Yesterday at the
TIDES meeting, Tekmira reported new efficacy data for its Ebola RNAi
Therapeutics development program. The non-human
primate data suggest that the main remaining hurdle before regulatory approval for this biodefense agent (on which any government stockpiling contract would hinge), safety in healthy
human volunteer studies, is now more realistic than ever.
Is second time's the charm?
In 2010, Tekmira and collaborators from the Geisbert lab and the US Army reported in The Lancet of a breakthrough in the post-exposure treatment of Ebola infection. In the gold-standard rhesus monkey model for Ebola infection, their were able to demonstrate that SNALP-RNAi could effectively rescue Ebola-infected animals from near-certain death.
The efficacy, however, depended on doses of 2.0mg/kg is likely too high a SNALP dose to be considered safe. Based on the SNALP human clinical trial experience to date, first dose-limiting toxicities are observed at 1.0mg/kg (note: SNALP potencies are very comparable between humans and monkeys). Moreover, at doses higher than 0.5mg/kg, sporadic signs of immune stimulations (flu-like symptoms) can be observed. These caused Alnylam and Tekmira to adopt precautionary transient immune suppressions with corticosteroids in some of their other SNALP-based clinical studies.
It therefore became important to take advantage of the improvements in SNALP potencies and develop more potent Ebola SNALP-RNAi candidates. Fortunately, Tekmira was able to get the blessing from the US Department of Defense for this, and announced in April that it would receive up to ~$7M in additional funding on top of the up to $34M initially agreed upon in order to bring such a candidate to the end of phase I clinical studies.
Importantly,
since Ebola efficacy trials cannot be conducted in humans, the regulatory
approval of TKM-Ebola will be according to the Animal Rule. The Animal Rule states that for indications where human efficacy trials are not possible due to ethical
considerations, it is sufficient to show efficacy in accepted animal models and
then establish drug safety at corresponding doses in healthy human volunteer
studies.
With the new
formulation, 12 out of 12 monkeys treated with the magic dose of 0.5mg/kg RNAi
stayed alive in a post-exposure treatment setting, compared to only 1 out of 6 treated with placebo. This means that should the human volunteer
trials show good safety at the same 0.5mg/kg dose level, Tekmira will stand a good
chance at gaining regulatory approval under the Animal Rule. Of note, the first Ebola trial were likely conducted in the absence of corticosteroid pre-treatment and it is very likely, also in light of Alnylam's recent announcement of tapering off corticosteroids in the ALN-TTR02 trial, that the future TKM-EBOLA studies will also be conducted without them.
Since 0.5mg/kg is right on the border, however, there still remains an element of risk before victory can be declared on the safety front. It is therefore good to hear that 4 out of 6 monkeys stayed alive at the 0.2mg/kg dose. This should provide a good safety cushion despite the aggressive daily treatments that will be required in this demanding setting.
Critical human safety data, ideally from repeat-dosing studies, should be forthcoming in 2014 as Tekmira has guided that it will commence
clinical studies with the new candidate by the end of 2013.
Update 16/5/2013: One issue on the efficacy side of the equation that I forgot to mention in the original post is that the DoD might ask the company to test TKM-EBOLA with longer delays after the infection in monkeys.
SNALP Shows Good Potency with
Subcutaneous Dosing
Comments
like these (which are very relevant for partnering purposes) and trends in the
industry to adopt subQ dosing, most notably Arrowhead’s DPCs and Alnylam’s GalNAc-conjugates, probably motivated Tekmira to explore this route of administration
with SNALP further.
Based on an
early ApoB patent application, Tekmira had clearly had some familiarity with subQ,
and I had always wondered why the company did not pursue this further. It could be that the more potent SNALP
chemistries now allow for much more potent and robust subQ RNAi gene knockdown.
The new data
show a very impressive 96% knockdown of transthyretin (TTR) with a single subQ administration of 1.0mg/kg SNALP in rodents. This
compares to a much more modest ~55% knockdown with ALN-TTRsc at 1.0mg/kg given
on 5 consecutive days, the subQ GalNAc-siRNA candidate by Alnylam which just entered clinical development for the FAC form of transthyretin
amyloidosis.
Of course,
we need to learn more about the safety of subQ SNALP to know whether it really is a
clinically viable strategy and superior to the competition. GalNAc-siRNAs in particular look quite
benign, albeit not very potent. However, since peak plasma
concentrations seem limiting for SNALP in terms of safety (infusion reactions can be managed by slowing the infusion), subQ, due to its slower systemic release might actually
turn out to be safer, not just more convenient. On the other hand,
my impression is that subQ SNALP could cause the type of ‘nuisance side effect’
that is frequently seen with phosphorothioate antisense.
The GalNAc
comparison is obvious since Alnylam developings both a SNALP- and a
GalNAc-based TTR RNAi Therapeutics in parallel.
In terms of competition for potential partnering, however, the DPCs by Arrowhead
Research would be the more appropriate and challenging comparison. I look forward to watching the race unfold as
healthy competition is propelling the RNAi Therapeutics field into a highly competitive industry.
