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.

Discrepancy in Claimed Injection Site Reaction Frequency with ISIS-ApoCIII

My fundamental believe as to why RNAi is fundamentally preferable over phosphorothioate (PS) antisense for therapeutic gene knockdown, is that PS antisense involves the saturation of various tissues in the body with a sticky chemistry that is associated with inflammation.  By contrast, with RNAi Therapeutics, you only need to transiently achieve relatively high tissue levels so that enough of the RNAi silencing machinery can be fed with the RNAi triggers.  Unincorporated oligonucleotides can, and usually are, then washed out without much or any loss of efficacy.

Especially in chronic settings and systemic administration, this persistent inflammatory herd raises the specter of multi-organ fibroses and other adverse immune effects, including vasculitis.  The mipomersen briefing docs showed that such concern is warranted, especially with the findings of vasculitis in non-human primates and frequent injection site reactions which, in contrast to ISIS management which routinely characterizes them as ‘cosmetic’ and ‘nuisance’ side effects, should be interpreted as indicators of what might be happening more systemically.

As you also know, I am equally wary of the reliability of ISIS’ forward and backward looking statements.

Obviously, when ISIS reported phase II data from theISIS-ApoCIII study showing a deep 88% knockdown of the target gene and impressive >70% reductions in serum triglycerides, the question of whether this is a real drug or another KYNAMRO/mipo-like dud hinges on its safety profile.  Unfortunately, no hard numbers were provided on this front in the initial press release.  Instead, there was much beating around the bush characterizing them as being very infrequent and mild in nature. 

However, in the conference call, one analyst apparently wasn’t satisfied with this and asked for a straightforward quantification of the injection site reactions (the following is an adaptation of the telcotranscript on Seeking Alpha):

Jim Birchenough – BMO Capital Markets

Yeah. Hi, guys. Congratulations on the data. A few questions…And then just final [third] question, if you could quantify injection site reaction profile and contrast it with KYNAMRO, I think that would be helpful…

Richard S Geary (ISIS Pharmaceuticals)

Good. This is Richard, and thank you for those questions...The third question, I don’t think I got.

Stanley T Crooke

Reactions compare and contrast to KYNAMRO.

Richard S Geary

So you will remember that in our Phase 1 experience we actually compared directly with three weeks study in normals and we saw almost a 90% reduction in the frequency of ISRs.

Stanley T Crooke

Compared to KYNAMRO.

Richard S Geary

Compared to KYNAMRO, and I would say that looking at these Phase 2 studies, this is being replicated very low frequency and much less severity. These are very mild and it’s almost all erythema that resolves very quickly.

Stanley T Crooke

So we’re seeing much more mild and much less frequent injection site reactions in this study as we saw in earlier work. Is that a fair way to say it, Richard?

Richard S Geary

Yes.

A 5-fold exaggeration of the reduction in injection site reactions

So while ISIS did not add much regarding the frequency of injection site reactions in the phase II study, at least a relative number was provided for ISIS-ApoCIIIRx.  Going back to the phase I trial for which the results were recently published (Graham et al. 2013), the following was said about the frequency of injection site reactions:

‘The most common adverse event was mild injection site reaction, a typical response to subcutaneously administered drugs.52 No subject dosed with placebo complained of injection site reactions, al- though 13 of 25 (52%) subjects dosed with ISIS 304801 experienced at least one. Approximately 1 of 6 injections (median, 17%) led to an injection site reaction, the majority of which resolved within an hour.’

To test the veracity of ISIS’ comments, you would then have to dig up the numbers for mipomersen.  In the FDA briefing docs, the following can be found about the frequency of injection site reactions:

‘ISRs were the most commonly reported AE in the clinical development program. In the pooled Phase 3 trials, 84.3% (220/261) of mipomersen-treated individuals experienced 3,683 ISR events and 33.3% (43/129) of individuals in the placebo group experienced 139 ISR events.’

Assuming for simplicity that the 261 subjects in the phase III studies received 52 injections minus X due to drop outs (note: this fudge factor actually favors ISIS’ numbers as it increases the injection site rate for mipo) we arrive at around 3683 injection site reactions from 10,000 injections, i.e. a rate of around 37%.  If ISIS’ comments on the 90% drop in injection site reaction frequency were then true, the rate for ApoCIII should be 3-4% and not 17% (according to ISIS the mipo injection site reaction rate would have to be 170% for the numbers to match up).  In a 13-week trial, a 17% injection site reaction rate also means that the majority of subjects will experience such reactions, some more often and severe than others.

Of course, I am just a molecular biologist and know little math. I therefore look forward to the ISIS bulls or even the company itself to point out where I went wrong in my calculations.