Sunday, March 11, 2018

Dicerna Supremely Confident About Clinical Pharmacology of its GalNAc Platform


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.



6 comments:

Steve_382 said...

Upcoming dates for Alnylam case:

03/13/2018 02:00 PM Civil H Rm 520 Rule 56 Hearing Leibensperger, Hon. Edward P Rescheduled
03/13/2018 03:00 PM Civil H Rm 520 Courtroom 520 Rule 56 Hearing Leibensperger, Hon. Edward P
04/12/2018 02:00 PM Civil H Rm 520 Final Pre-Trial Conference Leibensperger, Hon. Edward P
04/23/2018 09:00 AM Civil H Rm 520 Jury Trial Leibensperger, Hon. Edward P

Steve_382 said...

I also put some recent docket entries at the IV site:

https://www.investorvillage.com/smbd.asp?mb=569&mn=33992&pt=msg&mid=18085465

Steve Rubis said...

I am not sure I understand your conclusion. Are you saying that the trial will be positive or negative. That last paragraph lost me completely after reading a well-written and very thoughtful article.

Dirk Haussecker said...

Thank you both for your comments.

Steve R.: In the counterclaim by Dicerna against Alnylam, Dicerna has been arguing that it is a small company whose prospects of developing a unique drug for those desperately afflicted by primary hyperoxaluria are in doubt due to Alnylam trying to sue little Dicerna into bankruptcy.

A year ago, with a market cap well below $100M and little cash, this was probably true. Although fortunes have changed a bit, Dicerna may still want to keep up appearances at least until the trial by tying their fate largely to the PH drug candidate and not adding to the cash balance.

The other possibility: Dicerna has trouble finding investors for a $100M-type secondary in light of the upcoming trial.

Either way, I can sense some desperation from their recent actions and I don't think it's the technology they're doubting.

Steve Rubis said...

Thanks for the clarification, as I think what you described in your comment as making perfect sense. I would agree that they are likely waiting to disclose the second drug because of the legal battle. Thank you! keep up the great research!

Unknown said...

Dirk,

What's your opinion on today's price move for dicerna? Looks like some panics here.

thanks.
bob

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