Unlike all the major RNAi pure plays (Alnylam, Arrowhead,
Dicerna, and Silence Therapeutics), RXi Pharmaceuticals is not pursuing GalNAc-based gene knockdown in the liver.
Instead, it applies its self-delivering RNAi (sdRNAi) triggers to local and, more recently, ex vivo gene
suppression.
Its ex vivo efforts
involve the addition of the silencing triggers to immune cells in the absence of extraneous transfection reagents with the goal of enhancing the performance of cell therapy-based immune oncology. Immune oncology, of course, is a hot area in
drug development. Notable clinical successes mechanistically aim at immunologically unmasking tumor
cells (à
checkpoint inhibitors) or sending T-cell killers after them (à CAR-T).
Transient RNAi non-obvious application to cell therapy
When sdRNAi licensee MirImmune, now part of RXi came forward with the idea of applying transient
RNAi strategies to cell therapy, I was very skeptical. Cell
therapies after all suggest that long-lived pharmacodynamics are desired, whereas
RNAi gene silencing in dividing cells is known to be limited in duration, maybe a week or so. Wouldn’t therefore gene therapy and in
particular genome editing for gene ablation be much more useful? Or what about that half-forgotten
DNA-directed RNAi?
Certainly, for gene silencing effects that ideally should last throughout the active life of the adopted cells in the patient, transient RNAi
is not attractive given all the alternative technologies out there such as genome editing and of monoclonal antibodies.
On closer inspection, however, transient RNAi may
be able to uniquely achieve a number of goals that could uniquely enhance adoptive cell therapy
for cancer and potentially other applications, too. One of them is to simply increase
the number of cells with the desired phenotype. After all, the patient-derived cells used for adoptive cell transfer are a precious resource and manufacturing issues could result in cell numbers too low to be useful. Accordingly, self-delivering RNAi triggers may increase the number of useful cells either by expanding them, e.g. by targeting cell cycle-related genes, or by more effectively directing them to the desired phenotype (e.g. tumor-attacking vs protecting/tolerogenic cells).
Importantly, as sdRNAi does not require electroporation or transfection reagents, there is less risk that the procedure itself reduces cell numbers or has undesirable effects on the cell phenotype.
Out of the test tube and into patients, transient RNAi could
also be useful in helping in the early tasks of the adopted cells. One such early step is infiltrating the tumor which
is thought to have a major impact on immune oncology treatment success. While tumor infiltration can be expected to
be largely guided by proteins interacting on the cell surface and would seem a suitable application of monoclonal antibodies, monoclonal antibodies often have difficulties getting into tumors.
It is also conceivable that an early performance provided by transient RNAi may have a lasting effect on eventual therapeutic outcome, e.g. by hitting the cancer hard initially so that the risk of immunologic escape by mutation is minimized. This is similar to how early reductions in pathogens predict the treatment success of most infectious diseases such as HCV.
Finally, RNAi may be applied to multiple genes at once. This is more difficult to do with systemically administered monoclonal antibodies, and unlike monoclonal antibodies, RNAi can also inhibit proteins not accessible to monoclonal antibodies; multi-targeting is also less effective with genome editing.
Looking ahead
Transient RNAi for adoptive (immune) cell therapy is in its
early stages. Given some of its unique
characteristics, it could be a useful addition to the gene toolbox next to genome editing, DNA-directed RNAi, or simple gene addition. While RXi is planning to plod along with
preclinical proof-of-concept studies, as a non-immune oncology person and given
the poor capitalization of the company, I particularly look towards clinical collaborations
and corporate partnerships to judge just how compelling a tool transient RNAi really is here.
RXi as an investment or trade
RXi Pharmaceuticals is a small biotech company with a tiny
market cap of ~$13M and I would be remiss not to mention that I currently own
somewhat more than 2% of the outstanding shares (ticker: RXII). This is a relatively small gamble on my part,
but certainly enough to keep me interested and engaged.
Right now, it is probably not much more than a gamble given
that RXi’s management has displayed an extraordinary degree of naivete about
the capital markets. Accordingly, their continued operations currently largely rely on an ATM-type arrangement
with Lincoln Park Capital Fund which appears to only have accelerated putting down the stock, and possibly eventually the company down a death
spiral.
Near-term, RXII is therefore a bet that management will finally
stop this nonsense and instead rely on the upcoming multiple (!) clinical trial
outcomes catalysts by year-end from at least 3 (dermal scarring, cutaneous warts, consumer skin products) of its non-immune oncology portfolio to create some excitement about the stock. Results from a retinal scarring trial are expected in early 2018. Considering the tiny market cap of ~$13M, the sheer number of upcoming data read-outs alone could result in mouth-watering stock returns if the stock gets discovered. Such a run-up would of course also provide financing opportunities to feed its immune oncology ambitions, so please management: don't put a lid on it by activating the ATM.
