Wednesday, July 18, 2012

Simply SNALP: RNAi TTR Knockdown Data Impress


Clearly, RNAi Therapeutics is back in fashion.  Well, almost.

Alnylam’s announcement of profound gene knockdown in the ALN-TTR02 phase I study for the treatment of TTR amyloidosis was greeted with an over 50% jump in the stock price on very high volume.  Various observers pointed out that this might have been an over-reaction given the early nature of the data.  On the other hand, considering that the over 80% peak knockdowns achieved with only a single dose of 0.15mg/kg are representative of a widely applicable delivery strategy, namely Tekmira’s SNALP technology, and considering that an accelerated approval path  should be possible for this orphan disease, determining the fair value of a SNALP-based company like Alnylam becomes difficult.

Yes, this was a study that enrolled just 17 subjects, healthy volunteers at that.  But it may be this that makes the tight variability in the pharmacodynamic response (=TTR knockdown) even more remarkable so: less than 5% relative standard deviations in the 0.15mg/kg and 0.30 mg/kg 3-person dose cohorts, the relevant groups for this analysis.  

When I had mentally listed the technical risks of SNALP-mediated delivery several years ago when I did my fundamental research on SNALP delivery, intersubject knockdown variability was one of the major ones.  However, given the present results and those from the recent hypercholesterolemia study (ALN-PCS02), I am much less concerned about this now, also in patient groups where liver health may be affected.

Moreover, the dose-related TTR knockdown in humans was essentially what has been seen in non-human primates.  Although a number of analysts were apparently puzzled by the importance of this observation, its value to a scientist is obvious: you can essentially eliminate the risk that an SNALP program fails in phase I due to lack of knockdown efficacy (and if you are one of those scientists that also dabble in the stock markets, you can start investing in the stock based on the monkey data that you’ll see presented at an informal presentation).   

The safety profile with ALN-TTR02 in this study was good.  There was one infusion reaction seen in other SNALP studies before and that was managed by slowing the infusion rate.  This was said to be possibly related to the pre-treatment with corticosteroids, and not the liposomal formulation itself.  In any case, while corticosteroids and other transient immune suppressions will not be an issue for the initial patient populations in diseases like TTR amyloidosis, Tekmira and Alnylam should start to try and wean themselves of it.  The improved, more predictive immune stimulation assays may form a sound scientific basis for this.

The reason for why the study was limited to 17 healthy volunteers was mostly due to competitive concerns.  In particular, the ISIS/GSK TTR antisense compound is said to skip phase II studies altogether and go straight into a pivotal phase III.  In data presented in May of 2011, this antisense compound was reported to effect a 44% mean TTR reduction at the 200mg/week dose level when given for four weeks, and 81% knockdown at 400mg which was the next higher dose tested.  400mg/week, however, is a dose that I believe is too high for chronic phosphorothioate oligonucleotide administration.  Although ALN-TTR02 should thus be 100- to 200-fold more potent on a weight basis than the antisense drug candidate, being the first-to-market is seen by some as an important factor for the commercial success in this orphan market, especially since these compounds work by the same mechanism of action.


The value of SNALP delivery

Some readers of this blog may be tiring by now of reading me sing the praises of SNALP delivery technology and Tekmira.  Yes, I’m invested in the technology via my Tekmira shares.  In all fairness, however, it is the clinical data from the SNALP compounds, really starting last November with the ALN-TTR01 data (SNALP Works!) that are reviving the RNAi Therapeutics field: ALN-VSP, ALN-PCS, and ALN-TTR.  We have heard a lot about exciting new, revolutionary RNAi delivery technologies, often claiming to solve the putative problems with  SNALP technology.  However, in the end, it is SNALP that is set to unlock the first wave of RNAi Therapeutics value creation.

Even Arrowhead Research and Benitec which develop competing delivery and RNAi trigger technologies, respectively, admitted so much in congratulating Alnylam to the results.  Sadly, they missed the opportunity to also congratulate the real innovator behind SNALP technology, Tekmira.  It seems that since Alnylam is getting all the media attention, it was probably not a good PR strategy to do so.

RNAi delivery technologies are tough to develop and rare to find, but when they work, they open up a range of therapeutic opportunities.   


Preview: For my next post, I am planning to write something about last week’s MC3 paper and how it reveals that covering all the tracks is hopeless when a scheme is that elaborate (RE Tekmira-Alnylam litigation), and why Alnylam the stock may be a great short here. 

15 comments:

BioDueDiligence said...

You don't think stopping at 17 pts had something to do with adverse event in the 17th patient (and only one at that dose level)? Also will be crucial to see effect on wild-type and mutant protein levels in patients (not to mention to see if it actually reverses the disease). I hope ISIS doesn't burn themselves and the patients by rushing to phase 3 without any experience in patients.

Anonymous said...

As an investor in both Tekmira and Alnylam, I am hopeful that they will be able to settle their differences. If not, it seems to me that the law suit will boil down to a single issue. Is MC3 a novel formulation? There is no doubt that Tekmira gave Alnylam permission to develop novel formulations, and in its discussion of the development of MC3, Alnylam referred to it as a novel form of SNLP several times. Tekmira has been feverishly trying to rebut Alnylam's claims with press releases, but they sound desperate and don't seem to be gaining traction. Shorting Alnylam at this time may be a bit premature.

Dirk Haussecker said...

It could well have been a trigger, agreed. With the knockdown observed at 0.3mg/kg (~87% peak and well sustained), there was probably no luck then in testing their luck at higher doses. I am pretty much convinced that Alnylam and ISIS/GSK consider being first to market important, and with ISIS' recent announcement of going straight to phase III...

Dirk Haussecker said...

You mean changing the linker group by one carbon makes it a 'novel' lipid formulation when the critical finding from the KC series of lipids was (by the Alcana people when still being paid by Tekmira) that it is this variation that is very impactful?

Anonymous said...

Fellow Anonymous

After you read the judge's memo opinion on the motions for partial summary judgment, which are posted at Tekmira's home web page, the issue is a heck of a lot more than whether MC3 is a novel formulation. Alnylam is facing bad facts. Need a full court press to settle with Tekmira.

FMS said...

Dirk, I don't want to sound like a broken record, but do you dismiss Marina Biotech as irrevocably dead?

Anonymous said...

Dirk,
Nowadays the expression SNALP just stands for a certain controlled step-wise dilution method process for the formulation of i.e. LNPs – there is a difference between lipid chemistry and formulation procedure…
By the way, is it actually true that SNALP-wise formulated LNPs i.e. from the K- or M-series are more active in vivo than those made from preformed liposomes and those made in a non-step-wise dilution process, respectively? So far I haven’t seen solid data – does anyone know such references?
Anyway, thanks for this really interesting blog.
V.

Anonymous said...

Dirk,

Imagine, hypothetically, that a party possessed information material to the ALNY/TKMR legal proceedings that might be of benefit to TKMR.

Anonymous said...

Imagine, hypothetically, how a settlement benefiting a few suits and sharks, might actually benefit shareholders.

Dirk Haussecker said...

Form and particle distribution follows process: My understanding is that the formulation process is at least as critical as the lipid composition in terms of biological effect. Indeed, the formulation process is what has set Protiva/Tekmira apart from the competition and why Alnylam needed Tekmira (then Protiva) so desperately. Lots of companies have played around with liposomal delivery, only Tekmira so far have generated clinical-grade liposomes (not lipoplexes).

Marina Bio...didn't they cease all research operations?Doesn't seem like a viable company to me...

To the last anonymous commenter: it is Alnylam mgmt's problem that far too many know about what game it played with Tekmira. Many are former Alnylam employees, some gone from the company because they disagreed. Unfortunately, many of those that could blow the whistle live in fear of the consequences of doing so. All hypothetical, of course...

Anonymous said...

Your post above frames the the very real (and not hypothetical) dilemma.
Most individuals don't possess the financial or professional luxury of serving as a whistle blower.

Bear in mind everything that transpires at Alnylam, good, bad, and otherwise, bears John Maraganore's hand. Charming, personable, smart, and capable as her is, he runs the company like an autocrat. And he has given rise to a management culture where fealty and servitude are the coins of the realm.

Anonymous said...

Dirk,
I do really agree - the formulation process is really important for LNP production. People like P. Cullis, S. Semple and others did a great job, especially with respect to the development of spontaneous entrapment processes.

But distinguishing between liposomal and lipoplex delivery in this context seems to be somehow misleading...

Just remember, all LNPs are made at a pH value below the pKa of the cationic lipid: the old DOTAP formulations can be made at pH 7, MC3 or KC2 based formulations are always made at more or less pH 4 - just to ensure a really nice cationic charge of those lipids. The reason is quite simple: all these formulations rely on the lipoplex formation process (neg. oligos, cat. lipids, complexation, release of counter ions etc.). This active process guarantees in combination with lipid/oligo ratio and ethanol content high encapsulation efficacies and the control of size and lamellarity. In case of iLNPs there is of course a final pH shift back to pH 7. But does this make a difference? It just changes the overall particle surface charge. Does it change anything below the outer lipid bilayer?
I consider iLNPs as lipoplexes having a distinctive circular mono to multi lamellar morphology and a low surface charge at a certain pH value which enables them to target certain cell types in liver – without any doubts with striking results.
V.

Dirk Haussecker said...

V. Thanks for your comments, but I disagree with the notion that lipoplexes are just like iLNPs. The reason for this is that the +/- neutral surface charge at physiological pH is apparently indispensable to get the efficient ApoE-mediated delivery to hepatocytes. Alnylam published on this, Tekmira alleges that this had been a Tekmira trade secret and Alnylam inappropriately spilled the beans to take credit.

Also, mono- or multilammellar: a big difference in terms of biological performance. Too large/multilamellar and you do not get good enough tissue penetration and particles are readily taken up by phagocytic processes without producing much silencing. Regulating the shape through controlled formulation, again a Tekmira competitive strength.

Dirk Haussecker said...

About The Dilemma: There should also be confidential means of disclosing such material information without it hurting your career or other prospects. Loyalty is an important attribute if you are working for a company, but loyalty should also have boundaries.

If you feel like talking, I am sure there'll be willing ears to listen. Contact me if you feel that I could be of help here.

Anonymous said...

Dirk,
You are right – the almost neutral surface seems to be indispensable to get the efficient ApoE-mediated delivery to hepatocytes. But what is your point? I was actually arguing that these iLNPs are just a certain kind of lipoplexes (with a neutral surface charge, which is special) and the distinction between liposomal and lipoplex formulation is just incorrect.
Furthermore, there is no direct correlation between particle size and number of lamellae (mono- vs. multilamellar), it is rather the case that monolamellar structures are somehow more hollow whereas multilamellar structures are more “filled”. Really nice TEMs were already published by Semple, Cullis et al. (Biophys J. 2001;80(5):2310-26).
But you’ve got a point and I do really agree: there is definitely a difference in terms of performance between these morphologies; i.e. the release of oligos from multilamellar structures is of course different to that from monolamellar structures, the transformation to H-II morphologies as a precondition for the endosomal release, absolute particle numbers etc...
V.

By Dirk Haussecker. All rights reserved.

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