Merck Hot on the Trails of Dynamic PolyConjugates by Arrowhead Research

Not only was I impressed by the Dynamic PolyConjugate delivery data presented at the late 2012 OTS meeting, many others in this peer group were, too.  This included favorable comments and keen questioning by a Merck scientist in the following Q&A session.  Not entirely surprising therefore, the presentation at OTS by Merck at the meeting revealed that it has recently shifted its delivery focus onto DPCs.  This week then, published evidence of that activity emerged in the form of a publication in Bioconjugate Chemistry (Parmar etal. 2013).  The DPC work described therein is consistent with a strategy in which the company aims at internally replicating the industry’s most promising/advanced delivery technologies, possibly hoping that not only can they overcome the scientific and manufacturing challenges, but also will find holes in the originator company’s intellectual property.  

Learning the DPC ABCs

The paper is essentially a replication of the basic DPC studies published in 2007 by Rozema et al. in PNAS.  Accordingly, they encountered much of the same challenges that the scientists at Arrowhead Research (formerly Mirus Bio, then Roche) had encountered in building the DPC delivery platform and includes issues with manufacturing yield and solubility.  The major difference is that Merck utilized a polymer backbone incorporating  disulfide bonds that one might hypothesize to be degraded in the reductive cytoplasm of cells. The fact that the first published Arrowhead DPC was not biodegradable was cited as a key toxicity issue.  All this is consistent with what Arrowhead started to report last year in explaining which challenges had to be overcome before they were able to clinically mature the technology.  Overall, the consistency of the findings with those first reported by Arrowhead gives me a good feeling about the theoretical basis for and robustness of the technology.

Lavishly Screening for Improvements

In order to discover suitable disulfide-containing polymers, Merck generated a small library of amphiphilic polymers by reacting together three types of chemical groups: an amine, an imidazole, and hydrophobic tails.  Conjugation of the targeting ligand and other masking groups that define DPCs was via the same CDM chemistry pioneered and still utilized by Mirus/Arrowhead.

The library was winnowed down via a series of tests, starting with membrane lysis assays down to tissue culture and rodent knockdown activity tests.  

Curiously, the paper lacked an assessment of toxicity in animals which was stated to be the entire point of the library and the study.  Whatever the motivation for this early publication of DPC research, this illustrates the early stage of Merck’s DPC development efforts.  The absence of published toxicity results may also mask a basic flaw with the disulfide concept: a) in order for these DPCs to fully degrade in the body, they would all have to be taken up into the cytoplasm; or b) the source of the toxicity is exclusively due to the intracellular accumulation of polymers.  Neither a) nor b), however, are not plausible in my humble opinion.

In any case, Merck likes to perform screening when it comes to optimizing RNAi technologies.  The most amazing example of this is probably their RNAi trigger modification screen involving over a hundred different types of nucleic acid modifications.   Regardless of what one might think of the wisdom of such brute-force and logically possibly flawed efforts, the size of these investments illustrate that Merck likely outspends all other companies in RNAi Therapeutics development, including Alnylam.

Merck Strategy

I am struggling to understand Merck’s strategy with regard to RNAi delivery.  It is obvious that all they are doing is to try and replicate the industry’s most promising technologies.  First it was SNALP (which they are still pursuing according to the OTS 2012 presentation), now it is DPC that they have set their eyes on.  I can only come up with two mutually non-exclusive strategies behind the approach. 

According to the first strategy, Merck wants confirm the validity of the promising reports.  If the technologies perform well in their hands they go out and license in the IP.  Extensive internal technology validation would be insurance against spending millions on technologies that turn out to be duds in an industry in which most technologies have not lived up to promises made.  Importantly, the decision to License technologies from the inventors and therefore presumably real experts would accelerate their pipeline development by years.  Of note, Merck still has not brought an RNAi candidate into the clinic since their $1.1B acquisition of Sirna Therapeutics and the pressure to achieve that milestone should be building.  According to the second strategy, Merck hopes to recreate or even exceed the originators’ achievements, and with luck can use the technologies without concern of infringing IP.  

Given Merck's significant investments which would seem to exceed those necessary for simple due diligence, Merck seems to be pursuing strategy No. 2.  It seems to be a risky strategy though because of IP uncertainty in general.  I therefore personally favor a more flexible implementation of strategy No. 2, namely one that envisions licenses and R&D collaborations if the IP situation or insurmountable technical hurdles eventually demand them. 

In any case, Merck must be doing quite well given the generous time and money spent on such RNAi Therapeutics research.  Enviable.

Merck in Talks with Arrowhead?

There are some comments in the paper that leads me to believe that Merck is actually talking to Arrowhead Research directly.  Although there may be hints in the very recent patent literature and investor presentations that biodegradability had been an issue with first-generation DPCs (note: Arrowhead is now using biodegradable peptides as the polymer backbone), and/or some of that has emerged when Roche opened up their books during their RNAi sales process, I have not seen such comments in the still relatively sparse peer-reviewed DPC literature.  Yet strangely, Merck presents the rationale for the disulfide strategy as if it was common knowledge.

Merck is not entirely foreign to Arrowhead Research.  Just last year, they entered into a research alliance concerning Arrowhead’s new-fangled peptide drug conjugates (PDC).  So there are open lines of communication between the companies.  Whether it’s something to get excited about if you are an Arrowhead shareholder, I’m not sure: in this industry, lots of parties are talking to each other without it ever coming to a deal.  Having said this, the recent results with DPC technology have been tantalizing, and for RNAi Therapeutics at Merck to survive, I would think that they have to put something into the clinic over the next two years or so or face the cost-cutting axe of the new chief of Merck Research Labs, Roger Perlmutter.  DPCs would seem to be one of the few options they have to meet such timelines.