As a veteran armchair RNAi Therapeutics strategist, I am
frequently frustrated at the inflexibility of companies in the face of rapidly moving competitive and drug development environments. The worst offenders are those with management and Boards that view their positions as entitlements and could not care less about the science and acknowledge the flaws of their technology.
Often related to this, another common violation is a failure to cut your losses on an obviously
failed development program at the cost of the platform, a strategy though that sometimes works if you can find a greater fool (the ~$700M acquisition of Prosensa by Biomarin yesterday falls into that category).
Tekmira, too, has been at risk of suffering from such inflexibility in light of an industry-wide shift from nanoparticle-based to small conjugate-based delivery. This does not mean that nanoparticle-based delivery will not have an important role to play in the future of RNA(i) Therapeutics, but that you have to realize your relative strengths in a highly competitive space. In addition, Tekmira has been slow to realize the shifting regulatory and payor landscape making biomarker-focused orphan drug development in genetically defined patient populations highly attractive.
Having listened to the Tekmira Analyst Day last Friday, I
was therefore quite pleased that not only is Tekmira catching up by beginning to realize that it is running a business and not a scientific think tank, it can even be considered to take on a strategic leadership role in at least two regards:
1)
the adoption of multi-payload candidates thereby
addressing the i.v. nanoparticle versus single molecule subQ debate and leveraging key advantages of nanoparticle technology;
2)
running trials in parallel to quickly find out
which delivery chemistry platform
works best in humans.
1.
Multi-targeting: a key differentiator of
nanoparticle-enabled RNA(i) Therapeutics
At the Analyst Day, Tekmira re-iterated that it will put a multivalent HBV formulation into the clinic that will contain three RNAi triggers. In addition to ensuring that most patients
thus become a match for the therapy, just as the two-trigger ARC520 by Arrowhead
Research had been geared towards, Tekmira also wants multi-targeting to address viral
resistance of the kind it observed in the woodchuck model of HBV.
From that perspective, the intravenously
administered TKM-HBV is preferable to single molecule approaches by Alnylam and
ISIS Pharmaceuticals which are both administered subcutaneously.
Tekmira does not limit multivalent RNA Therapeutics to viral applications such as in their HBV and Ebola programs, it will also apply the concept outside that space such as in its
hypertriglyceridemia program where it is considering dual-targeting formulations
with ApoCIII, ANGPTL3, and DGAT2 as candidate targets.
Equally or even more intriguing, in the Q&A session it was hinted that other therapeutic strategies that the company is considering may not merely involve multiple payloads of the same type, but even payloads from different categories such as an mRNA and an
RNAi trigger. Obviously, such combinations could open up entirely new therapeutic strategies (e.g. mRNA-RNAi combos for alpha-1 antitrypsin),
or maximize potency (e.g. RNAi trigger-RNaseH ASO for HBV).
Scientifically, I see no reason why single molecule technologies such as GalNAc-siRNAs should not be amenable to certain (but not all, e.g. mRNA) multivalent approaches. Culturally, however, multi-valency takes away from the single molecule simplicity that
the pharmaceutical industry apparently loves, ideally in pill form. From a regulatory point of view, it seems to
be the case that nanoparticle-encapsulated RNAi products are seen as just one
drug no matter how many RNAi triggers it contains, and it remains to be seen what the
regulatory thinking would be when combining multiple single RNAi triggers (I can imagine Alnylam trying to combine their HBV mRNA-targeting GalNAc-siRNA with its PD-L1 GalNAc-siRNA).
In some ways, ARC520 (which is not a nanoparticle) strongly indicates that multi-targeting is not
an insurmountable challenge for the non-nanoparticle approaches, so that
regulatory advantage may not exist in the future.
Nevertheless, my prediction is that multi-targeting will be
mostly practiced in the nanoparticle and not the conjugate sector of RNAi
Therapeutics and nanoparticle-based companies ought to consider multi-targeting
almost a Must when there is direct conjugate delivery competition.
Although Tekmira is the most visible RNAi company for
multi-targeting, it should be added that multi-targeting has been the motto for
US-China-based Sirnaomics from the get-go in 2007.
2.
Testing Multiple Delivery Technologies in
Parallel
The RNAi Therapeutics field is both blessed and plagued by the rapid progress in refining particular delivery platforms. Tekmira has already arrived at the 4th generation of SNALP LNPs while Alnylam is now talking about GalNAcs with standard and enhanced chemistries. With a multitude of preclinically validated alternatives, it is often difficult to determine which one
should be prioritized for human development.
This can lead to protracted development timelines when a
first formulation yields unsatisfactory results in the clinic and the
payload has to be re-formulated into a new delivery chemistry. Especially in competitive environments this can be fatal. And even if you were
somewhat satisfied with the initial results, chances are that you left a lot of
money on the table by not finding out about the performance of other formulations in humans.
Needless to say, having multiple candidates for a target is
not a unique challenge in the pharmaceutical industry and if money were not an
issue, we would see a lot more parallel development programs. However, RNAi and related delivery is unique as
the investment can be amortized across the platform.
Moreover, in practical terms, RNAi offers a
number of opportunities to directly and accurately measure target engagement and thereby assess the impact of changing the formulation. This is one of the reasons why the early RNAi programs targeting genes in the liver involve targets which can be found in the blood. For other modalities (e.g. microRNA inhibition in the RNA
Therapeutics field), what you measure in your blood sample or other biopsies
may differ significantly from what is actually going on in the body.
For these reasons, namely to speed up time-to-market in a
competitive market and to inform which delivery formulations should be used
with other LNP-enabled candidates, Tekmira announced that it is about to put
two formulations of TKM-HBV in the clinic that will only differ in their
delivery chemistry while using the identical (3) RNAi triggers.
Tekmira investors are not seeing double: the company is becoming a modern drug developer.
