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.

Dicerna Behind Alnylam in GalNAc, But Early Data Suggest Clinical Relevance

As promised, RNAi Therapeutics fast-follower Dicerna for the first time disclosed last night data on GalNAc-conjugated Dicer-substrate technology.  It was not much that was shared, but a single-dose mouse ED50 value of ~2.0mg/kg (30% knockdown at 1mg/kg) suggests that similar to Alnylam, Regulus and ISIS Pharmaceuticals before, Dicerna also has achieved clinical relevancy with GalNAc-conjugates.  In other words, the data are consistent with robust clinical knockdowns with multi-dosing at doses of 10mg/kg or less.

By comparison, the single-dose ED50s for Alnylam’s first-generation GalNAc-siRNA ALN-TTRsc (OTS 2012 presentation) were between 1 and 5mg/kg in mice (20-25% knockdown at 1mg/kg) and 5mg/kg in Man (phase I study).

The data, both potency-wise and the fact that it was murine data only (not non-human primate data), however, also make it clear that Dicerna is at least 2 years behind Alnylam.  Accordingly, the company expects to file its first GalNAc IND in 2016, though it said it already has 4 candidates cooking for that purpose.

Due to the competitive disadvantage, it is understandable that Dicerna is keeping its gene targets secret (e.g. the data were against an undisclosed gene) as the primary hyperoxaluria and HBV histories have shown that Alnylam’s strategy is to suffocate its competition by announcing competing clinical candidates. 

On the other hand, with some luck and skill, Dicerna should be able to exploit its secrecy and build a large competitive lead in its chosen indications given that in going after ~2 dozen indications at once, Alnylam is spreading itself thin.   The alpha-1-antitrypsin history where Arrowhead has well overtaken Alnylam through focus supports this.  Similarly, Dicerna seems to have a good working relationship with the PH1 community which is very important in the ultra-orphan drug development field.

Overall, assuming that murine GalNAc data translate into non-human primates and humans, the promise of being able to knock down genes in the liver subcutaneously in a clinically relevant manner is important step forward for Dicerna which before that was without viable delivery technology.   

Other news

In last night's presentation, Dicerna also for the first time revealed non-human primate data for its lead primary hyperoxaluria program DCR-PH1 (note: investors should discount DCR-MYC).  The data show a near-elimination of the HAO1 target gene at monthly doses of 0.3mg/kg and due to the cumulative efficacy, a monthly repeat dose of ~0.1mg/kg should be feasible for a solid impact on disease-causing oxalate crystal formation.   Importantly, such a dose is expected to be safe, especially with the novel 'EX' strategy whereby Dicerna is adding anti-inflammatory activities in the RNAi trigger extension.

PS: from a scientific point-of-view, it shall be interesting to see data come out relating to the impact of the nucleic acid structure (e.g. length of double-strand RNA) added to a GalNAc ligand on functional delivery efficiency.  Such data would be informative on the mechanism of endo-lysosomal release and guide towards further optimization of the platform (e.g. utility of positive charge, lipophilicity, stability).