Thursday, May 16, 2013

RNAi Therapeutics Ebola Candidate Achieves Critical Milestone

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

Also at the TIDES meeting, Tekmira presented efficacy data for SNALP when given via the subcutaneous route of administration.  To wit, SNALP has largely been administered intravenously which may not be suitable for a number of indications, especially the lower risk, chronic diseases.  Pfizer once famously criticized the state of RNAi delivery as being limited to intravenous options.
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.


Henry said...

Always look forward to reading your blog posts, thank you Dirk

Just wondering if you could clarify 1 point and answer a few Q's
1) you wrote "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." can you explain this a little more to what it exactly means to/ for TKMR

2) For the human drug safety trial for the Ebola vaccine how long do the volunteer humans have to stay on the drugs, 1 week, 1 month? seems like if they start in end of '13 results should be out in early '14 How long did the 12/12 monkeys be observed for before they said this is enough.

3) How does this compare ( if at all) to SRPT MArburg vaccine, they had b/t 83-100% survival rates on 9mg/kg. could DoD ask TKMR to try their SNALP vaccine for Marburg to compare. I could be way off with this just wondering though?

thanks, Henry Stebbins

Anonymous said...

Dirk, do u have a theory y nothing moves this stock?

Anonymous said...

Dirk ... I appreciate your work ... Thanks!

What is the upside to Tekmira once their Ebola candidate is finally approved for D.O.D. stockpiling? Do they own the commercial rights to license distribution worldwide?
Do they receive a royalty on D.O.D. purchases?

Is SRPT still under contract to the DOD? I thought that they were booted after a contract review.

When could Tekmira be likely to start commercializing product candidates? 5 years? 10 years?

Is there a list of Alnylam targets available to Tekmira that we could see? Are Alnylam's targets fixed in number, or do they continue to acquire new targets that Tekmira could choose from? What additional target sources are available to Tekmira?
Have you been satisfied with Tekmira's target selection? Is it a case of slim pickings, mediocre target selection, ... or maybe you think Tekmira's selection is right on target!

Kindest regards,

Dirk Haussecker said...

Thanks for all the insightful questions and comments. I can't answer them right now, but suffice it to say that the Ebola stockpiling opportunity is significant for a company of its size and that for Tekmira to be discovered by the general market, they will have to hire a manic salesman-type CEO and relocate to Cambridge, Mass. Tekmira is far too technology-oriented. I know it can be frustrating, but in the end quality and tenacity could pay off.

Anonymous said...

Hey Dirk, this may be the most important near term catalyst for the company. Can you explain how TKMR/ALNY TTR 02 could be used for FAC? Or would this be considered off label? In the most recent ALNY cc the CEO stated it might be up to the physician to choose. This could imply TKMR could be a huge benefactor if FAC patients choose IV over sc. And, there will be at least a year of no sc competition as you know. This assume their Galnac works.

Dirk Haussecker said...

True. It will be interesting though how an ALN-TTR label would read, e.g. would it specify the types of mutations? This could determine success with reimbursement.

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