Dicerna has
just entered its GalNAc-RNAi conjugates into the clinic and by the looks of it, seems extremely confident
about being able to forecast its performance in humans.
Single-dose study
At least this
is what I am forced to interpret into their remarkable decision to merely conduct a single-dose
phase I/II study with DCR-PHXC for primary hyperoxaluria before going straight
into a planned (multi-dose) pivotal study in 2019.
There is, of course, precedent from Alnylam’s ample experience with a related GalNAc-RNAi
conjugate format and how animal studies have translated into humans and how repeat-dosing
in man have increased and extended the knockdown compared to single dose administrations.
Dicerna thus believes it will be able to predict the optimal dosing schedule for the all-important registrational study based on single-dose monkey-to-human translation and the
effect of repeat dosing in monkeys.
You’ll
probably be scratching your head already how accurate such modeling by
triangulation can be. Complicating matters, the primary aim is not to achieve a predetermined level of
target knockdown (lactate dehydrogenase A/LDHA), but in fact oxalate knockdown which is downstream from LDHA.
So a lot of moving parts between a single-dose
gene knockdown and therapeutic lowering of a toxic metabolite following
prolonged and pronounced multi-dose knockdown. And don’t
get me started on the impact of RNAi trigger formats, the nature of their chemical
modification as well as the target gene identity on gene silencing duration…and what about the small issue called 'safety'?
Dicerna: if
this rushed design is an effort to catch up with the competitive program by
Alnylam to better compete for patients for the pivotal trial, it’s probably not
worth it. Either you are greatly increasing the risk of phase III failure or, more likely, you'll be sent back into earlier-stage multi-dose studies by regulators (similar to what happened to the Alport program by Regulus Therapeutics).
Dicerna talking down value of mystery program
Following
DCR-PHXC, Dicerna plans to bring two additional drugs into the clinic in the
near future: one against HBV and another one for an undisclosed orphan disease.
Aside from
the fact that I believe that there is little point in keeping the target identity a secret since they have pretty much given it away by characterizing it as one
with >100,000 patients in the US alone (à alpha-1-antitrypsin-related liver
disease), it is remarkable that the CEO has said that they
are looking for a ‘risk-sharing’ partner at this early stage already.
Even more
surprising was the comment last week that Dicerna will even wait to partner the
program before entering it into clinical development!
This truly
is unheard of for a company in the red-hot genetic biotechnology space where
funding is relatively easy to come by these days for a company of a profile like Dicerna
(clinically ready genetic technology, $700M market cap). Here, the universally accepted name of the game is to get at least a
couple of drug candidates into the clinic with minimal ownership dilution (e.g. by partnering) early on. Developing an orphan candidate to clinical readiness and then idling it sends out a clear signal that the candidate is deemed to have disappointing prospects.
It would be easy for Dicerna,
with the stock up 100% since the recent offering, to do another ~$100M raise to
comfortably navigate three programs through proof-of-concept.
With these two unexplainable apparent unforced major errors, it got me thinking: can it be explained with the uncertainty around the trade secret litigation with Alnylam? According to the Q4 2017 conference call, a trial date has been set for April.
