Yesterday, Alnylam made the somewhat surprising announcement
that it partnered with the ~$1.6B market cap The Medicines Company to develop
and commercialize its RNAi Therapeutic program targeting PCSK9 for
hypercholesterolemia. This program includes ALN-PCS02 which had completed a phase I study last
year and contemplates subcutaneous formulations, too.
This means that as a number of PCSK9 monoclonal antibodies are moving forward in clinical development at lightning speed, including phase III trials involving more than 20k patients, the ambition here is not to have
a Big Pharma try and catch up (maybe they did try, but nobody was willing to
partner), but to carefully study the experiences of the monoclonals and exploit the biological
differentiation that an RNAi approach offers over antibody. With The Medicines Company on
board, some of that potential at least is seen in the hospital setting.
Mechanism of Action of RNAi vs Antibody
There are various points of differentiation which might
translate into a clinical benefit for RNAi. Expect the companies to look hard
for such evidence and, if found, beat the drum about it. These differences
include: 1) reduction of both intra- and extracellular PCSK9 thus replicating
human genetics from which PCSK9 emerged in the first place; antibodies merely
bind existing extracellular PCSK9; 2) because antibodies form complexes with
their targets and do not act catalytically, the percent target inhibition
efficiency of antibodies depends on target abundance; therefore, in patients
that have many more PCSK9 molecules than the number of antibodies you can fit
in a subQ syringe, PCSK9 antibodies will not work well; RNAi, however, works with similar percent knockdown efficiency more or less regardless of target gene
expression levels.
Efficacy
In general, the LDL cholesterol reductions with monoclonal
antibodies have been between 40-70% in multi-dosing regimens. In Alnylam’s single-dose phase I trial, the liposomal
ALN-PCS02 achieved a ~30% reduction (area under the curve).
Frankly, given the number of clinical trials involving PCSK9
monoclonals, I have given up tracking the results of each and every study. Having said that, in reviewing the phase II trials of the candidate that may be viewed as the most advanced/exciting one, AMG145 by Amgen, it seems that the higher end of LDLc reduction was only achieved when given on top of statins. Althought to me this seems a bit counterintuitive since
statins are thought to act mechanistically essentially the same as PCSK9 inhibitors, namely
via increasing LDL-receptors on hepatocytes, that's the way it looks right now, and the ALN-PCS02 trial may have
been disadvantaged as it was mono-therapy.
Finally, with continued improvements in the potency of RNAi
Therapeutics technologies, it should be possible to achieve similar LDLc
reductions with RNAi as with PCSK9 antibodies.
Acceptance
I like the fact that PCSK9 has become a small battleground between
RNAi and monoclonal antibodies as this may be the best way for RNAi
Therapeutics to work on its wider acceptance by the medical and investor community. Notably, the often glorified monoclonals
frequently suffer from injection reactions (some notable serious ones were observed in Regeneron’s PCSK9 trials), other immune-related issues and manufacturing
challenges to name a few issues. RNAi
Therapeutics, of course, are facing some of the same challenges, but it irks me that when
it comes to this technology, they suddenly are supposed to be show-stoppers.
Financials
The financials (including a $25M upfront, up to $180M in
sales and commercialization milestones and double-digit royalties) were not all
that exciting for Alnylam and reflect the fact that only one single-dose phase I trial had
been conducted. Also, as Alnylam cannot
claim a blocking IP any more and has licensed hepatic targeting rights to other
companies, including Roche/Arrowhead, the value of ALN-PCS as the only RNAi
candidate for PCSK9 has been lost.
Still, $25M is serious money for a company the size of The
Medicines Company and you do not turn this over just to help out an old
friend.
4 comments:
Dirk,
Alnylam hasn't granted a blanket hepatic targeting rights to all the diseases in the liver to any company. Alnylam has granted Roch/Arrowhead hepatic targeting rights to only a few select liver based diseases and I don't think it includes PCSK9 since Alnylam was already working on PCSK9 when an agreement with Roch was announced.
This would be interesting. I had thought that the field licenses Alnylam gave to the Roche and Takeda gave these companies essentially unrestricted access to targets in those fields. In their regulatory filings, in the risk section, Alnylam also notes that their licensees may become their competitors by selecting same targets. Having said that, I consider it plausible if there were (undisclosed) exceptions.
Here is an excerpt taken from 2007 Alnylam PR for their agreement with Roche :
" ....The alliance will initially cover four therapeutic areas: oncology, respiratory diseases, metabolic diseases and certain liver diseases."
It is very clear that it doesn't include all the liver diseases from the fact that Arrowhead had to go to Alnylam to get a license for their HBV target.
Novartis could have become a potential competitor had they exercised their option for a platform wide adoption license. But instead, they opted for 31 exclusive targets and obviously PCSK9 is not one of them.
Good point. I did not remember that for the liver they made an exception with 'certain'. The Takeda agreement though refers to 'metabolic disease' in general. Hypercholesterolemia should fall under that label. With regard to HepB and Arrowhead, I rationalized the need for a new license based on it maybe falling into the 'infectious disease' bucket if there was one.
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