I find it very interesting that they used TA65 as a Telomerase stimulator and found it did work as such.
TA65 is sold as a "Neutraceutical" and although it is derived from Geron is not an approved drug.
TA65 is sold as a "rejuvenator" for aging cells so this piece seems to indicate it has some efficacy at least in the pulmonary system.
"METHODS AND RESULTS:Marked TERT expression or activity was found in lungs from patients with idiopathic PH and from mice with PH induced by hypoxia or serotonin-transporter overexpression (SM22-5HTT(+) mice), chiefly within PA-SMCs. In cultured mouse PA-SMCs, TERT was expressed on growth stimulation by serum. The TERT inhibitor imetelstat and the TERT activator TA65 abrogated and stimulated PA-SMC growth, respectively. PA-SMCs from PH mice showed a heightened proliferative phenotype associated with increased TERT expression, which was suppressed by imetelstat treatment. TERC(-/-) mice at generation 2 and TERT(-/-) mice at generations 2, 3, and 4 developed less severe PH than did wild-type mice exposed to chronic hypoxia, with less distal pulmonary artery muscularization and fewer Ki67-stained proliferating PA-SMCs. Telomere length differed between TERC(-/-) and TERT(-/-) mice, whereas PH severity was similar in the 2 strains and across generations. Chronic imetelstat treatment reduced hypoxia-induced PH in wild-type mice or partially reversed established PH in SM22-5HTT(+) mice while simultaneously decreasing TERT expression. Opposite effects occurred in mice treated with TA65."
Sentiment: Strong Buy
I'm glad to see AST is planning to take VAC-1 forward into a Phase III trial.
Geron had never planned to do that but with data this good, even if it is patient specific and expensive due to low DLT's and with possible future applications in all types of cancers it is a good bet going forward.
I will be listening to tomorrows presentation, expecting more details. Maybe even a collaboration with check point inhibitors with big pharma, with money up front.
From todays news on the AML trial with VAC-1
"We are very encouraged by these promising new, long-term relapse findings, and excited by the opportunity of having a third clinical stage program at Asterias," said Pedro Lichtinger, President and CEO of Asterias. "AST-VAC1 becomes our most advanced clinical opportunity fitting our strategic focus on major unmet medical needs without adequate available therapies. We are forming our clinical development plan for AST-VAC1, and intend to explore all strategic alternatives to further advance this product for the benefit of patients, and to maximize value for Asterias shareholders."
Geron had always said GRN VAC-1 trial was for proof of concept and never intended to take it forward, instead choosing GRN VAC-2, which would ultimately be much cheaper, universal and off the shelf (ref) at any clinic for immediate application to any patient.
However AST sees such a terrific result in the Phase II of VAC-1 that it wisely plans to push it forward, and include immune checkpoint inhibitors. Unlike Dendreon's Provenge dendritic cell based therapy this patient specific therapy appears to give a high percentage of patients very long remission rates and will be well worth its cost.
I will watch carefully the progress of this program as it is the one best positioned to meet a large unmet need within a relatively short time frame.
It appears Jakafi impairs the function of Natural Killer (NK) celss of the immune system, leading to increased treatment related morbidities. Another reason for Imetelstat to become the treatment of choice for MF.
"JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms
2015 AACR Abstract
Ruxolitinib is a small-molecule inhibitor of the JAK kinases, which has been approved for the treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are also being conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib-treated patients, and natural killer (NK) cells are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of JAK inhibition on human NK cells in a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation, and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activity was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible long-term side effects associated with ruxolitinib treatment.
Cancer Res; 75(11); 2187–99. ©2015 AACR.
And it rules out Incyte trying to claim that if their Jak inhibitor was used they could have gotten as good a result.
Last five trading sessions ADXSW up over 50% higher than growth of value of ADXS.
Smart move buying warrants a while back. I have 50% more warrants than I would have got stock for the same money.
The DLT's for alvespimycin: " Common adverse events were gastrointestinal, liver function changes, and ocular"
So since thrombocytopenia and neutropenias are the main DLTs for Imetelstat with luck they can both be used at full dose strength together.
However the issue of liver function combined toxicities has to be watched out for.
I think the TA65 formulation was licensed out.
However Geron has never said that TA65 is the exact compound that they did their in vitro testing on, so if they are truly different then Geron still may some TA IP under its control.
Am I the only one to note an apparent mistake in the clinicaltrials.gov trial description under "Assigned Interventions?"
"Drug: Imetelstat 4.7 mg/kg
Participants will receive imetelstat intravenously as 9.4 mg/kg every 3 weeks. Study drug will be administered intravenously until disease progression, unacceptable toxicity, or study end"
This is the 4.7mg/kg arm but then it refers to 9.4 mg/kg every 3 weeks !!!
Too bad Geron opted not to go with it.
Unlike Dendreon's Provenge its cost would have been worth the benefit.
By reaching for perfection Geron passed on darn good and fell on its face.
Since their method of action are different I suppose there would be no obvious reason not to, as long as IMET doesn't by attaching to Telomerase modify it so much that the immune system stimulated by VAC2 can't recognize and attack cells expressing it. I do however doubt that would be the case.
However I doubt that combination would be tried early in trials but possibly after VAC2 and Imetelstat have been individually validated.
Early results have good efficacy and duration at low "dosage" levels.
Can't come up with the right descriptor for what they do.
Any idea of what a treatment cost would be if they get approval and scale up.
Process is customized for the patient so cannot be too cheap.
Sentiment: Strong Buy
ADXS not CART.
Modified Listeria vector.
Low cost, minimal side effects and out patient injection huge advantages over CAR-T therapies.
Expected synergy with Anti-PD-1/PD L-1
Yes. And the platform although initially aimed at Telomerase expressing cells could be used to target many other ailments that would respond to am immune system attack.