If the experts at Roche and other Big Pharma companies got you convinced that RNAi Therapeutics was about to disappear from the scene by pulling the plug on the technology…think again. Alnylam this morning reported tantalizing insights into the safety and efficacy of ALN-PCS02, a SNALP-formulated RNAi Therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. Given that PCSK9 is viewed as potentially the next biggest thing in cardiovascular drug development after statins have come off patent, and considering the results so far from the monoclonal antibody and antisense competition, this RNAi Therapeutic has the potential to become the field’s first blockbuster. As we know, a field does not need too many blockbusters to become more widely accepted, and it is acceptance, not so much lack of scientific progress, which has been lacking over the last 2-3 years. Together with the ALN-TTR01 results reported in November, I expect these results to dramatically change perceptions about RNAi Therapeutics in the pharmaceutical industry. And if I had to write the script, Alnylam will announce a share offering tomorrow or Friday afternoon in order to go hostile on Tekmira to remove the uncertainties arising from their use of Tekmira’s SNALP technology which critically enabled these results and on which most of Alnylam's $400M market cap depends on.
ALN-PCS02 Phase I Data
This trial was a simple single-dose escalation trial in subjects with slightly elevated levels of bad LDL cholesterol. Dosing in the 5 dose cohorts commenced at 0.015mg/kg and went up to 0.250mg/kg with each cohort consisting of 3 subjects receiving an intravenous infusion of ALN-PCS02 and 1 receiving placebo. As could have been expected with this particular rationally designed '2nd gen' SNALP formulation, robust target protein knockdown was observed at the highest dose tested with a mean 60% reduction in plasma PCSK9 levels presumably 3-5 days after administration. In line with PCSK9 genetics, this type of knockdown entailed a mean 39% reduction in bad LDL cholesterol. Importantly, and again consistent with the wealth of non-human primate data, this knockdown was sustained for days and weeks. Given that ALN-PCS02 apparently was well tolerated, with the only noted adverse event being a rash that was likely to be related to the mode of administration and not the drug itself, Alnylam now plans further dose escalation to a) increase knockdown potency, but b) also extend the duration of PCSK9/LDLc suppression. This is particularly desirable in light of the competitive situation.
The PCSK9 Competition
Needless to say, having now two examples in short order where RNAi Therapeutics unambiguously hit their targets, proof-of-concept of technical success can be claimed and one can now focus on the medical and commercial potential of these therapies. In this regard, the competition in the PCSK9 space is fierce. Big Pharma and Big Biotech have fielded their A-teams to develop monoclonal antibodies against PCSK9. Since much of the LDL-related effect is due to PCSK9 in the serum, this target is a particularly amenable to MAb technology.
Sanofi-Aventis/Regeneron are most advanced with REGN727 which is in the middle of a number of phase II studies. Amgen also reported recently phase I results with their PCSK9 MAb. Studies with both compounds have shown more potent LDLc reductions of around 65% compared to the 39% with ALN-PCS02 so far. This, of course, is a good reason for Alnylam to go ahead with its plans and continue dose escalation. However, once you achieve the type of 60-70% reductions in LDLc, the next major focus becomes safety, and so far the RNAi Therapeutic looks quite competitive in that regard.
As discussed in October, the PCSK9 antisense compounds by Santaris and ISIS have fallen a bit behind due to probably both safety (Santaris) and efficacy (ISIS) issues, although I expect ISIS to reciprocate tomorrow by presenting TTR knockdowns at their Investor Day tomorrow that are more pronounced than Alnylam’s first attempt with ALN-TTR01.
[Update 5Jan12: ISIS reported 44% mean TTR reductions at 200mg per week, very similar to ALN-TTR01 at 1mg/kg; and 81% reductions at 400mg per week, a dose that I consider too high for tolerability and commercialization; ISIS also disclosed that the BMS-partnered PCSK9 candidate was dropped citing a slow partner and regulatory concerns about PCSK9 as a drug target].
Overall, we can now conclude that the ALN-TTR01 results were no fluke (I never expected that to be the case anyway) and that in theory all targets in the liver are fair game now for RNAi Therapeutics. Moreover, the data show that the preclinical data with SNALPs translate very well into humans, removing a considerable uncertainty and opening up the prospect of further improvements in SNALP delivery based on what Tekmira and Alnylam have presented over the last few months.
A biotech company does not need many these PCSK9-type products to rise into the ranks of Big Biotech. While there is still a long clinical way to go, I believe that sometimes you are allowed to cheat and look at hard preclinical data, and in doing so I believe that today we may have seen the first glimpse of an RNAi Therapeutics blockbuster. I’m wondering how the Roches and Pfizers will be feeling over the coming months and years as the field of RNAi Therapeutics matures at this rate. It is also an opportunity for new entrants to build strong positions in the space with relatively small investments (still). Am I a bit vindictive today? Yes, definitely.