Focus on Mechanism of Action

[hiprock88]

The American Chemical Society recently put out a Top 40 list of Drugs in the Pipeline. Re. Imetelstat, they write:

“Intriguingly, the data suggest that the drug is not altering telomerase activity, but instead acting through an alt. cellular mechanism to halt blood cell proliferation.”

I recall during the Nov 2016 Stifel Conf, Dr. Scarlett was asked if it mattered whether Imetelstat was working through the telomerase inhibition mechanism, and he seemed to sidestep it slightly by stating the more relevant question is ‘how does Imetelstat work in hematologic malignancies’; ‘it looks like the drug is having an anti-proliferative affect on the malignant progenitor cell clones (the cause of these types of disease.)’

Is the drug’s utility on telomerase inhibition no longer the focus? Does it matter?

[Fishermangents]

I have read various reports from trials that say that imet does inhibit telomerase. I recall a studies that saw actually telomere shortening. If it is the MoA is a different question.

[hiprock88]

Agree Fish; If it’s determined for whatever reason(s) that Imetelstat isn’t having much affect on TI but is effective for other reasons, is that a big deal? It seems to me the narrative about Imetelstat has changed slightly over the last few CC's and wondering what your thoughts were. thx

[biotech_bs]

Scarlett at one point said he didn't know where the data for the journal article came from that made this claim and I believe that a Janssen poster at the most recent ASH presented research that debunked this conclusion that Imet doesn't inhibit telomerase. I don't recall which webcast it was but Chip pointed to this research to discredit the original source of this claim.

[Fishermangents]

biotech_bs, you are correct: it is this extended ET study that concluded the following:

'In the ET imetelstat cohort, driver mutation burden at baseline and best reduction during treatment correlate significantly with baseline telomere length.'
and:
'We demonstrate higher TLV after 9-10 months of therapy and a significant correlation with the reduction in the driver mutational burden'

(TLV = Telomere Length Values)

Link: http://www.geron.com/file.cfm/53/docs/H ... H-2016.pdf

It is the same study that concludes that imet is targeting the malignant clone, while favoring normal hematopoiesis. The study is the basis for the first claim on the first slide of the Jan 2017 Corporate Presentation:

'inhibiting telomerase activity impedes production of malignant cells'

Link: http://www.geron.com/file.cfm/53/docs/H ... H-2016.pdf

These are all very strong and dramatic claims. I think that the general public doesn't fully realizes what that means.

'Disease modifying activity' is another way of saying that imetelstat reduces the allelic burden and pushes back the disease. This has already been observed by Dr.T. in an early stage. They must have sufficient evidence by now, because they claim this capability in their corporate presentation.