Wednesday, January 6, 2010

2010 in RNAi Therapeutics Starts Off with Big Pharma Validations

If the first week is any guide, 2010 could develop into one of the most interesting years in RNAi Therapeutics history and comes after a somewhat lackluster 2009. Both the Dicerna-Kyowa Hakko platform collaboration announced earlier this week and the pre-IND milestone payment Alnylam received today from Big Pharma partner Roche are important proof-points that Big Pharma/Biotech (BBP) continues to invest in RNAi Therapeutics.

The Roche payment due to the initiation of IND-enabling studies marks the first time that a BBP is close to entering the clinic with its in-house developed RNAi Therapeutics candidate. The strength and clinical value of Alnylam’s strategy to further monetize on its mainly RNAi trigger IP has been increasingly questioned by skeptical investors as around half a billion dollars in realized IP funding has apparently not been enough thus far for one of its BPP partner to enter the clinic. This event should also be a boost to Tekmira Pharmaceuticals both in terms of platform validation and financially, as Roche has stated before that its first 2 RNAi Therapeutics INDs will involve SNALP delivery and Tekmira stands to collect ~$9M for each of the 2 candidates it helps Roche to get to the IND stage. For speculations about the indication of Roche’s first RNAi Therapeutics candidate, read the recent blog entry here.

While the Roche news is a definite plus for Alnylam, the Dicerna news has somewhat negative implications as it could be interpreted that BPP is becoming more hesitant to pay the Alnylam premium for what had been considered a toll-gate into RNAi Therapeutics. This is particularly so because Kyowa Hakko once paid Alnylam $15M upfront for Asian rights for Alnylam’s lead RNAi Therapeutics program for the treatment of RSV infection, and very little has been heard about the Kyowa relationship after ALN-RSV01 has been dropped as a candidate for development in pediatric populations. [update] However, as a reader rightly points out in the comments section, Kyowa's 'slight' may also simply reflect the fact that Takeda is Alnylam's exclusive Asian platform partner until 2013 and that Kyowa Hakko was sufficiently eager to speed up the development of its internal RNAi Therapeutics efforts by partnering with a pure-play RNAi Therapeutics company such as Dicerna.

Listening to some of Alnylam’s recent comments, especially its more frequent comparisons of RiSC vs Dicer-substrates, it also appears that Alnylam is not claiming to control the IP around Dicer-substrates. dsRNAs of 25bp and longer may therefore be a tempting, cheaper alternative into RNAi Therapeutics. I still believe that while Dicer-substrates are of comparable potency to Tuschl-type siRNAs, they are more complicated and therefore more costly to develop (especially innate immunity and more restricted chemical space due to requirement for Dicer-cleavage), although they these should not be considered show-stoppers and Dicer-substrates may actually allow for unique delivery strategies and in that regard may be considered complementary. The relatively early stage of Dicer-substrates, however, may explain why the immediate financial benefit to Dicerna was limited ($4M upfront, the rest biotech bucks), but should help the VC-stage company to raise further funds.

Price competition in RNAi trigger IP in the face of financially struggling competitors such as Dicerna, recent IP uncertainties, and the relatively increasing value attached to delivery vs RNAi trigger IP may indeed be responsible for Alnylam’s missed guidance of two major deals in 2009. While SNALP/LNP delivery is making great progress, Alnylam may have to offer more high-quality delivery options to further command terms similar to the Roche and Takeda collaborations. The decision of Novartis, which is about to spend $50B on eye-care provider Alcon, to pay Alnylam ~$100M this year for the broad adoption of Alnylam’s full RNAi Therapeutics IP, will be a good indication of the perceived strength of Alnylam’s IP if not the maturity of the technology.

Both the Alnylam-Roche and Dicerna-Kyowa news further underline the strong momentum of liposomal delivery and RNAi Therapeutics for cancer as also indicated by the Silence-Intradigm merger. Liposomal and lipid-based deliveries were highlighted in the delivery capabilities of Kyowa Hakko and Dicerna, respectively, and the first target picked by Kyowa was for oncology. Antibody-directed targeted delivery, also seems to gather pace as Kyowa Hakko further high-lighted such capabilities in the press release ('POTELLIGENT').

The two news items thus should be a good prelude to two other events this quarter that could decisively shift sentiment on the RNA Therapeutics sector into positive territory, namely the clinical trial results from Tekmira and ISIS Pharmaceuticals on their respective ApoB-lowering drug candidates.

Some RNAi Therapeutics Trivia: Dicerna almost appropriately means 'digested' in the Malay language.


6 comments:

Anonymous said...

Correct me if I'm wrong, but i remember reading that Takeda has platform exclusivity in asia for a limited time ex-RSV. In other word, Kyowa would not have gone to Alnylam for a platform alliance, because the Takeda deal precludes it.

-Henry

Dirk Haussecker said...

Thanks, Henry. I actually vaguely remembered something to this effect, but could not find the source. The 10Q, however, shows that you are right and that the exclusivity is for a term of 5 years. This is sufficiently important that I will add it to the blog.

Dima said...

Hey Dirk,

What do you think of the 2005 Nature Biotech Paper from Rossi's Lab showing that dicer substrates are more potent than siRNAs?

Dirk Haussecker said...

Dima- right now, I'm not sure whether that study was extensive enough to make that claim. It is more likely than not that if you start with a good Dicer substrate and then change the size of the duplex even when the precise cleavage/target site is unchanged that you will turn it into a worse Tuschl-type siRNA. The opposite is true, too. I think this is what happened in the Nature Biotech study as the overall picture that emerges is that Dicer-substrates and siRNAs are more or less similar in terms of absolute potency (Alnylam e.g. came to such a conclusion and extensive comparison looking at many different sites/dsRNAs). Even if Dicer substrates were on average slightly more potent, The more meaningful differentiation of the two approaches should be in delivery, maybe duration of silencing (TBD), tox etc

Nick said...

is this the PNAS paper from Alnylam you were talking about?
http://www.pnas.org/content/105/33/11915.abstract

The paper doesn't mention anything about "C12-200" though...

Dirk Haussecker said...

No, that's an older one. Try this link:
http://www.pnas.org/content/early/2010/01/06/0910603106.full.pdf+html
Happy Reading!

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