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mipomersen

Phase 3

Lipid Metabolism, Inborn Errors | Small molecule | Rare Disease |Ionis Pharmaceuticals, Inc.|Last Updated: Oct 21, 2016

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
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Trial Design
RandomizedDouble-BlindPLACEBO_CONTROLLEDDMCBiomarker
Total Trials4
Total Enrollment254
FDA Designations
No designations recorded
Clinical Trials (4)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT00694109An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-HypercholesterolemiaPHASE3 COMPLETED 144Apr 1, 2008Sep 1, 2014Sep 9, 201633 United States, Brazil +5
NCT00607373Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial HypercholesterolemiaPHASE3 COMPLETED 51Jul 1, 2007Mar 1, 2009Sep 9, 201610 United States, Brazil +5
NCT00477594Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial HypercholesterolemiaPHASE2 COMPLETED 21May 1, 2007Jul 1, 2011Sep 9, 20165 United States
NCT00362180Measure Liver Fat Content After ISIS 301012 (Mipomersen) AdministrationPHASE2 COMPLETED 38Jul 1, 2006Sep 1, 2010Oct 21, 20161 Netherlands
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Study Endpoints
Primary Endpoints
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C)
Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)

Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \>=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \<6 months from their last dose of mipomersen in their index study).

Percent Change From Baseline in Apolipoprotein B (Apo B)
Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)

Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \>=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \<6 months from their last dose of mipomersen in their index study).

Percent Change From Baseline in Total Cholesterol
Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)

Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \>=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \<6 months from their last dose of mipomersen in their index study).

Percent Change From Baseline in Non High Density Lipoprotein Cholesterol (Non-HDL-C)
Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)

Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \>=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered \<6 months from their last dose of mipomersen in their index study).

Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28

LDL-C was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides \<400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides \>=400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. If the Study Day 1 and screening LDL-C values were \>12% different (relative to the maximum value), then the screening value was not used, because the Study Day 1 value represents the best estimate of the patient's condition at the beginning of study drug administration. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

LDL-C at Baseline and the Primary Efficacy Time Point (PET)
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28

The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
Baseline and Weeks 52 and 104

LDL cholesterol was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides \<400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Low-density Lipoprotein Cholesterol (LDL-C) Over Time
Baseline and Weeks 52 and 104.

Samples were taken following an overnight fast. For patients with triglycerides \<400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Change From Baseline in Liver Triglyceride (TG) Content As Measured by Magnetic Resonance Spectroscopy (MRS)
Baseline, Day 26, Day 99

Localized proton MRS was used to quantify liver TG concentration. All MRS imaging of the liver was performed using the same 1.5T scanner. The instructions were to cover the entire liver (from just above the dome to just below the inferior tip) using a qualified imaging technique (Yokoo, 2009, Radiology). Liver fat quantification was performed by determining the liver fat fraction (%) derived from MRS using selected Regions of Interest (ROI). The analyst typically looked for the branching of the right portal vein and mapped slices from one scan to the next. There were typically 2 ROIs in the right lobe and 1 in the left lobe. Magnetic resonance spectroscopy imaging ROIs between different scans were selected using anatomical landmarks for both time points.

Secondary Endpoints
Percent Change From Baseline in Triglycerides
Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Lipoprotein (a)
Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in LDL Particles' Size (Total)
Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
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Study Design & Arms
AllocationNA
MaskingNONE
ModelSINGLE_GROUP
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
MipomersenEXPERIMENTALMipomersen Sodium once a week for up to 4 years (depending on participant's consent). Participants were followed for additional 24 week post-treatment.
PlaceboPLACEBO_COMPARATORParticipants received placebo as a subcutaneous injection once a week for 26 weeks.
Mipomersen 200 mg per weekEXPERIMENTALParticipants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.
Mipomersen 200 mg every other weekEXPERIMENTALParticipants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Cohort A: mipomersenEXPERIMENTALHealthy volunteers treated with 6 injections of mipomersen 200 mg over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22.
Cohort A: placeboPLACEBO_COMPARATORHealthy volunteers treated with 6 injections of placebo over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22.
Cohort D: mipomersenEXPERIMENTALParticipants with impaired fasting glucose and mixed dyslipidemia who were treated with 6 injections of mipomersen 200 mg over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22.
Cohort D: placeboPLACEBO_COMPARATORParticipants with impaired fasting glucose and mixed dyslipidemia who were treated with 6 injections of placebo over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22.
Cohort E: mipomersenEXPERIMENTALParticipants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly mipomersen 200 mg injections for 13 weeks.
Cohort E: placeboPLACEBO_COMPARATORParticipants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly placebo injections for 13 weeks.
Cohort F: no interventionNO_INTERVENTIONA reference group of participants with familial hypobetalipoproteinemia (FBHL) who did not receive a study intervention. Data gathered for 15 weeks.
Cohort G: mipomersenEXPERIMENTALParticipants with well-controlled Type 2 diabetes mellitus, hypercholesterolemia, and normal triglyceride levels were treated with mipomersen 200 mg weekly for 26 weeks, followed by open-label mipomersen 200 mg weekly for an additional 26 weeks.
Cohort G: placebo followed by mipomersenPLACEBO_COMPARATORParticipants with well-controlled Type 2 diabetes mellitus, hypercholesterolemia, and normal triglyceride levels were treated with placebo weekly for 26 weeks, followed by open-label mipomersen 200 mg weekly for an additional 26 weeks.
Interventions
NameTypeDescription
Mipomersen SodiumDRUGSubcutaneous injection as a single injection directly into the abdomen, thigh, or outer area of the upper arm.
mipomersenDRUG200 mg mipomersen administered once a week for 26 weeks as a 1 mL subcutaneous injection. Subjects weighing less than 50 kg received a lower dose of 160 mg (0.8mL) mipomersen.
PlaceboDRUG1 mL subcutaneous injection once a week for 26 weeks. Subjects weighing less than 50 kg received 0.8 mL subcutaneous injection.
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Eligibility Criteria
Age Range12 Years — N/A
SexALL
Healthy VolunteersNo
Study Sites33

Inclusion Criteria: * Satisfactory completion of dosing in their initial study (Protocol 301012-CS5 \[NCT00607373\], 301012-CS7 \[NCT00706849\], 301012-CS17 \[NCT00477594\], or MIPO3500108 \[NCT00794664\]) Exclusion Criteria: * Had any new condition or worsening of existing condition which in the...

Countries:United StatesBrazilCanadaSingaporeSouth AfricaTaiwanUnited KingdomNetherlands
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