Phase 3 Study to Evaluate the Efficacy and Safety of ARO-APOC3 in Chinese Adults With Familial Chylomicronemia Syndrome
Overview
- Phase
- Phase 3
- Intervention
- VSA001 injection
- Conditions
- Familial Chylomicronemia Syndrome
- Sponsor
- Visirna Therapeutics HK Limited
- Enrollment
- 37
- Locations
- 1
- Primary Endpoint
- Change of Fasting Triglyceride (TG) by Month 10
- Status
- Active, not recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
This is a randomized, double-blinded, placebo controlled, two periods phase 3 clinical study. The primary objective of the study is to evaluate the efficacy and safety of VSA001 injection in Chinese adults with familial chylomicronemia syndrome (FCS). A total of approximately 30 participants will be enrolled in the study.
Detailed Description
Familial chylomicronemia syndrome (FCS) is a severe and ultrarare genetic disease, with a prevalence of approximately 1 in 1,000,000, often caused by various monogenic mutations. FCS leads to extremely high fasting triglyceride (TG) levels, typically over 900 mg/dL. Such severe elevations lead to various serious signs and symptoms including acute pancreatitis (which can be fatal), chronic daily abdominal pain, type 2 diabetes mellitus, hepatic steatosis, and cognitive issues. APOC3 is an 8.8 kilodalton (kDa) protein component of triglyceride-rich lipoproteins (TRLs) such as very-low-density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL-C), chylomicrons, high-density lipoprotein cholesterol (HDL-C), and remnant particle lipoproteins. APOC3 is synthesized predominantly in hepatocytes. It inhibits the hydrolysis of TG on TRLs at the muscle and adipose tissue capillary level through inhibition of lipoprotein lipase (LPL), and delays clearance of lipoprotein remnants by the liver by inhibiting hepatocyte receptor-mediated uptake. APOC3 functions as a key regulator of fasting and postprandial plasma TG levels. VSA001 is a synthetic, double-stranded, hepatocyte-targeted RNA interference (RNAi) trigger (also referred to as a small interfering RNA \[siRNA\]) designed to specifically silence messenger RNA (mRNA) transcripts from the APOC3 gene using an RNAi mechanism. Given the important role of APOC3 in serum TG level modulation and its primary source of synthesis in hepatocytes, reduction of APOC3 through a hepatocyte-targeted RNAi strategy is likely to reduce circulating TG, benefiting several patient populations, including patients with FCS.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Males or nonpregnant (who do not plan to become pregnant), nonlactating females ≥18 years of age
- •Able and willing to provide written informed consent prior to the performance of any study-specific procedures
- •Fasting TG ≥10 mmol/L (\~880 mg/dL) at screening, that is refractory to standard lipid lowering therapy (sample drawn after at least the minimum time on stable lipid-lowering regimen described in protocol). Two repeat tests are allowed to qualify.
- •A diagnosis of FCS based on a documented history of fasting TG levels in excess of 1000 mg/dL on repeated testing (for at least one prior occasions), and at least one of the following:
- •A supportive genetic test (from a source-verifiable medical record or based on screening genotype). Supportive genetic testing includes but is not limited to homozygous, compound heterozygous, or double heterozygote for loss-of-function or otherwise inactivating mutations in genes affecting lipoprotein lipase activity including LPL, APOC2, APOA5, GPIHBP1, GPD1, or LMF1; or evidence of low LPL activity (\<20% of normal) based on source-verifiable documentation; or
- •Documented history of recurrent episodes of acute pancreatitis, not caused by alcohol or cholelithiasis; or
- •Documented history of recurrent hospitalizations for severe abdominal pain without other explainable cause; or
- •Documented history of childhood pancreatitis; or
- •Family history of hypertriglyceridemia-induced pancreatitis
- •Willing to follow dietary counseling as per PI judgment based on local standard of care, consistent with an intake of ≤20 g of fat per day during the study
Exclusion Criteria
- •Current use or use within the last 365 days from Day 1 of any hepatocyte-targeted siRNA or antisense oligonucleotide molecule
- •Diabetes mellitus with any of the following:
- •Newly diagnosed within 12 weeks of screening
- •HbA1c ≥9.0% at screening
- •Active pancreatitis within 12 weeks before Day 1
- •History of acute coronary syndrome event within 24 weeks of Day 1
- •History of major surgery within 12 weeks of Day 1
- •Any of the following laboratory values at screening:
- •ALT or AST ≥3×ULN at screening
- •Total bilirubin ≥1.5×ULN (if the participant has a prior diagnosis and documentation of Gilbert's syndrome, then total bilirubin must be ≤3 mg/dL at screening)
Arms & Interventions
VSA001 25 mg
VSA001 25 mg every 3 months
Intervention: VSA001 injection
VSA001 25 mg matching placebo
VSA001 25 mg matching placebo，every 3 months
Intervention: Placebo
VSA001 50 mg
VSA001 50 mg every 3 months
Intervention: VSA001 injection
VSA001 50 mg matching placebo
VSA001 50 mg matching placebo，every 3 months
Intervention: Placebo
Outcomes
Primary Outcomes
Change of Fasting Triglyceride (TG) by Month 10
Time Frame: Baseline, month 10
Percent change from baseline at Month 10 in fasting TG
Secondary Outcomes
- Change of Fasting TG at Months 10 and 12 (Averaged)(Baseline, Months 10 and 12 (averaged))
- Change of Fasting APOC3 by Month 10(Baseline, month 10)
- Change of Fasting APOC3 by Month 12(Baseline, month 12)
- Change of Fasting Serum Non-high Density Lipoprotein Cholesterol (Non-HDL-C) and HDL-C by Month 10(Baseline, month 10)
- Change of Fasting Serum TG, Non-HDL-C, and HDL-C by Month 12(Baseline, Month 12)
- Participants Achieving Fasting Serum TG of <500 mg/dL at Month 10(Month 10)
- Participants Achieving Fasting Serum TG of <500 mg/dL at Month 12(Month 12)
- Change From Baseline at Each Scheduled Assessment in Fasting Serum TG up to Month 12(From baseline up to Month 12)
- Percent Change From Baseline at Each Scheduled Assessment in Fasting Serum TG up to Month 12(From baseline up to Month 12)
- Incidence of TEAEs in the Participants(From treatment with VSA001 to 12 months)
- Incidence of Positively Adjudicated Events of Acute Pancreatitis(From treatment with VSA001 to 12 months)