Wednesday, March 12, 2014

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.

7 comments:

Anonymous said...

Thanks for the commentary. Considering one of the ET patients had been on the drug continuosly for almost 2 years without liver issues progressing be a pretty good sign?

Anonymous said...

Not actually Hy's Law given elevated ALP. That generally indicates some level of obstruction (cholestasis) rather than the massive liver damage indicated by Hy's Law.

Anonymous said...

Imatelstat was only tested in ET and PV to prove that it could be used in MF, MDS, AML, and Blast Phase MF. The 2 Trials on hold were about to end so is the FDA hold ment to make sure Geron collects this data to answer questions the FDA has. The trials that are not held are Tefferi's MF, Blast Phase MF, MDS,and AML as well as a Young patients with brain tumors trial.

Anonymous said...

Any reason that the lipid palmitoyl group, covalently conjugated to the oligonucleotide via a amino glycerol linker to "improves cell permeability in vivo" would not also be a potential issue? Possibly more then just the fact that it is a phosphorothioate oligo.

Anonymous said...

This is abstract on off target Imetelstat mechanism of action. This might explain the reversal of fibrosis. This was from the non small cell lung cancer trial. http://www.ncbi.nlm.nih.gov/pubmed/23545855

Anonymous said...

Well, please read the following

http://www.biopestlab.ucdavis.edu/files/195848.pdf

In light of that, your claim that imetelstat does not inhibit telomerase, to put it kindly, looks a bit ridiculous.

Dirk Haussecker said...

Seems like little anti-proliferative effect of imetelstat in the absence of p21 co-inhibition/absence. The intro also says that telomerase inhibition monotherapy unsuccessful so far, imetelstat notwithstanding.

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