Long-term treatment with PCSK9 is safe and reduces LDL-c in in pediatric HeFH patients
Paediatric patients with heterozygous familial hypercholesterolaemia treated with evolocumab for 80 weeks (HAUSER-OLE): a single-arm, multicentre, open-label extension of HAUSER-RCT
Introduction and methods
The HAUSER-RCT study showed that in pediatric patients with heterozygous familial hypercholesterolemia (HeFH), treatment with the PCSK9 inhibitor evolocumab for 24 weeks is safe and reduces LDL-c and other lipid parameter levels, compared with placebo . However, it is unclear whether long-term treatment with evolocumab is safe and effective in pediatric patients with HeFH.
Aim of the study
The aim of this study was to evaluate the safety and efficacy of long-term treatment with evolocumab in pediatric patients with HeFH.
This 80-week open-label extension study (HAUSER-OLE) was a follow-up to the HAUSER-RCT study. In this previous multicenter, double-blind, placebo-controlled phase 3 study, 157 pediatric patients with HeFH were randomized (2:1) to monthly, subcutaneous administration of evolocumab 420 mg or placebo for 24 weeks. Inclusion criteria were: age 10-17 years, HeFH by genetic testing or according to clinical diagnostic criteria and LDL-c levels ≥3.4 mmol/L, triglyceride levels ≤4.5 mmol/L and optimized statin therapy at screening.
Patients were eligible to participate in the HAUSER-OLE study if they had been treated with evolocumab or placebo for 24 weeks and no serious treatment-emergent adverse events (TEAEs) had occurred during treatment. In this single-arm study, 150 patients received monthly open-label evolocumab 420 mg subcutaneously for 80 weeks, in addition to statin therapy with or without ezetimibe.
The primary endpoint was the incidence of TEAEs. The secondary endpoint was efficacy, assessed by percentage and absolute changes in the levels of LDL-c, other lipid parameters (including non-HDL-c and apolipoprotein B) and PCSK9 between the start of the HAUSER-RCT study and the end of the HAUSER-OLE study (a total of 104 weeks).
- At least one TEAE occurred in 105 (70%) of 150 patients: 36 (74%) of 49 patients in the placebo-evolocumab group and 69 (68%) of 101 patients in the evolocumab-evolocumab group.
- Most TEAEs were of CTCAE grade 1 or 2.
- TEAEs occurring in 5% or more of patients were: nasopharyngitis (15%), headache (9%), influenza-like illness (9%), gastroenteritis (7%), upper respiratory tract infection (6%), oropharyngeal pain (6%), and fatigue (5%).
- Serious TEAEs occurred in 4 (3%) of 150 patients: 2 (4%) of 49 patients in the placebo-evolocumab group (perforated appendicitis and peritonitis in one patient, a wrist fracture in another) and 2 (2%) of 101 patients in the evolocumab-evolocumab group (anorexia nervosa in one patient, headache in another); none of the serious TEAEs was considered related to evolocumab.
- None of the TEAEs led to treatment discontinuation and no deaths occurred.
- The mean percentage and absolute change in LDL-c levels from the baseline of the HAUSER-RCT study to the end of the HAUSER-OLE study was -35.3% (SD: 28.0) and -1.7 mmol/L (SD: 1.4), respectively; the reduction in LDL-c levels was similar between the placebo-evolocumab and evolocumab-evolocumab groups.
- The other lipid parameters also improved during the treatment period, with similar patterns across the placebo-evolocumab and evolocumab-evolocumab groups.
- The mean percentage and absolute change in PCSK9 levels from the baseline of the HAUSER-RCT study to the end of the HAUSER-OLE study was -40.0% (SD: 46.7) and -1.7 mmol/L (SD: 1.8), respectively; the reduction in PCSK9 levels was similar between the placebo-evolocumab and evolocumab-evolocumab groups.
This open-label extension study (HAUSER-OLE) showed that monthly subcutaneous administration of evolocumab 420 mg for up to 104 weeks, in addition to statin therapy with or without ezetimibe, in pediatric patients with HeFH was safe, well tolerated and resulted in a reduction of LDL-c and other lipid parameter levels.