Wednesday, January 2, 2013

What to Expect from RNAi Therapeutics in 2013

2012 was the most exciting year in the ~12-year history of RNAi Therapeutics- both from a scientific and financial perspective.  Left for dead by most, unambiguous gene knockdown results in Man have allowed the technology to regain much-needed respectability.  With the start of 2013, the industry is looking to build on these successes with additional clinical trial results, interesting new therapeutic candidates and product-specific and platform-related deals, particularly in the area of delivery.  With appetite for innovation increasing in a low interest rate economy and with the orphan drug tsunami, 2013 could be a quite rewarding year for the discerning investor.

Clinical results to look out for

Clinical results in 2013 that will continue to shape perceptions of the technology include phase II study results for ALN-TTR02 in TTR-FAP by Alnylam, phase I results from its GalNAc conjugate version ALN-TTRsc, and phase I results from a number of other programs, foremost from oncology drug candidate TKM-PLK1 by Tekmira, ALN-AT3 for hemophilia by Alnylam, and finally RXI-109 for dermal scarring by RXi Pharmaceuticals.  

For ALN-TTR02, it will be important to confirm the impressive knockdown results from the phase I study, but over longer periods of time and with still acceptable safety.  ALN-TTRsc will be an important proof-of-concept for the subcutaneous delivery of RNAi Therapeutics and should provide a good idea of what to expect for ALN-AT3 which is based on the same GalNAc siRNA conjugate technology.  The success or lack thereof of Alnylam’s GalNAc technology will also affect the perception of Arrowhead’s DPC technology as either a competing or necessary subQ alternative to GalNAcs.

Tekmira’s TKM-PLK1 has not gotten much credit so far.  This, however, could change with the presentation of the full phase I results, possibly at this year’s ASCO.  I consider PLK1 as the single most attractive target for cancer RNAi and I am bullish that the molecular analyses will show molecular, if not clinical efficacy at this early stage.  And while TKM-PLK1 could overcome the safety-efficacy hurdle for some indications, the importance of PLK1 as a target demands that Tekmira will continuously work on improved follow-on versions.

Finally, RXi’s second phase into RNAi for skin applications.  I also consider dermal scarring as an interesting differentiated, because cosmeceutical RNAi product opportunity.  

Cool pipeline additions

As detailed in my last blog entry, there are two exciting infectious disease drug candidates for which clinical development will ramp up in 2013: Arrowhead’s ARC520 aiming to achieve for HBV what has recently been achieved in HCV (dramatically increased cure rates and less suffering from the side effects of interferons), and Calimmune’s ddRNAi-based HIV drug candidate aiming to keep the virus out of immune cells.

It looks like we will have to wait for clinical efficacy results from these programs for a while (2014-2015), either due to the nature of the cell competition approach involved in the HIV program or because of the use of healthy volunteers.  I believe the latter is what Arrowhead has guided for ARC520, but from an investor perspective this would be highly unforunate as this would delay the demonstration of gene knockdown with the DPC platform.  And from a medical perspective, I am struggling to see what the value or necessity of a volunteer trial would be.  

Deals and Big Pharma

In addition to clinical trial results, RNAi Therapeutics investors will be getting up each morning to check the internet for whether a deal has been announced.  Alnylam’s ALN-PCSK9 is the most imminent partnering candidate and will be an indicator of the mere differentiation value of RNAi Therapeutics.  While clinically more advanced monoclonal antibody-based programs for the industry’s most desired target, PCSK9, exist, should monoclonal antibody stumble as a class, RNAi Therapeutics and ALN-PCS could suddenly have the market for itself.  Considering the multi-billion $$$ potential of PCSK9, a gamble worth taking for a Big Pharma in my opinion.

Similarly to ALN-PCS in the hypercholesterolemia market, the size and complexity of the clinical program that would be required to turn ARC520 into a major HBV drug well exceeds Arrowhead capacities, and this could mean that we will see an early licensing deal around that asset, too.  While proof-of-concept clinical knockdown data would greatly increase the partnering value of ARC520, from a financial perspective (--> di-lu-tion!) early partnering may be prudent if no alternative non-dilutive capital alternative presented itself.

As delivery is gating for all of the above RNAi Therapeutics product opportunities, delivery naturally should be the subject of a few more platform-type relationships.  Tekmira’s SNALP technology for addressing diseases of the liver, lung, and cancer tops the list for a meaningful partnership (>$10M upfront), and also Arrowhead’s DPCs for liver-targeted gene knockdown ought to see some interest.  

Delivery-related deals should also reveal which Big Pharma company is still committed to the RNAi Therapeutics platform.  For the efforts at Takeda, Merck, and Novartis (the three most significant ones in terms of investment to-date), it could be a make-or-break year.  I cannot imagine that these groups are allowed to exist in their current forms for much longer before they get anything into the clinic.  For this, they probably need to swallow their own pride and accept that expert outside help is necessary for their delivery needs (rather than attempting home-brew versions).  Given the recent clinical and late preclinical results for SNALPs and DPCs, chances that they will finally do something have certainly increased.

A Happy New Year everybody.


Anonymous said...

no partner for Benitec?

Anonymous said...

Nothing in for Silence Therapeutics
with their ATU027 trial this year??

Anonymous said...

In 2013 Gradalis will complete data collection for a number of its clinical trials including Pll data for melanoma and ovarian cancer. I would have thought a possible cure for cancer would be worth a mention?

Anonymous said...

City oh Hope's HIV gene therapy trial, which includes a ddRNAi construct, is already 'dosing' patients in its second phase. This study phase using much higher transfected cell numbers than the safety study already completed. Interim data can be expected this year.

Anonymous said...

Happy New Year to you too Dirk. Great blog. Ireland's Genable also planning on entering the clinic this year with it's ddRNAi/gene replacement candidate for retinitis pigmentosa.

Dirk Haussecker said...

Benitec...pure IP play IMO with IP under siege by Carnegie. Also, Graham starting to be just one of few RNAi trigger patents required to practice ddRNAi. Not having a lab is coming to bite the company. I've been saying it ad nauseam.

Silence...share price gone up, but it has become very quiet on scientific and biz development progress at company. Not sure what's going on there.

Gradalis...sorry, hasn't passed my smell test.

City of Hope...yes, worth watching. Getting transduction efficiencies up will also be key for Calimmune program. CoH's triple constructs now outdated though.

Genable...yes, missed that one. Will be good if they can make some clinical progress.

Anonymous said...


Regarding Carnegie IP, what are the patents or patent prosecutions for you to say it's got Benitec IP under siege?

From what I have been able to tell, it seems to be other way around. eg: Carnegie abandoned their Fire/Mello patent application with the EPO after many years, interestingly after a CSIRO paper by De Feyter (Waterhouse / Graham plant scientist colleague) was submitted under a 3rd party prior art.

At the USPTO, the Fire Mello '599 patent has been changed recently to claim only animals, not organisms. Interestingly after the same patent hit interferences by the USPTO's BPAI from a CSIRO Waterhouse patent application.

Also a third party objection to a Graham patent in UK was recently withdrawn.

Anonymous said...

looks like Gradalis have passed someone's smell test though:

DALLAS, Jan. 3, 2013 -- /PRNewswire/ -- Gradalis, Inc. today announced that is has closed a $24 million Series B round of financing. Gradalis will use the funding to advance its autologous vaccine platform, FANG™, through late-stage clinical trials and expand manufacturing capabilities to accommodate commercial launch of FANG. In addition, the funding will be used to progress the clinical and preclinical development of the company's bifunctional shRNA platform.

Anonymous said...

City of Hope trial now fully enrolled.

Dirk Haussecker said...

Claim 6 of the recently issued Fire patent US 8,283,329 covers ddRNAi in 'mammals':

'6. A method of inhibiting expression of a target gene in an animal cell in a mammal comprising providing at least one ribonucleic acid (RNA) to the animal cell in an amount sufficient to inhibit the expression of a target gene, wherein said RNAis provided to the animal cell by synthesizing said RNA in said animal cell, wherein the RNA comprises or forms a double-stranded structure containing a first strand consisting essentially of a ribonucleotide sequence which corresponds to a nucleotide sequence of the target gene and a second ribonucleotide sequence which is complementary to the target gene, wherein the first and the second ribonucleotide sequences are complementary sequences that hybridize to each other to comprise or form said double-stranded structure, and wherein the RNA comprising or forming the double-stranded structure inhibits expression of target gene.'

The prosecution history shows that there was much fight as to whether 'mammals' would be covered by the Fire patent because of the interferon response in mammals. For essentially all the rather very broad claims, mammals were specifically excluded due to the 'undue experimental burden' argument due to the interferon issue. However, it seems that claim 6 survived this challenge, possibly because internally generated dsRNAs may not have been predicted to trigger the interferon response at the time.

If for this claim with 'mammal' humans are covered, the claim would clearly cover Graham subject matter (even broader because no length restrictions). I therefore would not be surprised if an Interference was called and in that case, it looks like Fire would enjoy priority (unless, of course, Graham swears behind an earlier invention date).

Steve_382 said...


I would be much more optimistic about the field as a whole if one of the majors could get something into the clinic. In spite of Alnylam's and other small outfits best efforts, we still haven't really cured anyone. It's hard to know what's real and what is just hope.

Anonymous said...

Thanks for the reference Dirk. From the Graham '099 re-exam submissions, i doubt CSIRO and Graham would have a problem in providing evidence and swearing of an earlier invention date than Fire, if required of them. Infact I think they already did, but it wasn't necessary to uphold the claims.

I doubt Carnegie would want to push their luck in putting a blow torch, such as a re-exam or interference test, to the very broad claims of the Fire patents. Their backing down when challenged at EPO suggests this.

Dirk Haussecker said...

Steve...I can understand your sentiment, but let's don't forget that the way Big Pharma has played RNAi Rx so far was amateur at best. To consider them bellwethers of the validity of RNAi Rx science would be a mistake.

Anonymous said...


I had a bit more of a look at this recently awarded Fire patent.

I don't believe this threatens Graham IP at all, as its filing date is 28 Sept 2007. Its concluding comment to overcome the Examiner's interferon response in mammalian cells says it all:

'Collectively, the present application and the state of the art at the time of filing fully informed and guided those of skill in the art on how to practice the claimed invention in mammalian cells'

It lists Graham and Waterhouse references.

So not a chance that it taught one skilled in the art, prior to Graham's 1998 patent, how to practice endogenous RNAi in mammalian cells.

Anonymous said...

Hello Dirk...and Happy New Year! Could you please comment on Solstice Biologics and there "NEW" RNA Delivery Tehnology? THANKS!

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