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19 December 2019
ANGPTL3 monoclonal antibody in hypertriglyceridemia

Evinacumab, a monoclonal antibody to ANGPTL3 (angiopoietin-like protein 3), produced substantial and sustained reduction in triglycerides in Phase I trials in patients with mild to moderate hypertriglyceridaemia.

Ahmad Z, Banerjee P, Hamon S et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation 2019; DOI: 10.1161/CIRCULATIONAHA.118.039107
Summary
Comments & References
STUDY SUMMARY
Objective: To evaluate the safety and efficacy of single and multiple ascending doses of evinacumab in subjects with mild to moderately elevated triglycerides (TG) and/or low-density lipoprotein cholesterol (LDL-C).
Study design: Two phase I studies: 1)  first-in-human, randomized, single ascending dose, placebo-controlled, double-blind study (evinacumab 75, 150, or 250 mg subcutaneously [SC], or 5, 10, or 20 mg/kg intravenously [IV]), trial identifier, NCT01749878, and 2) randomized, double-blind, placebo-controlled, multiple ascending dose study (evinacumab 150, 300, or 450 mg SC once weekly, 300 or 450 mg every 2 weeks, or 20 mg/kg IV once every 4 weeks up to day 56), trial identifier, NCT02107872.
Study population: The single dose study included healthy men and women with mixed dyslipidaemia (defined as elevated TG [150 to 450 mg/dL] or LDL-C [≥100 mg/dL]). The multiple dose study included healthy men and women with elevated TG (150 to 500 mg/dL inclusive) and LDL-C (≥100 mg/dL).
Efficacy variables:

· Safety and tolerability, as assessed by spontaneously reported adverse events (AEs), physical examination, vital signs, electrocardiogram data, and clinical evaluation. Acute administration reactions were defined as any AE that occurred during study drug administration or within 2 hours post-dose.

· Lipids levels over time: TG, very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, LDL-C, lipoprotein(a), HDL-C, apo A1, and total cholesterol.

Methods:

Single dose study: The study comprised a screening period (day −21 to day −2), a baseline visit, and treatment and observation periods. Patients were randomized at baseline (3:1 (evinacumab: placebo) to one of six sequential ascending-dose levels: three SC (75, 150, or 250 mg) and three IV (5, 10, or 20 mg/kg). Both SC and IV dose levels were divided into 2 cohorts based on the subjects’ lipid parameters at screening. Up to 12 subjects received evinacumab and 4 received placebo.  Subjects remained in the clinic until day 4 assessments had been completed, and returned to the clinic for outpatient visits at days 8, 11, 15, 22, 29, 43, 64, 85, and 106 (end of study) for the first four doses, and 8, 11, 15, 22, 29, 43, 64, 85, and 126 for the last two doses.

Multiple dose study: The study comprised three periods: screening (day −21 to day −2), double-blind treatment, and follow-up. At baseline, subjects were allocated to six cohorts of evinacumab dose level and regimen. Within each cohort, 8 subjects were randomized at an evinacumab:placebo ratio of 3:1. Subjects remained in the clinic until day 3 assessments had been completed, and returned to the clinic for outpatient visits at days 8, 15, 22, 29, 36, 43, 50, 57, 78, 99, 120, 141, 162, and 183 (end of study). The study treatment ended on day 50 for cohorts 1, 3, and 5, on day 43 for cohorts 2 and 4, and on day 29 for cohort 6.

Results:

Single dose study:

83 subjects were enrolled and randomized, 62 to evinacumab and 21 to placebo; all were included in safety analyses.

· No dose-limiting toxicities were observed.

· Treatment-emergent AEs were reported for 32 (51.6%) subjects in the evinacumab group and 9 (42.9%) in the placebo group; none were serious or led to treatment discontinuation.

· Single elevations in alanine aminotransferase (ALT) were reported for 7 (11.3%) subjects, aspartate aminotransferase (AST) for 4 (6.5%) subjects, and creatinine phosphokinase (CPK) 2 (3.2%) subjects. These were not dose related. No elevations in ALT, AST or CPK were reported for placebo.  

· Dose-dependent reduction in TG was observed; the maximum reduction was 76.9% at day 3 with 10 mg/kg IV.

Multiple dose study:

In total, 56 subjects (46 in the SC regimen, 10 in the IV regimen) were randomized, of whom 52 (43 SC, 9 IV) received study treatment. Nine subjects withdrew prematurely from the study: 7 (15.2%) SC and 2 (20.0%) IV. The primary reasons for study discontinuation were investigator/sponsor decision and withdrawal of consent.

· Overall, 21 (67.7%) subjects on SC evinacumab versus 9 (75.0%) on placebo and 6 (85.7%) on IV evinacumab versus 1 (50.0%) on placebo reported treatment-emergent AEs.  None were serious or led to treatment discontinuation.

· Single elevation in CPK was reported for one patient.

· Median reductions in TG at day 57 were ~70% for evinacumab 300 mg weekly SC, 450 mg weekly SC, and 20 mg/kg IV. The maximum reduction in TG was 83.1% at day 2 with 20 mg/kg IV once every 4 weeks.

Conclusion: Evinacumab was well-tolerated in two Phase 1 studies. Lipid changes in hypertriglyceridaemic subjects were similar to those observed with ANGPTL3 loss-of-function mutations. Because the latter is associated with reduced cardiovascular risk, ANGPTL3 inhibition may improve clinical outcomes.

COMMENT

Current therapeutic options for managing elevated TG are limited. Beyond statins, these include the fibrates (peroxisome proliferator-activated receptor alpha agonists) and omega-3 fatty acids; while effective, clinical use may be limited by side effects and drug-drug interactions.1 New options are clearly needed, particularly in the light of accumulating evidence that elevated TG, a marker for TG-rich lipoproteins and their remnants, contribute to the residual cardiovascular risk that persists in statin-treated patients.2,3

 Of a number of potential targets for therapeutic intervention, ANGPTL3, which plays a role in the regulation of plasma lipid metabolism by controlling three major lipid traits - LDL-C, HDL-C, and TG - has attracted attention.4 ANGPTL3 primarily acts to inhibit lipoprotein lipase, which hydrolyzes triglyceride in circulating triglyceride-rich lipoproteins, and also inhibits endothelial lipase to modulate HDL-C metabolism. Previous studies have identified associations between loss-of-function genetic variants in the ANGPTL3 gene and low levels of plasma LDL-C, HDL-C, and triglycerides,5-7 as well as reduced risk of coronary heart disease in humans.8  These findings provided a rationale for the development of novel therapeutic strategies targeting ANGPTL3.

 Evinacumab is a fully human monoclonal antibody therapy directed against ANGPTL3. In previous studies, evinacumab reduced TG, non-HDL-C, and LDL-C in healthy human volunteers, as well as in patients with homozygous familial hypercholesterolemia,9,10 although in the latter case, the mechanism(s) remain(s) indeterminate. The findings from the current study show the safety, tolerability and TG-lowering efficacy of evinacumab in patients with mild to moderately elevated TG, and thus support further development of this novel agent in larger studies in this clinical setting.

References

1. Florentin M, Kostapanos MS, Anagnostis P, Liamis G. Recent developments in pharmacotherapy for hypertriglyceridemia: what's the current state of the art? Expert Opin Pharmacother 2019:1-14.

2. Toth PP, Granowitz C, Hull M, et al. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018;7:e008740.

3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35

4. Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat Rev Endocrinol 2017;13:731-9.

5. Willer C.J., Sanna S., Jackson A.U. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–9.

6. Musunuru K, Pirruccello JP, Do R. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010;363:2220–7.

7. Romeo S, Yin W, Kozlitina J. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009;119:70–79

8. Stitziel NO, Khera AV, Wang X. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054–2063

9. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017;377:211–221.

10. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017;377:296–297.

Key words   hypertriglyceridemia; evinacumab; angiopoietin-like protein 3; residual cardiovascular risk