancer Trial Database for placebo to match danazol