Summary | Targeting PCSK9 in clinical practice: Guidance & future

Prof. John Kastelein discussed targeting PCSK9 in clinical practice, focusing on issues surrounding prescription of PCSK9 monoclonal antibodies and looked into the future on what’s next. He started with a short introduction on ASCVD, which is not only a major cause of death and disease, but also of health care costs [30].

In his opinion we may have become a bit complacent over the last decade, with people thinking that we do not need new drugs to lower LDL-c. However, when looking at recent literature, he thinks the numbers are very disappointing. Only 80% of patients with ASCVD show LDL <70 mg/dL (1.8 mmol/L), despite optimal therapy [31-33]. There are so many perceived or real side effects of therapy that the adherence in ASCVD is suboptimal and there are some registry data that suggest that only 30% of people who should receive high intensity statins, in fact do. And then interestingly, most of the discussion on the PCSK9 monoclonal antibodies has focused on costs, while theoretically with these drugs it should be possible that more than 99% of all ASCVD patients will achieve LDL <70 mg/dL (1.8 mmol/L) [31-33]. Thus, Kastelein concludes that we have somewhat of a dissociate between what is possible, and what in fact is currently done.

Another issue is that recent scientific evidence has taught us in the last five years that it is cumulative LDL-c exposure that matters: lifetime exposure. The consequence of that observation is that the real important thing is to start at a younger age. And we have also learned from the FOURIER data that we can basically go as low with LDL-c as we want. These two lessons are still very far from being realized in clinical practice.

The PCSK9 monoclonal antibodies can address this unmet need. We know that the only available alternative, ezetimibe, is not potent enough. The question is who should receive them. In theory everyone would benefit, but currently eligible patients are only those with ASCVD and high LDL-c, those with heterozygous or homozygous FH and some patients with statin intolerance. Some people think that statin intolerance would be a major market for PCSK9 monoclonal antibodies, but so far, Kastelein perceives that the regulators and the payers have really resisted this idea.

The next question is where we go from here. To answer this question, Kastelein continued with three subjects. The first being the advent of low-frequency injectables. Most monoclonal antibodies need to be injected at least 26 times a year. As monoclonal antibodies are made with biology, not with chemistry, the costs are high. Secondly, there is the statin intolerance issue, which is important because in randomized trials there are not that many side effects, but in reality, it is very different. In lipid clinics, statin intolerance is now the most important reason for referral from both cardiologists and general practitioners. And finally, there are a number of other lipid targets that actually are not addressed by PCSK9 monoclonal antibodies, such as lipoprotein (a) (Lp(a)), apoC-III and triglycerides and AngPTL3.

The first low-frequency injectable that will come to market is inclisiran, an siRNA that is now being tested in a phase 3 program. It acts on the RISC complex in the nucleus and prevents synthesis of the PCSK9 protein, so there is no longer PCSK9 coming out of the liver. Exciting data published in the New England Journal last year showed that with a two-yearly injection of 300 mg, LDL-c levels can be reduced by about 80% for at least 12 months [34,35]. This offers hope that with less frequent dosing this drug could become an important adjunct to our armamentarium.

It is also very interesting that, when looking at the placebo arm in the ORION-1 trial, and comparing it to the treatment arm, it can be seen that injection of siRNA basically takes away the variability observed in patients who are just on statins. In the placebo arm, subjects were on a statin. However, people do not take their medication as they are supposed to; some people suddenly start taking their statin, and some people suddenly do not take it anymore. This is the reason for the immense variability in LDL-c levels. If you inject an siRNA you take that out, which is important because we know that LDL-c variability is associated with high risk of ASCVD [34].

Where are we with inclisiran now? More than 1,550 patient-years of safety data are available. Phase 3 is fully enrolled with 3,660 subjects. And the ORION-4 Cardiovascular Outcome Trial will recruit its first patient soon. Thus, the safety data, which are paramount in a program like this, are accumulating rapidly.

Then statin intolerance, which has become a major issue in ASCVD. The total number of patients who are eligible for a statin across North America, Western Europe, and Japan, is about 350 million. But a number of large surveys show that 10.3% of patients cannot tolerate any statin [36-40]. Thus, this is not minor side issue and it is actually an extremely important reason for events. It is now estimated that in Europe 9% of all MACE events every year are due to the fact that patients are not taking statins at all, or are not taking adequate doses of statins. This is a major gap in therapeutic ASCVD prevention. There are several alternatives for statin-intolerant patients: PCSK9 inhibitors are very effective but costly; ezetimibe is safe and modestly effective; bempedoic acid is in development and is especially promising in combination with ezetimibe; CETP inhibition is still in development.

Bempedoic acid has been studied in four phase 3 lipid lowering studies. In combination with ezetimibe, up to 48% LDL-c reduction is shown. Especially the bempedoic acid/ezetimibe fixed dose combination may be a valuable option for statin-intolerant patients.

We now understand that the HDL-c increase with CETP inhibition is totally irrelevant and that it is the apoB reduction that matters. Lowering LDL-c apoB with a CETP inhibitor in statin-intolerant patients could become an important issue. This has come to light in the last year with publications by Brian Ference in JAMA [41], and also a post hoc in the REVEAL trial, in which patients on low doses of atorvastatin showed better MACE reduction than patients on high doses [42].

Other lipoproteins to pursue are Lp(a) which can be targeted by messenger RNA inhibitors, apoC-III, which can be targeted by siRNA inhibitors, and monoclonal antibodies for AngPTL3. The incredible reduction in Lp(a) levels achieved with the antisense oligonucleotide went up to 80% with a weekly dose [40,43]. The clinical potential of Lp(a) inhibition is great; however, Mendelian randomization data suggest that in order to get a 22% reduction in MACE, you need to reduce Lp(a) by 110mg/dL (2.8 mmol/L) [44,45]. This is a hefty assignment, which will mean that the baseline Lp(a) in the outcome trial will need to be really elevated.

Kastelein concluded that there is no reason for complacency. Statins are not enough for the majority of patients at very high ASCVD risk. Currently, the only answer is PCSK9 inhibition, but low-frequency injectables like inclisiran might even have a more profound impact on improving global ASCVD burden. It is important to mention that cumulative LDL-c exposure matters: start young, go low. A major clinical problem is statin intolerance, with the bempedoic acid/ezetimibe combination and the CETP inhibitor with great promise for the future. Improved understanding of Lp(a) apoC-III, and remnant lipoproteins is needed to open a multitude of new therapeutic avenues. Altogether, the future will not be boring in the next ten years. There is a whole host of new drugs that we can add to our armamentarium.

References

Educational information

This is a summary of the presentation given by John Kastelein, during the PACE symposium entitled 'PCSK9 inhibition: Science, outcomes & guidance', held during ESC in Munich, Germany, on August 25, 2018.

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