Familial Chylomicronemia Syndrome
Conditions
Interventions
ISIS 678354 or placebo will be administered as subcutaneous (SC) injections.
Doses of 50 mg or 80 mg once every 4 weeks were chosen based on the
pre-clinical data and the pharmacodynamic and safety
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Inclusion criteria
Inclusion criteria: 1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements 2. Aged >= 18 years at the time of informed consent 3. A diagnosis of Familial Chylomicronemia Syndrome (type 1 Hyperlipoproteinemia) by documentation of confirmed homozygote, compound heterozygote or double heterozygote for loss-of-function mutations in type 1-causing genes (such as LPL, GPIHBP1, APOA5, APOC2, GPD1, or LMF1) 4. Fasting TG >= 880 mg/dL (10 mmol/L) at Screening. If the fasting TG is 55 years of age or, in females <= 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved) iii. abstinent* or iv. if engaged in sexual relations of child-bearing potential, agree to use a highly effective contraceptive method from the time of signing the informed consent form until at least 17 weeks after the last dose of Study Drug (ISIS 678354 or placebo) b. Males: Surgically sterile, abstinent*, or if engaged in sexual relations with a female of child-bearing potential, patient is utilizing a highly effective contraceptive method from the time of signing the informed consent form until at least 17 weeks after the last dose of Study Drug (ISIS 678354 or placebo) * Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception 9. Atypical antipsychotic medications (e.g., olanzapine and clozapine) will be allowed if on a stable dose for at least 3 months prior to Screening and dose and regimen expected to remain constant through the end of their participation in this study 10. The following concomitant medications will be allowed if on a stable dose for at least 4 weeks prior to Screening and dose and regimen expected to remain constant through the end of their participation in this study (occasional or intermittent use of over-the-counter (OTC) medications will be allowed at Investigator*s discretion):
Exclusion criteria
Exclusion criteria: 1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening) or physical examination 2. Active pancreatitis within 4 weeks prior to Screening 3. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion: a. Platelet count 3.0 × upper limit of normal (ULN) c. Total bilirubin > ULN unless due to Gilbert*s syndrome d. Estimated GFR= 500 mg/g or urine albumin/creatinine ratio (UACR) >= 300 mg/g 4. Uncontrolled arterial hypertension (blood pressure [BP] > 160/100 mmHg) 5. History of bleeding diathesis or coagulopathy or clinically significant abnormality in coagulation parameters at Screening 6. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 or active Covid-19 infection with or without therapy that will not be resolved by Study Day 1. 7. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B diagnosed by initial serological testing and confirmed with RNA testing, or prior treatment for hepatitis C. Patients at Screening who test positive by serology, but negative by RNA may be allowed in consultation with the Sponsor Medical Monitor 8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor 9. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 60 days of Screening 10. Treatment with another investigational drug (non-oligonucleotide), biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 11. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening, or 5 half-lives, whichever is longer. This exclusion does not apply to vaccines. 12. Concomitant medication/procedure restrictions: a. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Screening and during the study unless approved by the Sponsor Medical Monitor b. Plasma apheresis within 4 weeks prior to Screening or planned during the study 13. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 14. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the Study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is the percent change in fasting TG from Baseline at 6 months (average of Weeks 23, 25 and 27) compared to placebo | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints include the following: • Percent change in fasting TG from Baseline at 12 months (average of Week 51 and Week 53) compared to placebo • Proportion of patients who achieve >= 40% reduction in fasting TG from baseline at 6 months compared to placebo • Percent change in fasting apoB-48 from Baseline at 6 months compared to placebo • Proportion of patients who achieve fasting TG = 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment • Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 through Week 53) compared to placebo • Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo in patients with >= 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment • Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo • Proportion of patients who achieve >= 70% reduction in fasting TG from Baseline at 6 months compared to placebo • Proportion of patients who achieve fasting TG | — |
Countries
Netherlands
Outcome results
None listed