Monday, November 24, 2014

Tekmira with Multi-Trigger and Parallel Development Plans

As a veteran armchair RNAi Therapeutics strategist, I am frequently frustrated at the inflexibility of companies in the face of rapidly moving competitive and drug development environments.  The worst offenders are those with management and Boards that view their positions as entitlements and could not care less about the science and acknowledge the flaws of their technology.  

Often related to this, another common violation is a failure to cut your losses on an obviously failed development program at the cost of the platform, a strategy though that sometimes works if you can find a greater fool (the ~$700M acquisition of Prosensa by Biomarin yesterday falls into that category).  

Tekmira, too, has been at risk of suffering from such inflexibility in light of an industry-wide shift from nanoparticle-based to small conjugate-based delivery.  This does not mean that nanoparticle-based delivery will not have an important role to play in the future of RNA(i) Therapeutics, but that you have to realize your relative strengths in a highly competitive space.  In addition, Tekmira has been slow to realize the shifting regulatory and payor landscape making biomarker-focused orphan drug development in genetically defined patient populations highly attractive.

Having listened to the Tekmira Analyst Day last Friday, I was therefore quite pleased that not only is Tekmira catching up by beginning to realize that it is running a business and not a scientific think tank, it can even be considered to take on a strategic leadership role in at least two regards:

1)      the adoption of multi-payload candidates thereby addressing the i.v. nanoparticle versus single molecule subQ debate and leveraging key advantages of nanoparticle technology;

2)      running trials in parallel to quickly find out which delivery chemistry platform works best in humans.

1.       Multi-targeting: a key differentiator of nanoparticle-enabled RNA(i) Therapeutics

At the Analyst Day, Tekmira re-iterated that it will put a multivalent HBV formulation into the clinic that will contain three RNAi triggers.  In addition to ensuring that most patients thus become a match for the therapy, just as the two-trigger ARC520 by Arrowhead Research had been geared towards, Tekmira also wants multi-targeting to address viral resistance of the kind it observed in the woodchuck model of HBV.  

From that perspective, the intravenously administered TKM-HBV is preferable to single molecule approaches by Alnylam and ISIS Pharmaceuticals which are both administered subcutaneously.
Tekmira does not limit multivalent RNA Therapeutics to viral applications such as in their HBV and Ebola programs, it will also apply the concept outside that space such as in its hypertriglyceridemia program where it is considering dual-targeting formulations with ApoCIII, ANGPTL3, and DGAT2 as candidate targets.  

Equally or even more intriguing, in the Q&A session it was hinted that other therapeutic strategies that the company is considering may not merely involve multiple payloads of the same type, but even payloads from different categories such as an mRNA and an RNAi trigger.  Obviously, such combinations could open up entirely new therapeutic strategies (e.g. mRNA-RNAi combos for alpha-1 antitrypsin), or maximize potency (e.g. RNAi trigger-RNaseH ASO for HBV).

Scientifically, I see no reason why single molecule technologies such as GalNAc-siRNAs should not be amenable to certain (but not all, e.g. mRNA) multivalent approaches.  Culturally, however, multi-valency takes away from the single molecule simplicity that the pharmaceutical industry apparently loves, ideally in pill form.  From a regulatory point of view, it seems to be the case that nanoparticle-encapsulated RNAi products are seen as just one drug no matter how many RNAi triggers it contains, and it remains to be seen what the regulatory thinking would be when combining multiple single RNAi triggers (I can imagine Alnylam trying to combine their HBV mRNA-targeting GalNAc-siRNA with its PD-L1 GalNAc-siRNA).

In some ways, ARC520 (which is not a nanoparticle) strongly indicates that multi-targeting is not an insurmountable challenge for the non-nanoparticle approaches, so that regulatory advantage may not exist in the future. 

Nevertheless, my prediction is that multi-targeting will be mostly practiced in the nanoparticle and not the conjugate sector of RNAi Therapeutics and nanoparticle-based companies ought to consider multi-targeting almost a Must when there is direct conjugate delivery competition.

Although Tekmira is the most visible RNAi company for multi-targeting, it should be added that multi-targeting has been the motto for US-China-based Sirnaomics from the get-go in 2007.

2.       Testing Multiple Delivery Technologies in Parallel

The RNAi Therapeutics field is both blessed and plagued by the rapid progress in refining particular delivery platforms.  Tekmira has already arrived at the 4th generation of SNALP LNPs while Alnylam is now talking about GalNAcs with standard and enhanced chemistries.  With a multitude of preclinically validated alternatives, it is often difficult to determine which one should be prioritized for human development. 

This can lead to protracted development timelines when a first formulation yields unsatisfactory results in the clinic and the payload has to be re-formulated into a new delivery chemistry.  Especially in competitive environments this can be fatal.  And even if you were somewhat satisfied with the initial results, chances are that you left a lot of money on the table by not finding out about the performance of other formulations in humans.

Needless to say, having multiple candidates for a target is not a unique challenge in the pharmaceutical industry and if money were not an issue, we would see a lot more parallel development programs.  However, RNAi and related delivery is unique as the investment can be amortized across the platform.  

Moreover, in practical terms, RNAi offers a number of opportunities to directly and accurately measure target engagement and thereby assess the impact of changing the formulation.  This is one of the reasons why the early RNAi programs targeting genes in the liver involve targets which can be found in the blood.  For other modalities (e.g. microRNA inhibition in the RNA Therapeutics field), what you measure in your blood sample or other biopsies may differ significantly from what is actually going on in the body.

For these reasons, namely to speed up time-to-market in a competitive market and to inform which delivery formulations should be used with other LNP-enabled candidates, Tekmira announced that it is about to put two formulations of TKM-HBV in the clinic that will only differ in their delivery chemistry while using the identical (3) RNAi triggers.

Tekmira investors are not seeing double: the company is becoming a modern drug developer.


Newsurfer said...

Didn't anyone notice that in the race to develop an HBV functional cure, TKMR's Analyst Day revealed a significant advantage for ARWR?

Previously, TKMR had claimed it would skip phase 1 trials and go straight to phase 2 because their compound had already been proven safe in humans. Now we know that TKMR will conduct phase 1 safety trials and hopes to start same in January 2015. If all goes according to plan, TKMR will move to phase 2 sometime in the second half of 2015.

ARWR says it hopes to start phase 2b trials in January 2015. Now if ARWR can achieve the knockdown needed with ARC-520 (whether at the 3, 4 or higher mgs/kg remains to be seen), it may not matter that ARC-520 is significantly less potent than either the TKMR or ALNY (not yet in the clinic) compounds.

Dirk's comment chose to focus on the broad implications for drug development that were revealed during TKMR's Analyst Day. But in the race to the HBV finish line, ARWR just widened its lead (assuming they can eventually cross the finish line).

Anonymous said...

According to Alnylam, robust HBV market is going to be around for at least another 30 years. So we are still in a very early stage of the evolving HBV market. Current lead in the market by any company doesn't mean much. Even if any company gets only 1% of the huge HBV market, it could have a tremendous impact on their share price. All the players in the HBV market are destined to prosper if they can achieve functional cure.

Anonymous said...

Then it's all eyes on Benitec's TT-034 cohort 1 data read for HCV at end of the year. According to the Co. if TT-034 goes well much of the HBV path to clinical trial will be cleared.
Interesting given they've taken their HBV programme back from the Chinese Biomics Co and are running with it in their very own lab in California now!

Anonymous said...

BLT will never amount to anything. We have seen through ALNY, ARWR and TKMR as well as several others that it pays to follow the leaders in biotech investing, then get out before you get fried.

One of those leaders is the fabulous Baker Bros. And this is their latest purchase: CIR.

So what do you think is going to happen to the sp in CIR Dirk?

Anonymous said...

Multi targeting has its own pros and cons. Each target has its own risk factor. Multi targeting multiplies those risks. It is better to have two separate small volume Subq injections than to have a single Subq injection for two targets. I am not sure what advantage Tekmira has over its competition by multi targeting APOCIII & ANGPTL3.

Dirk Haussecker said...

It's an interesting debate and it probably depends on which targets you combine. E.g. when the right targets are combined, you might get away with less knockdown of each, but with a greater therapeutic benefit. I'm thinking here of issues such as fat accumulation in the liver when the goal is to lower trigs in circulation.

Anonymous said...

What can we expect from Phase I/II trial of TKM-PLK1 GI-NET, ACC tumor results, to be released before end of 2014?

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