Summary | PCSK9 inhibition across a wide spectrum of patients: One size fits all?
Prof. Hovingh started by emphasizing that PCSK9 is a new step on the roadmap towards complete acceptance of the LDL-c hypothesis. Anitschkow first formulated the hypothesis in 1913 and several important findings since then have bolstered the hypothesis that LDL-c plays a causal role in CV events. One of the main steps in the last two decades is the finding by Abifadel who identified PCSK9 as a culprit gene in LDL-c metabolism. Hovingh believes that this century is going to be a new LDL century, as we are facing huge changes in the coming years.
One of the reasons why patients do not reach their LDL-c target level is the lack of potency of LDL-c lowering therapy. Also, LDL-c target levels tend to decrease with subsequent guidelines11 and patients do not always tolerate the lipid-lowering therapies they are prescribed.12
Once the PCSK9 inhibitor evolocumab was injected, the level of PCSK9 decreased directly and basically dropped to zero in a phase Ib trial of 57 hyperlipidemic adults on stable statin therapy.13 As a result, LDL-c level decreased dramatically as well for 2 weeks, after which levels rose again. Consequently, in the clinical setting PCSK9 inhibitors are injected every 2 weeks. Robinson et al. reported a similar 60% decrease in LDL-c levels in patients with hypercholesterolemia randomized to evolocumab while on moderate to high statin therapy.14 Treatment with alirocumab, another monoclonal antibody against PCSK9, showed a very similar decrease in LDL-c levels (~60% decrease) in patients at high risk for CV events.15
Both evolocumab and alirocumab treatment result in stable LDL-c lowering over time.
Some patients start with very high levels, making it difficult to meet the LDL-c target, such as patients with FH, a genetic disorder that is characterized by extremely high LDL-c levels and a high CV risk. Data by Pijlman et al. in 200916 and also more recent studies demonstrated that the majority of FH patients did not reach the LDL-c target level. When 2.5 mmol/L LDL-c was considered as the target level, only 20% of patients reached that goal, as shown in an S-shaped curve of LDL-c target level against the percentage attainment of target. Treatment with evolocumab in a population of heterozygous FH in the RUTHERFORD trial showed a 60% decrease in LDL-c levels after 12 weeks.17 Prolonged LDL-c lowering was also observed with treatment of alirocumab after 78 weeks of follow-up.18 Both evolocumab and alirocumab treatment result in stable LDL-c lowering over time. The TAUSSIG trial enrolled >100 patients with homozygous FH on apheresis or not on apheresis who were randomized to evolocumab.19 As expected, patients had high baseline LDL-c levels, regardless of apheresis. After 12 and 48 weeks, reductions of 20.6% and 23.3%, respectively, were observed when all patients were grouped together, with a smaller change in patients on apheresis. Considering that these patients have 2 dysfunctional LDL-receptors, a reduction of 26.7% in the non-apheresis group is quite striking.
Prof. Hovingh then asked the question how many individuals with heterozygous FH in the S-shaped curve16 who had not reached their LDL-c target level, would theoretically have reached it if they were given a high dose of statin, ezetimibe and evolocumab or alirocumab. To answer this question, a Dutch database of adults with heterozygous FH was used, comprising data of 10.000 individuals. Assuming full adherence to medication, 50% of patients would reach the LDL-c target level with high dose statin and ezetimibe. Addition of a PCSK9 inhibitor would result in a sharp increase in the number of individuals reaching their target (>90%). This would shift the S-shaped curve dramatically. However, adherence to medication might be different in real life, and therefore real life data is needed to see what the effect of PCSK9 inhibition is in clinical settings. In this study, consistent LDL-c lowering was observed, as shown by waterfall plots with an LDL-c reduction >25% in the majority of patients (Hartgers et al., submitted).
He showed the full clinical trial program of three monoclonal antibodies against PCSK9; alirocumab, evolocumab, and bococizumab. Development of the latter was stopped because of the development of neutralizing antibodies in the large SPIRE outcome trials.20 The first two drugs have been tested in all kinds of patient populations, among which statin-intolerant patients. In the ODYSSEY Alternative Study, patients were randomized to alirocumab, ezetimibe, or atorvastatin, and the primary outcome was LDL-c reduction at 24 weeks. As expected, a 45-55% reduction in LDL-c levels was observed in those randomized to alirocumab compared to a reduction of 15-17% in the ezetimibe group.21 More importantly, fewer skeletal muscle adverse events were seen in the alirocumab-treated patients compared to the atorvastatin group.
PCSK9 inhibition in diabetes patients was recently examined in the ODYSSEY trials. Type 2 diabetes patients were randomized to 75 mg alirocumab or standard care in a 2:1 ratio.22 The primary endpoint was the reduction in non-HDL-c levels, the prime driver of outcomes, at 24 weeks. A reduction of 37.3% was observed in the alirocumab group compared to a 4.7% reduction with standard care. Ongoing studies examine patients with renal impairment and those with HIV. We are also waiting for the study results of specific patient categories who are at high risk for CV endpoints.
Patients with FH, statin intolerance, and diabetes all seem to respond similarly to PCSK9 inhibition in terms of LDL-c lowering.
In addition to monoclonal antibodies to PCSK9, also adnectins, vaccines, small interfering (si)RNA and small molecules are being developed. The ORION-1 trial evaluated treatment with inclisiran, a 3rd generation siRNA specifically targeting PCSK9, in 500 individuals with high CVD risk.23 Patients were treated with either one or two starting dose regimens of siRNA, resulting in a very large reduction in LDL-c levels. Injection site reactions were observed in some patients, but not considered serious. A sharp decrease in PCSK9 level (> 60% reduction) resulted in large reductions of LDL-c level (50%) after only 2 injections of siRNA. The waterfall plots showed that all individuals responded with lowering of LDL-c levels.
Many roads may lead to PCSK9 inhibition, for example using the CRISPR approach or vaccines. Treatment with antibodies is ahead of the game, but data from the ORION trial suggest similar results with a different approach. Prof. Hovingh concluded that he believes that in case of PCSK9 inhibition one size fits all; patients with FH, statin intolerance, and diabetes all seem to respond similarly to PCSK9 inhibition in terms of LDL-c lowering.