Tuesday, December 16, 2014

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).

13 comments:

Anonymous said...

DCR-PH1 can't compete with Alnylam PH1 drug. Monthly I.V vs monthly (or less frequent) Subq from Alnylam? No way it can compete. Patients/doctors don't care who is first to the market. They only care which is the best drug.

It also seems time line on DCR-PH1 has slipped a little bit. Initially they guided to report P1 data in 2H2015. Now they are guiding they will file IND in 2H2015. So Alnylam is less than a year behind them. Any first mover advantage would be temporary at best.

Anonymous said...

Alnylam is spreading itself kind of thin with all these initiatives to try and be the master of all RNAi IP.

As noted in the blog, Arrowhead has well overtaken Alnylam through focus support on alpha-1-antitrypsin, Dicerna will be the next to follow this process to focus its efforts more effectively than Alnylam.

Anonymous said...

Bet DRNA won't be able to do a NVGN on todays performance. Even BLUE didn't come close.

Stunning. Breakthrough in melanoma.

Anonymous said...

We can only assume Dirk did not have it in his portfolio. Thus, no mention of it before or after. Instead we should all be buying CYCC and ride his coattails.

Anonymous said...

As we wait for the nadir of the current phase to be reached before the mother of all transactions is made, Xmas Eve makes for an interesting observation.

Should the announcement be made after close then, any stock bought or sold after the announcement would not settle til the New Year.

Would that make it the deal of 2014 or 2015?

Worthy of note is option expiry on the 20th and Hannukah ending on Xmas Eve.

About now, you kinda almost expect JM to come out with a five or more deals by the end of the year statement.

Anonymous said...

NVGN just a pump and dump ahead of a capital raise. Placement to those on the inside coming in over the top of existing holders with those in the know getting out.

Pretty cynical management to pull a stunt like that.

Endosome escape hatch patentee, Phylogica (ASX:PYC), that is to say NOT ARWR, had some strong movement yesterday for the first time in a very long time.

Suspect something similar to NVGN is about to happen.

Anonymous said...

shRNAs efficacious in pancreatic cancer.
C'mon Dirk, get with the program.... BLT.

Furthermore, we demonstrated that silencing ╬▓III-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs.

Anonymous said...

The poster of PYC comments got his or her answer today.

Genentech takes a licence. $500k up front. $142m total. Targeted space is novel anti-microbials.

It is nothing to do with ARWR or endosome escape hatch technology.

This comes hard, first day of business hard, on the back of ALNY taking on the CBST's CEO and MRK buying CBST out. Not to mention the goings on at TKMR and some strange trading on the close and in after hours in the like of RGLS, ISIS and ARWR on Friday.

One should not forget the deal ALNY made with MRK earlier on in the year to buy their Sirna remnants. Nor should they ignore the paper MRK published the other day about peptide delivery of siRNA when after terminating their partnership with Galapagos currently have no peptide partner.

Dirk, is there an elephant in the room nobody wants to talk about?

Anonymous said...

I think if you want to make money on the stockmarket, people should ride Dirk's example and buy in to CYCC.

Anonymous said...

"As we wait for the nadir of the current phase to be reached before the mother of all transactions is made"

This mother is the TPP. I believe the intent is to close it out in Jan. IP rights are central to the agreement.

Republican's need to grant fast track authority to ensure it can be closed out expeditiously.

Until then, the shorts will always be in control.

Anonymous said...

The approach to analysis on this blog seems to have a presumptive pick-the-winner attitude without much regard for the functional elements of the products and the facts behind definitive differences. The companies aren't the same either.
Two issues.

1. What is actually different in the chemistries/processes and WHY does that matter in current evals AND the pipeline (or an acquirer's pipeline)? Said more plainly, should an investor in a foundational area like RNAi care if one PH1 approach is ahead of another?
2. People seem to ignore the elephantine differences in MCap between emerging RNAi companies. The dosage level observations are good to know. However, at what level is the dosage level good enough? Does it really matter financially if the dosages are ever smaller? Angels/pin? Remember, we're dealing with very targeted chemistry, not old-time large protein effects. Given the historic delivery issues, those difference would seem to be important. Does the tiny company have a marked superiority (for a broad pipeline) compared to the massive MCap company?
And what can be said about the difference in MCap? When one is valued at less than one percent of the "leader," maybe the financial outcome is better with the #2, or maybe the #2 is actually a better solution, but as in point 1 above, how would we know?

PS. Great blog page. This is not bashing - more of a frustrated search for meaning among the noise. Happy Holidays all.

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Anonymous said...

DRNA on a tear today. Looking very, very strong ahead of JPM fest next week.

Lot of expectation riding on this years meeting.

Could the two be correlated? Dirk?

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