The punch line to the joke, “Why did the PCSK9 inhibitor not work?” is usually, “Because the patient never took it!” But occasionally, people will get a less-than-expected response in LDL-C lowering to PCSK9 inhibitors.  This is quite unusual, but a more granular understanding of the entire process beyond my usual fun metaphors can help us better make sense of the potential reasons this may occur. (THIS ARTICLE is a great reference for the discussion below).

So typically, the LDL receptor (LDLr) binds to an LDL particle and together the LDLr-LDL complex enters the early endosome, which is a cellular sorting compartment.  The pH in the endosome is acidic, which is an ideal condition for the LDL receptor to “sneak out” to the cell surface to continue clearing additional LDL particles. The LDLr is able to “sneak out” via a sorting nexin protein called SNX17 (“SNEAKX away” from the LDL and out of the endosome back to the cell surface).  Meanwhile the LDL continues onto the lysosome, which is the cellular garbage disposal, and is degraded. 

However, if PCSK9 is internalized along with the LDLR-LDL complex, the acidic pH of the endosome FURTHER STRENGTHENS the binding of the PCSK9-LDLR-LDL complex…and the LDL receptor is unable to SNEAK AWAY.  SNX17 is unable to liberate the LDLr, and the entire LDLr-LDL-PCSK9 complex is degraded in the lysosome.  This ultimately results in less LDL receptor activity and reduced clearance of LDL particles.

Class 5 Mutations in the LDLR gene lead to a defect in the LDLr recycling back to the cell surface, and these mutations can result in PCSK9 inhibitors having less-than-expected efficacy.  This makes sense, because typically PCSK9 is the “bad guy” in preventing LDLr recycling.  PCSK9 prevents SNX17 from helping the LDLr “sneak out” of the endosome.  But if there are other factors beyond PCSK9 involved, then inhibiting the inhibitor may not have its usual robust effect.