Imetelstat Off-Target Mechanism Might Be Its Therapeutic Mechanism of Action

This morning’s biotech news featured a clinical hold on Geron’s imetelstat, a 13-mer lipid-conjugated N3’-P5’ thio-phosphoroamidate oligonucleotide telomerase inhibitor.  Since maintaining chromosome ends by telomerase is important for repeated cell replication, it is not surprising that the company is aiming this compound at proliferative disorders such as cancers and essential thrombocythemia (ET).  The latter is a condition in which there are too many platelets.

The clinical hold imposed by the FDA relates to apparent liver toxicity.  Liver toxicity as evidenced by elevated liver enzymes has been a known side effect of imetelstat with 90% of subjects in the phase II trial of imetelstat exhibiting low-grade elevated liver enzymes.  What is more, about 30% of the subjects had concurrent increases in bilirubin.  Taken together this strongly smells like cases of Hy’s Law, the nuclear liver tox bomb of drug development.

No wonder the alarm bells at the FDA are ringing.  According to the press release by Geron this morning, the agency is concerned about the reversibility of these elevations.  If not reversible, chronic liver disease, if not failure might ensue.  

I am not too surprised by these developments.  What surprises me is that the stock market apparently has not picked up on the concurrent liver enzyme/bilirubin increases since these had already been known.

The reason why I am not surprised is that phosphorothioate oligonucleotides can be expected to result in liver injury at the ~10mg/kg very high dosages given in the ET trial (dosage similar to the 640mg phase III prostate cancer trial of OncoGeneX discussed yesterday).  Note that ISIS Pharmaceuticals generally settles with 200mg, at most 300mg of systemically administered phosphorothioates and Santaris had to terminate two candidates targeting genes expressed in the liver due to liver tox.

It should be added here that the Geron, ISIS, and Santaris chemistries are slightly different, but share the phosphorothioate modification which in my opinion is what is causing these toxicities.

Given that the half-lives of phosphorothioate oligonucleotides in the liver are about 1 month, one would expect the low-grade liver enzyme elevations to go away with time and they might not be a show-stopper for non-chronic applications of imetelstat.   

That’s the somewhat good news.

The bad news: applying a phosphorothioate oligonucleotide-based telomerase inhibitor for the treatment of cancer and increases in platelet counts sounds like a bad joke.  Thrombocytopenia (decreases in platelet counts) and anti-proliferative immunostimulation are well known side effects of large doses of phosphorothioate oligonucleotides.  In light of that, claiming that imetelstat works via telomerase inhibition seems a bit optimistic to put it kindly.