ApoCIII Genetic Studies Suggest Oligonucleotide Therapeutics to Generate Next Statin

With ISIS Pharmaceuticals having presented strong phase II data showing that ISIS-ApoCIIIRx leads to ~65% reductions in serum triglycerides, it is now in the lead position to exploit the next statin-like opportunity in cardiovascular disease: ApoCIII inhibition.

Large population studies published yesterday in the New England Journal of Medicine (here and here) have now confirmed that not only very high triglyceride levels are problematic for health (e.g. pancreatitis), but that even normal triglyceride levels may not be optimal.  This is because in those people that harbor a mutation that reduces the activity of the ApoCIII gene by just 50% have roughly half the risk of those with ‘normal genes’ of suffering from a cardiovascular event.  As such, (ApoCIII-related) triglyceride levels have become the second important independent risk factor for cardiovascular disease.

ApoCIII inhibitors like ISIS-ApoCIIIRx are particularly valuable for the industry to develop and commercialize for at least 2 reasons. 

For one, the new studies provide human proof-of-concept that triglyceride lowering via the ApoCIIII route should be beneficial and therefore dramatically lower the risk and cost of outcomes studies.  There may be other ways of lowering triglycerides, but from the experience in lipoproteins, it may not just be a matter of down-regulating triglycerides per se, but also the mechanism of achieving how that goal is achieved.  This could e.g. have critical impact on which forms of triglycerides are affected.

The other reason is that unlike the fish oils (20-30% lowering) and niacins (35-50% lowering with significant side effects) which have achieved only moderate triglyceride reductions, inhibiting the ‘undruggable’ ApoCIII with oligonucleotides has been shown by ISIS to have a much more profound impact on triglyceride levels with additional benefits such as ~40-50% increases in the ‘good’ HDL cholesterol.

As a result, ApoCIII inhibitors could in fact be the real ‘next statin’ for the industry, not the PCSK9 inhibitors which address the same risk factor as statins (LDL cholesterol) and may be largely relegated to the millions that do not tolerate statins.

ISIS Path Forward

Being ahead of the competition by 2 clinical phases for such an exciting target is highly valuable, but also represents challenges to ISIS Pharmaceuticals as the race to competing ApoCIII inhibitors is now officially on.  It is e.g. almost certain that Alnylam will develop an RNAi-based inhibitor, and I would expect the same from Tekmira.

Given the impressive lipid profile of ISIS-ApoCIIIRx and the well-established link between very high triglyceride levels and disease, the subcutaneous ISIS-ApoCIIIRx had been expected to readily obtain marketing approvals for those patient populations (e.g. >500mg/dL) without outcome studies.  Even fish-oil competitor Amarin with much less triglyceride lowering was able to do so.  

However, given the new population genetic evidence and the fact that ISIS-ApoCIIIRx is much more effective in lowering triglycerides, I am wondering whether the threshold for approval without outcomes studies will be somewhat lowered and the initial patient populations therefore widened, including in patients at high-risk of suffering (another) cardiovascular event, but that do not necessarily have very high triglyceride levels.

The next step after that would be outcomes studies in broader populations.  This could be done with ISIS-ApoCIIIRx.  A better idea, however, might be to develop a GalNAc-targeted gen2.5 ASO which would be orally available.  Such a differentiation strategy would also facilitate partnering strategies that the company would pursue and I am almost certain that ISIS-ApoCIIIRx2 will be ISIS' first oral antisense drug.  

And after ApoCIII...how about Apo 'little A' for which ISIS also has clinical studies under way already?