ImetelChat

Fish saw your note about asking Anna about the new abstract. I would not expect her to respond. All we have in the public domaine is a title with no actual abstract until later today. At that point we might get some comment as part of todays Q4 2016 summary from Dr. S. He is confined to the "four corners" of the abstract once the embargo is released so there will be no discussion until the study is formally presented on April 3 at ACCR. But the data will speak for itself. The last Lane group paper showed a dramatic longevity effect, this study should trump that easily. Multiple senior J and J scientists should present a high quality preclinical study. That the G conference is scheduled for 430 EST today and the abstract becomes public at the same time is no scheduling coincidence. I think Dr. S will probably drop a few tidbits while we wait for the Q2 2017 Imerge/Imbark review. bp

New abstract has been release from embargo. I am sure Fish will post. Results very interesting. Combo resulted in significant apoptosis in vitro and significant life extension in 40% of mice 77 days after therapy stopped. I would love to know how many if any of the 40% survivors showed evidence for recurrence or if they were disease free the implications would be astounding...maybe when the presentation occurs we can get an answer to that. GLTA bp

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.

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

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.

77 days is an unusual number of days to arbitrarily stop a study and almost surely reflects the deadline required for study completion and submission of the abstract. This of course means on April 3rd additional data can be presented that I hope will include more up to date additional mouse longevity data. Maybe some of them will still be alive. Also maybe we can glean some sense as to whether longevity is a reflection of complete freedom from disease for that period. I suspect the mouse data reflects "one course" of combo therapy. The effect of maintenance dosing or multiple courses of therapy, a more likely clinical correlate are as yet unknown and could hope a lot of hope. Cheng if you are reading this can you comment as to whether the cell lines MOLM-13 represent a narrow therapeutic target? I believe they are monocytic in origin so I wonder just how reflective the results are of a broader variety of AML cell lines. The study did test in vitro other cell lines but I wonder if they were not specifically noted since perhaps efficacy may not have been as dramatic. Thoughts? bp

Just for interest, the doubling time for MOLM-13 cells is 50 hours. 77 days and 40 % survival suggests a wipe out of CSC's. Cheng where are you and do you think that could possibly be correct? bp