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.

SNALP Works!

The long wait is finally over: Systemic RNAi delivery has been proven in Man. No 'ifs' or 'buts'. Alnylam just announced that Tekmira’s SNALP-enabled ALN-TTR01 reduced target transthyretin (TTR) protein levels in ATTR patients in a dose-dependent manner- without causing an elevation of liver enzymes or serious adverse event (SAE).

Following preliminary evidence in Tekmira’s TKM-ApoB study, this is the long-awaited moment where there is no doubt that successful systemic RNAi delivery has been achieved. With already about half a dozen SNALP-based programs in or very close to the clinic, this result de-risks a major segment of the RNAi Therapeutics pipeline and should stimulate further investments in SNALP-enabled RNAi Therapeutics development as well as provide a boost of confidence to the entire sector.

Today's presentation at the FAP meeting in Kumamoto can be found here. For a more detailed background on ALN-TTR01 for ATTR, please read yesterday’s blog entry.

In the phase I study (single-dose, dose-escalating), 5 patients received 1mg/kg, the highest planned dose. At this dose, there was a mean reduction of 41% in serum TTR levels from baseline. Despite the small patient numbers and natural TTR variability, this was stat significant at p=0.02 relative to placebo. While this level of knockdown may not seem dramatic and may or may not be useful for eventually achieving a therapeutic effect in ATTR patients, it is important to keep in mind that the other liver-targeted SNALP programs employ formulations that should be at least 10x more potent than the one used in TTR01 and probably also slightly better tolerated. As such, this was a stringent test for the safety and tolerability of SNALP technology and bodes well for the commercial potential of particularly the liver-targeted SNALP pipeline following TTR01, including TTR02 for which an IND is expected by year end.

The time course of TTR protein suppression in one patient provided a picture-book example of bona fide RNAi knockdown in Man. Consistent with the now extensive experience with SNALP in pre-clinical animal models, including non-human primates, this patient exhibited a rapid onset of knockdown (63% reduction at 48 hours) which became a peak knockdown of 81% a week after drug administration with 50% suppression still being observable 4 weeks after this single dose. There is no doubt that this was an RNAi-mediated response.

Preclinical repeat dosing studies have shown that in order to maintain the same level of gene suppression, one can reduce the amount of drug given at subsequent doses. This also means that perhaps giving patients two or three loading doses of 1mg/kg within a week or so may allow one to achieve the 70-80% knockdown with ALN-TTR01 not just in select patients.

Importantly, the safety profile seems to exceed even my own expectations. Unless Alnylam will reveal major immune stimulations in the upcoming conference call (at 8.30am Eastern Time; note added in proof 11/23: none were revealed), the only mild-to-moderate adverse reactions seemed to be infusion reactions that were experienced by 3 out of the 23 TTR01-treated subjects and which was well controlled by simply slowing the infusion rate. As the same was seen in the SNALP-enabled ALN-VSP02 study, it seems that this risk factor is indeed well manageable. What is more, even at the high dose of 1mg/kg, there were no signs of liver toxicity as evidenced by increases in liver function tests. As SNALP-RNAi for ATTR will be a chronic treatment, this should be the major safety focus in the future.

Whatever Alnylam decides to do with ALN-TTR01 (I expect it to remain on the shelf as a viable alternative pending TTR02 results), today represents a milestone in the history of RNAi Therapeutics and I do believe that we have seen the bottom in RNAi Therapeutics. Credit belongs to Alnylam for pushing ahead with the SNALP clinical studies. Alnylam has a truly gifted, and in many ways inspirational drug development team, but it is probably also this talent that has made them blind to what they are actually entitled to. My sympathies are therefore with Tekmira today as it has developed (and owns) the delivery technology that is turning out to be quite literally the savior of RNAi Therapeutics: SNALP. Clinical results eventually follow strong science.

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