Thursday, June 6, 2013

RXi Reports Dose-Related Knockdown Three Months Following Single Injection

RXi Pharmaceuticals today reported top-line results from the first of two phase I studies with RXi-109 in dermal scarring.  Intriguingly, the company claims to observe target gene knockdown three months following a single intradermal injection of their self-deliverable RNAi trigger (p=0.02) in a manner that was apparently dose-related. 

Such a drug-dependent and dose-related knockdown would exceed my expectations from this trial as stated in a recent preview here.  The reason why I merely expected to see a correlation between CTGF levels and phenotypic effect on dermal scarring being reported today is that I did not have high confidence that the tissue residence time of RXI109 would be prolonged enough to observe a bona fide RNAi knockdown. 

To wit, the tissue biopsy on which this data rests was obtained during a tummy tuck three months after the intradermal injection of the RNAi.  To assess whether there was an RNAi knockdown in such a single-dose study, I would have thought that an early time-point such as two weeks after injection would have been more appropriate, also because it is likely that some of the CTGF-producing cells might be proliferating in this setting (RNAi duration inversely correlated to proliferation status).

The notion that a correlation between CTGF levels and wound healing would be observed was based on CTGF reflecting tissue inflammation.  So regardless of whether there was an RNAi effect or not, you might expect to see such a correlation.  It is difficult, however, to explain a drug-dependent and dose-related target gene knockdown with this notion, except for by a rare coincidence.

These results then bode well for the multi-dose phase I studies from which results will be reported in time for the Investor and Analyst Symposium on July 12.  While safety was the primary focus of the first study (no adverse event on the early wound healing process confirmed), the effect of RXi-109 on wound healing will be the focus of the second study.  It should be added though that given the small size of the trials and the patient population which is not predisposed to scarring, spotting the difference will be tough.

Disclosure: long RXII.

10 comments:

Anonymous said...


dirk, why did you illustrate this post with a horrible scar? My immediate response was very negative because I associated the scar with the RXi study. If you had included a faint scar as an illustration of what RXi is trying to accomplish, it would have been better, but no illustration would have been best.

Anonymous said...

What do you think of Benitec's recent $7 million placement to fund HCV and lung cancer trials?

Anonymous said...

Ian Ross is at Benitec.need we say more?

Dirk Haussecker said...

Benitec raise...probably the best they could do and looks fair to small investors. On the other hand, I am afraid that times for HCV gene therapy are over and how do you deliver plasmids to lung cancer cells? It's hard enough to delivery siRNAs to cytoplasm, but large DNA to nucleus of sufficient cells with polymers??

Anonymous said...

Dirk, what do think of the research Benitec has completed with Medistem combining ddRNAi with adult stem cells over the past few years? I think they investigated rheumatoid arthritis and tissue rejection after transplantation.

Anonymous said...

"I am afraid that times for HCV gene therapy are over".

Sounds like they are just beginning to me. RAC unanimously (17/0) endorsed TT-034 and there was much hope and excitment in the room for a one-shot treatment. Benitec, despite it's miniscule share price, just may be the first RNAi company to have a product in commercialisation.

Anonymous said...

Yeap. The RAC acknowledged that the latest HCV drugs will be big improvement but there was still a real need for a one shot HCV treatment because in many countries it won't be possible to ensure that patients get all the course of treatment required for the oral regimes. This is an endorsement of Benitec's reasoning.

Anonymous said...

Dirk,
You should write an entry about how the Supreme Court's decision that genes in their natural state cannot be patented actually makes RNAi drug delivery technologies even more valuable since value shifts from owning genes to creating the best drug to silence them.

Anonymous said...

The scarce resource now is silencing the genes in the most effective way. Viral and human genes are now plentiful since nobody can own them.

Dirk Haussecker said...

Myriad Supreme decision...it's an interesting thought whether it affects RNAi Rx. However, since the IP coming closest to the Myriad issue in the space concerns patents that protect RNAi triggers directed at genes, and not the genes themselves, I do not see the ruling to change much here. The ruling does, however, make it less likely that you can discover a gene, including the new class of long noncoding RNAs (usually of unknown medical relevance initially) and then carpet bomb them with a slew of RNAi triggers to essentially own that gene as a drug target. This approach, however, has become less and less feasible anyway.

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