ApoC III Confirmed as High Potential Gene Knockdown Target

Small molecules, monoclonal antibodies, and fish oils move out!  Combining the power of genetics and therapeutic gene knockdown, ISIS Pharmaceuticals presented last night by far the most profound reduction in serum triglycerides which are thought to be an important risk factor in cardiovascular disease and other less common conditions such as pancreatitis: a 72% reduction of serum triglycerides following an 88% gene knockdown of ApoC III with a bonus 40% elevation of the good HDL cholesterol in a phase II study of ISIS-ApoCIIIRx presented at the Amercian Diabetes Association. This confirms in Man that ApoC III antagonizes the metabolism of triglycerides.

The ApoC III knockdown results were not unexpected.  In the preceding phase I study, 71% and 78% ApoC knockdowns were seen at the 200mg/week and 400mg/week dose levels, respectively.  The enhanced, 88% knockdown seen in this phase II study at the 300mg/week level can be explained by the fact that the study drug in the first study was only given for 4 weeks, at which point the phosphorothioate oligonucleotide may not have reached saturation in the liver, whereas in this study it was given for 13 weeks.  

More surprising was the deep 72% reduction in serum triglycerides.  In the phase I studies, 'merely' 43-44% reductions were observed, although this to my knowledge is still superior to e.g. Amarin’s glorified and controversial fish oil.  It is possible that this result is due to a non-linear relationship between ApoC III and serum triglyceride lowering.

Obviously, questions remain unanswered following this small and still early-stage study.  I was surprised to learn that data were reported for only 11 patients with 200 and 500 mg/dL serum triglycerides and type 2 diabetes (the enrolment criteria) although the clinicaltrials.gov entry indicates that 24 was the originally planned number for the blinded, placebo-controlled study.

Secondly, it will be important to learn about the safety and tolerability profile of ISIS-ApoC IIIRx, also in light of the clinical trial experience with the ApoB-targeting, LDL cholesterol-lowering mipomersen (aka KYNAMRO).  To wit, ‘nuisance’ side effects such as injection site reactions and flu-like symptoms contributed to frequent discontinuations in the trials and likely explain what appears to be a very slow uptake after marketing approval.  Of course, Dr. Stan Crooke, the ever-so optimistic CEO of ISIS Pharmaceuticals is convinced that ISIS-ApoCIIIRx has no such issues due to improved screening  methods.  As a reminder, in the phase I study with ISIS-ApoCIIIRx, one out of six injections were associated with injection site reactions.

Thirdly, the link between ApoC III and cardiovascular risk is still debated.  Moreover, similar to ApoB, ApoCIII is thought to contribute to VLDL efflux and inhibiting it may lead to an elevation of liver triglycerides.  This is particularly problematic given that the target patient population is already at an increased risk of hepatosteatosis.

While phosphorothioate antisense company ISIS Pharmaceuticals clearly has a head-start on ApoC III, given the ability of various RNAi technologies to potently knock down genes in the liver, ApoC III is an attractive target for the RNAi Therapeutics industry.  Such a candidate could either be positioned as a best-in-class alternative (à safety; I particularly like here the prospect of a subQ DPC version) or possibly as part of a multi-targeting cocktail against cardiovascular disease (attractive for SNALPs).  It is also one with an attractive partnering potential for some of the smaller companies in the space (early clinical POC, maybe partnering even before clinical development).