Study of AKCEA-ANGPTL3-LRx (ISIS 703802) in Participants With Familial Partial Lipodystrophy (FPL)

An Open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered Subcutaneously to Subjects With Familial Partial Lipodystrophy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03514420

Enrollment

Registered

2018-05-02

Start date

2018-06-15

Completion date

2019-08-21

Last updated

2021-02-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Familial Partial Lipodystrophy

Keywords

Lipodystrophy, Lipodystrophy, Familial Partial, Lipid Metabolism Disorders, Dyslipidemias, Kobberling-Dunnigan syndrome (type 1 and 2), Lipoatrophic Diabetes

Brief summary

This is a single-center, open-label study to evaluate the efficacy of AKCEA-ANGPTL3-LRx for reduction of fasting triglycerides in participants with familial partial lipodystrophy.

Interventions

DRUGAKCEA-ANGPTL3-LRx

AKCEA-ANGPTL3-LRx solution for SC injection.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * Must give written informed consent to participate in the study. * Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 2 diabetes mellitus and hypertriglyceridemia. * Diagnosis of diabetes mellitus, made at least 6 months prior to the Screening with hemoglobin A1c (HbA1c) ≥ 7% to ≤ 12% at Screening and on anti-diabetic therapy as defined in study protocol. * Hypertriglyceridemia as defined by fasting triglycerides (TG) levels ≥ 500 milligrams per deciliter (mg/dL) at both Screening and Qualification visits. Participants with the clinical diagnosis of FPL and with fasting TG levels ≥ 200 (≥ 2.26 millimoles per liter \[mmol/L\]) to \< 500 mg/dL (≥ 5.7 mmol/L) who meet the genetic or family history criteria for study inclusion may be further screened and enrolled in the study. * Presence of hepatosteatosis (fatty liver), as evidenced by a Screening magnetic resonance imaging (MRI) indicating a hepatic fat fraction (HFF) ≥ 6.4%. Key

Exclusion criteria

* Diagnosis of generalized lipodystrophy. * Diagnosis of acquired partial lipodystrophy (APL). * Acute pancreatitis within 4 weeks of Screening. * Acute coronary syndrome within 6 months of Screening. * Major surgery within 3 months of Screening. * Have any other conditions in the opinion of the investigator which could interfere with the participant participating in or completing the study.

Design outcomes

Primary

Measure	Time frame	Description
Percent Change From Baseline in Fasting Triglycerides Levels at End of the Treatment (Week 27)	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.

Secondary

Measure	Time frame	Description
Change From Baseline in AUC of Serum Insulin as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of Serum Insulin was assessed.
Change From Baseline in AUC of Serum C-peptide as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of Serum C-peptide was assessed.
Change From Baseline in AUC of Free Fatty Acid (FFA) as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of FFA was assessed.
Change From Baseline in AUC of Serum Ghrelin as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of Serum Ghrelin was assessed.
Change From Baseline in AUC of Incretin Hormone (Gastric Inhibitory Polypeptide [GIP]) as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of Incretin Hormone: GIP was assessed.
Change From Baseline in AUC of Incretin Hormone (Glucagon-like Peptide -1 [GLP-1]) as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of Incretin Hormone: GLP-1 was assessed.
Change From Baseline in AUC of Peptide Tyrosine Tyrosine (PYY) as Assessed by MMT at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the AUC of PYY was assessed.
Change From Baseline in HDL-C at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in LDL-C at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment. LDL-C calculated using ultracentrifugation method.
Change From Baseline in Total Cholesterol (TC) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in VLDL-C at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment. VLDL-C was calculated using direct test method.
Change From Baseline in Non-HDL-C at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoB at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoB-48 at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in Apolipoprotein B 100 (ApoB-100) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoA-1 at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoC-III at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoC-III: Chylomicron at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoC-III: VLDL at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoC-III: LDL at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in ApoC-III: HDL at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in Lipoprotein a (Lp[a]) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in Free Fatty Acid (FFA) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in Glycerol Levels at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in Lipoprotein Particle Size at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the Day 1 pre-dose fasting assessment. Lipoprotein Particle size included: HDL size, LDL size and VLDL size.
Change From Baseline in Hemoglobin A1c (HbA1c) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the last non-missing assessment prior to the first dose of study drug.
Change From Baseline in Homeostasis Model Assessment-Estimated Insulin Resistance (HOMA-IR)	Baseline and End of the Treatment (Week 27)	The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.
Change From Baseline in Adiponectin at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the Day 1 pre-dose fasting assessment.
Change From Baseline in and Leptin at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the Day 1 pre-dose fasting assessment
Change From Baseline in Hepatic Fat Fraction (HFF) as Assessed by Magnetic Resonance Imaging (MRI) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the last non-missing assessment prior to the first dose of study drug.
Changes From Baseline in Body Fat Distribution for Various Areas in the Body as Measured by Skinfold Thickness at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the last assessment prior to the first dose of study drug. Change in body fat distribution was measured as right anterior thigh skinfold thickness and right tricep skinfold thickness by Skinfold Thickness.
Changes From Baseline in Body Fat Distribution for Various Areas in the Body as Measured by Dual-Energy X-ray Absorptiometry (DEXA) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the Screening assessment. Change in body fat distribution (arm bone mass, arm fat mass, arm lean mass, arm total mass, leg bone mass, leg fat mass, leg lean mass, leg total mass, total bone mass, total fat mass, total lean mass, total total mass , trunk bone mass, trunk fat mass, trunk lean mass and trunk total mass) was measures obtained from DEXA.
Changes From Baseline in Body Fat Distribution for Total Bone Mineral Density in the Body as Measured by Dual-Energy X-ray Absorptiometry (DEXA) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as Screening assessment. Change in body fat distribution for total Bone mineral density was measures obtained from DEXA.
Change From Baseline in Visceral Adipose Tissue (VAT) as Measured by Magnetic Resonance Imaging (MRI) at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the last assessment prior to the first dose of study drug.
Change From Baseline in Subcutaneous Adipose Tissue (SAT) as MRI at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the last assessment prior to the first dose of study drug.
Change From Baseline in Body Weight at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the Day 1 pre-dose assessment.
Change From Baseline in Area Under the Curve (AUC) of Plasma Glucose as Assessed by Mixed Meal Test (MMT) at End of the Treatment	Baseline and End of the Treatment (Week 27)	Change from Baseline to Week 27 in the area under the curve (AUC) of Plasma Glucose was assessed.
Change From Baseline in Waist/Hip Ratio at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as screening assessment.
Change From Baseline in Quality of Life (QoL)	Baseline and End of the Treatment (Week 27)	The baseline was defined as the screening assessment. Quality of life measures the severity of fatigue, severity of trouble thinking or remembering and severity of waking up tired in participants, on a scale ranging from 0 to 3, where, 0= No problem, 1= Mild, 2= Moderate and 3= severe. Higher scores indicates more severity or more impact on quality of life.
Change From Baseline in Pain Score at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as a Screening assessment. Pain score is used to determine disease activity in participants, on a scale ranging from 0 to 5 where 0= never, 1= hardly noticed, 2= slightly, 3= moderately, 4= strongly, and 5= very strongly where higher scores indicated higher degree of pain.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From signing of informed consent to end of follow up period (Up to week 40)	An adverse event (AE) is any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A treatment-emergent adverse event (TEAE) is defined as any AE starting on or after the first dose of the study drug
Change From Baseline in Waist Circumference at End of the Treatment	Baseline and End of the Treatment (Week 27)	The baseline was defined as the Screening assessment.

Countries

United States

Participant flow

Recruitment details

This study was conducted at a single center in the United States of America from 15 June 2018 to 21 August 2019.

Pre-assignment details

A total of 8 participants diagnosed with familial partial lipodystrophy (FPL) were screened, out of which 4 participants were treated with AKCEA-ANGPTL3-LRx 20 milligrams (mg). All 4 participants completed the study.

Participants by arm

Arm	Count
AKCEA-ANGPTL3-LRx 20 mg Participants received AKCEA-ANGPTL3-LRx 20 mg administered every week for 26 weeks by SC injection.	4
Total	4

Baseline characteristics

Characteristic	AKCEA-ANGPTL3-LRx 20 mg
Age, Continuous	42.3 years STANDARD_DEVIATION 3.77
Area Under Curve (AUC) of Plasma Glucose	257 milligram/deciliterminute (mg/dLmin) STANDARD_DEVIATION 45.2622
AUC of Free Fatty Acid	1.57 milliequivalents/litermin (mEq/Lmin) STANDARD_DEVIATION 0.458
AUC of Gastric Inhibitory Polypeptide (GIP)	46.02 picograms/milliliterminute (pg/mLmin) STANDARD_DEVIATION 38.555
AUC of Glucagon-like Peptide 1 (GLP-1)	23.35 picomoles/literminute (pmol/Lmin) STANDARD_DEVIATION 17.065
AUC of Peptide Tyrosine Tyrosine (PYY)	80.412 pg/mL*min STANDARD_DEVIATION 99.559
AUC of Serum C-peptide	3.266 nanogram/milliliterminute (ng/mLmin) STANDARD_DEVIATION 1.234
AUC of Serum Ghrelin	27.955 pg/mL*min STANDARD_DEVIATION 15.127
AUC of Serum Insulin	42.625 milli international units/ liter*minute STANDARD_DEVIATION 4.852748
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Fasting Apolipoprotein A-I (Apo A-1)	121.3 mg/dL STANDARD_DEVIATION 9.67
Fasting Apolipoprotein B-48 (Apo B-48)	5.109 mg/dL STANDARD_DEVIATION 0.5588
Fasting Apolipoprotein B (ApoB)	124.95 mg/dL STANDARD_DEVIATION 24.972
Fasting Apolipoprotein C-III (Apo CIII)	28.435 mg/dL STANDARD_DEVIATION 11.8481
Fasting High Density Lipoprotein- Cholesterol (HDL-C)	25.13 mg/dL STANDARD_DEVIATION 3.473
Fasting Low Density Lipoprotein Cholesterol (LDL-C)	93.3 mg/dL STANDARD_DEVIATION 24.38
Fasting Non-High Density Lipoprotein- Cholesterol (Non-HDL-C)	223.4 mg/dL STANDARD_DEVIATION 22.03
Fasting Triglycerides (TG)	817.8 milligram per deciliter (mg/dL) STANDARD_DEVIATION 431.89
Fasting Very low Density Lipoprotein-Cholesterol (VLDL-C)	130.3 mg/dL STANDARD_DEVIATION 22.9
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	4 Participants
Sex: Female, Male Female	3 Participants
Sex: Female, Male Male	1 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 4
other Total, other adverse events	4 / 4
serious Total, serious adverse events	3 / 4

Outcome results

Primary

Percent Change From Baseline in Fasting Triglycerides Levels at End of the Treatment (Week 27)

The baseline was defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment.