Severe Hypertriglyceridemia
Conditions
Keywords
Hypertriglyceridemia, Dyslipidemia, Lipid disorder, FGF21
Brief summary
This study is designed to assess the efficacy, safety, and tolerability of different doses and dose regimens (once weekly \[QW\] or every 2 weeks \[Q2W\]), subcutaneous (SC) dosing of BIO89-100 (pegozafermin) compared to placebo in participants with severe hypertriglyceridemia (SHTG).
Interventions
DRUGPegozafermin
Subcutaneous injection
DRUGPlacebo
Matching placebo
Sponsors
89bio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female age ≥21 to ≤75 years. 2. Screening fasting triglyceride ≥500 milligrams (mg)/deciliters (dL) and ≤2000 mg/dL. 3. Willing to maintain current eating and exercise habits from time of signing the informed consent and for the duration of the study. 4. Participants could be taking statins and/or prescription fish oil as background therapy or not be taking any background therapy. 5. Magnetic resonance imaging - whole liver proton density fat fraction (MRI-PDFF) of ≥6% for participants screened for the Fibrate Expansion cohort.
Exclusion criteria
1. Uncontrolled or newly diagnosed hypertension. 2. Body mass index \>45 kilograms (kg)/meters squared (m\^2). 3. Receiving niacin, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, or supplements that could lower lipid levels. 4. Type 1 diabetes mellitus. 5. Diagnosis of Type 2 diabetes mellitus \<6 months prior to screening. 6. History of malignancy within 5 years prior to screening. 7. Participants with known lipoprotein lipase impairment or deficiency (Fredrickson Type 1), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type 3). 8. Clinically or otherwise documented cardiovascular or cerebrovascular disease. 9. Weight change ≥5% in 3 months prior to first screening visit or weight change ≥5% during screening or planning to try to lose weight during conduct of study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline to Week 8 in Serum Triglyceride (TG) | Baseline, Week 8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | Baseline, Week 8 | Least Squares Means were calculated using mixed-model repeated measures (MMRM). |
| Percent Change From Baseline to Week 8 in Very Low-density Lipoprotein Cholesterol (VLDL-C) and VLDL-TG | Baseline, Week 8 | — |
| Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Baseline, Week 8 | Least Squares Mean was calculated using MMRM. |
| Number of Participants Who Achieved TG <500 mg/dL at Week 8 | Week 8 | — |
| Percent Change From Baseline to Week 8 in High-sensitivity C-reactive Protein (hsCRP) | Baseline, Week 8 | — |
| Percent Change From Baseline to Week 8 in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) | Baseline, Week 8 | Least Squares Mean was calculated using MMRM. |
| Percent Change From Baseline to Week 8 in Liver Fat as Assessed by Magnetic Resonance Imaging - Whole Liver Proton Density Fat Fraction (MRI-PDFF) | Baseline, Week 8 | Least Squares Mean was calculated using analysis of covariance (ANCOVA). |
Countries
Czechia, Hungary, Poland, United States
Participant flow
Pre-assignment details
As per the Statistical Analysis Plan (SAP), since a low number of participants enrolled in the fibrate cohort (3 on placebo and 3 on active treatment \[pegozafermin\]), participants in the pegozafermin 27 mg QW fibrate cohort were combined with the pegozafermin 27 mg QW main cohort, forming a pooled pegozafermin 27 mg QW group for analyses. Similarly, the placebo participants in the fibrate cohort were combined with the main placebo group (pooled) for analyses.
Participants by arm
| Arm | Count |
|---|---|
| Pegozafermin 9 mg QW Pegozafermin 9 mg QW was administered as a SC injection. | 12 |
| Pegozafermin 18 mg QW Pegozafermin 18 mg QW was administered as an SC injection. | 21 |
| Pegozafermin 27 mg QW Pegozafermin 27 mg QW was administered as an SC injection. The Main Study cohort and Fibrate Expansion cohort for pegozafermin 27 mg were pooled together due to low sample size in the expansion cohort. | 18 |
| Pegozafermin 36 mg Q2W Pegozafermin 36 mg Q2W was administered as an SC injection. | 16 |
| Placebo Matching placebo was injected at matching frequency per assigned cohort. Main Study cohort and Fibrate Expansion cohort for placebo were pooled together due to low sample size in the expansion cohort. | 18 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Fibrate Expansion Study | Other than Specified | 0 | 0 | 0 | 0 | 1 |
| Main Study | Adverse Event | 0 | 0 | 4 | 0 | 0 |
| Main Study | COVID-19-related Dose Interruption | 0 | 0 | 0 | 0 | 1 |
| Main Study | Investigator Decision | 0 | 0 | 1 | 1 | 0 |
| Main Study | Randomized in Error Not Treated | 0 | 0 | 1 | 0 | 0 |
| Main Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Pegozafermin 9 mg QW | Pegozafermin 18 mg QW | Pegozafermin 27 mg QW | Pegozafermin 36 mg Q2W | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 14.12 | 51.3 years STANDARD_DEVIATION 10.81 | 53.9 years STANDARD_DEVIATION 7.18 | 53.1 years STANDARD_DEVIATION 12.36 | 57.5 years STANDARD_DEVIATION 10.3 | 53.7 years STANDARD_DEVIATION 10.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 4 Participants | 5 Participants | 3 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 19 Participants | 14 Participants | 11 Participants | 15 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 11 Participants | 21 Participants | 18 Participants | 14 Participants | 17 Participants | 81 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 5 Participants | 2 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Male | 8 Participants | 17 Participants | 13 Participants | 14 Participants | 12 Participants | 64 Participants |
| Triglyceride (TG) Level <750 mg/dL | 9 Participants | 14 Participants | 12 Participants | 9 Participants | 13 Participants | 57 Participants |
| Triglyceride (TG) Level ≥750 mg/dL | 3 Participants | 7 Participants | 6 Participants | 7 Participants | 5 Participants | 28 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 21 | 0 / 18 | 0 / 16 | 0 / 18 |
| other Total, other adverse events | 7 / 12 | 13 / 21 | 13 / 18 | 7 / 16 | 9 / 18 |
| serious Total, serious adverse events | 0 / 12 | 0 / 21 | 1 / 18 | 0 / 16 | 0 / 18 |
Outcome results
Primary
Percent Change From Baseline to Week 8 in Serum Triglyceride (TG)
Time frame: Baseline, Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegozafermin | Percent Change From Baseline to Week 8 in Serum Triglyceride (TG) | -57.33 percent change from Baseline |
| Placebo | Percent Change From Baseline to Week 8 in Serum Triglyceride (TG) | -11.85 percent change from Baseline |
p-value: <0.00195% CI: [-57.08, -30.31]van Elteren test
Secondary
Number of Participants Who Achieved TG <500 mg/dL at Week 8
Time frame: Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pegozafermin | Number of Participants Who Achieved TG <500 mg/dL at Week 8 | 51 Participants |
| Placebo | Number of Participants Who Achieved TG <500 mg/dL at Week 8 | 5 Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline to Week 8 in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
Least Squares Mean was calculated using MMRM.
Time frame: Baseline, Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pegozafermin | Percent Change From Baseline to Week 8 in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) | ALT | -4.28 percent change from Baseline | Standard Error 4.549 |
| Pegozafermin | Percent Change From Baseline to Week 8 in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) | AST | -11.50 percent change from Baseline | Standard Error 3.341 |
| Placebo | Percent Change From Baseline to Week 8 in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) | ALT | 0.43 percent change from Baseline | Standard Error 8.881 |
| Placebo | Percent Change From Baseline to Week 8 in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) | AST | 0.51 percent change from Baseline | Standard Error 6.597 |
Secondary
Percent Change From Baseline to Week 8 in High-sensitivity C-reactive Protein (hsCRP)
Time frame: Baseline, Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegozafermin | Percent Change From Baseline to Week 8 in High-sensitivity C-reactive Protein (hsCRP) | -21.43 percent change from Baseline |
| Placebo | Percent Change From Baseline to Week 8 in High-sensitivity C-reactive Protein (hsCRP) | -1.10 percent change from Baseline |
Secondary
Percent Change From Baseline to Week 8 in Liver Fat as Assessed by Magnetic Resonance Imaging - Whole Liver Proton Density Fat Fraction (MRI-PDFF)
Least Squares Mean was calculated using analysis of covariance (ANCOVA).
Time frame: Baseline, Week 8
Population: All participants in the FAS who had baseline and a follow-up MRI-PDFF assessment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pegozafermin | Percent Change From Baseline to Week 8 in Liver Fat as Assessed by Magnetic Resonance Imaging - Whole Liver Proton Density Fat Fraction (MRI-PDFF) | -42.18 percent change from Baseline | Standard Error 6.207 |
| Placebo | Percent Change From Baseline to Week 8 in Liver Fat as Assessed by Magnetic Resonance Imaging - Whole Liver Proton Density Fat Fraction (MRI-PDFF) | -8.26 percent change from Baseline | Standard Error 11.214 |
p-value: 0.012ANCOVA
Secondary
Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C)
Least Squares Means were calculated using mixed-model repeated measures (MMRM).
Time frame: Baseline, Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pegozafermin | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | Non-HDL-C | -18.29 percent change from Baseline | Standard Error 2.943 |
| Pegozafermin | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | ApoB | -10.51 percent change from Baseline | Standard Error 2.238 |
| Pegozafermin | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | LDL-C | 10.44 percent change from Baseline | Standard Error 4.654 |
| Pegozafermin | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | HDL-C | 24.65 percent change from Baseline | Standard Error 3.752 |
| Placebo | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | HDL-C | 9.67 percent change from Baseline | Standard Error 7.045 |
| Placebo | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | Non-HDL-C | -0.57 percent change from Baseline | Standard Error 5.586 |
| Placebo | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | LDL-C | 8.72 percent change from Baseline | Standard Error 9.018 |
| Placebo | Percent Change From Baseline to Week 8 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B100 (ApoB), Low-density Lipoprotein Cholesterol (LDL-C), and High-density Lipoprotein Cholesterol (HDL-C) | ApoB | 1.07 percent change from Baseline | Standard Error 4.309 |
Comparison: MMRM analysis of non-HDL-C comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.00795% CI: [-30.67, -5.07]MMRM
Comparison: MMRM analysis of ApoB comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.01995% CI: [-21.48, -2.01]MMRM
Comparison: MMRM analysis of LDL-C comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.8795% CI: [-19.21, 22.68]MMRM
Comparison: MMRM analysis of HDL-C comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.06495% CI: [-0.89, 31.7]MMRM
Secondary
Percent Change From Baseline to Week 8 in Very Low-density Lipoprotein Cholesterol (VLDL-C) and VLDL-TG
Time frame: Baseline, Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pegozafermin | Percent Change From Baseline to Week 8 in Very Low-density Lipoprotein Cholesterol (VLDL-C) and VLDL-TG | VLDL-C | -47.96 percent change from Baseline |
| Pegozafermin | Percent Change From Baseline to Week 8 in Very Low-density Lipoprotein Cholesterol (VLDL-C) and VLDL-TG | VLDL-TG | -58.50 percent change from Baseline |
| Placebo | Percent Change From Baseline to Week 8 in Very Low-density Lipoprotein Cholesterol (VLDL-C) and VLDL-TG | VLDL-C | -0.41 percent change from Baseline |
| Placebo | Percent Change From Baseline to Week 8 in Very Low-density Lipoprotein Cholesterol (VLDL-C) and VLDL-TG | VLDL-TG | -0.85 percent change from Baseline |
Comparison: Nonparametric analysis of VLDL-C comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.006van Elteren Test
Comparison: Nonparametric analysis of VLDL-TG comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.002van Elteren test
Secondary
Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight
Least Squares Mean was calculated using MMRM.
Time frame: Baseline, Week 8
Population: FAS: Participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline TG measurement not including EOS visit. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. As pre-specified in the SAP, the sample size in each arm (by dose group) was insufficient (under powered) to effectively evaluate differences in efficacy by dose, therefore, efficacy analysis was performed using total pegozafermin and placebo groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pegozafermin | Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Fasting Plasma Glucose | -3.90 percent change from Baseline | Standard Error 2.681 |
| Pegozafermin | Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Adiponectin | 69.53 percent change from Baseline | Standard Error 7.383 |
| Pegozafermin | Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Body Weight | -0.15 percent change from Baseline | Standard Error 0.339 |
| Placebo | Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Fasting Plasma Glucose | -2.67 percent change from Baseline | Standard Error 5.23 |
| Placebo | Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Adiponectin | 5.70 percent change from Baseline | Standard Error 14.556 |
| Placebo | Percent Change in Baseline to Week 8 in Fasting Plasma Glucose, Adiponectin, and Body Weight | Body Weight | -0.14 percent change from Baseline | Standard Error 0.654 |
Comparison: MMRM analysis of fasting plasma glucose comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.809MMRM
Comparison: MMRM analysis of adiponectin comparison between pegozafermin pooled versus placebo pooled group.p-value: <0.001MMRM
Comparison: MMRM analysis of body weight comparison between pegozafermin pooled versus placebo pooled group.p-value: 0.973MMRM