Sunday, February 10, 2013

Is Alnylam Foolishly Betting the Farm on GalNAcs?

It is remarkable that Alnylam seems to be embracing GalNAc subcutaneous delivery for all pipeline candidates, but for perhaps ALN-TTR02, that are most important to its 5x15TM development and commercialization strategy: ALN-TTRsc (TTR amyloidosis), ALN-AT3 (hemophilia), and ALN-AS1 (acute intermittent porphyria).  Considering that gene knockdown has not been demonstrated in Man with GalNAc conjugates, and potency could be a critical issue determining whether this really is a subQ approach, this apparent high-risk strategy is uncharacteristic of a company with the laudable attitude of raising capital when the company does not need it.   

ALN-TTRsc: The Missing Clinical Trial

One possible reflection of the fact that management does not really feel as confident about the strategy as it may seem, is the missing entry of the ALN-TTRsc phase I clinical trial on (and other registries I looked at).

I like to look at clinical trial registries, esp., also for the reason that information contained therein often provide interesting clues into otherwise undisclosed safety and efficacy issues.  For example, is it a single and/or multiple dose, what are the dosing ranges, etc. 

With ALN-TTRsc, I do not expect safety to be necessarily the dose limiting factor.  Rather, it may well be the ability to show robust efficacy with an injection volume of 1ml or less, the magic upper limit for subQ approaches.  It turns out that adequate efficacy was seen in non-human primates only starting at 2.5mg/kg which apparently corresponds to the 1ml volume in humans.  Moreover, the dose-response curve is relatively shallow making it difficult to extrapolate predicted doses from preclinical models into humans (being off by a factor of 2 in the ED50 could already prove disastrous).

Is the omission to list ALN-TTRsc on an attempt at hiding that the dose escalation schedule indicates that 2.5mg/kg is an optimistic guess? Of course, the secrecy could also be for competitive reasons in light of its race with the competing antisense approach by GSK-ISIS.  But for a company that so far has listed every clinical trial, including ALN-TTR01 and ALN-TTR02 all of which have been conducted exclusively outside the US, there will be a reason for it and doubts about GalNAc potency is a plausible one.

GalNAc Steals Spotlight from DPCs

Recently, Arrowhead scientists presented impressive subQ hepatic knockdown data with the DPC polyconjugate platform.  While the response to the presentation at the Oligonucleotide Society Meeting in Boston last year was tremendous, possibly the most enthusiastic one among all the presentations (and one of the reasons why I am bullish that there is wider industry demand for DPCs), Arrowhead has been getting no love from the financial markets, thus putting it at a disadvantage in any licensing negotiations.  One factor for that might be GalNAcs which take away in the typical investor’s mind the uniqueness about it being a subQ RNAi delivery approach.  So if Alnylam eventually realizes that it needs an alternative, it might get access to it on more affordable terms.  The phase I ALN-TTRsc results expected mid-year could be the critical event in that dynamic: poor results would benefit Arrowhead Research.

GalNAc Plus

Of course, the confidence in GalNAcs may rest in the knowledge that ALN-TTRsc is actually the pipeline candidate with the weakest potency, and if IT shows efficacy, it will be a stroll for all the others.  These apparently have proven to be more potent in preclinical studies.  

I consider this a possibility, but am not fully convinced that these conjugates can really be called GalNAc-siRNA conjugates.  This is because the TTR siRNA is a particularly potent one already and I am wondering how you would achieve a 10x increase in potency from ALN-TTRsc to ALN-PCSsc with stabilizing nucleic acid chemistry alone.  Moreover, it is a small miracle already that a simple siRNA with a targeting ligand can achieve ED50s in the low mg/kg, because the related cytoplasmic release would likely rely on spontaneous endosome rupture (miracle probably explained by the high volume ASGPR receptor-mediated trafficking).

Consequently, my feeling is that the GalNAc Plus conjugates involve additional functional moieties beyond stabilizing chemistries such as 2'-o-methyl and 2'-F…such as endosomolytic activities.  In a 2009 patent application by Manoharan et al. (WO 2009/126933) such endosomal release activities, melittin included, were indeed contemplated in the context of GalNAc-siRNAs.  In fact, the claims would cover GalNAc-targeted DPCs such as the one described in the Mirus/Arrowhead in the 2007 PNAS paper (Mirus cientists Publish Elegant Paper on Targeted siRNA Delivery to Hepatocytes).

The patent application, somewhat of an attempt at an early land-grap being devoid of any actual experimental data, is not very remarkable really as it is obvious to somebody skilled in the art that in order to significantly enhance GalNAc-siRNAs such functionalities will be highly desirable, so a lot of it would come down again to chemistry and figuring out which exact compositions are functional and safe.

In my mind, it is fair game to pursue promising (delivery) technologies, especially under the Research Exemption in the US.  However, as the Tekmira-Alnylam relationship has shown, it is foolish for two companies to collaborate on delivery when both are working on GalNAc conjugates internally.  At best, the technology is useless and the whole thing will be forgotten.  At worst, the technology is valuable and both parties will try to control it and not pay the other party their dues.   

Overall, I think that betting the farm on GalNAcs is taking on more risk than warranted considering the advancements and validation achieved with SNALP technology.  Also, if Alnylam considered the subcutaneous approach to be that much more attractive than intravenous, you would think DPCs are the logical fall-back, if not more desirable than simple GalNAcs.  But maybe GalNAc Plus and DPCs are not all that dissimilar and we are on the same page after all.

Note added in proof (March 27, 2013): the ALN-TTRsc entry has now appeared.  As expected, however, no insights were provided into the dosing range. Only interesting tidbit: the volume of the placebo injection will be matched to that of ALN-TTRsc.  Injection volumes will be critical.


Anonymous said...

A little premature to be raising suspicions about missing entries, isn't it? The just received approval to start the ALN-TTRac trial, after all.

Also, consider that SNALP has not proven itself in multi-dose studies. You can get away with a sketchy safety profile in oncology, but not in chronic, orphan diseases. Wonder why Alnylam stopped their ALN-PCS trial before reaching the predefined max dose in their Phase I?

Dirk Haussecker said...

Agreed, Alnylam on January 3 reported that they had filed the CTA, so at minimum it's now 1 1/2 after filing the application. However, if they are not starting to recruit by now, then how are they going to meet guidance of results by mid-2013?

In any case, the conclusion of the blog entry stands: TTRsc seems to have borderline activity and betting on this particular chemistry would seem very risky, unless GalNAc Plus is substantially different. If the clinicaltrials entry appears, then even better and let's look at the dosages.

Anonymous said...


Obviously you haven't done the proper DD before posting your blog.

From the past archive, Alnylam filed their CTA for TTR02 Phase 1 on January 06, 2012 and it didn't go on to until March 19, 2012 and they completed that trial by the end of May. So to be consistent with their past record, I expect TTRsc will go on to by the middle of March when they start dosing in the patients and expect the trial to be completed by the middle of 2013.

Alnylam has already made it clear that the trial will involve both single and multiple ascending doses. They don't have to disclose dose range for competitive reason. Tekmira & Isis also didn't disclose the dose range when they started their respective trials for PLK-1 and TTR.

You are also making false assumption that the reported TTRsc potency data is the most recent data. For the obvious competitive reasons, we will not have the actual potency data until after the trial is complete. For their AT3, they have achieved a remarkable potency with repeat dosing of ED80 of only 0.5 mg/kg. This is well under 1ml of volume. And they need to achieve only ED50 for clinical benefits in the patients.

And as per your concern that GalNAc has never been tried in the humans before, this is no different then when they first tried tried MC3 In human trial based on NHP data alone. Their TTR02 human data were consistent with NHP data. At this time there is no reason to be believe that GalNAc human trial data will not be consistent with NHP data.

Contrary to your position, I see Alnylam's aggressive move into GalNAc delivery platform as a sign of confidence. It is Alnylam who took the risk of moving MC3 into human clinic and prove it out into humans. And gain it will be Alnylam that will prove out GalNAc into humans and prove skeptics like you wrong.

Dirk Haussecker said...

The non-human primate ALN-TTRsc data they presented is with the formulation that will go into the clinic and this is where I get the 2.5mg/kg number from. Anything else would have been grossly misleading.

With MC3, they did not have much of a choice but to take on the significant risk. The situation is different now.

Anonymous said...

Companies that don't take risk when opportunities are presented, remain in the doghouse for ever. Passing on the opportunities only allows the potential competition to march ahead.

Alnylam has a unique opportunity to accert its independence from Tekmira and establish itself as an undisputed leader in the field of RNAi. Success with GalNAc will open the floodgates for new partnership opportunities for Almylam.

Anonymous said...


Question: What if Alnylam holds off going into a Phase III or pivotal trial with ALN-TTR2 until the results of the Phase I of ALN-TTRsc are received (which will likely show some efficacy data even though designed more for escalating dose/safety). If ALN-TTRsc Phase I shows significant progress/promise, what if Alnylam then decides not to press forward with Phase III for ALN-TTRsc? Would that mean that Tekmira won't get the $5 million due to it, since there would not be a pivotal/Phase III for TTR2? Just wondering, and perhaps is the reason for Alnylam's push to bet on GalNAc.

Dirk Haussecker said...

It's conceivable, but not likely due to the competition with ISIS and GSK. They care about being first-to-market and signing those patients on.

Anonymous said...

Dirk, very interesting blog and comments. I have a question that has been haunting me for some time as an investor in siRNA development companies. Has any evidence surfaced that would suggest that the efficacy of siRNA modalities declines over time in the treatment of individuals? Such a decline would be very problematic.

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