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

Literature - Raal FJ, Hovingh GK, Blom D, et al., - Lancet Diabetes Endocrinol. 2017 Feb 16. doi: 10.1016/S2213-8587(17)30044-X

Background

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 [6]. 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.

Main results

  • 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.

Conclusion

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.

References

1. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014; 35: 2146–57.

2 Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012; 223: 262–68.

3 Cuchel M, Meagher EA, du Toit TH, et al, for the Phase 3 HoFH Lomitapide Study investigators. Effi cacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous

familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381: 40–46.

4 Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 998–1006.

5 Stein EA. What role will proprotein convertase subtilisin/kexin type 9 inhibitors play in hyperlipidemia management? Curr Opin Endocrinol Diabetes Obes 2016; 23: 97–105.

6 Raal FJ, Honarpour N, Blom DJ, et al, for the TESLA investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 341–50.

Find this article online at Lancet Diabetes Endocrinol.

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