Wednesday, July 30, 2008

Pfizer and Quark Progress RNAi Therapeutic for Diabetic Macular Edema into Phase II

Quark Pharmaceuticals today announced that development partner Pfizer has initiated dosing of the first patient in a phase II trial of the RNAi Therapeutic candidate PF-4523655/RTP801i-14) for diabetic macular edema (DME). The start of the phase II trials is a vote of confidence in RNAi Therapeutics for eye diseases by a major pharmaceutical company with a considerable eye care franchise and growing ambitions in RNAi Therapeutics.

The 160-person safety and efficacy trial follows phase I/II studies conducted by Quark that showed the drug to be safe and well tolerated in patients with wet age-related macular degeneration (wet AMD). Similar to DME which affects about 10% of type I and II diabetics, wet AMD is caused by the growth of leaky blood vessels in the back of the eye leading to blurred vision, and in some cases blindness. For this reason, it is not uncommon that a given compound is being tested for both indications.

The reason that Pfizer has chosen DME instead of wet AMD as the indication for this trial may be related to the fact that the wet AMD RNAi Therapeutics space has become crowded with Opko Health and Sirna Therapeutics/Merck having wet AMD RNAi Therapeutics in phase III and II studies, respectively. Opko Health also has a phase II study for DME using the same compound. It may also be related to the recent controversy caused by a Nature paper that showed that dsRNA-triggered immune responses alone may be anti-angiogenic in a mouse model for wet AMD and that this may have led to mis-interpretations of data from related pre-clinical RNAi Therapeutics studies.

However, PF-4523655 is unlike Sirna’s and Opko’s compounds in that it is intended to prevent abnormal blood vessel growth and leakage in a VEGF-independent manner. It is also a 19bp blunt-ended compound and therefore unlikely to trigger non-specific TLR3 responses (21bp seems to be the cut-off where you have to take TLR3 signaling into account). I trust that the former Coley Pharmaceutical’s folks with their deep understanding of TLR biology and that are now running the RNAi Therapeutics show at Pfizer will have closely looked at the issue.

Quark received an undisclosed amount for the initiation of the trials, Silence Therapeutics which had originally licensed the AtuRNAi technology to Quark collected $1.9M, and Alnylam from which a technology license was subsequently obtained on Pfizer’s insistence another undisclosed amount. Clearly, with today's allowance of Silence Therapeutics’ 10/633630 patent in the US which specifically claims AtuRNAi molecules of 18 or 19 base-pairs the IP battles are about to begin, and will be addressed in a follow-up blog entry. In any case, it is an interesting coincidence that the initiation of the phase II studies and the patent allowance occurred on the same day.

Independent of all these patent issues, I look forward to the results of this compound which has the makings of a safe and differentiated RNAi Therapeutic for DME.

13 comments:

GS said...

Hi Dirk

The allowed claims of 10/633630 cover 15-23 nucleotides.

Dirk Haussecker said...

Thanks. Is there a link to the allowed claims? Seems to directly conflict with Kreutzer-Limmer in Europe.

Jtrader said...

Dirk,
Did pfizer make quark get an ALNY license?
Thanks

Dirk Haussecker said...

Jtrader- quite definitely. The Alnylam license and the Quark-Pfizer RTP-801 alliance were announced the same day (September 26, 2006).

GS said...

I've emailed the claims over.

I think that Silence's claims are allowed because they are restricted by the blunt ends. ie. something K-L didnt claim.

Dirk Haussecker said...

GS- Fundamental patents, by their nature, are broad. One could argue that blunt ends are implicitly claimed by generic double-stranded RNAs of the same lengths.

GS said...

Yes. However, blunt ends alone didnt apparently work well enough. As such, why should Tuschl et al claim aspects of inventions that didnt work until others found ways of making them work?
The US and EU examiners of course have agreed that such modifications are novel.

Presume you now agree that the allowed claims of 10/633630 cover 15-23 nucleotides?

Dirk Haussecker said...

GS- Not really, 15-23 base-pair dsRNAs yes, but only if they "comprise" of the alternating nucleic acid modifications. Doesn't automatically mean that Kreutzer-Limmer will not be considered fundamental to that claim, and I therefore highly doubt Silence has FTO based on that patent allowance alone.

Ironically, the reason why Tuschl II does not claim blunt dsRNAs is not because they did not work at all, but because it might have been vulnerable to Kreutzer-Limmer. You should look at the data disclosed in Tuschl II before you make such a claim.

GS said...

My point was simply that the allowed claims cover 15-23 nuctleotides - with whatever other specifications are stated. Not
"which specifically claims AtuRNAi molecules of 18 or 19 base-pairs", as you wrote.

Furthermore, I stated "didnt 'apparently' work well enough" - quite different from saying "because they did not work at all" as you seem to make out!

If Tuschl et al had got blunt ends to work sufficiently, they'd have documented it in some form - so as at least to prevent others from patenting it, if not being able to get allowed claims themselves?

The debate here was not whether Silence has freedom to operate, but that the USPTO has deemed their claims to be allowable and thus, not claimed within the prior art of Tuschl, Kreutzer-Limmer, or other.

Dirk Haussecker said...

"Furthermore, I stated "didnt 'apparently' work well enough" - quite different from saying "because they did not work at all" as you seem to make out!

If Tuschl et al had got blunt ends to work sufficiently, they'd have documented it in some form - so as at least to prevent others from patenting it, if not being able to get allowed claims themselves?"

Well, I'm surprised that Silence has never published a systematic comparison of unmodified blunt-end dsRNAs and blunt-end dsRNAs modified with the breakthrough AtuRNAi modification technology. Wouldn't that be the best, and btw very easy-to-do answer, to put to rest any doubts as to the superior nature of "AtuRNAi"? I would expect a journal like Nature to be more than glad to publish such ground-breaking research, as they did Tuschl's work in 2001.

And, as you would have to admit, the discussion is about Silence's FTO, why even bother discussing this patent allowance otherwise?

GS said...

I was originally simply pointing out your error regarding the number of bp covered in the claims.

"Well, I'm surprised that Silence has never published a systematic comparison of unmodified blunt-end dsRNAs and blunt-end dsRNAs modified with the breakthrough AtuRNAi modification technology. Wouldn't that be the best, and btw very easy-to-do answer, to put to rest any doubts as to the superior nature of "AtuRNAi"? "

Agreed.

Dirk Haussecker said...

GS- fair enough. I was looking at the original patent application from 2003, which was much broader in scope and put a lot of emphasis on 18-19 base-pairs (see original claims 2 and 3):

http://www.google.com/patents?id=v2efAAAAEBAJ&dq=10/633630

Forgive me, but I'm slowly getting confused as to what Silence believes/claims is the (non-obvious) optimal siRNA length.

In any case, it will be interesting to see whether any major Pharma would want to stake their RNAi future on "AtuRNAi" IP.

GS said...

Aside from AZ, yes.
I must admit, I share your concerns.

I guess that Silence are banking on either getting Kreutzer-Limmer revoked and going with 18-19 nt molecules

OR
hoping that Tuschl I will never be allowed

If pharmas share this view, then they'll go for deals. However, it seems likely this is why Silence havent had a molecule deal for over a year?

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