2012 was the most exciting year in the ~12-year history of
RNAi Therapeutics- both from a scientific and financial perspective. Left for dead by
most, unambiguous gene knockdown results in Man have allowed the technology to regain much-needed respectability. With the start of 2013, the
industry is looking to build on these successes with additional clinical trial
results, interesting new therapeutic candidates and product-specific and
platform-related deals, particularly in the area of delivery. With appetite for innovation increasing in a
low interest rate economy and with the orphan drug tsunami, 2013 could be a quite rewarding year for the discerning investor.
Clinical results to look out for
Clinical results in 2013 that will continue to shape perceptions of the
technology include phase II study results for ALN-TTR02 in TTR-FAP by Alnylam, phase I
results from its GalNAc conjugate version ALN-TTRsc, and phase I results from a
number of other programs, foremost from oncology drug candidate TKM-PLK1 by
Tekmira, ALN-AT3 for hemophilia by Alnylam, and
finally RXI-109 for dermal scarring by RXi Pharmaceuticals.
For ALN-TTR02, it will be important to confirm the impressive
knockdown results from the phase I study, but over longer periods of time and
with still acceptable safety. ALN-TTRsc will
be an important proof-of-concept for the subcutaneous delivery of RNAi Therapeutics and
should provide a good idea of what to expect for ALN-AT3 which is based on the
same GalNAc siRNA conjugate technology. The success or
lack thereof of Alnylam’s GalNAc technology will also affect the perception of
Arrowhead’s DPC technology as either a competing or necessary subQ alternative
to GalNAcs.
Tekmira’s TKM-PLK1 has not gotten much credit so far. This, however, could change with the
presentation of the full phase I results, possibly at this year’s ASCO.
I consider PLK1 as the single most
attractive target for cancer RNAi and I am bullish that the molecular analyses
will show molecular, if not clinical efficacy at this early stage. And while
TKM-PLK1 could overcome the safety-efficacy hurdle for some indications, the
importance of PLK1 as a target demands that Tekmira will continuously work on improved
follow-on versions.
Finally, RXi’s second phase into RNAi for skin applications.
I also consider dermal scarring as an interesting differentiated, because cosmeceutical RNAi product opportunity.
Cool pipeline additions
As detailed in my last blog entry, there are two exciting
infectious disease drug candidates for which clinical development will ramp up in 2013: Arrowhead’s ARC520 aiming to achieve for HBV what has recently been
achieved in HCV (dramatically increased cure rates and less suffering from the side effects of interferons), and Calimmune’s ddRNAi-based HIV drug candidate aiming to keep the virus out
of immune cells.
It looks like we will have to wait for clinical efficacy results from
these programs for a while (2014-2015), either due to the nature of the cell
competition approach involved in the HIV program or because of the use of healthy volunteers. I believe the latter is what
Arrowhead has guided for ARC520, but from an investor perspective this would be highly unforunate as this would delay the demonstration of gene knockdown with the
DPC platform. And from a medical
perspective, I am struggling to see what the value or necessity of a volunteer
trial would be.
Deals and Big Pharma
In addition to clinical trial results, RNAi Therapeutics
investors will be getting up each morning to check the internet for whether a deal has been announced. Alnylam’s ALN-PCSK9 is the most imminent
partnering candidate and will be an indicator of the mere differentiation value
of RNAi Therapeutics. While
clinically more advanced monoclonal antibody-based programs for the industry’s
most desired target, PCSK9, exist, should monoclonal antibody stumble as a
class, RNAi Therapeutics and ALN-PCS could suddenly have the market for itself. Considering the multi-billion $$$ potential of
PCSK9, a gamble worth taking for a Big Pharma in my opinion.
Similarly to ALN-PCS in the hypercholesterolemia
market, the size and complexity of the clinical program that would be required to turn ARC520 into a major HBV drug well exceeds Arrowhead capacities, and this could mean that we will see an early licensing
deal around that asset, too. While proof-of-concept clinical knockdown
data would greatly increase the partnering value of ARC520, from a financial
perspective (--> di-lu-tion!) early partnering
may be prudent if no alternative non-dilutive capital alternative presented itself.
As delivery is gating for all of the above RNAi Therapeutics product
opportunities, delivery naturally should be the subject of a few more platform-type
relationships. Tekmira’s SNALP
technology for addressing diseases of the liver, lung, and cancer tops the list
for a meaningful partnership (>$10M upfront), and also Arrowhead’s DPCs for
liver-targeted gene knockdown ought to see some interest.
Delivery-related deals should also reveal which Big Pharma
company is still committed to the RNAi Therapeutics platform. For the efforts at Takeda, Merck, and Novartis
(the three most significant ones in terms of investment to-date), it could be a
make-or-break year. I cannot imagine
that these groups are allowed to exist in their current forms for much longer
before they get anything into the clinic. For this, they probably need to swallow their
own pride and accept that expert outside help is necessary for their delivery
needs (rather than attempting home-brew versions). Given the recent clinical and late preclinical
results for SNALPs and DPCs, chances that they will finally do something have
certainly increased.
A Happy New Year everybody.
