Longer-term treatment with PCSK9 antibody safely lowers LDL-c in HoFH patients
Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study
Untreated patients with homozygous familial hypercholesterolaemia (HoFH) have substantially reduced clearance of plasma LDL cholesterol, and consequently typically their LDL-c concentrations can be greater than 13 mmol/L. A reduction of almost 90% is needed to reach the goal of <1.8 mmol/L, recommended for those with very high CVD risk [1,2].
In addition to modestly effective conventional therapy such as statins and ezetimibe, LDL apheresis can be used, when available. Inhibitors of apolipoprotein B synthesis (mipomersen) and microsomal triglyceride transfer protein (lomitapide) can yield additional LDL-c lowering, but their use is hampered by substantial side-effects, high costs and poor long-term adherence [3-5]. Moreover, even with these drugs, LDL-c concentrations in HoFH patients remain far from optimal, and apheresis is still frequently required.
The PCSK9-directed antibody evolocumab (given 420 mg monthly) has been shown to reduce LDL-c by 31% compared with placebo, in HoFH patients . This is an interim analysis of the ongoing open-label TAUSSIG study evaluating the long-term safety and efficacy of evolocumab in a subset of study participants with HoFH (n=106, 105 with genetic diagnosis) receiving evolocumab, with (n=34) or without apheresis (n=72). The TAUSSIG study will follow patients for 5 years, but in the current analysis, patients received a minimum of 12 weeks, and mean study exposure was 1.7 years (SD: 0.63). Patients received evolocumab 420 mg every month, or every 2 weeks if on apheresis, immediately after apheresis. After 12 weeks, in those not on apheresis, the dose could be increased to 420 mg every 2 weeks at the investigators’ discretion.
- Overall, evolocumab treatment resulted in significant reductions of LDL-c by 20.6% (SD: 24.4) at week 12 (mean absolute reduction from baseline: 1.50 mmol/L, SD: 1.92) and by 23.3% (SD: 30.8) at week 48 (mean absolute change: 1.79 mmol/L, SD: 2.31).
- The 47 patients not on apheresis, who increased evolocumab dosing to every 2 weeks showed an additional mean reduction of 8.3% (SD: 13.0, mean absolute decrease: 0.77 mmol/L, SD: 1.38).
- Patients on apheresis had lower baseline LDL-c and apolipoprotein B concentrations, but not lipoprotein(a). Patients in the apheresis group had more severe mutations in LDLR.
- In the 34 patients receiving apheresis and bi-weekly evolocumab, mean LDL-c reduction at week 12 was 17.3% (SD: 28.4), as compared with 22.2% (SD: 22.3%) in the 72 patients receiving only drug therapy and monthly evolocumab.At week 48, a 15.8% (SD: 25.8) LDL-c reduction was seen in the apheresis group, as compared with 26.7% in the non-apheresis group.
LDL-c reductions in those on apheresis at week 12 and 48 did not significantly differ from reductions achieved in those only receiving drug therapy.
- Four patients receiving apheresis reduced the frequency to a monthly procedure or less, and two patients discontinued apheresis (one for over 2 years). Two persons in the non-apheresis group started apheresis therapy.
- Changes in apolipoprotein B levels paralleled those of LDL-c, with a greater reduction at week 48 than at week 12. Smaller decreases in lipoprotein(a) were seen, but changes were not significant in those on apheresis.
- HDL-c showed significant increases of 5.0-8.9% at both week 12 and 48, similar for both treatment groups.
- In 48 receptor-defective patients, the mean LDL-c reduction was 20.0% (SD: 19.6) at week 12 and 23.9% (SD: 21.9) at week 48. Eight patients who were receptor negative showed a poor response to evolocumab.
- Evolocumab was generally well tolerated. The reported treatment-emergent adverse events in 82 (77%) patients were mostly minor (nasopharyngitis, influenza, headache, upper respiratory tract infection), and their frequency did not differ between those who did and did not receive apheresis. Injection-site reactions occurred more often in those undergoing apheresis, mostly due to a higher number of study visits.
This interim analysis represents the largest and longest study of lipid-lowering medication in HoFH patients to date, the results of which support the long-term tolerability and safety of the PCSK9 antibody evolocumab. 95% of patients were still in the study at 48 weeks. Evolocumab substantially reduced LDL-c concentrations in HoFH patients on standard lipid-lowering therapy, with or without apheresis.
The study also describes treatment of adolescent patients, who showed a decreased treatment response, but numbers were low.