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?

Taking Full Advantage of RNAi Therapeutics in Lowering Trigylcerides

Today at BIO CEO 2014, Tekmira presented tantalizing preclinical data (slide 11) showing more than 95% reductions in serum triglycerides, the lipids that clog up your arteries (think heart disease and stroke) and in extremely high cases cause severe bouts of pancreatitis.    Such reductions in triglycerides are unprecedented as fiddling around with fish oils, fibrates, and niacins has become a worn, unsatisfactory edge in managing this important lipid.

Enter RNA(i) Therapeutics.  By taking full advantage of the technology in being able to target any gene in the pathways leading up to triglyceride production and accumulation, we are not far away from achieving much more pronounced lowerings than the current standard of medical care.  This was impressively illustrated by the 70-80% lowerings of serum triglyceride in the phase II studies with ISIS-ApoCIIIRx, an RNaseH antisense compound by ISIS Pharmaceuticals.     

If you have been following my blog, however, I believe that despite the ISIS head-start, this lunch will eventually be eaten by RNAi Therapeutics.  In addition to their superior ability to effect gene knockdown in the liver, the Tekmira data went one step further to fully take advantage of the mechanistic opportunities offered by RNAi Therapeutics, in particular those delivered by technologies such as SNALP LNPs: multi-targeting.

As pioneered by SNALP-enabled TKM-EBOLA and ALN-VSP02 (for liver cancer), SNALP LNPs lend themselves to targeting multiple genes in a single drug.  As a consequence, it should be relatively easy to come up with a target combination that can not only lower serum triglycerides more potently than could be achieved by targeting a single gene such as ApoCIIIRx, but also lower liver triglycerides (à fatty liver, fibrosis), improve insulin sensitivity and the lipid profile on other fronts such as LDL-cholesterol.  Such a profile would be highly attractive since a given patient often will suffer from a number of these conditions (metabolic syndrome).

For Tekmira, as for ISIS Pharmaceuticals, the first markets, however, will be the severe orphan diseases related to triglycerides such as those involving severely elevated levels of serum triglycerides (>500) leading to pancreatitis.  Depending on the safety and tolerability profile, the market potential beyond these indications could be considerable and possibly limited by the inconvenience of having to go for monthly infusions.

But seriously, if you are going to take a medicine that costs on the order of $100k a year, you better take what is medically best for you and it would most likely still be a pharmacoeconomic steal if you charged the system for taking a stretch limousine to the infusion center to take care of the inconvenience (I'm particularly keeping an eye here on how the MS market evolves).  At least this primacy of efficacy is where I am hoping the healthcare cost discussion will steer the market in the future.  As such, Tekmira should not by shy in focusing on its competitive strength of achieving maximal target knockdowns.

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).