Myelofibrosis, Post-polycythemia Vera Myelofibrosis (PPV-MF), Post-essential Thrombocythemia Myelofibrosis (PET-MF), Primary Myelofibrosis (PMF)
Conditions
Keywords
LSD1
Brief summary
This is a Phase 1/2 open-label study to evaluate the safety, tolerability, steady-state pharmacokinetic (PK) and pharmacodynamics (PD) of a lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat (IMG-7289/MK-3543), administered orally once daily in participants with myelofibrosis. The primary hypothesis is that bomedemstat is a safe and tolerable orally available agent when administered to participants with myelofibrosis including primary myelofibrosis (PMF), post-polycythaemia vera-myelofibrosis (PPVMF), and post-essential thrombocythaemia-myelofibrosis (PET-MF) (collectively referred to as 'MF'); inhibition of LSD1 by bomedemstat will reduce spleen size in those with splenomegaly, improve haematopoiesis and reduce constitutional symptoms associated with these disorders.
Detailed description
This study initiated as a Phase 1/2a study assessing the safety of the starting dose, an 85-day duration of treatment, and the PK and PD effects of bomedemstat, with transition to a Phase 2b study incorporating changes supported by the Phase 1/2a data.
Interventions
DRUGBomedemstat
Oral (capsule) administration according to dose allocation.
Sponsors
Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* \>18 years of age * Diagnosis of either PMF per World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms, or PPV-MF or PET-MF per the International Working Group for Myelofibrosis Research and Treatment * High or intermediate-2 risk disease
Exclusion criteria
* Receiving other treatments for the condition (with exceptions and time limits) * Major surgery in last 4 weeks, any surgery in the last 2 weeks * History of, or scheduled, hematopoietic stem cell transplant within 24 weeks of Screening * History of splenectomy * Current use of prohibited medications * A concurrent second active and nonstable malignancy * Known human immunodeficiency virus infection or active Hepatitis B or Hepatitis C virus infection * Other hematologic/biochemistry requirements, as per protocol * Use of an investigational agent within last 14 days * Pregnant or lactating females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat | Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing. | Cmax was defined as the maximum observed concentration after administration obtained directly from the concentration time profile. Blood and plasma samples were collected at pre-specified timepoints to calculate Cmax in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis. |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Up to Day 7 of the ITP | DLT was defined as any one of the following adverse events (AEs) that occured through Day 7 of the Initial Treatment Period (ITP) and was considered by the Investigator to be possibly, probably or definitely related to bomedemstat: * Thrombocytopenia leading to clinically significant sequelae (i.e., a clinically significant bleeding event or the need for prophylactic transfusions) * A clinically significant bleeding event in a participant with a platelet count \>50 x 10\^9/L (50 k/μL) * Any Grade 4 or 5 non-haematologic adverse event * Any Grade 3 non-haematologic adverse event with failure to recover to Grade 2 within 7 days of drug cessation, with the following exceptions: ≥ Grade 3 nausea, vomiting or diarrhea that responds to standard medical care; ≥ Grade 3 aesthenia lasting less than 14 days; any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and persisting greater than 24 hours. The number of participants with a DLT were reported. |
| Number of Participants With Serious Adverse Events | Up to approximately 30 months | An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. Serious AEs (SAEs) were any AE that resulted in death, life-threatening experience, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly, or important medical events. The number of participants with at least one treatment-emergent (TE) SAE was reported for each arm. |
| Number of Participants With Adverse Events | Up to approximately 30 months | An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants with at least one TE AE was reported for each arm. |
| Number of Participants That Discontinued Study Treatment Due To AEs | Up to approximately 29 months | An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants that discontinued study treatment with bomedemstat due to a TE AE was reported for each arm. |
| Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat | Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing. | Tmax was defined as the time to maximum concentration after administration obtained by inspection. Blood and plasma samples were collected at pre-specified timepoints to calculate Tmax in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis. |
| Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat From Time 0 to 24 Hours Post-dose (AUC0-24) | Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing. | AUC0-24 was defined as the area under the concentration versus time curve calculated using the linear trapezoidal rule from the zero time-point to the 24-hour time-point concentration. Blood and plasma samples were collected at pre-specified timepoints to calculate AUC0-24 in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis. |
| Phase 1/2a Portion: Apparent Total Clearance (CL/F) of Bomedemstat After Oral Administration | Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing. | CL/F was defined as the apparent total clearance of drug after oral administration. Blood and plasma samples were collected at pre-specified timepoints to calculate CL/F in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis. |
| Percentage Change From Baseline in Spleen Volume | Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337) | Change in spleen volume was assessed based on calculated spleen volume (ml) measured by magnetic resonance imaging (MRI), or computerized tomography (CT) scan (where locally permitted) if the participant was not a candidate for MRI from Day 0. Percentage change from baseline in spleen volume was reported at Initial Treatment Period (ITP) Day 84, ITP Day 168, Additional Treatment Period 1 (ATP1) Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337). |
| Percentage Change From Baseline in Spleen Size | Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591) | Change in spleen size was assessed based on spleen palpation (in cm) at each visit. Percentage change from baseline in spleen size was reported at ITP Day 84, ITP Day 168, ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591). As prespecified by the Statistical Analysis Plan, assessments for the Phase 1/2 groups were summarized using visit windowing after the Day 84 visit of the ITP to allow for comparison with the Phase 2b groups at ITP Day 168. |
Countries
Australia, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Participants with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF) were recruited for this study.
Pre-assignment details
Eighteen participants were enrolled in the Phase 1/2a portion of this study and 72 participants were enrolled in the Phase 2b portion of this study.
Participants by arm
| Arm | Count |
|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d In the Phase 1/2a portion of the study, PMF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 9 |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d In the Phase 1/2a portion of the study, PPV-MF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 3 |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d In the Phase 1/2a portion of the study, PET-MF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 6 |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d In the Phase 2b portion of the study, PMF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 8 |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d In the Phase 2b portion of the study, PPV-MF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 5 |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d In the Phase 2b portion of the study, PET-MF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 11 |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d In the Phase 2b portion of the study, PMF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 24 |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d In the Phase 2b portion of the study, PPV-MF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 11 |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d In the Phase 2b portion of the study, PET-MF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator. | 13 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 3 | 1 | 2 | 2 | 5 | 1 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Not Reported | 4 | 1 | 0 | 1 | 0 | 2 | 1 | 1 | 0 |
| Overall Study | Physician Decision | 3 | 1 | 1 | 2 | 1 | 2 | 1 | 0 | 1 |
| Overall Study | Protocol Defined Disease Progression | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 1 | 1 | 1 | 2 | 3 | 3 |
Baseline characteristics
| Characteristic | Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Total | Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 12.43 | 65.7 Years STANDARD_DEVIATION 10.51 | 61.3 Years STANDARD_DEVIATION 12.07 | 66.7 Years STANDARD_DEVIATION 9.27 | 65.2 Years STANDARD_DEVIATION 9.42 | 69.4 Years STANDARD_DEVIATION 14.4 | 64.8 Years STANDARD_DEVIATION 7.46 | 69.6 Years STANDARD_DEVIATION 8.38 | 64.7 Years STANDARD_DEVIATION 6.59 | 74.7 Years STANDARD_DEVIATION 5.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 80 Participants | 9 Participants | 11 Participants | 22 Participants | 10 Participants | 4 Participants | 8 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 7 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 21 Participants | 5 Participants | 5 Participants | 10 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 59 Participants | 6 Participants | 6 Participants | 12 Participants | 9 Participants | 4 Participants | 7 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 43 Participants | 4 Participants | 8 Participants | 12 Participants | 6 Participants | 4 Participants | 4 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 47 Participants | 9 Participants | 3 Participants | 12 Participants | 5 Participants | 1 Participants | 4 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 3 | 0 / 6 | 1 / 8 | 1 / 5 | 0 / 11 | 1 / 24 | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 9 / 9 | 3 / 3 | 6 / 6 | 8 / 8 | 5 / 5 | 11 / 11 | 23 / 24 | 10 / 11 | 12 / 13 |
| serious Total, serious adverse events | 4 / 9 | 2 / 3 | 5 / 6 | 4 / 8 | 4 / 5 | 7 / 11 | 12 / 24 | 3 / 11 | 3 / 13 |
Outcome results
Primary
Number of Participants That Discontinued Study Treatment Due To AEs
An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants that discontinued study treatment with bomedemstat due to a TE AE was reported for each arm.
Time frame: Up to approximately 29 months
Population: All participants receiving at least one dose of bomedemstat were included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 0 Participants |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 1 Participants |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 5 Participants |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 1 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 2 Participants |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 4 Participants |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 5 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 2 Participants |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants That Discontinued Study Treatment Due To AEs | 3 Participants |
Primary
Number of Participants With Adverse Events
An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants with at least one TE AE was reported for each arm.
Time frame: Up to approximately 30 months
Population: All participants receiving at least one dose of bomedemstat were included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Adverse Events | 9 Participants |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Adverse Events | 3 Participants |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Adverse Events | 6 Participants |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Adverse Events | 8 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Adverse Events | 5 Participants |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Adverse Events | 11 Participants |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Adverse Events | 23 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Adverse Events | 10 Participants |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Adverse Events | 12 Participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
DLT was defined as any one of the following adverse events (AEs) that occured through Day 7 of the Initial Treatment Period (ITP) and was considered by the Investigator to be possibly, probably or definitely related to bomedemstat: * Thrombocytopenia leading to clinically significant sequelae (i.e., a clinically significant bleeding event or the need for prophylactic transfusions) * A clinically significant bleeding event in a participant with a platelet count \>50 x 10\^9/L (50 k/μL) * Any Grade 4 or 5 non-haematologic adverse event * Any Grade 3 non-haematologic adverse event with failure to recover to Grade 2 within 7 days of drug cessation, with the following exceptions: ≥ Grade 3 nausea, vomiting or diarrhea that responds to standard medical care; ≥ Grade 3 aesthenia lasting less than 14 days; any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and persisting greater than 24 hours. The number of participants with a DLT were reported.
Time frame: Up to Day 7 of the ITP
Population: All participants receiving at least one dose of bomedemstat were included in the DLT analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Number of Participants With Serious Adverse Events
An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. Serious AEs (SAEs) were any AE that resulted in death, life-threatening experience, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly, or important medical events. The number of participants with at least one treatment-emergent (TE) SAE was reported for each arm.
Time frame: Up to approximately 30 months
Population: All participants receiving at least one dose of bomedemstat were included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Serious Adverse Events | 4 Participants |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Serious Adverse Events | 2 Participants |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Number of Participants With Serious Adverse Events | 5 Participants |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Serious Adverse Events | 4 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Serious Adverse Events | 4 Participants |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Number of Participants With Serious Adverse Events | 7 Participants |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Serious Adverse Events | 12 Participants |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Serious Adverse Events | 3 Participants |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Number of Participants With Serious Adverse Events | 3 Participants |
Primary
Percentage Change From Baseline in Spleen Size
Change in spleen size was assessed based on spleen palpation (in cm) at each visit. Percentage change from baseline in spleen size was reported at ITP Day 84, ITP Day 168, ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591). As prespecified by the Statistical Analysis Plan, assessments for the Phase 1/2 groups were summarized using visit windowing after the Day 84 visit of the ITP to allow for comparison with the Phase 2b groups at ITP Day 168.
Time frame: Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591)
Population: All allocated participants who received at least one dose of treatment and had available spleen size data.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | -36.5 Percentage Change |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 168 (Study Day 337) | -19.0 Percentage Change |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -20.7 Percentage Change |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP2 Day 84 (Study Day 422) | -4.8 Percentage Change |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -39.6 Percentage Change |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | 9.6 Percentage Change |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | 116.3 Percentage Change |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | 24.1 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | 20.7 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 168 (Study Day 337) | -27.8 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 84 (Study Day 253) | -27.8 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -27.8 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | -28.1 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | 11.0 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP2 Day 168 (Study Day 506) | -22.0 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP2 Day 84 (Study Day 422) | -37.5 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP3 Day 84 (Study Day 591) | -11.1 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -36.1 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 84 (Study Day 253) | -36.1 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 168 (Study Day 337) | -38.9 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | -34.7 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -24.8 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 84 (Study Day 253) | -27.9 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 168 (Study Day 337) | -1.9 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -28.5 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 168 (Study Day 337) | -38.9 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | -38.2 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP2 Day 84 (Study Day 422) | -44.4 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 84 (Study Day 253) | -50.4 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 168 (Study Day 168) | -41.2 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ITP Day 84 (Study Day 84) | -59.6 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 84 (Study Day 253) | -28.4 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Size | ATP1 Day 168 (Study Day 337) | -82.4 Percentage Change |
Primary
Percentage Change From Baseline in Spleen Volume
Change in spleen volume was assessed based on calculated spleen volume (ml) measured by magnetic resonance imaging (MRI), or computerized tomography (CT) scan (where locally permitted) if the participant was not a candidate for MRI from Day 0. Percentage change from baseline in spleen volume was reported at Initial Treatment Period (ITP) Day 84, ITP Day 168, Additional Treatment Period 1 (ATP1) Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337).
Time frame: Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337)
Population: All allocated participants who received at least one dose of treatment and had available spleen volume data.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | 3.3 Percentage Change |
| Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | -13.7 Percentage Change |
| Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | 2.2 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ATP1 Day 168 (Study Day 337) | -36.5 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 168 (Study Day 168) | -23.9 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | -9.1 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | -7.2 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 168 (Study Day 168) | -19.6 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ATP1 Day 168 (Study Day 337) | -38.9 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | 0.3 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ATP1 Day 84 (Study Day 253) | -27.7 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 168 (Study Day 168) | -33.7 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ATP1 Day 168 (Study Day 337) | 37.4 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | 10.0 Percentage Change |
| Ph 2b PMF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 168 (Study Day 168) | 12.3 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | -2.3 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 168 (Study Day 168) | -15.4 Percentage Change |
| Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ATP1 Day 168 (Study Day 337) | 6.0 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 84 (Study Day 84) | 1.2 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ATP1 Day 168 (Study Day 337) | -15.0 Percentage Change |
| Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d | Percentage Change From Baseline in Spleen Volume | ITP Day 168 (Study Day 168) | -4.4 Percentage Change |
Primary
Phase 1/2a Portion: Apparent Total Clearance (CL/F) of Bomedemstat After Oral Administration
CL/F was defined as the apparent total clearance of drug after oral administration. Blood and plasma samples were collected at pre-specified timepoints to calculate CL/F in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.
Time frame: Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.
Population: As pre-specified by the PAP, only participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF) per protocol. Phase 2b participants were excluded from this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Apparent Total Clearance (CL/F) of Bomedemstat After Oral Administration | Plasma | 12787.43 mL/min | Geometric Coefficient of Variation 63.72 |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Apparent Total Clearance (CL/F) of Bomedemstat After Oral Administration | Blood | 3067.57 mL/min | Geometric Coefficient of Variation 85.78 |
Primary
Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat From Time 0 to 24 Hours Post-dose (AUC0-24)
AUC0-24 was defined as the area under the concentration versus time curve calculated using the linear trapezoidal rule from the zero time-point to the 24-hour time-point concentration. Blood and plasma samples were collected at pre-specified timepoints to calculate AUC0-24 in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.
Time frame: Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.
Population: As pre-specified by the PAP, all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF) per protocol. Phase 2b participants were excluded from this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat From Time 0 to 24 Hours Post-dose (AUC0-24) | Plasma | 63.90 hour•ng/mL | Geometric Coefficient of Variation 68.56 |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat From Time 0 to 24 Hours Post-dose (AUC0-24) | Blood | 265.92 hour•ng/mL | Geometric Coefficient of Variation 68.92 |
Primary
Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat
Cmax was defined as the maximum observed concentration after administration obtained directly from the concentration time profile. Blood and plasma samples were collected at pre-specified timepoints to calculate Cmax in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.
Time frame: Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.
Population: As pre-specified by the PAP, all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF) per protocol. Phase 2b participants were excluded from this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat | Plasma | 12.63 ng/mL | Geometric Coefficient of Variation 104.41 |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat | Blood | 26.27 ng/mL | Geometric Coefficient of Variation 66.76 |
Primary
Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat
Tmax was defined as the time to maximum concentration after administration obtained by inspection. Blood and plasma samples were collected at pre-specified timepoints to calculate Tmax in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.
Time frame: Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.
Population: As pre-specified by the PAP, all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF) per protocol. Phase 2b participants were excluded from this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat | Plasma | 1.00 hour |
| Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d | Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat | Blood | 1.05 hour |