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.
