Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia: 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial.

Koren MJ, Giugliano RP, Raal FJ, for the OSLER Investigators
Circulation. 2013 Nov 19. [Epub ahead of print]

Background

The observation that more aggressive lowering of LDL-c levels leads to lower rates of vascular disease complications, has led to the interest in developing treatments that reduce serum LDL-c below levels achievable with statin therapy alone [1]. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising new approach for treating hypercholesterolaemia [2]. Monoclonal antibodies against PCSK9 can reduce LDL-c substantially, either when given alone or in combination with statin therapy [3-10].
Evolucumab (AMG 145) is a fully human monoclonal antibody against PCSK9, and has been shown to reduce LDL-c with up to 65%, with an encouraging safety and tolerability profile in four phase II clinical trials in over 1300 hypercholesterolemic patients [4,5,7,10]. No large studies have been performed that tested PCSK9 inhibitors for up to one year, in a diverse patient population.
Patients completing any of the four previous phase II trials could participate in the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER), which was a global, multicenter, randomised, controlled extension trial. Background standard-of-care (SOC) therapy could be adjusted in OSLER, after 12 weeks. Efficacy and safety results after one year in OSLER are now presented. Of the 1104 patients enrolled in OSLER, 736 were randomised to evolocumab 420 mg every 4 weeks subcutaneously+SOC and 368 were randomised to SOC only. More patients in the evolocumab+SOC group (64.9%) received statin therapy at baseline than in the SOC group (57.9%).

Main results

• Patients who did not take evolocumab in the phase II parent study had large initial LDL-c drops 12 weeks after the start of OSLER (51.8% + SE 1.6% from parent study baseline, P<0.0001), and reductions were maintained over 52 weeks (52.3% +SE 1.8% at week 52, P<0.0001).
• Patients who did receive evolocumab in the parent studies (1 of 6 dosing regimens) and in OSLER, showed persistent reductions in LDL-c: from 50.4% + SE 0.8% at the end of the parent study to 52.1% + SE: 1.2% after 52 weeks (paired t-test: P=0.31).  
• Patients who received evolocumab in the parent study, but were randomised to SOC only  in OSLER showed smaller mean reductions in LDL-c at week 4 (17.9% + 1.2%) and close to baseline levels (5.8% + SE 1.2%) within 12 weeks (without rebound effect), as compared to 53.1% +1.2% reduction at the start of OSLER.
• In patients of whom LDL-c ultracentrifugation values were determined at each visit, LDL-c < 2.6 mmol/L (100 mg/dL) was achieved at every visit by 72.1% in the evolocumab+SOC group, as compared to only 3.3% in the SOC group (P<0.0001). The proportions of patients achieving LDL-c <1.8 mmol/L (70 mg/dL) at each visit were 37.8% and 0%.
• Adverse events (AE) occurred in 269 patients (73.1%) in the SOC group, and in 599 patients (81.4%) in the evolocumab+SOC group, most commonly nasopharyngitis, upper respiratory tract infections, influenza, arthralgia and back pain. 5.6% of all AEs were considered to be possibly related to evolocumab.
  Six patients (1.6%) in the SOC group and 13 (1.8%) in the evolocumab+SOC group had alanine aminotransferase or aspartate aminotransferase > three times the upper limit of normal.
  Serious AEs occurred in 23 SOC patients (6.3%) and 52 patients (7.1%) in the evolocumab+SOC group. No specific serious AE was considered to be possibly related to evolocumab.
• No neutralising antibodies to evolocumab were detected during OSLER.

Conclusion

The OSLER trial was the first large longer-term evaluation of PCSK9 inhibition, which extends previous findings that evolocumab treatment reduces LDL-c by ~50% beyond the reduction achieved with optimal SOC in different hypercholesterolemic patient populations. LDL-c reductions obtained after 12 weeks of treatment with evolocumab were maintained over the course of the study. Discontinuation of evolocumab on the other hand yielded a fairly rapid return to baseline levels, without showing a rebound effect.
Evolocumab was generally well tolerated, and similar rates of AEs were seen in both treatment groups.
Therapy with antibodies directed against PCSK9 may lead to greater numbers of patients achieving and maintaining goals for LDL-c. These promising results of PCSK9 inhibition in hypercholesterolemic patients should be confirmed in outcomes trials.

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