Dicerna Keeps Searching for Its Identity

Dicerna Pharmaceuticals recent move from Watertown to Cambridge is symbolic for its continued search for a place in the RNAi Therapeutics landscape.  Following some setbacks in its cancer and home-brew LNP efforts, the company now pins its hope on that it can compete head-on with Alnylam in the development of GalNAc-RNAi trigger conjugates for gene knockdown in the liver.

Oncology on hold

Like others in the field, confidence in its cancer program (DCR-MYC in phase I/II studies for solid cancers and HCC) seems to be low.  In the absence of clear-cut early development-stage cancer responses and confirmation of bona fide tumor-wide gene knockdown, cancer drug development remains a hit-and-usually-miss for the Oligonucleotide Therapeutics industry.

As a result, Dicerna seems to view their own mouse data with skepticism just as I myself have yet to see data supporting tumor penetration and bona fide knockdown in well-controlled studies.  The company has to be credited that it is now setting the bar for DCR-MYC quite high when clinical data from higher-dose cohorts is expected to emerge around year-end.  If DCR-MYC does not make the cut, Dicerna will likely cut its losses in cancer drug development and LNP research in general.

DCR-PH1 close call

Dicerna management was also surprisingly frank about their hesitations about the technical success of their most interesting current program, namely DCR-PH1 for the treatment of hyperoxaluria type I. 

After reviewing the latest non-human primate studies, it now appears that at least an 85% mRNA knockdown of the HAO-1 target gene will be required to see the key oxalate biomarkers ‘move’, and over 90% for more robust movement.  Based on rodent data, the company had thought that 75% might be sufficient.

In NHP studies of DCR-PH1, an 84% average peak knockdown was seen following a single dose of 0.3mg/kg of a Tekmira SNALP LNP formulation with 68% knockdown remaining at week 4.  0.3mg/kg seems to be the current well-tolerated upper dose of Tekmira’s LNP formulations and almost identical (protein) knockdowns were observed with 0.3mg/kg of Tekmira LNP-formulated ALN-TTR02. 

In clinical 3-weekly multi-dose studies of ALN-TTR02, this translated into sustained 80-85% target gene knockdowns.  This means that Dicerna now relies on the safety of DCR-PH1 to allow for doses of around 0.5mg/kg.  Not impossible, but probably a close call given the history of SNALP LNP and further exposes DCR-PH1 to competitive threats.

GalNAcs coming

Given the stage of their internal cancer and LNP efforts, Dicerna is now pinning its hopes on taking on Alnylam with GalNAc-RNAi trigger.  This is where Dicerna is currently investing most of its R&D efforts in.

It has now disclosed non-human primate data from those efforts, with 5 consecutive daily doses of 2.5mg/kg GalNAc-Dicer substrates resulting in ~70% knockdown of HAO-1 2-3 weeks after this loading dose.  Given the larger molecular size of the extended Dicer-substrates versus Tuschl-type siRNAs, this corresponds on a molar basis to ~1.5mg/kg of Alnylam’s GalNAc-siRNAs.  

This is somewhat less than what Alnylam presented for their PH1 program at OTS 2014 (ED80s in rodents of ~2.5mg/kg weekly) and Dicerna's GalNAcs would seem to require some further refinements to be competitive.

But in this case, they will end up with something that has little pharmacological distinction, is 3-4 years behind Alnylam, which in turn is not shy to put legal/IP pressure on its competition.

In my opinion, Dicerna management and Board need to put in quality time to find their true identity.

Disclosure: I am short DRNA as a relative valuation short for my ARWR long position. DRNA has a slightly larger market cap than ARWR, but ARWR has a distinguished, more mature DPC pipeline with ARC-520 and ARC-AAT two attractive candidates in the clinic whereas DRNA has nothing in the clinic it apparently has confidence in.  It's possible that both stocks are grossly undervalued, but relative valuation is one of my main RNAi investment methods and this is why I'm applying it here. Nothing personal.

Follow-Up to Simplified GalNAc-RNAi Trigger Discussion

Just days after the Matsuda et al. publication on simplified, non-triantennary GalNAc-RNAi triggers (the subject of the previous blog entry), another related paper from Alnylam came out (Rajeev et al. 2015). 

The Rajeev et al. publication further supports that monomeric GalNAc designs as pioneered by Arrowhead Research for the use in RNAi Therapeutics and others (e.g. Matulic-Adamic et al., 2002) before for non-RNAi Oligo Therapeutics applications allow for effective ASGPR receptor recognition and subsequent gene silencing.  

The main difference to the Matsuda paper was that instead of GalNAc-modified nucleotide monomers, non-nucleosidic GalNAc monomers were employed (note: the Matulic-Adamic et al. also explored both nucleoside- and non-nucleoside-based monomeric clustering GalNAc strategies). They, however, were also appended to the 3’ end of the passenger strand as part of the phosphoramidite-based RNA synthesis.

The use of non-nucleosidic phosphoramidite monomers further simplifies the chemistry demands and thus cost of goods of GalNAc-siRNAs.

Ironically, not only does this paper also fail to cite the seminal Arrowhead and Matulic-Adamic research, this significant effort to get away from the apparently costly triantennary design is also at odds with Alnylam’s claims in July 2014 that a patent covering bi- and triantennary conjugates designs ‘broadly cover[ed] conjugate-based delivery of RNA Therapeutics’.

Obviously, if non-bi- and triantennary designs work, then one cannot consider the issued patent to broadly cover conjugate-RNAi triggers.

It will now be interesting to see how broad the claims will be that the patent offices will grant related to the simplified designs.  The re-writing of history effort obviously is not aimed at impressing investors or enabling the field, but part of a GalNAc IP landgrab effort, ideally resulting in the issuance of claims covering any monomeric GalNAc designs.

The one thing that I would like to give Alnylam credit for is that they will put significant resources behind the technologies they consider promising- whether they invented, own, or have a license to them or not- and thus advance RNAi Therapeutics as a field.

GalNAc Advance by ISIS Means Oral Oligonucleotide Therapeutics around the Corner

Last week, the long-awaited first publication on ISIS’ GalNAc-targeted antisense oligonucleotides appeared in a ‘NAR Breakthrough Article’ (Prakash et al., 2014)  Living up to that label, the data with RNaseH antisense oligonucleotides (ASOs) conjugated to triantennary GalNAc sugars showed that this strategy increases potency by nearly an order of magnitude.  In combination with high-affinity chemistries (in this case cET) that facilitate the use of short (12-14nt vs ~20nt) oligonucleotides which has been shown to improve in vivo potency (Santaris research by Straarup et al., 2010), oral delivery for antisense modulation of hepatic gene expression has essentially been solved. 

Moreover, the lower dosages that can now be used in addition to the improved biodistribution profile that is now heavily slanted away from non-hepatocytic cell types in the liver and the kidney in favor of hepatocytes, means that the other major benefit of GalNAc-ASOs with immediate applicability is that the safety of therapeutic ASOs for liver-directed applications will be much improved.

The conclusion that oral antisense therapeutics are just around the corner is based on the observation that a relatively crude caprate-based phosphorothioate oligonucleotide formulation enabled a ~10% bioavailability following oral administration already (intravenous = 100%; Tillman et al., 2008).  This, in addition to some inter-subject variability that might have been linked to gastric emptying times, meant that too much oligonucleotide would have had to be administered orally with previous antisense oligonucleotides. 

Granted, this first piece of GalNAc-ASO literature did not explore oral delivery. The fact, however, that the combined use of GalNAc conjugation with high-affinity chemistry improved parenteral ASO potency by 60-fold is predicted to mean that oral GalNAc-cETs are already more potent (~6x) than subQ-administered 2^nd gen ASOs.  These have already produced impressive phase II data for targets such as Factor XI and ApoCIII.

The potency improvement in terms of oral delivery may actually be larger than 60-fold.  This is because oral delivery strategies such as caprate co-formulation which aim at increasing intercellular drug permeability are size dependent.  This means that there should be an added benefit of the smaller oligonucleotide size facilitated by cET chemistry with oral delivery.

Of course, the data leave open some questions.  My most pressing, applicable to both oral and non-oral uses of GalNAc-ASOs is how the rodent data translate into non-human primates and ultimately humans.  This is because for unconjugated phosphorothioate oligonucleotides, the potency on a mg/kg basis improves with the size of the organism.  The discussion above is based on an assumption that GalNAc-targeting will not change that.  I have been unable to make a determination yet as to whether this should hold true or not.

Other than that, the antisense weather forecast is blue skies ahead, though with a chance of thunderstorms in the form of IP skirmishes with their good friends over at Alnylam as they have pioneered GalNAc conjugation in oligonucleotide therapeutics, but may now be ironically penalized for it from a competitive point of view.  Alnylam is not the type of company that just lets competitive threats happen to them.

The GalNAc Wars

‘All roads lead to GalNAc’ was the thoughtful, almost philosophical response by Alnylam’s CEO John Maraganore when asked about the GalNAc-conjugate challenge mounted by ISIS Pharmaceuticals for gene silencing in hepatocytes. 

With 20mg per week (corresponding to less than 0.1mg/kg per week) and a much improved hepatocyte-specific biodistribution of otherwise more promiscuous phosphorothioate chemistry, GalNAc-antisense has suddenly re-emerged as a significant competitive threat to the hepatocyte-targeted RNAi delivery solutions by Alnylam, Arrowhead Research, and potentially other undisclosed efforts.  By comparison, 1^st gen GalNAc-based ALN-TTRsc by Alnylam required at least 10x more oligonucleotides to effect potent gene silencing in a phase Istudy in TTR amyloidosis. 

2^nd gen ESC GalNAc-conjugates are claimed to be significantly more potent, but I suspect that they won’t be that much more potent than GalNAc-ASOs and will have to win the GalNAc battle based on safety.  Arrowhead’s GalNAc-targeted single-molecule DPCs should still be the most potent of the bunch, but it is about time for them to advance them into the clinic as the first-in-class train is leaving the station for an increased number of targets and it is feeling the most-potent-in-class heat in its lead HBV indication that is based on 2-molecule DPC.

With GalNAcs applied in such a ubiquitous manner, you’d think that the likes of Alnylam and ISIS Pharmaceuticals, not known for sitting on their hands when it comes to claiming ownership over technologies would start flexing their IP muscles.  As I noted in a post from AsiaTIDES earlier this year, the word on the lab floors is that GalNAcs per se are an old, non-patentable free-for-all such that the IP focus should shift to other aspects of the GalNAc-targeting approach such as linker chemistries and economical manufacturing methods.

As much as it is an interesting twist that ISIS would adopt Alnylam technology to become competitive again for liver-directed gene silencing, the IP situation is intriguing given the cross-licensing relationship between the two companies.  The original arrangement going back to over a decade ago gave Alnylam access to IP from ISIS for the use in double-stranded oligonucleotide therapeutics, and in return ISIS got access to IP from Alnylam for use in single-stranded oligonucleotide therapeutics.  Whether this IP exchange includes IP that does not directly impinge on oligonucleotide chemistry, such as aspects of delivery will be a critical element in how easily an outright IP war could be triggered. 

If Regulus Therapeutics which has rights to Alnylam’s GalNAcs as evidenced by its anti-miR122 candidate is a guide, the IP exchange would be broader than just oligonucleotide chemistry.  On the other hand, I would be very surprised if strategy- and IP-savvy Alnylam did not foresee the potential perils of also giving ISIS access to its delivery technologies.

In any case, after the first verbal skirmishes, expect the saber-rattling around GalNAc to increase with IP adding a new dimension to what has largely been a battle based on potency and safety considerations.