Friday, July 12, 2013

RXi Reports 43% CTGF Knockdown in Multi-Dose Dermal Anti-Scarring Trial

Today, RXi Pharmaceuticals announced the results from its multi-dose phase I study of RXI-109, the company’s self-delivering RNAi compound for dermal anti-scarring.  Importantly, in the two highest of the three dose cohorts a credible 43% (average) gene knockdown was observed three days after the last (=third) intradermal injection of RXI-109.  It is the first time that a knockdown was reported for the so-called ‘self-delivering’ class of RNAi triggers.

The results followed those from a single-dose study lastmonth where dose-dependent gene knockdowns were claimed three months after the single injection (note the difference in the time points).  Turns out that this was a slightly misleading conclusion as in my book a numerical 15% target reduction does not constitute a clinically meaningful knockdown for the vast majority of target genes and indications, and I'm not even discussing the precision of gene expression measurements.

Whether a 43% knockdown of CTGF is clinically meaningful also remains to be seen as no data were presented on the actual impact of RXI-109 on scar formation.   Pfizer, following its acquisition of dermal scarring antisense company Excaliard, would probably know best what type of knockdown was required.
In a broader sense, the 43% number also raises the question of whether self-delivering RNAi triggers by RXi Pharmaceuticals will be a class of gene silencing agents that will struggle to achieve 50% gene silencing, instead of 70, 80, 90% and more that might be required for most indications.

Overall, mediocre results and it stands to reason that the future of RXi Pharmaceuticals will be in ocular indications and not in dermal anti-scarring.

Comment on Alnylam's $3B market cap

I, like many of you, have watched with wide open eyes Alnylam reaching a $3B market cap today. In less than two weeks, this company added over $1B in valuation based on highlighting in their press releases the best single datapoints from individual patients (e.g. 'over 80% knockdown' for ALN-TTRsc), instead of average knockdowns, area under the curves, and dosages.

While that does not entirely surprise me as a veteran of reading between 'topline data', a more intriguing question is what the company will do with such a low cost of capital.  Remember, the situation was similar about 5 years ago when Alnylam failed to either raise capital and/or acquire Tekmira to avoid the litigation.  I expect the company to act this time on its share price, a view supported by constant analysts upgrade on any news piece the company throws in front of them (--> fees for investment banking business).


Beau Bassett said...

How much money have you lost on ALNY?

Terry Chrisomalis said...

Dirk not bad for phase 1 also they mentioned in their phase 2 studies they will optimize the doses more! So couldn't they achieve better results with higher dosing? Anyways I notied you were always disclosing that you were long on RXII! are you still long RXII and do you believe in the self delivery technology after today's results shown?

experiencedmentor said...

I'm reminded of Phase I news back around 2008 that spiked the share price of Alnylam above $34 (I sold most at that time and bought Tekmira). The Phase I news turned out to be much ado about nothing, so the price dropped below $7. Their treatment of Tekmira, their settlement after denying their actions, the trouble they caused with their lies...have ruined me on this company's management. I'll invest vicariously in the science through underpriced Tekmira.

Terry Chrisomalis said...

Dirk to add another question. I see that RXII is giving hard numbers for their positive results. In the article you claimed that Excaliard would know the right percentage of knockdown.

But when I look online for Excaliard phase 2 positive trials they don't list any percentage of gene knockdown at all. They just say better than placebo but they don't give a hard number. So how do we know what number is needed as you say to achieve a good knockdown for anti scarring? We never got to see Excaliards phase 2 results fully!

Dirk Haussecker said...

I've also looked in vain for Excaliard's knockdown numbers from the clinical studies. I'm long RXi, but feel misled by their single-dose knockdown claim.

Anonymous said...

Looks like Alnylam is in a strong financial position to gobble up one of those companies. Any predictions?

Terry Chrisomalis said...

Dirk did you listen to the RXI CEO interview with CEO and Griffin securities? The CEO mentioned that Excaliard achieved 30 to 40% CTGF reduction in their phase 1 testing. It's under events and webcast on official RXII site. So it seems Excaliard achieved less Results on their phase 1 testing.

Dirk Haussecker said...

Yes, I listened to it and was quite surprised about the apparently weak knockdown of the Excaliard/Pfizer compound. Do you know the dosing schedule for those studies? Maybe they optimized subsequently to improve knockdown?

If 30-40% was really the knockdown number for the Excaliard compound, it raises the question whether everything is an off-target phosphorothioate antisense class effect.

Terry Chrisomalis said...

From what I understand Dirk from the CEO of RXII in the interview Excaliard/Pfizer phase 1 of 30% to 40% gene knockdown was with a higher dosing regimen than RXII. Meaning RXII achieved slightly higher at 43% with lower dosing than Excaliard.

Also I understood what the CEO of RXII was saying as comparison between RXII and alnylam. in Alnylam you want the high gene knockdown of 80% or greater, but in anti scarring you don't want it that high, because it is possible to have a negative effect on wound healing. Meaning inhibiting the healing completely. So we can't compare the 2 because they treat something entirely different.

Stanley said...

you're wrong dude

Must read this article: RXi Pharma Hopes For a Quick Breakthrough

By Steve Haas | More Articles
July 27, 2013
Page 2 of 5view all
2. In light of your Phase 1 results, you may have noticed the results Alnylam (NYSE:ALNY) presented last week for their clinical program. Where do you place their 80 percent reduction in protein in context with your 43 percent reduction in mRNA level?
I was surprised when I noticed that some people have actually tried to compare these 2 compounds. It makes no sense, as it is like comparing apples and oranges. First of all, we have looked at protein levels of CTGF as well as the mRNA levels for that protein; and RXI-109 targets abnormal scarring of the skin. The Alnylam compound is targeting a completely different and genetically altered protein and focuses on amyloidosis in the liver. CTGF is a normal protein that is needed for wound healing, and hence complete silencing of the protein could have a negative consequence on the normal wound healing process. Consequently it is good for RXI-109 not to suppress the CTGF production completely.

In the case of TTR, we are talking about a mutated protein that is causing issues in the liver. The more you can suppress the formation of that protein, the better for the patient. Also, the doses and route of administration are quite different. The Alnylam compound is used systemically at 2.5 mg/kg. Our compound RXI-109 is used intradermally at doses of approximately 100 microgram/kg, i.e. at 25 times a lower dose. Bottom-line a comparison between the 2 does not make much sense.

By Dirk Haussecker. All rights reserved.

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