The imminent announcement of phase I results for RXI109 will
be a clinical highlight of RNAi Therapeutics in 2013. RXI109 is the self-delivering RNAi trigger
against dermal scarring and is developed by RXi Pharmaceuticals. Needless to say, as the company is committing
90% of its resources to this trial and indication, the results should cause
major volatility in the stock.
While the dermal anti-scarring landscape is complex, RXI109
for the present indication can safely be categorized as a cosmeceutical. According to RXi Pharmaceuticals, already $100M are spent each year in the US on non-FDA approved ointments against dermal scarring. The interest in RXI109 is thus for its
commercial potential and the clinical results are a milestone in the development of so-called ‘self-delivering
RNAi triggers’.
Self-delivering RNAi triggers are a concept coined first by Dharmacon (although one could argue that was largely a branding achievement as it essentially involved known cholesterol conjugation), but is getting more widely adopted these days. Beyond its local indications for which they self-delivering RNAi triggers were initially developed, I expect the concept to also be applied to certain systemic delivery strategies. I could imagine that in an effort to render GalNAc-siRNAs more potent, self-delivering chemistries will be useful.
Self-delivering RNAi triggers are a concept coined first by Dharmacon (although one could argue that was largely a branding achievement as it essentially involved known cholesterol conjugation), but is getting more widely adopted these days. Beyond its local indications for which they self-delivering RNAi triggers were initially developed, I expect the concept to also be applied to certain systemic delivery strategies. I could imagine that in an effort to render GalNAc-siRNAs more potent, self-delivering chemistries will be useful.
Phase I studies
RXi has conducted two phase I studies. In both studies, volunteers got multiple surgical incisions
symmetrically on both sides of the abdomen. For each pair of incisions, one side either received RXI109 or
placebo by intradermal injection. In the first study, RXI109 was given
just once before incision, from 1mg to 10mg per 2cm incision (similar range as in the Excaliard antisense trials). In the second study, RXI109 was given three
times within two weeks from 2.5mg to 7.5mg per 2 cm incision.
In addition to safety and tolerability, the important
endpoints will be a visual assessment of scarring and then, based on a biopsy
obtained from a tummy tuck at Day 84, important biomarker data in the form of CTGF levels (the target gene) and a histological evaluation of the
scar tissue.
Although this is a blinded study, the company has discussed
blinded results in extenso. On the
safety front, there seems to be little cause for concern, and adverse events
are consistent with what you would expect from an incision. Management appears to be very bullish on the
therapeutic outcomes since in many cases left and right sides look different. So if they are different, the side that looks
better should have been given RXI109, right?
Unfortunately, you have to look very hard to spot the differences. In one example shown, the ‘average
differences’ in scar tissue area were 31%.
Since they will put their best foot forward with this example, the
largest effect size that we can expect is 31%.
And this assumes that in each case, it is the drug-treated side that
outperforms the placebo-treated side.
It is thus difficult for me to be optimistic that this trial
allows for a therapeutic effect to be demonstrated. For this, the natural wound healing
variability would have to be really small (I admittedly don't know what this is).
On the other hand, it is with this symmetrical, intra-patient control design
that such small differences might be teased out. Regardless, I expect enough data to be
collected from the studies that it will make for a nice headline and
narrative about how RXI109 had improved wound healing and the correlation with
CTGF (I bet there will be a correlation, whether due to knockdown or not).
So while I think that RXI109 is a decent RNAi Therapeutics
(not the best possible one given the short dsRNA length), it will be important
to conduct future studies in patient populations more prone to scarring to
increase signal to noise. This could be
for example in the scar-revision setting or in Asian populations.
Trading the event
As I expect major volatility and have some confidence in the
science behind RXI109, I have taken a long position ahead of the event. It is not clear whether the results from the
two studies will be presented separately or together. I suspect the latter given that the CEO of
RXi in February/March guided the results from the first study to be
forthcoming in April. Since it is almost
June already, it is likely that the company expects the biggest bang from presenting
the results together. This should happen before July. Once again, given that there
is so much potential for data-mining, I expect positive headlines- justified or
not.
