We have dueling PCSK9 antibodies on the market – Praluent (alirocumab) and Repatha (evolocumab) – and they’re both out there lowering LDL levels as we speak. (Whether these have the desired long-term outcomes remains to be seen; there’s no other way to find out than to wait and watch). But there’s another approach to this same pathway, as detailed in this release: a vaccine.
A new cholesterol-lowering vaccine leads to reductions in ‘bad’ LDL cholesterol in mice and macaques, according to research published in Vaccine. The authors of the study, from the University of New Mexico and the National Institutes of health in the United States, say the vaccine has the potential to be a more powerful treatment than statins alone.
Well, yeah, but taking the approved drugs has the potential for that, too, and that’s a better comparison. What does the vaccine bring that the antibody therapies don’t? One the one hand, the vaccine might be a one-time-only treatment, and that’s good. On the other hand, the downside is that the vaccine might be a one-time-only treatment, and that’s bad: you can’t turn it off, the way that you can decide to stop taking the antibody.
The authors have thought about this, but their first reason for the desirability of a vaccine is the cost of the antibody therapies, followed by patient compliance, and followed by the development of an immune response to the antibodies themselves and corresponding dropoffs in efficacy.
The induction of anti-self antibody responses understandably raises some safety concerns and should be reserved for those targets where the consequences of antibody-mediated inhibition are well known and the benefits of vaccination outweigh potential risks. At this point, PCSK9 appears to meet these criteria. PCSK9 mAb clinical trials have not revealed any major safety concerns and humans with mutations that abolish PCSK9 expression are apparently healthy. Nevertheless, vaccination would presumably elicit longer lasting antibody responses to PCSK9 and, in contrast to mAb-based therapies, it would not be possible to rapidly decrease the serum Ab levels in response to adverse side effects.
They suggest that a vaccine route might be particularly useful in developing countries, but I wonder if you’re still a developing country in that sense if high LDL levels are a major public health concern. Overall, I’d say that if it turns out that modern humans are better off without PCSK9 function, then so be it – we should knock it down with whatever tools are at hand. But I think that we can afford to approach that idea slowly – Chesterton’s fence and all that. A billion years of evolution have done some funny things and made some funny connections, and it would be worth watching the antibody performance for a few years before going further.