At the annual gathering of the gene therapy community today, Tekmira presented an update on
their ongoing phase I trial with TKM-Ebola, the company’s biodefense
candidate for the treatment of Ebola infection developed with funding by the US government (press release here, presentation here). I have long considered this to be a 'thankless' trial, a real ‘Haertetest’ of SNALP delivery because a) Tekmira took the risk
of not employing transient immune suppression as it otherwise does, and b) the multi-ascending dose
schedule (5x daily) would be as intense as in no other setting. While taking on all these safety risks, the
company would not be able to balance any safety findings with efficacy/knockdown data in this safety trial.
Indeed, what we got today was an update from the
single-ascending dose part of the study which showed a dose-limiting toxicity (DLT) in the form of immune stimulation resulting in the potentially serious condition of
hypotension at the top, 0.5mg/kg dose level.
From the many emails I have received and message board postings
that I have read on InvestorVillage, it seems that a common misinterpretation of the data was that they reflected poorly on the safety of 3rd gen SNALP delivery, the most recent and
most potent version of SNALP.
It is important to emphasize that the reason why we saw this DLT in this study, but not in the various,
preceding SNALP-enabled studies such as TKM-PLK1 (1st gen),
ALN-TTR01 (1st gen), ALN-TTR02 (2nd gen), or
ALN-PCS02 (2nd gen), is because Tekmira did not employ the transient
immune suppression around the time of dosing that has become routine for SNALP
technology following a similar finding of immune stimulation in the first-ever
trial with SNALP-RNAi, TKM-ApoB (2009/2010).
What it means for the pipeline
This means that if the company re-adopted transient immune
suppression for their other pipeline candidates, there would not be all that
much to worry about with regard to encountering this type of immune stimulation again. Transient immune suppression will not
matter much for most of the diseases of high unmet need and severity pursued by
Tekmira and partners (e.g. cancer, TTR amyloidosis).
The reason why Tekmira likely did not employ transient
immune suppression for TKM-Ebola is because the help by the immune
system is thought to be an important adjunct mechanism to achieving cures with an RNAi
approach to this highly severe, acute infection. Moreover, suppressing the immune
system might actually make the Ebola infection worse than it already is.
For other viral infections, especially HBV, the issues become more
complex. For example, it is known that
with immune suppression such as steroids or certain monoclonal antibody
therapies, HBV may dangerously reactivate.
However, if the immune suppression was only transient (~1 day versus an
RNAi duration of activity of weeks), I am not aware that the same risks exist. Moreover, doing something to get
the virus out of its hiding place and then coming in to knock it down may actually result in the highest cure rates just as the likelihood of e-antigen seroconversion
increases in immune active versus immune silent patients.
Another part of the equation would be whether doses anywhere
near 0.5mg/kg would be required for 3rd generation SNALP-based TKM-HBV. If say 0.15mg/kg or less would be enough,
transient immune suppression may not need to be considered.
What it means for TKM-EBOLA
Today’s data raises most uncertainty with regard to
TKM-EBOLA and the timeline of potential stockpiling. In the non-human primate studies, it was the
0.5mg/kg dose that resulted in 100% protection in a post-exposure treatment
setting. If the 0.5mg/kg dose level
would have been clean in the current trial, I would have been very optimistic
about the prospect of accelerated stockpiling, even before full FDA
approval. At 0.2mg/kg in the NHP
studies, protection was incomplete with 2/3 of the animal surviving.
In their presentation, Tekmira points to pharmacokinetic
data, especially the maximal drug concentration in serum that was higher in
humans than the monkeys at the same mg/kg dose levels. In other words, Tekmira makes the case that a 0.24mg/kg dose in humans would be therapeutically equivalent to the therapeutic 0.5mg/kg
dose in the monkeys.
It is true that under the Animal Rule, you have to
demonstrate sufficient safety in humans at doses that are pharmacologically
equivalent to those found to be therapeutic in the animal models, and these do
not have to be numerically the same on a mg/kg basis.
However, based on the limited monkey-human PK-PD bridging data provided, I am yet to be fully convinced by this argument. Ideally, there would
be knockdown efficacy data for 3rd gen SNALP available already, data showing that
on a mg/kg basis, 3rd gen knocks down genes slightly more efficiently in humans than in non-human primates.
The best sign that Tekmira is getting crucial buy-in from the FDA
and DoD would be if these agencies were in support of the dose levels chosen by
Tekmira for the multi-ascending dose part of the study that is planned to
start next month (0.06mg/kg, 0.12mg/kg, 0.24mg/kg). The presentation indicated that the
single-ascending dose data is under review by the FDA, and the MAD going ahead
could be a positive sign with regard to agency support.
Long-term research
challenge: new modifications
Long-term, it is still desirable for SNALP to fully wean
itself off from any transient immune suppression at any dose and in any
indication to maximize the therapeutic opportunities. One avenue which I have not seen Tekmira adequately
explore is the use of chemical RNAi trigger modifications beyond 2’-O-methyl. Although Tekmira scientists have nicely shown
that 2-O-methylation can be very effective in dampening the innate
immunostimulatory potential of an RNAi trigger sequence, comparative chemistry studies by ISIS and the
clinical experience by Prosensa indicate that larger modifications on the 2’
position are even more effective in circumventing recognition by innate immune
sensors such as toll-like receptors.
With the healthy cash balance, I would expect Tekmira to reinvigorate
their efforts in identifying even better immune-reducing RNAi trigger chemistries. It could also be a worthwhile endeavor to be
funded under the EBOLA contract as it has been a very successful program so far
in furthering the platform while at the same time developing a biodefense
agent.
