Long-term PCSK9 inhibition consistently lowers LDL-C in open-label extension study
PCSK9 antibody evolocumab consistently lowered LDL-C levels for an average of 44 months in a diverse patient population with hypercholesterolemia, and was well tolerated.
Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of HypercholesterolemiaLiterature - Koren MJ, Sabatine MS, Giugliano RP, et al. - JAMA Cardiol 2017; published online ahead of print
Background
Two PCSK9 inhibitors, evolocumab and alirocumab, are approved as lipid-lowering therapies when LDL-C is not adequately controlled with maximally tolerated statin therapy, in patients with cardiovascular disease or heterozygous familial hypercholesterolemia (FH), and evolocumab is also approved in patients with homozygous FH [1-4]. The development of a third PCSK9 antibody, bococizumab, was discontinued, due to inadequate long-term efficacy, and higher levels of immunogenicity and injection-site reactions [5].
In this analysis, the long-term lipid-lowering efficacy and safety of evolocumab were evaluated in the still ongoing open-label extension OSLER-1, an extension on 5 double-blind phase 2 parent studies performed at 192 sites in 18 countries, for up to 4 years. Of the 1650 eligible patients who completed a parent study without having experienced a serious adverse event, 1324 (80.2%) continued the OSLER-1 extension study. Of those, 882 patients were randomised to evolocumab plus standard of care (SOC) and 442 patients to SOC alone.
Main results
- For patients on placebo in parent studies, evolocumab lowered lipid levels significantly within 12 weeks.
- For patients on evolocumab in parent studies, who were randomised to SOC alone in OSLER-1, LDL-C levels returned almost to baseline, without a rebound effect.
- Patients on evolocumab both in the parent study, as well as in OSLER-1, had no net changes in lipid levels during the first year of observation.
- Baseline LDL-C levels varied among patients enrolled from the 5 parent studies, but the percentage changes in LDL-C levels in OSLER-1, in patients on evolocumab plus SOC, did not vary significantly by parent study.
- After 52 weeks of open-label therapy, median LDL-C levels in patients on evolocumab plus SOC were reduced by 61% (95% CI −63 to −60%) from baseline compared with 2% (95% CI −5 to −0.2%) for those on SOC alone.
- At weeks 100, 160 and 208 of OSLER-1 follow-up, the median absolute LDL-C level reductions compared with baseline in the parent studies were 76.5, 78.5 and 75 mg/dL and median LDL-C levels were 57, 55 and 60mg/dL, respectively.
- At weeks 64, 100, 160 and 208 of OSLER-1 follow-up, the median percentage reductions in LDL-C levels compared with baseline in the parent studies were 60% (95% CI −61 to −59%), 59% (95% CI −60 to −57%), 59% (95% CI −61 to −58%) and 57% (95% CI −59 to −55%).
- At weeks 64, 100, 160 and 208 of OSLER-1 follow-up, the median percentage reductions in Lp(a) across the cohort compared with baseline in the parent studies were 32%, 29%, 30% and 31%.
- The incidences of adverse events (AEs) were comparable between the 2 OSLER-1 treatment groups the first year and specific AEs did not increase with cumulative exposure to evolocumab. No neutralising antibodies were observed.
- Rates of persistence on therapy were very good, particularly among high-risk patients.
Conclusion
In OSLER-1, an open-label extension study of 5 double-blind phase 2 parent studies, evolocumab consistently lowered LDL-C levels for an average of 44 months, in a diverse patient population with hypercholesterolemia. There were no concerning safety signals and no neutralising antibodies. These data suggest that long-term evolocumab therapy is beneficial and well tolerated.
Editorial comment
In this editorial article, Stone points out the limitations of the study of Koren et al, which include the lack of a placebo group, the restricted sample size, and the open-label design, in which responders dominate the results. The author concludes: ‘What is new is not the substantial initial LDL-C level lowering seen with PCSK9 inhibitors, but the maintenance of that lowering for up to 4 years with evolocumab. It is reassuring to find no significant levels of measured neutralizing antibodies with this fully human PCSK9 inhibitor. The adherence achieved in this open-label extension study is adequate, but it should be noted that participants were shielded from the current high cost of these drugs. It is hoped that if outcome trial data are shown to be beneficial, cost will not be a limiting factor for those who would have the largest incremental benefit.’
References
1. Raal FJ, Stein EA, Dufour R, et al; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-340.
2. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003.
3. Raal FJ, Honarpour N, Blom DJ, et al; TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-350.
4. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383(9911):60-68.
5. Pfizer. Pfizer discontinues global development of bococizumab, its investigational PCSK9 inhibitor [press release]. pfizer.com/news /press-release/press-release-detail/pfizer _discontinues_global_development_of_bococizumab _its_investigational_pcsk9_inhibitor. Published November 1, 2016. Accessed February 14, 2017.
6. Stone NJ. Factors Affecting the Cost of Airplanes and Use of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors. JAMA Cardiol 2017; published online ahead of print.