Very Low Risk, Low Risk, or Intermediate Risk MDS Per IPSS-R
Conditions
Keywords
Anemia, Myelodysplastic Syndromes, MDS, Pyruvate Kinase, Activator, Transfusion dependent, FT-4202, Etavopivat, IPSS-R very low risk, IPSS-R low risk, IPSS-R intermediate risk, ESA refractory, ESA intolerant, Luspatercept refractory, Luspatercept intolerant
Brief summary
The purpose of this study is to evaluate the safety and efficacy of etavopivat (FT-4202) for the treatment of anemia in adult patients with very low risk, low risk, or intermediate risk MDS.
Interventions
DRUGEtavopivat
400 mg once daily
Sponsors
Forma Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient has provided documented informed consent; the informed consent form (ICF) must be reviewed and signed by each patient prior to any study-related assessments/procedures being conducted. 2. Age ≥ 18 years at time of first dose. 3. Patients, if female and of childbearing potential, must agree to use acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and who if male are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug. 4. Documented diagnosis of idiopathic/de novo MDS according to World Health Organization (WHO) classification that meets the IPSS-R classification of very low, low, or intermediate risk disease, and: * \< 5% blasts in bone marrow based on local pathology review * \< Intermediate risk cytogenetic abnormalities per IPSS-R 5. Anemia defined as: * Non-transfusion dependent (NTD): Subjects with mean Hb concentration \< 10.0 g/dL of 2 measurements (1 performed within 3 days prior to Day 1 and the other performed 7 to 28 days prior to Day 1, not influenced by RBC transfusion within 7 days of measurement) and \< 3 RBC transfusions for anemia in the prior 16 weeks before Day 1 of etavopivat dosing OR * Transfusion dependent (TD): Subjects having received ≥ 3 units of RBCs for the treatment of anemia within 16 weeks prior to Day 1 6. Serum erythropoietin level \> 200 U/L, OR, if ≤ 200 U/L, subject is non-responsive, refractory, or intolerant to erythropoiesis-stimulating agents, or erythropoiesis-stimulating agents are contraindicated or unavailable. 7. ECOG performance status of ≤ 2 8. Subject is non-responsive, refractory, or intolerant to luspatercept, or luspatercept is contraindicated or not indicated. 9. No alternative treatment options are available and/or appropriate for the subject, at the discretion of the investigator. 10. Patient is willing and able to adhere to the study visit schedule and other protocol requirements
Exclusion criteria
\[MDS History\] 1. MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality 2. Therapy-associated MDS (eg. t-MDS) that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases 3. Known history of acute myeloid leukemia (AML) \[Medical Conditions\] 4. Female who is breast feeding or pregnant 5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding 6. Absolute neutrophil count \< 500/µL (0.5 x 10\^9/L) 7. Platelet count \< 50,000/µL (50 x 10\^9/L) without transfusion support within 2 weeks 8. Hepatic dysfunction characterized by: * Alanine aminotransferase (ALT) \> 5.0 × upper limit of normal (ULN) * Total bilirubin \> 3.0 × ULN * History of cirrhosis 9. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory \< 30 mL/min/1.73 m\^2 ) or on chronic dialysis. 10. Patients with clinically significant and active bacterial, fungal, parasitic, or viral infection. * Patients with acute bacterial, fungal, parasitic, or viral infection requiring systemic therapy should delay Screening/ enrollment until active therapy has been completed. * Patients with acute viral infections without available therapies (eg, coronavirus disease 2019 \[COVID-19\]) should delay Screening/ enrollment until the acute infection has resolved. Note: Infection prophylaxis is allowed. 11. Known human immunodeficiency virus (HIV) positivity 12. Active infection with hepatitis B virus (hepatitis B surface antigen \[HepBsAg\] and hepatitis B core antibody \[HepBcAb\] positive) 13. Active hepatitis C infection 14. History of malignancy, other than MDS, within the past 2 years prior to treatment Day 1 requiring systemic chemotherapy and/or radiation. * Patients with malignancy considered surgically cured are eligible (eg, non-melanoma skin cancer, carcinoma in situ of the cervix, or carcinoma in situ of the breast) * Patients with incidental histologic findings of prostate cancer (T1a or T1b) are eligible 15. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following: * Unstable angina pectoris or myocardial infarction or elective coronary intervention * Heart disease, heart failure as classified by the New York Heart Association classification 3 or higher, or significant arrhythmia requiring treatment, * Pulmonary fibrosis or pulmonary hypertension which are clinically significant ie, ≥ Grade 3 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (or higher) 16. Uncontrolled hypertension, defined as repeated elevation of diastolic blood pressure ≥ 100 mmHg despite adequate treatment 17. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable). \[Prior/Concomitant Therapy\] 18. Prior treatment with azacitidine (injectable or oral) or decitabine 19. Use of erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of starting study treatment or anticipated need for such agents during the study. 20. Prior use of luspatercept: * NTD patients must not have received luspatercept within 30 days prior to Day 1 treatment * TD patients must not have received luspatercept within 16 weeks prior to Day 1 treatment 21. Receiving or use of concomitant medications that are strong inducers of cytochrome P450 (CYP)3A4/5 (see Appendix F) within 2 weeks of starting study treatment or anticipated need for such agents during the study. 22. Prior allogeneic or autologous stem cell transplant 23. Initiation of a new chelation therapy within 3 months before the first dose of study treatment. \[Prior/Concurrent Clinical Study Experience\] 24. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device). \[Other Exclusions\] 25. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for >=8 Weeks Within 24 Weeks of Etavopivat Treatment | From Baseline to Week 24 | This outcome measure reported on the combined incidence of NTD, LTB and HTB in terms of (HI-E) response for \>=8 weeks duration in participants with myelodysplastic syndromes (MDS) within 24 weeks. The participants were allocated to the following arms which were defined as: 1) NTD: \>=1.5 grams per deciliter (g/dL) increase in haemoglobin (Hb) from baseline maintained \>=8 consecutive weeks and no transfusion of RBC units for anemia over a continuous 8-week treatment period; 2) LTB: absence of any transfusion for \>=8 consecutive weeks; and 3) HTB: reduction by \>=50 percent (%) of RBC units for \>=8 consecutive weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hematologic Improvement-Erythroid (HI-E) Response for =>8 Weeks Within 16 and 48 Weeks of Etavopivat | 48 weeks | This outcome measure focused on the combined incidence of NTD, LTB and HTB participants, evaluating HI-E lasting =\>8 weeks in individuals with MDS within 16 weeks and 48 weeks. Participant's response were defined as follows: 1) NTD: an increase of =\>1.5 g/dL in Hb maintained for =\>8 consecutive weeks without any RBC transfusions for anemia; 2) LTB: no transfusions over =\>8 consecutive weeks; and 3) HTB: a reduction of =\>50% in RBC units for =\>8 consecutive weeks. |
| Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for =>16 Weeks Within 24 and 48 Weeks of Etavopivat | 48 weeks | This outcome measure focused on the combined incidence of NDT, LTB and HTB participants, evaluating HI-E response lasting =\>16 weeks in individuals with MDS within 24 weeks and 48 weeks. Participant's response were defined as follows: 1) NTD: an increase of =\>1.5 g/dL in Hb maintained for =\>16 consecutive weeks without any RBC transfusions for anemia; 2) LTB: no transfusions over =\>16 consecutive weeks; and 3) HTB: a reduction of =\>50% in RBC units for =\>16 consecutive weeks. |
| Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | From baseline up to 48 weeks | This outcome measures the total number of AEs and SAEs in participants, including AEs related to etavopivat. AEs are any unfavorable medical occurrences in participants taking the medicinal product, regardless of causality. They include new or worsening symptoms, abnormal lab findings, and exacerbations of existing conditions, documented from the first dose through 28 days after the last dose. SAEs are severe AEs that result in death, are life-threatening, require hospitalization, lead to significant disability, or involve congenital anomalies. Important medical events posing risks to the participants are also classified as SAEs. Treatment Emergent Adverse Events (TEAEs) are AEs occurring after treatment initiation, aiding in the safety assessment of etavopivat. TEAEs will be considered drug-related if assessed by the Investigator as possibly related or related, or if relationship is missing. |
| Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Within 48 weeks | The outcome measures the total number of premature discontinuations, dose interruptions and dose reductions. Premature discontinuation was defined as any discontinuation prior to week 48. A dose interruption is a temporary halt in treatment due to an AE, while a dose reduction involves lowering the dosage of the drug when AEs occur. If a participant tolerates a reduced dose for 14 days, a rechallenge with the original dose may occur after a clinic visit, but any new Grade 3 or higher AEs require treatment discontinuation and consultation with the Global Medical Monitor before resuming. |
| Overall Response Rate | Up to 48 weeks | The Overall Response Rate (ORR) is defined as the percentage of participants who achieve a predefined level of response according to the 2006 International Working Group (IWG) criteria, assessed at each scheduled evaluation. |
| Duration of Response | Up to 48 weeks | This outcome measure reported duration of response which was defined as duration of response will be summarized with quantiles based on product limit estimates (ie, Kaplan-Meier). Duration of response is defined as the time from date of first known incidence of a 2006 IWG criteria response to the most recent date that the 2006 IWG (International Working Group) criteria is not met following the initial response. If the participant has met IWG criteria throughout the period following the initial response, the participant will be censored at the latest date of end of study, loss to follow-up, or death. |
| Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Up to 48 weeks | This outcome measure reports reduction in RBC transfusion by 8-week interval in participants with LTB and HTB. |
| Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Up to 48 weeks | This outcome measure is percent change in RBC transfusion by 8-week interval in participants with LTB and HTB. Percent reduction from baseline in RBC transfusion burden is defined as -100×(Total RBC Units Transfused During Interval)/(Baseline RBC Units Transfused Per 8 Weeks). |
| Change From Baseline in Neutrophils and/or Platelets Counts | Baseline (week 0), week 48 | This outcome measure reports the change from baseline in neutrophils and/or platelets counts from baseline to week 48 |
| Decrease in Ferritin and Transferrin Saturation (TSAT) | Up to 48 weeks | This outcome measure were to report decrease in ferritin and TSAT from baseline to Week 48. |
| Decrease in Iron Chelation Therapy | up to 48 weeks | This outcome measure were to report decrease of Iron chelation therapy and will be recorded at Screening and on an ongoing basis throughout the study. |
| Overall Survival | Within 48 weeks | Overall survival is defined as the time from first dose to date of death. If the participant was alive at last contact, the end date will be censored at the latest of either end of study, loss to follow-up, or study discontinuation. |
| Etavopivat Plasma Concentrations | Weeks 1 and 4 pre-dose, post-dose 1, 2, 4, 6 hours.Week 2 and EOT (week 48):pre-dose, post-dose 1, 2 hours | This outcome measure reported Etavopivat plasma concentrations in order to assess the PK properties of etavopivat in participants with MDS. PK parameters included but not limited to were: Time to maximum observed plasma concentration, area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last), from time zero to infinity (AUC0-inf), for a dosing interval (AUCtau/AUC0-24).) However due to early termination of the study, the PK parameters were not assessed and only the plasma concentrations could be assessed. |
| RBC 2,3-diphosphoglycerate (2,3-DPG) and Adenosine Triphosphate (ATP) Levels Over Time | Within 48 weeks | Etavopivat plasma concentrations were collected in order to assess the pharmacodynamic (PD) properties of etavopivat in participants with MDS. |
Countries
Canada, France, Germany, United States
Contacts
STUDY_DIRECTORClinical Transparency (dept. 2834), MD
Novo Nordisk A/S
Participant flow
Recruitment details
The trial was conducted at 10 sites in 4 countries.
Pre-assignment details
The study was planned for 58 weeks, including 6 weeks for screening, 24 weeks for treatment, 24 weeks for extension, and 4 weeks for follow-up. It was terminated early after meeting a predefined quality tolerance limit (QTL). Of the 45 participants targeted, only 24 were screened, and 17 were enrolled into three groups: Non-transfusion dependent (NTD) N=3, Low transfusion burden (LTB) N=5, and High transfusion burden (HTB) N=9. Each participant received 400 mg of etavopivat daily.
Participants by arm
| Arm | Count |
|---|---|
| Non-transfusion Dependent Non transfusion dependent participants who had received less than equal to \<= 2 RBC transfusions for anaemia within the prior 16 weeks, orally received 400 mg of etavopivat once daily for up to 48 weeks. | 3 |
| Low Transfusion Burden Low transfusion burden participants who had received 3 to 7 RBC transfusions for anaemia within the prior 16 weeks, orally received 400 mg of etavopivat once daily for up to 48 weeks. | 5 |
| High Transfusion Burden High transfusion burden participants who had received greater than equal \>= 8 RBC transfusions for anaemia within the prior 16 weeks, orally received 400 mg of etavopivat once daily for up to 48 weeks. | 9 |
| Total | 17 |
Baseline characteristics
| Characteristic | Non-transfusion Dependent | Low Transfusion Burden | High Transfusion Burden | Total |
|---|---|---|---|---|
| Age, Continuous | 77.3 Years STANDARD_DEVIATION 5.69 | 80.2 Years STANDARD_DEVIATION 3.49 | 71.2 Years STANDARD_DEVIATION 8.11 | 74.9 Years STANDARD_DEVIATION 7.58 |
| Race/Ethnicity, Customized Ethnicity: Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 3 Participants | 4 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized Ethnicity: Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race: Not reported | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race: White | 3 Participants | 4 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 | 0 / 9 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 8 / 9 |
| serious Total, serious adverse events | 1 / 3 | 0 / 5 | 3 / 9 |
Outcome results
Primary
Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for >=8 Weeks Within 24 Weeks of Etavopivat Treatment
This outcome measure reported on the combined incidence of NTD, LTB and HTB in terms of (HI-E) response for \>=8 weeks duration in participants with myelodysplastic syndromes (MDS) within 24 weeks. The participants were allocated to the following arms which were defined as: 1) NTD: \>=1.5 grams per deciliter (g/dL) increase in haemoglobin (Hb) from baseline maintained \>=8 consecutive weeks and no transfusion of RBC units for anemia over a continuous 8-week treatment period; 2) LTB: absence of any transfusion for \>=8 consecutive weeks; and 3) HTB: reduction by \>=50 percent (%) of RBC units for \>=8 consecutive weeks.
Time frame: From Baseline to Week 24
Population: EES: All participants in the FAS who have completed the week 24 response visit and who have a baseline record of the primary endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-transfusion Dependent | Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for >=8 Weeks Within 24 Weeks of Etavopivat Treatment | 0 Percentage of participants |
| Low Transfusion Burden | Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for >=8 Weeks Within 24 Weeks of Etavopivat Treatment | 50 Percentage of participants |
| High Transfusion Burden | Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for >=8 Weeks Within 24 Weeks of Etavopivat Treatment | 25 Percentage of participants |
Secondary
Change From Baseline in Neutrophils and/or Platelets Counts
This outcome measure reports the change from baseline in neutrophils and/or platelets counts from baseline to week 48
Time frame: Baseline (week 0), week 48
Population: The Safety Set includes all participants who receive at least one dose of etavopivat (including partial dosing). Here, n (number analysed) = Participants with available data for a specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-transfusion Dependent | Change From Baseline in Neutrophils and/or Platelets Counts | Neutrophils | -3.200 10^9 cells per liter | — |
| Non-transfusion Dependent | Change From Baseline in Neutrophils and/or Platelets Counts | Platelets counts | 43.0 10^9 cells per liter | — |
| Low Transfusion Burden | Change From Baseline in Neutrophils and/or Platelets Counts | Neutrophils | -0.950 10^9 cells per liter | Standard Deviation 0.0707 |
| Low Transfusion Burden | Change From Baseline in Neutrophils and/or Platelets Counts | Platelets counts | -51.0 10^9 cells per liter | Standard Deviation 205.06 |
| High Transfusion Burden | Change From Baseline in Neutrophils and/or Platelets Counts | Neutrophils | -0.100 10^9 cells per liter | — |
| High Transfusion Burden | Change From Baseline in Neutrophils and/or Platelets Counts | Platelets counts | -8.0 10^9 cells per liter | — |
Secondary
Decrease in Ferritin and Transferrin Saturation (TSAT)
This outcome measure were to report decrease in ferritin and TSAT from baseline to Week 48.
Time frame: Up to 48 weeks
Population: Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Decrease in Iron Chelation Therapy
This outcome measure were to report decrease of Iron chelation therapy and will be recorded at Screening and on an ongoing basis throughout the study.
Time frame: up to 48 weeks
Population: Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Duration of Response
This outcome measure reported duration of response which was defined as duration of response will be summarized with quantiles based on product limit estimates (ie, Kaplan-Meier). Duration of response is defined as the time from date of first known incidence of a 2006 IWG criteria response to the most recent date that the 2006 IWG (International Working Group) criteria is not met following the initial response. If the participant has met IWG criteria throughout the period following the initial response, the participant will be censored at the latest date of end of study, loss to follow-up, or death.
Time frame: Up to 48 weeks
Population: Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Etavopivat Plasma Concentrations
This outcome measure reported Etavopivat plasma concentrations in order to assess the PK properties of etavopivat in participants with MDS. PK parameters included but not limited to were: Time to maximum observed plasma concentration, area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last), from time zero to infinity (AUC0-inf), for a dosing interval (AUCtau/AUC0-24).) However due to early termination of the study, the PK parameters were not assessed and only the plasma concentrations could be assessed.
Time frame: Weeks 1 and 4 pre-dose, post-dose 1, 2, 4, 6 hours.Week 2 and EOT (week 48):pre-dose, post-dose 1, 2 hours
Population: The PK set includes all safety set participants who have at least one evaluable concentration for etavopivat at a scheduled PK time point after the start of dosing. Here, n (number analysed) = Participants with available data for a specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 1 post-dose 1 hour | 379.77 ng/mL | Standard Deviation 292.748 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 4 predose | 17.04 ng/mL | Standard Deviation 11.54 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 2 pre-dose | 27.20 ng/mL | Standard Deviation 17.843 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 4 post-dose 4 hour | 151.50 ng/mL | Standard Deviation 12.021 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 2 post-dose 2 hour | 927.00 ng/mL | Standard Deviation 310.14 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 2 post-dose 1 hour | 1156.00 ng/mL | Standard Deviation 371.198 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 1 post-dose 2 hour | 751.67 ng/mL | Standard Deviation 393.465 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 1 predose | 0 ng/mL | Standard Deviation 0 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 4 post-dose 2 hour | 526.00 ng/mL | Standard Deviation 134.35 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 1 post-dose 4 hour | 274.50 ng/mL | Standard Deviation 86.974 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 4 post-dose 6 hour | 60.75 ng/mL | Standard Deviation 11.526 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 4 post-dose 1 hour | 1050.00 ng/mL | Standard Deviation 28.284 |
| Non-transfusion Dependent | Etavopivat Plasma Concentrations | Week 1 post-dose 6 hour | 63.50 ng/mL | — |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 4 hour | 383.73 ng/mL | Standard Deviation 261.103 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 predose | 0 ng/mL | Standard Deviation 0 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 2 hour | 579.60 ng/mL | Standard Deviation 403.593 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 4 hour | 203.80 ng/mL | Standard Deviation 134.884 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 6 hour | 101.02 ng/mL | Standard Deviation 67.693 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 2 pre-dose | 19.08 ng/mL | Standard Deviation 9.037 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 2 post-dose 1 hour | 899.40 ng/mL | Standard Deviation 442.555 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 2 post-dose 2 hour | 1024.00 ng/mL | Standard Deviation 530.102 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 predose | 24.34 ng/mL | Standard Deviation 23.333 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 1 hour | 386.90 ng/mL | Standard Deviation 214.249 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 2 hour | 453.40 ng/mL | Standard Deviation 179.14 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 1 hour | 904.80 ng/mL | Standard Deviation 521 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 6 hour | 148.13 ng/mL | Standard Deviation 113.65 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | End of treatment pre-dose | 21.60 ng/mL | Standard Deviation 5.798 |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | End of treatment post-dose 1 hours | 1620.00 ng/mL | — |
| Low Transfusion Burden | Etavopivat Plasma Concentrations | End of treatment post-dose 2 hours | 571.00 ng/mL | — |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 1 hour | 913.20 ng/mL | Standard Deviation 1013.207 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 2 hour | 519.11 ng/mL | Standard Deviation 273.776 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | End of treatment post-dose 1 hours | 1680.00 ng/mL | — |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 2 hour | 678.49 ng/mL | Standard Deviation 379.918 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 1 hour | 1016.78 ng/mL | Standard Deviation 794.503 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | End of treatment pre-dose | 24.20 ng/mL | — |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 4 hour | 297.90 ng/mL | Standard Deviation 282.646 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 2 post-dose 1 hour | 1076.44 ng/mL | Standard Deviation 693.907 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 2 pre-dose | 19.20 ng/mL | Standard Deviation 12.24 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 predose | 0 ng/mL | Standard Deviation 0 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 2 post-dose 2 hour | 661.78 ng/mL | Standard Deviation 392.238 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 6 hour | 83.74 ng/mL | Standard Deviation 40.17 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | End of treatment post-dose 2 hours | 815.00 ng/mL | — |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 predose | 20.26 ng/mL | Standard Deviation 9.289 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 1 post-dose 4 hour | 165.16 ng/mL | Standard Deviation 64.895 |
| High Transfusion Burden | Etavopivat Plasma Concentrations | Week 4 post-dose 6 hour | 121.34 ng/mL | Standard Deviation 115.306 |
Secondary
Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat
This outcome measures the total number of AEs and SAEs in participants, including AEs related to etavopivat. AEs are any unfavorable medical occurrences in participants taking the medicinal product, regardless of causality. They include new or worsening symptoms, abnormal lab findings, and exacerbations of existing conditions, documented from the first dose through 28 days after the last dose. SAEs are severe AEs that result in death, are life-threatening, require hospitalization, lead to significant disability, or involve congenital anomalies. Important medical events posing risks to the participants are also classified as SAEs. Treatment Emergent Adverse Events (TEAEs) are AEs occurring after treatment initiation, aiding in the safety assessment of etavopivat. TEAEs will be considered drug-related if assessed by the Investigator as possibly related or related, or if relationship is missing.
Time frame: From baseline up to 48 weeks
Population: Safety population includes all participants who received at least one dose of etavopivat (including partial dosing).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-transfusion Dependent | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AE | 33 Events |
| Non-transfusion Dependent | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | SAE | 1 Events |
| Non-transfusion Dependent | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AEs related to etavopivat | 0 Events |
| Non-transfusion Dependent | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AEs possibly related etavopivat | 8 Events |
| Low Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AEs possibly related etavopivat | 3 Events |
| Low Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AE | 33 Events |
| Low Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AEs related to etavopivat | 0 Events |
| Low Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | SAE | 0 Events |
| High Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AEs possibly related etavopivat | 6 Events |
| High Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | SAE | 6 Events |
| High Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AEs related to etavopivat | 1 Events |
| High Transfusion Burden | Number of All Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Related to Etavopivat | AE | 54 Events |
Secondary
Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions
The outcome measures the total number of premature discontinuations, dose interruptions and dose reductions. Premature discontinuation was defined as any discontinuation prior to week 48. A dose interruption is a temporary halt in treatment due to an AE, while a dose reduction involves lowering the dosage of the drug when AEs occur. If a participant tolerates a reduced dose for 14 days, a rechallenge with the original dose may occur after a clinic visit, but any new Grade 3 or higher AEs require treatment discontinuation and consultation with the Global Medical Monitor before resuming.
Time frame: Within 48 weeks
Population: Safety population included all participants who receive at least one dose of etavopivat (including partial dosing).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-transfusion Dependent | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Dose interruptions | 0 Events |
| Non-transfusion Dependent | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Premature discontinuations | 1 Events |
| Non-transfusion Dependent | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Dose reductions | 0 Events |
| Low Transfusion Burden | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Dose interruptions | 0 Events |
| Low Transfusion Burden | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Premature discontinuations | 0 Events |
| Low Transfusion Burden | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Dose reductions | 0 Events |
| High Transfusion Burden | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Premature discontinuations | 0 Events |
| High Transfusion Burden | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Dose reductions | 0 Events |
| High Transfusion Burden | Number of Premature Discontinuations, Dose Interruptions, and Dose Reductions | Dose interruptions | 2 Events |
Secondary
Overall Response Rate
The Overall Response Rate (ORR) is defined as the percentage of participants who achieve a predefined level of response according to the 2006 International Working Group (IWG) criteria, assessed at each scheduled evaluation.
Time frame: Up to 48 weeks
Population: Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Overall Survival
Overall survival is defined as the time from first dose to date of death. If the participant was alive at last contact, the end date will be censored at the latest of either end of study, loss to follow-up, or study discontinuation.
Time frame: Within 48 weeks
Population: Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Percentage of Participants With Hematologic Improvement- Erythroid (HI-E) Response for =>16 Weeks Within 24 and 48 Weeks of Etavopivat
This outcome measure focused on the combined incidence of NDT, LTB and HTB participants, evaluating HI-E response lasting =\>16 weeks in individuals with MDS within 24 weeks and 48 weeks. Participant's response were defined as follows: 1) NTD: an increase of =\>1.5 g/dL in Hb maintained for =\>16 consecutive weeks without any RBC transfusions for anemia; 2) LTB: no transfusions over =\>16 consecutive weeks; and 3) HTB: a reduction of =\>50% in RBC units for =\>16 consecutive weeks.
Time frame: 48 weeks
Population: FAS: All participants who signed the informed consent and received at least 1 dose of etavopivat. Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Percentage of Participants With Hematologic Improvement-Erythroid (HI-E) Response for =>8 Weeks Within 16 and 48 Weeks of Etavopivat
This outcome measure focused on the combined incidence of NTD, LTB and HTB participants, evaluating HI-E lasting =\>8 weeks in individuals with MDS within 16 weeks and 48 weeks. Participant's response were defined as follows: 1) NTD: an increase of =\>1.5 g/dL in Hb maintained for =\>8 consecutive weeks without any RBC transfusions for anemia; 2) LTB: no transfusions over =\>8 consecutive weeks; and 3) HTB: a reduction of =\>50% in RBC units for =\>8 consecutive weeks.
Time frame: 48 weeks
Population: FAS: All participants who signed the informed consent and received at least 1 dose of etavopivat. Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in statistical analysis plan (SAP).
Secondary
Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry
This outcome measure is percent change in RBC transfusion by 8-week interval in participants with LTB and HTB. Percent reduction from baseline in RBC transfusion burden is defined as -100×(Total RBC Units Transfused During Interval)/(Baseline RBC Units Transfused Per 8 Weeks).
Time frame: Up to 48 weeks
Population: EES: All participants in the FAS who have completed the week 24 response visit and who have a baseline record of the primary endpoint. n (number analysed) = participants with available data for a specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-transfusion Dependent | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 1-8 | -20.83 Percent change of total RBC units | Standard Deviation 64.818 |
| Non-transfusion Dependent | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 9-16 | -33.33 Percent change of total RBC units | Standard Deviation 47.14 |
| Non-transfusion Dependent | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 17-24 | -4.17 Percent change of total RBC units | Standard Deviation 41.248 |
| Non-transfusion Dependent | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 25-32 | 58.33 Percent change of total RBC units | Standard Deviation 11.785 |
| Non-transfusion Dependent | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 33-40 | 33.33 Percent change of total RBC units | Standard Deviation 94.281 |
| Non-transfusion Dependent | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 41-48 | 25.00 Percent change of total RBC units | Standard Deviation 35.355 |
| Low Transfusion Burden | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 33-40 | 94.44 Percent change of total RBC units | Standard Deviation 91.793 |
| Low Transfusion Burden | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 1-8 | 68.75 Percent change of total RBC units | Standard Deviation 156.994 |
| Low Transfusion Burden | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 25-32 | 127.78 Percent change of total RBC units | Standard Deviation 149.381 |
| Low Transfusion Burden | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 9-16 | 68.75 Percent change of total RBC units | Standard Deviation 98.219 |
| Low Transfusion Burden | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 41-48 | 50.00 Percent change of total RBC units | Standard Deviation 0 |
| Low Transfusion Burden | Percent Change From Baseline in RBC Transfusion Independence for =>8 Weeks in Participants With LTB or HTB at Study Entry | Week 17-24 | 120.83 Percent change of total RBC units | Standard Deviation 191.183 |
Secondary
RBC 2,3-diphosphoglycerate (2,3-DPG) and Adenosine Triphosphate (ATP) Levels Over Time
Etavopivat plasma concentrations were collected in order to assess the pharmacodynamic (PD) properties of etavopivat in participants with MDS.
Time frame: Within 48 weeks
Population: Data for this outcome is not analyzed due to early study termination and have been excluded from planned analyses as prespecified in SAP.
Secondary
Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry
This outcome measure reports reduction in RBC transfusion by 8-week interval in participants with LTB and HTB.
Time frame: Up to 48 weeks
Population: EES: All participants in the FAS who have completed the week 24 response visit and who have a baseline record of the primary endpoint. n (number analysed) = Participants with available data for a specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-transfusion Dependent | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 1-8 | 3.0 Total RBS units | Standard Deviation 2.83 |
| Non-transfusion Dependent | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 9-16 | 2.5 Total RBS units | Standard Deviation 2.12 |
| Non-transfusion Dependent | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 17-24 | 3.5 Total RBS units | Standard Deviation 2.12 |
| Non-transfusion Dependent | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 25-32 | 5.5 Total RBS units | Standard Deviation 0.71 |
| Non-transfusion Dependent | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 33-40 | 5.0 Total RBS units | Standard Deviation 4.24 |
| Non-transfusion Dependent | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 41-48 | 4.5 Total RBS units | Standard Deviation 2.12 |
| Low Transfusion Burden | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 33-40 | 6.7 Total RBS units | Standard Deviation 1.15 |
| Low Transfusion Burden | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 1-8 | 5.8 Total RBS units | Standard Deviation 2.63 |
| Low Transfusion Burden | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 25-32 | 7.3 Total RBS units | Standard Deviation 1.15 |
| Low Transfusion Burden | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 9-16 | 6.3 Total RBS units | Standard Deviation 1.71 |
| Low Transfusion Burden | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 41-48 | 7.5 Total RBS units | Standard Deviation 2.12 |
| Low Transfusion Burden | Reduction in RBC Transfusions for >=8 Weeks in Participants With LTB or HTB at Study Entry | Week 17-24 | 7.5 Total RBS units | Standard Deviation 3 |