Friday, July 4, 2014

Implications of Ebola data for Tekmira HBV Program

Like it or not, it is the HBV program that is driving the interest in Tekmira, at least in the near-term.  Therefore, the 15% sell-off in the stock yesterday following the Clinical Hold imposed by the FDA can be interpreted to be due to the uncertainty of what it means for the HBV program.

It is my working hypothesis that for the treatment of HBV via the immune reactivation pathway, the use of even transient immune suppression is to be avoided.  On the other hand, the recent Ebola clinical results by Tekmira suggest that transient immune suppression may also be desirable for 3rd gen SNALP delivery.  As TKM-HBV is expected to utilize '3rd gen' SNALP delivery, too, the Ebola results with immune activation seem like a bad omen.

While this cannot be ignored, there are a few reasons to believe that this might be too simplistic.

1.       Difference in dose

Although there was an apparent tendency for immune stimulation throughout the dose escalation with TKM-EBOLA, it was only at the high dose of 0.5mg/kg where a dose-limiting toxicity was observed. And according the yesterday's press release on the Clinical Hold, it is in particular cytokine elevations that were observed at 'higher doses' that are the issue.  

 Since unlike Ebola, HBV only replicates in hepatocytes, and because SNALP potency is highest in hepatocytes, the efficacious dose for HBV may be well below 0.5mg/kg with 3rd gen formulations.  Of note, even 2nd gen SNALPs are highly effective at 0.3mg/kg based on the Tekmira-enabled ALN-TTR02 candidate now in phase III.

2.       Different sequence, different immune stimulation

It is known (e.g. Judge et al. 2005: Sequence-dependent immune stimulation of the mammalian innate immune response by synthetic siRNAs) that immune stimulation by RNAi, especially when liposomally formulated, is highly dependent on the actual sequence and modification pattern of the RNAi trigger.  Since TKM-EBOLA and TKM-HBV are different in that regard, it is well possible that while one 3rd gen formulation is immunostimulatory, the other is not.

3.       Immunostimulatory by design/by screen

Scientifically, I was most disappointed by the Ebola immune stimulations as Tekmira made a big deal in the wake of similar observation in 2010 with TKM-ApoB that with improved, more predictive immune stimulation assays, they would now be able to screen out the immunostimulatory formulations.  In a black-and-white world you would conclude ‘obviously not!’.

In a world of shades of grey, I can imagine that TKM-EBOLA might have happened to slip through this part of the screening process.  The reason is that since Ebola infects a number of cell types besides hepatocytes (endothelial cells, phagocytes etc), the impressive efficacy of TKM-EBOLA always stood out as something quite unusual.  So while containing the spread of the virus by hitting it particularly hard in the liver might be part of the mechanism, I am quite receptive to the notion that the scientists did not mind all that much some immune stimulation when the RNAi formulation had so much efficacy.
With HBV, however, the company might be much more careful in screening out immunostimulatory potential.

I can now hear Sarepta investors yell ‘it’s an artefact’, but I would caution them that Sarepta and the morpholino field at large is proposing morpholinos with cationic appendices for infectious diseases while these are not really considered for genetic diseases.  What I don’t understand is that why a modification that is supposed to be helpful in e.g. suppressing viral gene expression should not likewise be useful for suppressing human gene expression.  So maybe the value of these modifications is in tickling the immune system?

4.       Not all 3rd gen are created equal

In response to a questioner in the Q1 financial conference call, the CEO of Tekmira said that the definitions of the various SNALP generations is not as clean as you would like from a chemical point-of-view.  Instead, the definition largely is a reflection of the potency improvements of the formulations.  Therefore, since TKM-EBOLA has a different set of target cells than TKM-HBV, it is well possible, even expected, that the formulations will also differ in their lipid compositions.  Since lipids are an amplifier of the liposomal-RNAi immune response, differences therein could have big implications as to the immune stimulation of the various formulations.

Disclosure: I am long Tekmira and only partially heeded my own advice of stepping out of the TKM-Ebola ‘Haertetest’ (trial provided not much upside to investors).  On the other hand, Tekmira has upside potential from a number of non-Ebola programs especially HBV and mRNA delivery.  As the worst case scenario, an outright termination of TKM-EBOLA, is a real risk, it becomes more and more difficult to get the timing right ahead of the upcoming TKM-HBV data.  If, however, you don’t mind volatility and are a long-term investor, it’s another matter.  However, at least for me, Tekmira is not the stock any more to maintain a 100% position in.


Anonymous said...

Thank you wery much for your article! A couple of questions:

1) Is it not in fact somewhat premature drawing conclusions regarding TKM-HBV from the EBOV results? As the company states that:

"Because HBV is a viral infection of the liver, the TKM-HBV therapeutic will employ a liver-centric-LNP formulation that is more potent and has a broader therapeutic index than any LNP currently in clinical development."

I would think that the formulation is wastly different than the LNP-formulation used in EBOV. Furthermore, you indicated in the article that the definition of 2nd gen, 3rd gen LNPs isn't that clear cut. To me it therefore sounds more like TKM-HBV technically will be LNP 4th gen or at least 3.1 gen.

2) Do you have any thouguts regarding the HED (human equivalent dose) question concerning EBOV?, i.e. that there is no salient a priori reason to belive that 0.5 mg/kg in monkeys should be 0.5 mg/kg in humans (and that the same efficasy can be obtained with ~ 1/3 of that dose)?

3) As ARC-520 apparently uses premedication, do we not get the answer on whether this would be an efficasy problem soon when ARWR releases the P IIa (indication) and IIb (confirmation) results this year? Then only the potential commercial issue remains if ALNYs HBV candidate could work without any premedication.

4) Do you think there is any possibility that: a) FDA demands steroid/histamine premedication in the PI trial; or b) demands that that pre-medication is used both in the trial and after approval; or c) demands that pre-medication is used only in the PI trial on the healthy subjects but not after approval when used on a patient with a 9/10 chance of death without TKM-EBOV? Option c) would of course be quite exceptional, but when you consider the side-effects allowed in non-curing cancer drugs and that no sick patients can be tested pre approval?

For me the main problem thus far is that the management clearly cannot communicate with the FDA or the shareholders in an explanatory and clear manner. In Addtion I'm quite pissed of if the probable EBOV stockpiling now is delayd or scramped alltoghetger, as this would have funded the HBV and probably the other programs through PIII and perhaps even given some actual EPS!

Anonymous said...

People following rnai should be aware that just in the last month two separate ddRNAi trials have met significant milestones. It's true gene therapy, so slowy slowy but surely.

Anonymous said...

If Ebola had any real impact on HBV or other products TKMR would be far further down. It does not.

We give steroids to chronic HBV and cirrhotic patients frequently for a multitude of causes, on or off nucleosides. It is not an issue with regard to seroconversion etc. Why would it be with RNAi anymore than anyother premedicated other drug LNP administration e.g. TTR? 200mg Solumedrol is almost a vitamin in these patients. I wouldnt pick a drug on whether it needed or did not need steroid cover, I would pick it on efficacy.

Anonymous said...

WHOA! TKMR are the masters of timing, in both good and bad:

1) capital raise at abslute peak;

2)bad news just a few days after a sector specific mini-correction (June 7th)and just a ~week before a larger makro eeduced sector panik!

If ownly two of the latter three would have happend at the same day the pps would probably be 15% higher.

How do you as a science guy feel about this "Yellen event", one would feel that this would be a superb chanse to BUYBUYBUY!! However, I am a bit anxious on two accounts; It could of course allways be possible that it is the retail investors on the buy-side of this massive sell off, psychologicaly it seems unlikely, but you newer konow. This, in turn, brings me to the following musement: Considering the binary nature of biotech companies and the many moving parts, i.e. clinicians and others, who most certainly have inside information even on double blind trials, then would not this Yellen biotech comment be like a true carte blanche for the big tutes and hedgies to do all the insider info trading in the world, both playing sucess and more often faliure! Hence the "be greedy approach would seem quite intimidating for the little guy (more so than with other sectors and during a complete market crash).

Interested to hear if you trust your science regarding your companies (not TKMR in particular) and buy or if you just wathch, or trade?

Congratz und herzliche gluckwunchen re. Die Manschaft! Es war super Toll!!

Anonymous said...

Where is Tekmira's production facility? I would be watching for a marked increase in activity there in the coming weeks.

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