Tuesday, January 28, 2014

Antisense Comparison Provides Hope for RXi’s Dermal Scarring Drug Candidate

In early December, RXi reported phase I data from new cohorts that were added to the multi-dose study of RXI-109 in dermal scarring.  Accordingly, by increasing the dose to 10mg self-delivering RNAi trigger from previously 7.5mg per injection site, the company was now able to achieve a 50% target CTGF gene knockdown (5 and 7.5mgs: 43%). 

Based on the meager 30-40% knockdowns and apparent efficacy that were observed in comparable clinical studies targeting the same CTGF with a phosphorotioated antisense compound at 5mg per cm scarline­, the prospects of RXI-109 would suddenly appear to be much brighter.  Of course, the ISIS compound was spun out into Excaliard which was then acquired by Pfizer in late 2011 for the apparently promising data observed with the dermal scarring candidate EXC001.  EXC001 is now in late-stage clinical development.

Of course, there are a number of caveats with this reasoning.  For one, although the study protocols appear very similar, it is possible that the tissue biopsies taken to obtain the CTGF knockdown measures were of dissimilar sizes.  Given that CTGF knockdown can be expected to wane quickly away from the injection site, such differences could have a material effect on the apparent knockdown efficacy. 

On the darker side, when you consider a nice visual therapeutic effect (see picture) in light of a 30-40% knockdown, you start to wonder whether the actual effect on scarring was less due to blunting of CTGF expression and more due to some non-specific immune-related effect of the phosphorothioate backbone in the antisense compound.  The RXI-109 compound may not ‘benefit’ from such an effect.


Nevertheless, the 10mg dose results are a step forward and form a useful basis for the phase II studies that RXi Pharmaceuticals will be rolling out this year in lower abdominal scar revision (already initiated), keloid scar revision, and scar revision following cosmetic breast surgery.  

Unfortunately, prospects would have been even brighter had the company employed a more potent RNAi trigger design.  And when the CEO, in 2014, still shows a slide with Kreutzer-Limmer controlling dsRNA lengths of 15bp and over (to justify the use of dsRNA < 15bp), I would suggest they update their presentation slides.  Similarly, it would be honest to not talk about a market cap of $50M, but to present their more meaningful capital structure, including preferreds and the like.

2 comments:

Stanislav Stupka said...

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.

Terry Chrisomalis said...

I agree stanislav some people don't get it still. The meager 43% gene knockdown is because anti scarring need only up to 40 to 50% because an 80 to 90% gene knockdown actually stops the wound from healing completely. Many people still don't understand this point.

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