Wednesday, January 4, 2012

ALN-PCS02 Results Provide Glimpse of First RNAi Therapeutics Blockbuster

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.


Anonymous said...

Why vindictive, do you mean vindicated?

Dirk Haussecker said...

I'm a native German speaker, but I'm pretty sure I meant vindictive. You cannot imagine the damaging effect particularly the Roche pull-out had on the field. What I'm criticizing here is the herd mentality.

Anonymous said...

Dirk, why would Alnylam need to dilute its share base to "go hostile" on Tekmira. What do you estimate going hostile would entail and what would it cost?

Dirk Haussecker said...

They may not have to, but Alnylam mgmt may have gotten used to operating in the comfort of a large cash cushion. It is not just the $150M shelf that makes me suspicious, but also the 30minutes of questioning by analysts/investment bankers today (it is still 'only' a phase I trial in the World of Wall Street). Many of the names had been absent the last 2 years as there was little money to be earned from investment banking with ALNY. Now, they are all back. I doubt it's their love for the technology. They are here for mainly one reason: investment banking fees (and some of the trading around it).

Anonymous said...

Alnylam have a shelf sufficient to raise $150M. That should probably do it if they want to take out Tekmira.

anon said...

A few things trouble me about the human data. In mice and monkeys the IC50 to KD a target was ~ 10 ug/kg, right? Yet in humans it looks like they need to give 10X the dose - why? Will they run into problems with therapeutic index? Also, IV infusion doesn't normally cause a rash, so why isn't the rash drug-related? Further, isn't IV infusion a much less desirable way to give drug than the SC administration being used in the antisense trials? If the MAb can be given SC, why wouldn't that be preferred over the RNAi?
Thanks for your blog, which I always find interesting.

Dirk Haussecker said...

Thank you for your questions.

I believe that the 10ug/kg value was for the MC3 formulation in rodents. What happens is that there is a shift in potency as you work your way up into bigger subjects. In the clinical trial the ED50 was around 0.15mg/kg- still the ~10-fold improvement in potency compared to the TTR01 formulation (which used an apparently more powerful siRNA), and incidentally at least 50-fold more potent in terms of oligo given a month (not even talking about body exposure).

There were 2 rashes in placebo (saline) and 3 on PCS02. Given that there was a 3:1 (drug:placebo) randomization, you could conclude that being infused the placebo increased your chance of having a rash.

We have to see how route of administration will play out on the competitive field. I'm not too focussed on it right now as I believe the therapeutic and safety profiles will be much more important, especially since once a month and especially twice a month take the pressure off an intravenous therapy.

Look e.g. example at the MS field ('Tysabri'). There had been long worries that oral drugs will take over due to patient convenience. Hasn't happened. In diseases like that patients and caregivers still care about treatment success.

Dirk Haussecker said...

...50-fold improvement in oligo given per month relative to antisense, I meant.

Anonymous said...

Dirk, I think it is a little naive to claim victory on this result...for God's sake it's just a single dose! Let's talk again when the drug can be administered repeatedly in a safe manner. It would also be nice if you could be a little more neutral on your reporting.

Dirk Haussecker said...

Rome wasn't built in a day. These steps are every bit as important as that large randomized phase III result. Next step: multi-dose. My optimism is based on the basic pre-clinical literature (which includes more detailed tox, repeat admin etc). If I ignore this and start from the beginning with the clinical results, then yes, I totally agree with you and in fact many biomedical analysts do this.

There are phase I results like with Vertex' HCV drug a few years ago or mipomersen in the antisense space where you can sense that the stories have legs to make it at least onto the market. TTR and PCS are such stories.

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