Background:
Hypertriglyceridemia (HTG) increases the risk of acute pancreatitis and atherosclerosis. In a Phase 1 study (NCT03783377), single subcutaneous doses of investigational RNA interference (RNAi) therapeutic ARO-APOC3 (10, 25, 50, and 100 mg; N=24) demonstrated deep and prolonged reductions in apolipoprotein C3 (APOC3) and triglycerides (TG) and increases in HDL-C in healthy volunteers with good tolerability, compared with placebo (N=16).
Purpose:
We report initial results of the effects of ARO-APOC3 in patients with HTG (fasting TG ≥ 300 mg/dL) or multifactorial chylomicronemia (MCM; fasting TG ≥ 880 mg/dL).
Methods:
Up to 40 subjects with HTG and 20 subjects with MCM will receive ARO-APOC3 or placebo on days 1 and 29. Pharmacodynamic responses include serum APOC3, TG, and other lipid parameters reported up to week 4 prior to the 2
nd
dose.
Results:
At the data cutoff (16 March 2020), the first 4 enrolled patients with HTG and 6 enrolled patients with MCM were administered ARO-APOC3 50 mg. ARO-APOC3 substantially reduced mean (range) APOC3 levels by 96% (88-99%) in both patient groups at Week 4 (Table). ARO-APOC3 substantially reduced mean (range) TG by 78% (67-87%) in HTG patients and by 92% (90-95%) in MCM patients at Week 4. Three of 4 HTG patients and 3 of 6 MCM patients had TG levels below 150 mg/dL. All MCM patients had TG ≤ 500 mg/dL. To date, ARO-APOC3 has been generally well tolerated with no reports of treatment-related serious or severe adverse events. Two of the 6 unblinded MCM patients experienced a transient ALT elevation to >3X ULN that returned to approximate pre-dose baseline by Day 113.
Conclusions:
Preliminary results indicate that a single dose of ARO-APOC3 reduces APOC3 levels by >90% and TG by ~80% 4 weeks after treatment in patients with HTG and MCM. The magnitude of treatment effect was similar in both populations and ARO-APOC3 had a favorable safety profile. Using RNAi to silence expression of APOC3 appears promising for treating patients with HTG and MCM.
Background:
Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administered ARO-APOC3 reduced serum apolipoprotein C3 (APOC3) and TG in healthy volunteers and participants (pts) with HTG and was well tolerated.
Purpose:
To report on the safety/pharmacodynamic (PD) effects of ARO-APOC3 in both FCS pts with biallelic pathogenic variants and pts with severely elevated TG at screening (>880 mg/dL) but without biallelic pathogenic variants (chylomicronemia (MCM)).
Methods:
Four genetically confirmed FCS pts received 50 mg ARO-APOC3 and 26 MCM pts received 10, 25, 50, or 100 mg ARO-APOC3 on Days 1 and 29. Since similar PD responses were observed among MCM pts, results were pooled across dose levels. Safety and PD responses were examined. Maximal mean/median changes from baseline for APOC3, TG, non-HDL-C, and HDL-C were reported.
Results:
Baseline/demographics were comparable between groups, except for mean BMI (22.1 [FCS] and 30.5 [MCM] kg/m
2
), and mean baseline HDL-C , which were lower in FCS pts (Table 1) (p<0.0001 for both). Mean APOC3 was reduced by 98% and 96% in FCS and MCM pts, respectively. Both groups also showed similar maximum median reductions in TG of 91% and 90%, respectively. Similar to the full study, non-HDL-C was reduced and HDL-C increased with treatment in both groups (Table 1). AEs were similar between groups, suggesting a comparable safety profile.
Conclusions:
In patients with severe HTG, ARO-APOC3 was safe, and consistently decreased APOC3, TG, and non-HDL-C, and increased HDL-C, regardless of underlying genetic cause of HTG, and may represent a promising RNAi therapeutic for the treatment of severe HTG.
Background
NVX-CoV2373 is an efficacious COVID-19 vaccine comprising full-length 5-µg recombinant SARS-CoV-2 spike (rS) glycoprotein and Matrix-M™ adjuvant. Phase 2 of a randomized, placebo-controlled, phase 1/2 trial in healthy adults (18-84 years) previously reported good safety/tolerability and robust humoral immunogenicity.
Methods
Participants were randomized to placebo or 1 or 2 doses of 5-µg or 25-µg rS with 50 µg Matrix-M adjuvant 21 days apart. CD4+ T-cell responses to SARS-CoV-2 intact S or pooled peptide stimulation (with ancestral or variant S sequences) were measured via enzyme-linked immunosorbent spot (ELISpot) assay and intracellular cytokine staining (ICCS).
Results
A clearly discernable spike antigen-specific CD4+ T-cell response was induced after 1 dose, but markedly enhanced after 2 doses. Counts and fold-increases in cells producing Th1 cytokines exceeded those secreting Th2 cytokines, although both phenotypes were clearly present. Interferon-γ responses to rS were detected in 93.5% of 2-dose 5-µg recipients. A polyfunctional CD4+ T-cell response was cross-reactive and of equivalent magnitude to all tested variants, including Omicron BA.1/BA.5.
Conclusions
NVX-CoV2373 elicits a moderately Th1-biased CD4+ T-cell response that is cross-reactive with ancestral and variant S proteins after 2 doses.
Clinical Trial Registration
NCT04368988.
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