Wednesday, April 22, 2015

First RNAi Therapeutic Nearing Finish Line

ALN-TTR02 for the treatment of TTR amyloidosis is the most advanced RNAi Therapeutic in clinical development and has been carrying the torch for the field as whole. Expectations are therefore high and a stumble in this program as a result of the therapeutic hypothesis underlying the program not panning out would likely trigger a temporary*, but steep sector-wide sell-off.  

* it should be clear, however, that with the current ability to robustly knock down genes in the liver, RNAi Therapeutics will result in a number of successful treatments.

It therefore came as a relief yesterday when Alnylam presented (press release here, data slides here) 12-month data from an open-label extension phase II study of ALN-TTR02 in the polyneuropathy form of the disease (FAP) showing

a)      continued robust gene knockdowns for more than a year (88-80% reductions peak/trough in 3-week cycle);

b)      disease stabilization (if not improvement) when the Natural History of the disease would have predicted marked deterioration (predicted mNIS+7 at 12 months of +18 in Natural History vs ~-2.5 on ALN-TTR02).

Furthermore, the safety of this liposomal formulation enabled by Tekmira seemed more than sufficient for a disease as severe as FAP TTR amyloidosis (5-15 year survival following diagnosis) with the most significant adverse events being related to the intravenous route of administration meaning that ALN-TTR02 should be given under trained medical surveillance.

There are some questions that remain open, some of which should be answered by the ongoing phase III APOLLO study which should complete sometime in 2016 (with an 18 month primary endpoint).

Firstly, it will be important to show disease stabilization to be strictly related to ALN-TTR02.  In the phase II study, most patients (20 of 27) were on tetramer stabilizers which have previously shown to result in very modest (tafamidis) to moderate (diflusinal) therapeutic benefits.  While neither tafamidis nor diflusinal have shown disease stabilization after 12 months, the concern remains that they could have contributed to the apparent therapeutic benefit seen in the phase II study.

To my surprise, the 7 patients not taking tetramer stabilizers on top of ALN-TTR02 seemed to do even better, at least numerically than those taking them (-6.5+/-9.2 vs -1.1+/2.5).  Although the number was quite small, the fact that this is the opposite result from what one might have expected, it is possible that a slight placebo effect may have played a role in this open-label study: those for which ALN-TTR02 was the only medical intervention might have had a greater ALN-TTR02-driven placebo effect.

Other more complicated explanations based on TTR lowering affecting the PK/PD relationship of tetramer stabilizers are also possible if this phenomenon is for real.

Fortunately, the blinded phase III APOLLO study will compare ALN-TTR02 to patients taking no tetramer stabilizers to treat their FAP.  Finally, it would be of interest to look at the effect of ALN-TTR02 on the spleen in the APOLLO study as spleen toxicity due to lipid stability might be the most important safety parameter with chronic dosing.    


In summary, yesterday’s 12-month data removed important overhangs over the RNAi sector and we are on track for the first commercial RNAi drug in 2017. Seeing is believing.

7 comments:

Anonymous said...

The choice of picture is an... interesting one.

Anonymous said...

Yes. The real champion will come to the fore in good time.

Anonymous said...

Very good news for both Alnylam and Tekmira but more importantly the whole RNAi space, well done Dirk on all your good work in helping this naicent industry mature.

Anonymous said...

no way Alnylam's study reads out in 2016. Late 2017 is more likely. The first RNAi drug to receive FDA approval will be Tekmira's TKM-Ebola.

Anonymous said...

You looked past the fact that NT-proBNP actually got 30% worse over 12 months. A drug that stabilized neuropathy but worsens cardiac function is not going to get approved

Anonymous said...

You need to look at the natural history of FAC patients presented by Alnylam. There is a large variation in NT-proBNP in FAC patients as they progress in the decease and it is totally unpredictive of how the patients are doing. I am not even sure why NT-proBNP is even listed as one of the biomarkers.

Anonymous said...

What about Quark's finished Phase II study with systemic siRNA for prophylaxis of delayed graft function? It was a double-blind study in >300 patients with positive results in a subset of >80% of all the patients - those that received transplants from donors older than 35 years. They are likely heading for Phase III this year.

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