Tuesday, March 4, 2014

The Ebola Clinical Trial a Real ‘Haertetest’ for SNALP LNP Delivery

In German, a Haertetest is a test that challenges the performance of something under the most exacting conditions.  

It is therefore an apt description for the Ebola clinical trial now underway which is testing the safety and tolerability of SNALP LNP delivery following multiple consecutive daily administrations.  This compares to once-weekly and once-a-monthly regimens tested so far.  If SNALP LNP comes out positive from this, it would provide great comfort around the safety and tolerability of the industry’s most potent delivery technology for gene knockdown in the liver, in addition to paving the way towards more biodefense applications.

Teething problems with 1st gen SNALP LNP

In January 2010, Tekmira reported clinical results from the phase I study of TKM-ApoB, the first clinical candidate employing SNALP LNP technology.  This trial was terminated prematurely due to immune stimulations observed at 0.6mg/kg, a dose at which only minimal target knockdown was observed at that.

This event triggered a healthy amount of soul searching and meant that subsequent SNALP LNP trials had to employ transient immune suppression.  A number of important practical lessons were learned from this.  

Firstly, it showed that the preclinical immune stimulation tests had been inadequate and this prompted the development and adoption of a more predictive test to better screen out candidates that are immunostimulatory before they enter humans.  Secondly, the phase I results were consistent with the notion that the DLinDMA lipid itself (and not just the RNAi trigger), the basis for the 1st gen SNALP formulations, was immunostimulatory and that new lipids were needed.  And lastly, it highlighted the need to develop more potent SNALP formulations, including new lipids.

Research rises to the challenge

Three years following these events, all three challenges have been successfully addressed.  Today, the potency of SNALP LNP has increased ~30 fold from 1st gen to 3rd gen formulations (based on measuring gene knockdown in the liver), with the 2nd gen MC3-based SNALP generation already with a confirmed 10-fold improvement in clinical potency based on phase I and II results of ALN-TTR02.

Tekmira not shy to ask the tough questions

Despite the progress, detractors of the technology like to point out that (transient) immune suppressions has still been employed in subsequent clinical trials.  With the recent initiation of the phase I study of TKM-Ebola by Tekmira, this has changed however.  Not only that, transient immune suppression has been dropped even as administration intensity is ratcheted up to 5-7 daily administrations. This compares to once-a-month and once-a-week dosing schedules anticipated for SNALP LNP applications involving gene knockdown in the liver and solid cancers, respectively.

The reason why TKM-Ebola necessitates daily administrations is due to the rapid progression of the otherwise fatal Ebola virus.  Therefore, in order to get it approved under the Animal Rule, Tekmira needs to demonstrate the safety and tolerability of SNALP LNP in human volunteers under conditions where they are able to rescue monkeys from succumbing to otherwise fatal infections.  

Moreover, while 0.2mg/kg already provided good protection in the monkey studies (2/3 survival), it was the 0.5mg/kg dose that complete protections were achieved.  0.5mg/kg also happens to be the ‘magic’ dose for SNALP LNPs following which idiosyncratic immune stimulations and other side effects may be expected.

The reason why I am pretty sure that TKM-EBOLA, despite the daily administrations and up to 0.5mg/kg dose, should not involve immune suppression is because it would be incompatible in a viral infection.  There is also no evidence that such pre-treatments are planned in the clinicaltrials.gov entry nor when Tekmira reported the monkey results.  The same considerations apply to the HBV candidate by Tekmira for which an IND is expected by year-end.

Should Tekmira come out of this trial unscathed, it would further de-risk the entire SNALP LNP platform and solidify its position as the most potent oligonucleotide therapeutics technology for gene knockdown in the liver, for hemorrhagic fever applications, and possibly oncology.

Where some see risk, others see opportunity.    


Steve_382 said...

The CT sites shows results expected by July 2014. Do you expect any info before then? Also, when looking at the CT site, that's a quite extensive inclusion/exclusion list. Compare that to the ALN-TTRsc list for example. Is there anything to be read into that?


Dirk Haussecker said...

Inclusion/exclusion criteria what expected for 'healthy' volunteer trial. Taking out confounding variables such as alcohol consumption will facilitate interpretation of trial results.

Anonymous said...

Is there a connection between TKMRs shelf and the one RGLS filed today? Common thread being mRNA and ALNY. ALNY closed their partnership out with GENZ the other day. Wonder if ALNY, GENZ or someone else is about to take a stake in TKMR and RGLS.
ExperiencedMentor's bigger fish pic looms large.

Gerald Pontificus said...

Hello, thanks for the great article!

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