Chemistry explains toxicity profile difference vs. Prosensa
Today's news about GSK/Prosensa PRO051 (Drisapersen) clinical toxicity/hospitalizations warrants a review of the inherent differences in chemistry that favors SRPT eteplirsen. Its all about sulfur! PRO051 has an RNA sugar ring with a sulfur for the non-bound oxygen in the backbone (changing it to a phosphorothioate linkage). Eteplirsen replaces the sugar ring of RNA with a morpholino ring and has nitrogen in the backbone. This phosphorodiamidate morpholino oligomer (PMO) is uncharged in contrast to natural RNA and PRO051 where the oxygen and sulfur is negatively charged. When filtered by the kidney, the released sulfur contributes to the tubular necrosis inside the kidney. This explains all the protein excreted in the urine (proteinuria). The higher the dose of PRO051, the greater the proteinuria. Thus the dosage limitation far below what can be given with eteplirsen (and where better efficacy occurs). Phosphorothioate also has greater binding to serum proteins and accumulation in the liver, which can affect coagulation due to binding of the drug to thrombin.. This results in bleeding, injection site reactions, flu-like symptoms, inflammatory reactions, etc. Kynamro, which is similar to PRO051 in containing sulfur, has reported the same clinical toxicities. Clearly there is a class effect not seen to date with PMO molecules like eteplirsen, and is fully explained by the chemistry & resultant pharmacologic differences.
Great comment. I was wondering if you had any references you could cite, or any good reviews. I'd like to read up on the different modified oligonucleotides. Particularly pre-clinical, I've read some of the clinical reports on drugs like Kynamro.
So all of this was predicted years and years ago. At least expected. Yet the race had to be run because there was a chance either "car" would fail due to non-chemical reasons. In the end the chemistries were left on the field to challenge each other without any extraneous events affecting the ultimate outcome. And as you say, our chemistry was always destined to win and theirs always destined to lose. Politics, bad management, short sellers destroying a small biotech....all that was avoided....and we won on the merits. As was always assumed by the science - the chemistry. Now it's up to the PPMO the PMOplus and the various PMOX's to carry the chemical ball forward into the other indications. If they can, we have this field to ourselves. Of course the basic PMO is npw off patent and anybody can come up with their own PMO-?s" or PMO-Whatevers for better delivery to this kind of targeted cell or that kind. We don't have to win them all, but we're way way ahead of anyone else on that score. Is there anyone else even trying yet? Oxford....but they're with us for now anyway. Anyone else? We should see more pretty soon, I'd guess.
Bingo copp this is the whole equation and always has been. The chemistry of being non polar/ neutral charge is seen in the early pharmacokinetics. Follow the clearance in urine as a first order kinetic. The best of those stufies or most instructional studies were done long ago. But it was always the chemistry.