ImetelChat

Abstract for ASCO2017, April 3, 2017, 8:00 - 12:00 PM

Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia

Abstract is fully by Jansen, but still embargoed. I will eat my shoes if this isn't to be an important indicator for the upcoming AML trial.

Link: http://www.abstractsonline.com/pp8/#!/4 ... ation/6931

Nice find. "in vivo"! must be in mice but it looks like they picked their combo agent. bp

Awesome. All of the Presenter/Authors are Janssen employees. Makes it much more significant than just some more university preclinical findings. Janssen is moving the Imet ball down the field nicely. This may be the combo preclinical work that was needed to set up the IND dosing along with the 2Q MF/MDS dosing data.

This is an interesting video about venetoclax. The onco-community seems to be excited about this drug:

http://www.onclive.com/peer-exchange/am ... lax-in-aml

This is the full text of the abstract:

Background/Aims:
Acute myeloid leukemia (AML) is an aggressive cancer with limited treatment options outside of chemotherapy. Improved therapies with novel mechanisms of action are desperately needed to fill this need. Both hTERT, the catalytic subunit of telomerase, and BCL-2, an apoptotic regulator, are overexpressed in AML, correlating with disease severity and poor prognosis respectively. Imetelstat is a novel, first-in-class competitive inhibitor of telomerase with clinical activity in hematologic malignancies. Venetoclax, an approved BCL-2 inhibitor for CLL, has shown a promising clinical benefit in AML patients. Preclinical evidence shows that downregulation of hTERT induces apoptosis via disruptions of hTERT and BCL-2 interaction; we hypothesize that inhibiting both targets would yield greater anti-tumor activity in AML compared to treatment with either agent alone.
Methods: AML cell lines and AML patient’s PBMC samples were treated with imetelstat or venetoclax alone, or in combination, and viable and apoptotic populations of cells were evaluated by flow cytometry. Telomerase activity, hTERT expression and mitochondrial dysfunction were investigated for mechanism of action. Furthermore, an in vivo study in the MOLM-13 AML disseminated model was conducted to assess efficacy and survival.

Results:
A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the MOLM-13 cell line, single-agent imetelstat and venetoclax had modest apoptotic activity after 48 hours (22% and 30% respectively), but the combination achieved 88% at 48 hours and nearly 100% at 96 hours. Similarly enhanced apoptotic activity was also observed in PBMCs purified from 4 AML patient whole blood samples. Molecular analyses showed combining imetelstat with venetoclax reduced hTERT expression and telomerase activity much more strongly than either agent alone. Furthermore, in vivo studies showed all mice tolerated the combination of imetelstat with ABT-199 well, with increased life span as compared to the vehicle control (68.1%, p=0.0001), to imetelstat (39.6%, p=0.0011) alone, or to venetoclax (23.3%, p=0.0001) alone. In the combination group, 40% of treated mice were alive 77-days after treatment discontinued whereas all mice of the other single agent arms died within two weeks, demonstrating a significant survival benefit.

Conclusions:
To our knowledge, this is the first investigation combining imetelstat with venetoclax in AML, and the results demonstrated a synergistic effect on induction of apoptosis in cell lines and patient samples in vitro, which translated into prolonged survival in xenograft models, thus providing a strong rationale for clinical exploration of this combination.

My take aways from this abstract:
- "In the combination group, 40% of treated mice were alive 77-days after treatment discontinued whereas all mice of the other single agent arms died within two weeks, demonstrating a significant survival benefit."
- "a strong rationale for clinical exploration of this combination."

In the two single arms mice died within two weeks after discontinuation. In the combo arm 40% of the mice still lived after 11 weeks after discontinuation. Quite impressive, I would say. The abstract is authored by 10 JnJ researchers (of which one a VP), and not by a academic group looking for next round funding. I see this abstract is the upbeat for a potential upcoming AML combo trial for humans.