Hypercholesterolemia, Hyperlipoproteinemia Type II
Conditions
Keywords
hypercholesterolemia, apolipoprotein E, First in Human, Apolipoprotein E (ApoE), Apolipoprotein E Mimetic (AEM)
Brief summary
The purpose of the first part of this study is to determine the safety and tolerability of a single dose of AEM-28, an apolipoprotein E mimetic, in subjects with high total cholesterol who are otherwise healthy subjects. The pharmacokinetics and pharmacodynamics of AEM-28 will also be evaluated. The second part of this study will be a multiple ascending dose evaluation of AEM-28 in patients with refractory hypercholesterolemia. AEM-28 has demonstrated significant lipid lowering activity and positive effects on the artery wall. AEM-28 is being developed for the treatment of homozygous familial hypercholesterolemia.
Interventions
DRUGAEM-28
Solution for injection
DRUGNormal Saline
0.9% saline for injection
Sponsors
LipimetiX Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Single Ascending Dose (SAD) Study: * Male or female non-smoker, ≥18 and ≤55 years of age, with BMI \>18.5 and \< 32.0 kg/m² * Total cholesterol greater or equal to 5.0 mmol/L (≥194 mg/dL) at screening Multiple Ascending Dose (MAD) Study: * Male or female non-smoker, ≥18 and ≤75 years of age, with BMI \>18.5 and \< 35.0 kg/m² * Diagnosis of refractory hypercholesterolemia with LDL cholesterol levels \> 2.5 mmol/L (97 mg/mL) at screening. * On stable lipid lowering therapy for ≥ 8 weeks * On stable diet for ≥ 12 weeks.
Exclusion criteria
SAD Study: * Any clinically significant abnormality or abnormal laboratory test results found during medical screening or positive test for hepatitis B, hepatitis C, or HIV found during medical screening. * History of allergic reactions to diphenhydramine, ranitidine, methylprednisone or other related drugs, or history of significant allergic or hypersensitivity reaction (e.g. angioedema) to any substance. MAD Study: * Significant health problems within 6 months prior to screening, which in the opinion of the Medical Sub-Investigator would prevent the subject from participating in the study, including but not limited to: unstable coronary heart disease; transient ischemic attack; stroke; revascularization procedure; uncontrolled hyperthyroidism; coagulation disorder; peptic ulcers or GI bleeding; significant disease of the central nervous system; liver or renal disease. * History of allergic reactions to diphenhydramine, ranitidine, methylprednisone or other related drugs, or history of significant allergic or hypersensitivity reaction (e.g. angioedema) to any substance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Incurred at Least One Treatment Emergent Event | Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57 | Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics. |
| Number of Participants Who Incurred Mild Treatment Emergent Adverse Events | Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57 | Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics. |
| Number of Participants Who Incurred Moderate Treatment Emergent Events | Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57 | Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A (SAD): Day 1 to Day 15; Part B (MAD): Day 1 to Day 57 | Maximum observed percentage change in VLDL-C level relative to baseline for all time points measured in Parts A or Part B with highest dose, i.e. 3.54 mg/kg. |
Countries
Australia
Participant flow
Recruitment details
Study conducted at Linear Clinical Research Ltd, a medical clinic in Nedlands WA Australia.
Participants by arm
| Arm | Count |
|---|---|
| AEM-28 Single Ascending Dose: Single IV dose for each cohort; dose range 0.032 mg/mL to 3.54 mg/mL
Multiple Ascending Dose: Three (3) IV doses for each cohort, one (1) dose every two (2) weeks; dose range 1 mg/kg to 3.54 mg/kg.
AEM-28: Solution for injection | 37 |
| Normal Saline Single Ascending Dose: Single IV dose for each cohort.
Multiple Ascending Dose: Three (3) IV doses for each cohort, one (1) dose every two (2) weeks.
Normal Saline: 0.9% saline for injection | 15 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Multiple Ascending Dose | Adverse Event | 2 | 0 |
| Multiple Ascending Dose | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | AEM-28 | Normal Saline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 15 Participants | 50 Participants |
| Age, Continuous | 35.7 years | 32 years | 34.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 15 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 31 Participants | 11 Participants | 42 Participants |
| Region of Enrollment Australia | 37 participants | 15 participants | 52 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 30 Participants | 10 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 37 | 10 / 15 |
| serious Total, serious adverse events | 0 / 37 | 0 / 15 |
Outcome results
Primary
Number of Participants Who Incurred at Least One Treatment Emergent Event
Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics.
Time frame: Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AEM-28 | Number of Participants Who Incurred at Least One Treatment Emergent Event | 33 participants |
| Normal Saline | Number of Participants Who Incurred at Least One Treatment Emergent Event | 10 participants |
Primary
Number of Participants Who Incurred Mild Treatment Emergent Adverse Events
Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics.
Time frame: Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AEM-28 | Number of Participants Who Incurred Mild Treatment Emergent Adverse Events | 33 Number of Participants |
| Normal Saline | Number of Participants Who Incurred Mild Treatment Emergent Adverse Events | 10 Number of Participants |
Primary
Number of Participants Who Incurred Moderate Treatment Emergent Events
Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics.
Time frame: Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AEM-28 | Number of Participants Who Incurred Moderate Treatment Emergent Events | 7 Number of Participants |
| Normal Saline | Number of Participants Who Incurred Moderate Treatment Emergent Events | 0 Number of Participants |
Secondary
Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change
Maximum observed percentage change in VLDL-C level relative to baseline for all time points measured in Parts A or Part B with highest dose, i.e. 3.54 mg/kg.
Time frame: Part A (SAD): Day 1 to Day 15; Part B (MAD): Day 1 to Day 57
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AEM-28 | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A: 3.54 mg/kg | -72.1 Max % Change Versus Baseline | Standard Deviation 15.1 |
| AEM-28 | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part B: 3.54 mg/kg | -79.2 Max % Change Versus Baseline | Standard Deviation 13.5 |
| AEM-28 | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A: 2.0 mg/kg | -76.3 Max % Change Versus Baseline | Standard Deviation 7.25 |
| AEM-28 | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part B: 2.0 mg/kg | -73.3 Max % Change Versus Baseline | Standard Deviation 6.36 |
| AEM-28 | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A: 1.0 mg/kg | -47.9 Max % Change Versus Baseline | Standard Deviation 19.7 |
| AEM-28 | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part B: 1.0 mg/kg | -51.8 Max % Change Versus Baseline | Standard Deviation 24.7 |
| Normal Saline | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A: 1.0 mg/kg | -0.23 Max % Change Versus Baseline | Standard Deviation 0.15 |
| Normal Saline | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A: 3.54 mg/kg | -0.33 Max % Change Versus Baseline | Standard Deviation 0.17 |
| Normal Saline | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part B: 2.0 mg/kg | -0.52 Max % Change Versus Baseline | Standard Deviation 0.15 |
| Normal Saline | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part B: 3.54 mg/kg | -0.58 Max % Change Versus Baseline | Standard Deviation 0.31 |
| Normal Saline | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part B: 1.0 mg/kg | -0.38 Max % Change Versus Baseline | Standard Deviation 0.19 |
| Normal Saline | Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change | Part A: 2.0 mg/kg | -0.35 Max % Change Versus Baseline | Standard Deviation 0.13 |