The primary objective of the study is to determine the proportion of patients with elevated TGs, without Familial ChylomicronemiaSyndrome (FCS) due to loss of function (LoF) mutations in lipoprotein lipase (LPL), and a history of…
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Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy: The primary endpoint is for efficacy: the proportion of
patients with at least 1 positively adjudicated AP episode during the 52 weeks
of the DBTP.
Secondary Efficacy:
Key Secondary Efficacy:
• Percent change in ApoC3 from baseline to week 52
• Percent change in fasting TGs from baseline to week 52
Other Secondary Efficacy:
• Percent change in other fasting standard lipid profile parameters (total
cholesterol [TC], non-high-density lipoprotein cholesterol [non-HDL-C]) from
baseline to week 52
• Percent change in other fasting specialty lipoprotein parameters (ApoB48,
ApoB100 levels, and NMR-determined particle size and number) from baseline to
week 52
• Number of independently adjudicated episodes of AP per patient during 52
weeks of the DBTP
Safety Endpoints:
• Incidence and severity of treatment-emergent adverse event (TEAEs), serious
adverse events (SAEs), laboratory abnormalities, and other safety variables in
patients treated with evinacumab throughout the study
• Incidence of treatment-emergent ADA and NAb
Procedures and Assessments
Efficacy will be assessed by measurement of adjudicated events of AP, and
measurement of lipids and lipoproteins. Safety will be monitored via AE
reporting, physical examinations, routine vital signs, clinical laboratory
tests (blood chemistry and hematology), and standard 12-lead ECG. Serum samples
for the determination of total evinacumab and total ANGPTL3 concentrations, and
ADA and NAb will be collected. Serum and plasma samples will be collected for
analysis of additional biomarkers.
Secondary outcome
Other Endpoints:
• The percent change in fasting HDL-C and LDL-C from baseline to week 52
• Concentrations of total evinacumab and total ANGPTL3 over time
Background summary
Severely elevated levels of serum triglycerides (TGs) are associated with an
increased risk for acute pancreatitis (AP). Episodes of AP secondary to severe
hypertriglyceridemia (sHTG; TG >880 mg/dL [10 mmol/L]) frequently require
hospitalization, and while most events can be treated with conservative therapy
such as intravenous fluids and pain management, approximately 20% of patients
suffer severe attacks associated with prolonged hospitalization and significant
morbidity and mortality. Further, a prior episode of sHTG-associated AP
markedly increases the risk for recurrent AP. While current lipid guidelines
recommend lifestyle interventions and medications to lower TG levels to prevent
AP, patients with sHTG often require robust (>50%) reductions in TG to lower
the risk of AP. Indeed, a substantial proportion of patients have persistent
hypertriglyceridemia (HTG), despite the use of multiple medications to lower TG
levels. Current available therapies for lowering TG levels (eg, statins,
fibrates, niacin, omega-3 fatty acids) typically provide 20% to 50% reductions
in TG levels, which is often insufficient to lower TGs to a target level of
<500 mg/dL (5.6 mmol/L).
Patients with TGs >880 mg/dL (>10 mmol/L) typically have chylomicronemia that
may be either multifactorial (polygenic and environmental) in origin, or much
more rarely, due to the presence of highly penetrant gene mutations in
lipoprotein lipase (LPL) or genes encoding proteins in the LPL pathway (APOA5,
APOC2, GPIHBP1, and LMF1), as observed in Familial Chylomicronemia Syndrome
(FCS). Lipoprotein lipase is an endothelial bound enzyme involved in the
hydrolysis of the TG content of very-low-density lipoproteins (VLDL) and
chylomicron lipoproteins. Mutations in the LPL gene lead to varying levels of
loss of LPL functional activity and elevated levels of plasma TGs, especially
in chylomicrons. However, there is a high degree of genetic polymorphism and
combinatorial effects of genes, diseases (such as type 2 diabetes), and
environment. There is an unmet medical need for additional treatment options
for patients with sHTG and a history of AP to further lower TG levels and the
risk of recurrent attacks of AP, regardless of their genetic background.
Angiopoietin-like 3 (ANGPTL3) acts as a natural inhibitor of LPL and has
emerged as a target for the treatment of elevated levels of TG and low-density
lipoprotein cholesterol (LDL C). Loss of function of ANGPTL3 in humans has been
associated with reductions in TG and LDL C.
Evinacumab (REGN1500) is a human IgG4 monoclonal antibody (mAb) specific for
ANGPTL3. It is currently approved as an adjunctive treatment for homozygous
familial hypercholesterolemia (HoFH, EvkeezaTM) and is being evaluated for
treatment of dyslipidemia including HTG. Evinacumab has been studied in
approximately 580 individuals with elevations in LDL C and TG and has been
generally well tolerated up to single doses of 20 mg/kg intravenously (IV) and
in multiple subcutaneous (SC) doses up to 450 mg administered weekly (QW), and
20 mg/kg IV administered every 4 weeks (Q4W) for approximately 8 weeks (ie 2
doses).
A phase 2, randomized, placebo-controlled study (R1500-HTG-1522) was conducted
to evaluate the safety and TG-lowering effects of evinacumab in patients with
various causes of sHTG, and at risk for AP, including homozygous/heterozygous
loss of function (LoF) gene mutations in LPL, mutations in other genes in the
LPL pathway, and other polygenic/environmental causes of severely elevated TGs.
The 12-week, double-blind treatment period (DBTP) enrolled 52 patients who were
randomized to receive either evinacumab 15 mg/kg or matching placebo
administered IV Q4W, followed by a 12-week, single-blind treatment period
(SBTP) in which all patients (N=47) received evinacumab Q4W.
The primary endpoint was predefined as the mean within-patient change in TGs,
and the study did not meet the threshold of a clinically important reduction
(>40%). This applied to the overall study population and also for genotypic
strata based on the presence of LPL pathway LoF mutations. Several factors may
have contributed to a lack of efficacy. There was large variability in TGs,
which was compounded by the absence of a diet-stabilization period and efficacy
determined by a single post-treatment TG measurement. In addition, there was
variability in drug exposure, where patients with the lowest trough levels of
evinacumab had little to no treatment response. In this context, when examining
median percent changes to minimize the impact of outliers, the evinacumab
treated patients overall showed a clinically important reduction (>40%) in
fasting TGs at each post-baseline visit, culminating in a median reduction of
approximately 57% at week 12 during the DBTP. The treatment effect was even
more pronounced when excluding patients with FCS, where non-FCS patients had a
median reduction in TGs of approximately 80%. When including patients that
switched to evinacumab during the SBTP, the median percent reduction in TGs
after 12 weeks of evinacumab exposure was approximately 70% for non FCS
patients.
In the DBTP, 5 patients (3 in the evinacumab group; 2 in the placebo group)
experienced an episode of AP (all serious adverse events or SAEs); all resolved
within 7 days. For the evinacumab-treated patients, 1 participant had FCS and
did not have a TG response to therapy; 1 patient had an episode of AP within 48
hours after receiving his first dose of evinacumab; 1 patient had persistently
low trough concentrations of evinacumab. Treatment-emergent adverse events
(TEAEs) that occurred more frequently in the evinacumab group compared to the
placebo group included Abdominal pain (14.3% versus 12.5%), Headache (11.4%
versus 6.3%), and Constipation (8.6% versus 0). In the SBTP, 12 (25.5%)
patients had SAEs of Acute pancreatitis; none was considered related to the
study drug. The majority of episodes occurred during the off-drug period (>4
weeks after the last dose of evinacumab) and episodes of AP were not
independently adjudicated, with some patients diagnosed with AP despite the
absence of pathologic findings on pancreatic imaging and/or elevated
lipase/amylase levels.
The current study is a phase 2b randomized, placebo-controlled study intended
to demonstrate that evinacumab can prevent recurrent episodes of HTG-associated
AP in patients with sHTG, but without FCS due to mutations in LPL. The
secondary aims are to evaluate the effects of evinacumab on safety and changes
in biomarkers of TG-rich lipoprotein metabolism, including serum TG, ApoC3,
ApoB48, and ApoB100 in this patient population.
Additional background information on the study drug and development program can
be found in the Investigator*s Brochure.
Study objective
The primary objective of the study is to determine the proportion of patients
with elevated TGs, without Familial Chylomicronemia
Syndrome (FCS) due to loss of function (LoF) mutations in lipoprotein lipase
(LPL), and a history of hypertriglyceridemia (HTG)-associated acute
pancreatitis (AP*) who experience a recurrent episode of AP after treatment
with evinacumab versus placebo.
The secondary objectives of the study are:
• To determine the change in the standard lipid profile after therapy with
evinacumab versus placebo
• To determine the changes in specialty lipoprotein parameters (ApoC3, ApoB48,
ApoB100, and nuclear magnetic resonance [NMR] lipid profile) after therapy with
evinacumab versus placebo
• To measure the number of AP episodes per patient
• To assess the safety and tolerability of evinacumab
• To assess the potential immunogenicity of evinacumab
• To assess the concentrations of total evinacumab and total angiopoietin-like
3 (ANGPTL3)
*Includes adult patients with 1) elevated baseline fasting TGs >880 mg/dL and
history of 1 HTGassociated AP within 24 months of screening or 2) elevated
baseline fasting TG values >500 mg/dL in patients with a history of 2 or more
HTG-associated AP within 24 months or 3) elevated baseline fasting TG values
>500 mg/dL with a prior documented fasted TG values >1000 mg/dL and a history
of 1 or more HTG- associated AP within 24 months. All participants are without
FCS due to LPL loss of function mutations.
Study design
This is a phase 2b, multicenter, international, randomized, placebo-controlled
study intended to demonstrate that evinacumab can prevent recurrent AP in
patients with severe hypertriglyceridemia (sHTG) and a recent history of
HTG-associated AP. Approximately 120 adult patients will be randomized 1:1 to
receive evinacumab or matching placebo.
The study consists of 3 periods: a screening period, a double-blind treatment
period (DBTP), and a safety follow-up period. The screening period of up to 28
days will determine participant eligibility and will include an evaluation of
prior episodes of HTG-associated AP, genotyping to exclude patients with
familial chylomicronemia syndrome (FCS) due to loss of function mutations in
lipoprotein lipase, and 2 measurements of fasting TG levels separated by at
least 2 days. Patients must have baseline fasting TGs
>880 mg/dL on each of the 2 measurements and a history of HTG-associated AP
within 15 months of screening to be enrolled in the study. Patients who fulfill
all the eligibility criteria will be randomized and receive their first dose of
assigned study drug on day 1, with subsequent doses administered approximately
every 4 weeks (Q4W) during the 52-week DBTP. This will be followed by a 48-week
off-drug follow-up period. Efficacy will be assessed by measuring the number of
patients with at least 1 independently adjudicated positive event of AP over 52
weeks of treatment with evinacumab versus placebo. The study will have an
independent committee to adjudicate these episodes in accordance with clinical
standards for diagnosis of AP. Efficacy will also be assessed by clinical
laboratory evaluation of lipid levels at pre-specified time points throughout
the study. Safety will be assessed throughout the study by comparing the
frequency and severity of adverse events (AEs) between the evinacumab and
placebo groups, as well as evaluating abnormal laboratory findings,
electrocardiogram (ECG) findings, and anti-drug antibody (ADA) and neutralizing
antibodies (NAb) assessments.
Intervention
Study Drug: Evinacumab
Dose/Route/Schedule: 20 mg/kg administered intravenously (IV) over a 1-hour
infusion Q4W, ±4 days
Placebo: Matching placebo
Route/Schedule: Intravenous infusion Q4W (±4 days)
Study burden and risks
See section 3.3 of the protocol Benefit/Risk assessment.
Old Saw Mill River Road 777
Tarrytown, NY 10591
US
Old Saw Mill River Road 777
Tarrytown, NY 10591
US
Listed location countries
Age
Inclusion criteria
A patient must meet the following criteria to be eligible for inclusion in the
study:
1. Adults 18 to 80 years of age without FCS due to LPL loss of function
mutations
2. Documented history of 1 HTG-associated AP episode within 24 months of
screening (can be determined by study investigator; does not need to be
confirmed by independent adjudication committee).
3. Fasting serum TG value >880 mg/dL (10 mmol/L) on 2 occasions at least 2 days
apart determined during the screening period. Triglyceride measurement can be
repeated once for values >500 mg/dL (5.6 mmol/L) but <880 mg/dL (10 mmol/L)
OR
Fasting serum TG value >500 mg/dL (5.6 mmol/L) determined during the screening
period in patients with a history of 2 or more HTGassociated AP episodes within
24 months of screening
OR
Fasting serum TG value >500 mg/dL (5.6 mmol/L) determined during the screening
period and a documented fasted serum TG value >1000 mg/dL (11.3 mmol/L) and a
history of 1 or more HTG-associated AP episode(s) within 24 months of screening.
4. Stable dose of lipid-lowering therapy (>=8 weeks) and willingness to maintain
a stable regimen throughout the study
5. Body mass index >=18.0 and <=45.0 kg/m2
6. Compliance with a stable diet and exercise regimen at screening and
willingness to continue the diet through the end of the study
7. Willing and able to comply with clinic visits and study-related procedures
8. Provide informed consent signed by study patient or legally acceptable
representative
9. Able to understand and complete study-related questionnaires
Exclusion criteria
A patient who meets any of the following criteria will be excluded from the
study:
1. Hospitalization for AP within 4 weeks of screening
2. Known genetic FCS defined as homozygous or compound heterozygous LoF
mutations in LPL, as documented by prior genotype result or determined from FCS
genotyping at screening (see Section 9.2.7).
3. Symptomatic gallstone disease within 6 months prior to screening. Incidental
and/or asymptomatic gallstones are permitted. Patients with symptomatic
gallstone disease in the past 6 months who have undergone cholecystectomy >3
months prior to screening are permitted.
4. Use of any medication or nutraceutical known to alter serum lipids which has
not been part of a stable therapeutic regimen for at least 8 weeks, and there
are no plans to change the regimen during the study
5. Presence of any clinically significant, uncontrolled endocrine disease known
to influence serum lipids, including but not limited to:
a. Newly diagnosed (within 3 months) diabetes by medical history, including
screening value glycosylated hemoglobin (HbA1c) >6.5% without a prior history
of diabetes
b. Diabetes with HbA1c >10.0%
c. Thyroid disease with thyroid-stimulating hormone (TSH) normal (LLN) or >1.5x ULN
d. Thyroid replacement therapy that has not been stable for at least 12 weeks
Note: For laboratory values, 1 repeat measurement is allowed. Other laboratory
values that meet the inclusion/exclusion criteria do not need to be repeated.
6. Use of estrogen or testosterone therapy unless the regimen has been stable
in the past 6 weeks and there are no plans to change the regimen during the
study
7. Any clinically significant abnormality identified at the time of screening
that, in the judgment of the investigator or any sub-investigator, would
preclude safe completion of the study or constrain endpoints assessment; eg,
major systemic diseases, patients with short life expectancy, or considered by
the investigator or any sub-investigator as inappropriate for this study for
any reason, including but not limited to:
a. Deemed unable to meet specific protocol requirements, such as scheduled
visits
b. Deemed unable to tolerate injections, as per the patient or the investigator
c. Part of a vulnerable population such as the institutionalized
d. Presence of any other conditions (eg, geographic or social), either actual
or anticipated, that the investigator feels would restrict or limit the
patient*s participation for the duration of the study
8. Laboratory findings (for the reason that patients with these findings, who
have a higher likelihood of liver, muscle, or kidney adverse events regardless
of treatment assignment, are expected to be rare, they may not be evenly
distributed across treatment groups and thus may confound the analysis of
safety):
a. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 according to
4 variable Modification of Diet in Renal Disease study equation (MDRD,
calculated by central laboratory)
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x ULN at
screening
c. Creatine phosphokinase (CPK) >3x ULN at screening
Note: For all laboratory values, 1 repeat measurement is allowed.
9. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at
the screening visit or time of randomization (1 repeat allowed). The uneven
distribution of these patients across treatment groups could confound the
analysis of safety.
10. History of heart failure (New York Heart Association [NYHA] Class III-IV)
within 12 months before screening. The uneven distribution of these patients
across treatment groups could confound the analysis of safety.
11. Within 3 months of screening, a history of myocardial infarction (MI),
unstable angina leading to hospitalization, coronary artery bypass grafting
(CABG) surgery, percutaneous coronary interventions (PCI), uncontrolled cardiac
arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack
(TIA), carotid revascularization, endovascular procedure, or surgical
intervention for peripheral vascular disease. The uneven distribution of these
patients across treatment groups could confound the analysis of safety.
12. Significant concomitant illness including, but not limited to: cardiac,
renal, neurological, endocrinological, hepatic, metabolic, or lymphatic
disease, that would adversely affect the patient*s participation in the study
13. History of cancer within the past 5 years, except for adequately treated
basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
See protocol for further inclusion criteria
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000437-13-NL |
| ClinicalTrials.gov | NCT04863014 |
| CCMO | NL78035.100.21 |