ISIS Pharmaceutical Reveals Dynamic PolyConjugate Efforts

When Arrowhead Research made a splash 1 ½ years ago at the Boston OTS meeting in late October 2012 with impressive subQ DPC knockdown efficacy in monkeys, there was a large number of meeting participants crowding the speaker after his presentation.  Although I sat a few rows away, the most eager questioner was an employee from ISIS Pharmaceuticals who managed to beat the Merck representative to the podium!

There were times when I believed that the interest of large companies in the technology of small companies boded well for partnership potential.  It has become clear to me, however, that while this may be true to some extent, the first instinct by the large guys is to get close to the innovators so that they can appropriate as much of the technology as possible without paying a dime.

While I have long shelved Merck into that category and DPCs will now be a research priority at Alnylam following their acquisition of Sirna/Merck, a now published patent application by ISIS Pharmaceuticals on melittin-based, GalNAc-targeted single-stranded antisense delivery (ssRNAi and conventional ASO) demonstrates that ISIS ticks no different.

With a priority date of WO 2014/089146 A1 of December 4, 2012, this poor employee and collaborating patent agent had to stitch together a patent application in just a month after returning home from the conference.  Unsurprisingly, the patent application lacks any actual experimental data to support the 'ínvention'.

I don’t want to be too cynical about this as this is how the industry and the patent system function.  It is an important lesson for small companies though that they should not get overly excited about interest they generate for their technology and they should only engage in deeper relationships once they have established that the larger party is not just trying to steal their technology by pretending to collaborate with them.

It is this unwillingness to share and attendant mistrust that in my experience impedes much business development that makes great sense on paper.  This ultimately delays timelines, leads to litigation, and makes the pie smaller for everybody.

And for the future of gene knockdown in the liver…if ~5mg per week may be possible for GalNAc-targeted gen 2.5 RNaseH ASOs, one can only wonder what a melittin-type escape mechanism would add to its potency, and safety. 

Comment on Seeking Alpha bear article on ISIS Pharmaceuticals

Last night, a detailed bear article on ISIS came out that shook the market in after-hours trading.  In summary, the thesis rests on the poor safety profile, especially immunogenicity of gen 2.0-based KYNAMRO (2’MOE gapmer) and that this is likely to translate to all other gen 2.0 drugs based on shared chemical composition and the (in my opinion idiotic) claim by the CEO of ISIS that KYNAMRO is a success and is representative for gen 2.0.  Talk about shooting yourself in the foot.

While I agree that the KYNAMRO data have raised legitimate questions around the safety of gen 2.0 phosphorothioate oligonucleotides, the bear article conveniently ignores the abundant clinical data that have emerged since for a number of other antisense drugs based on gen 2.0 chemistry.  These support the claim by ISIS that through improved screening, they are now able to better weed out the sequences that will likely prove immunogenic in the clinic. 

Importantly, in oligonucleotide therapeutics in general, while nucleic acid chemistry has a great influence on whether a molecule is immunogenic, it is the exact sequence composition that ultimately decides whether this is actually the case.

This is illustrated by the recent phase II clinical results for ApoCIII (no discontinuations noted), Factor XI, and GCGR.  Not only were robust gene knockdowns achieved, in sharp contrast to KYNAMRO, the company claimed that they were no flu-like symptoms, chills and other symptoms indicative of the immunostimulatory potential of oligonucleotides.  By contrast, about 1/3 in the KYNAMRO studies exhibited such events, with even higher numbers in the open-label extension phase.

Granted, given that these were 13-week studies, it is impossible to disprove the thesis that things are bound to get worse over the long-run.  However, no flu-like symptoms versus 1/3 of patients exhibiting flu-like symptoms in studies of comparable duration is a dramatic difference and allows one to extrapolate that the safety of the follow-on drugs will similarly be greatly superior to KYNAMRO over time.

While I had been tempted to let the Seeking Alpha article by Dr. Anonymous pass as raising legitimate concerns, the blatant failure to mention the more recent experience with gen 2.0 and the after-hours action last night makes this article suspect and outright useless given the lack of new information or insight.