The long wait is finally over: Systemic RNAi delivery has been proven in
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.
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
The time course of TTR protein suppression in one patient provided a picture-book example of bona fide RNAi knockdown in
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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