ImetelChat

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Curiosity Killed The Cat, Contributor
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I’m not sure everyone is fully understanding the point I was trying to make. Using the ibrutinib example, there’s no synergy to be had by combining imetelstat and ibrutinib (Imbruvica). Bruton’s tyrosine kinase (BTK), the protein to which ibrutinib binds, has no known modulatory effect on telomerase, and vice-versa. So combining imetelstat with ibrutinib, while a plausible scenario, would not be synergistic but would create a combination where the two drugs act independently to create the desired result. Combining Venetoclax with imetelstat, however, is an entirely different story.
Venetoclax inhibits Bcl-2. Inhibiting Bcl-2 inhibits telomerase.
http://bit.ly/2mxnYTi
Imetelstat also inhibits telomerase. Combining imetelstat with Venetoclax should synergistically have a greater effect on inhibiting telomerase than either agent acting independently. And this is exactly what the Janssen study found: “Molecular analyses showed combining imetelstat with venetoclax reduced hTERT expression and telomerase activity much more strongly than either agent alone.”
Inhibiting Bcl-2 leads to apoptosis (cancer cell death). Telomerase works to prevent apoptosis when Bcl-2 is inhibited.
http://go.nature.com/2...
Venetoclax/imetelstat acting together have a much stronger impact on reducing telomerase. The less telomerase available to interfere, the more successful inhibiting Bcl-2 should be in causing apoptosis. This is exactly what the Janssen study found. “A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax.”
Telomerase is overexpressed in most cancers. Bcl-2 is overexpressed in many cancers. Because there is such a close relationship between telomerase and Bcl-2, the Venetoclac/imetelstat combination may have widespread potential.
Side note: From the first link I provided above: “Our findings of the modulation of telomerase activity by a widely deregulated survival factor, Bcl-2, may serve an important model to study the regulation of telomerase activity by an apoptotic pathway and could open new possibilities to develop novel strategies to control cancer cell growth by co-targeting both pathways.” This study was conducted at M.D. Anderson in 1997. So the potential for the Venetoclax/imetelstat combination has been known for a long time.
Side note: One of you messaged me and asked about imetelstat’s potential for use solely as a combination drug. Answer: The second best-selling cancer drug in history (Herceptin $65 Billion+ lifetime sales) was approved for and is used solely as a combination/adjuvant drug.
16 Mar 2017, 08:09 AM ][/quote]

Hoosier57, This is beautifully summarized by CKTC. Your second link does not work, just FYI. Thank you for sharing the post. This binary approach to apoptosis is very impressive. On another note we are now over six months from the September announcement. This means that all patients in MF study are approaching or have surpassed the median survival predicted for patients who are R/R Jakafi. If any patients are still alive for the analysis to be made public Q2 that would support longevity effect. bp

Great post from CKTC. Thanks for sharing it here, HOOSIER.

If deaths have occurred during the present GERN/Janssen MF trial is that a material fact that must be disclosed not only to the FDA but also to GERN shareholders? If so, when must such deaths be reported? In other words, what is considered a timely disclosure?

If the death rate was higher than expected and the protocol considered a danger to patients they would have to disclose. Deaths due to disease natural history or those attributed to factors outside of med toxicity would likely not be disclosed. I am sure a data safety monitoring board has been reviewing this periodically. bp

BP,

Thanks for the clarification. What you are saying, then, is one cannot assume there have been no deaths in a clinical trial simply because no such deaths have been reported.

Exactly, there almost certainly have been deaths, but hopefully fewer than expected without therapy. bp