Sergei Gryaznov: the interview
Posted: Tue Sep 27, 2016 3:07 pm
Dr. Kanak Kanti De had an interview with Dr. Gryaznov on 16th of February 2015, not long after the collaboration agreement between Geron and JnJ was sealed. Dr. Gryaznov, being responsible for a large part of Geron's current IP, is now engaged by JnJ and will give a presenation about imetelstat on 28 September. These developments bring this interview into the center of our attention again.
Sergei Gryaznov: the interview
1. My readers would be interested in the history of development of the GRN163L molecule. When did you discover it? How, or by what process? Who else, if any, were involved in the discovery?
GRN163L was actually relationally designed, ( I did it based on my prior work with Dr. Robert Letsinger at Northwestern University, and also in my own lab at Lynx Therapeutics, prior to Geron), then prepared and tested, first in cell-free assays, and then in cells (in vitro) circa early summer of 2001. Lipid-less version of the molecule, which was called GRN163 was designed and tested first. We’ve obtained a lot of interesting data with GRN163, including our first in vivo anti-telomerase and anti-cancer activity, which was published in Cancer Research, Oncogene, and NeuroOncology journals. We also came to the realization of certain features of GRN163, which could have been improved, especially with regards to its cellular uptake and in vivo PK/PD properties. That’s when and how GRN163L was design - by attaching a lipid group (C16) to GRN163, to increase the molecules cellular uptake and also biodistribution, etc.
2. Can GRN163L be a monotherapy for any type of cancer? Please explain the technology reasons here in layperson's terms.
GRN163L (as well as GRN 163 for some indications, such as GBM, for instance), can be a mono-therapy for telomerase-positive cancers, (cancers with high telomerase activity may also be preferred), with relative homogeneous telomeres, with are extremely short, such as ET, for instance.
3. Please give us your views on the '615 patent that you invented. Is this, like some of us believe, an advancement over Imet? In what ways? Please see points 8-10 in my article http://seekingalpha.com/article/2854996 ... 1423672205 for my views. Many of my readers are very keen on understanding this patent.
“615” patent very broadly describes/protects a new and highly attractive class of oligonucleotides, called 2’-arabino-fluoro N3’-P5’phosphoramidates, which could be used for various indications, as RNA targeting molecules, including, of course, as compounds designed to target telomerase RNA, and as telomerase inhibitors in general; this is as much as I can say on this matter at the moment.
(Interviewer Notes: The '615 patent has been of considerable interest to the Geron investors community lately, because it seems to discuss a molecule that looks like an advanced form of Imetelstat. The business aspects of that radical idea has been discussed widely in my articles and elsewhere. Dr Gryaznov's comments here on the '615 patent is therefore very interesting.)
4. Why the hematology focus on Imet? Can it work for other cancers that express telomerase activity? if yes, why did you/Geron choose to focus on hematology? In what way, if any, can we say Imet is a pan-cancer drug? That seems to interest my readers a lot.
Clinical indications for GRN163L are defined primarily by the compounds PK/PD properties, telomere length of the targeted tumors, as well as by the tumor dependency to telomerase inhibition. It appears the myeloid lineage tumors respond very well to GRN163l treatment, in a part due to the factors, which I’ve noted above, and in other part due to the additional other properties of GRN163L, such as its ability to affect cancer cells cellular adhesion and migration, likely due to the formation of so called G-Quadruplex structures. This very interesting and therapeutically important part of the story was published in collaboration with Dr. Jerry Shay from UTSW in Cancer Research journal a while ago, I think in 2007 or so, and also a bit later with Dr. Gunnur Dikmen and her colleagues.
5. If/when Imet comes to the market, which indication do you think it will first come for - MF, MDS, AML?
I really do not know, my guess will be MF, and I hope in PCV and ET, provided those two indications will be clinically pursued soon
6. 3 things you would do to make the market more interested in Geron and Imet. In 25 years, why hasn't Geron been able to bring a drug to the market? I can't think of another biotech this slow to come to the market with such a potentially blockbuster product.
I really can’t tell what I think about these questions. But if it would be my company to run, I’d emphasize:
a) Second generation and back-ups for GRN163L with better therapeutic index
b) Potent and unique oligonucleotide chemistry platform, (there is no of a such platform anywhere else) which allows to target many more cancers via telomerase, telomeres, etc, as well as non-telomerase targets in cancer
c) Small molecule telomerase and telomere targeting compounds in cancer, with novel/distinct mechanism of actions vis-à-vis GRN163L
7. Why did you leave Geron? Sorry if that's a personal question, but many of my readers want to know. And what research are you doing at Aurasense at present?
It was not my own decision to leave Geron, unfortunately. The company was going through a serious reorganizations, re-structuring and re-focusing, and my departure was a part of that process. At AuraSense I’m primery involved in the design and development of novel anti-cancer agents based on ImmunoModulatory properties of some 3-D nucleic acid structures. I hope the initial accounts of my work at Aurasense will be published soon (paper is under review at this moment in PNAS)
Full interview: http://drkkd.com/sergei-gryaznov-the-interview/
Sergei Gryaznov: the interview
1. My readers would be interested in the history of development of the GRN163L molecule. When did you discover it? How, or by what process? Who else, if any, were involved in the discovery?
GRN163L was actually relationally designed, ( I did it based on my prior work with Dr. Robert Letsinger at Northwestern University, and also in my own lab at Lynx Therapeutics, prior to Geron), then prepared and tested, first in cell-free assays, and then in cells (in vitro) circa early summer of 2001. Lipid-less version of the molecule, which was called GRN163 was designed and tested first. We’ve obtained a lot of interesting data with GRN163, including our first in vivo anti-telomerase and anti-cancer activity, which was published in Cancer Research, Oncogene, and NeuroOncology journals. We also came to the realization of certain features of GRN163, which could have been improved, especially with regards to its cellular uptake and in vivo PK/PD properties. That’s when and how GRN163L was design - by attaching a lipid group (C16) to GRN163, to increase the molecules cellular uptake and also biodistribution, etc.
2. Can GRN163L be a monotherapy for any type of cancer? Please explain the technology reasons here in layperson's terms.
GRN163L (as well as GRN 163 for some indications, such as GBM, for instance), can be a mono-therapy for telomerase-positive cancers, (cancers with high telomerase activity may also be preferred), with relative homogeneous telomeres, with are extremely short, such as ET, for instance.
3. Please give us your views on the '615 patent that you invented. Is this, like some of us believe, an advancement over Imet? In what ways? Please see points 8-10 in my article http://seekingalpha.com/article/2854996 ... 1423672205 for my views. Many of my readers are very keen on understanding this patent.
“615” patent very broadly describes/protects a new and highly attractive class of oligonucleotides, called 2’-arabino-fluoro N3’-P5’phosphoramidates, which could be used for various indications, as RNA targeting molecules, including, of course, as compounds designed to target telomerase RNA, and as telomerase inhibitors in general; this is as much as I can say on this matter at the moment.
(Interviewer Notes: The '615 patent has been of considerable interest to the Geron investors community lately, because it seems to discuss a molecule that looks like an advanced form of Imetelstat. The business aspects of that radical idea has been discussed widely in my articles and elsewhere. Dr Gryaznov's comments here on the '615 patent is therefore very interesting.)
4. Why the hematology focus on Imet? Can it work for other cancers that express telomerase activity? if yes, why did you/Geron choose to focus on hematology? In what way, if any, can we say Imet is a pan-cancer drug? That seems to interest my readers a lot.
Clinical indications for GRN163L are defined primarily by the compounds PK/PD properties, telomere length of the targeted tumors, as well as by the tumor dependency to telomerase inhibition. It appears the myeloid lineage tumors respond very well to GRN163l treatment, in a part due to the factors, which I’ve noted above, and in other part due to the additional other properties of GRN163L, such as its ability to affect cancer cells cellular adhesion and migration, likely due to the formation of so called G-Quadruplex structures. This very interesting and therapeutically important part of the story was published in collaboration with Dr. Jerry Shay from UTSW in Cancer Research journal a while ago, I think in 2007 or so, and also a bit later with Dr. Gunnur Dikmen and her colleagues.
5. If/when Imet comes to the market, which indication do you think it will first come for - MF, MDS, AML?
I really do not know, my guess will be MF, and I hope in PCV and ET, provided those two indications will be clinically pursued soon
6. 3 things you would do to make the market more interested in Geron and Imet. In 25 years, why hasn't Geron been able to bring a drug to the market? I can't think of another biotech this slow to come to the market with such a potentially blockbuster product.
I really can’t tell what I think about these questions. But if it would be my company to run, I’d emphasize:
a) Second generation and back-ups for GRN163L with better therapeutic index
b) Potent and unique oligonucleotide chemistry platform, (there is no of a such platform anywhere else) which allows to target many more cancers via telomerase, telomeres, etc, as well as non-telomerase targets in cancer
c) Small molecule telomerase and telomere targeting compounds in cancer, with novel/distinct mechanism of actions vis-à-vis GRN163L
7. Why did you leave Geron? Sorry if that's a personal question, but many of my readers want to know. And what research are you doing at Aurasense at present?
It was not my own decision to leave Geron, unfortunately. The company was going through a serious reorganizations, re-structuring and re-focusing, and my departure was a part of that process. At AuraSense I’m primery involved in the design and development of novel anti-cancer agents based on ImmunoModulatory properties of some 3-D nucleic acid structures. I hope the initial accounts of my work at Aurasense will be published soon (paper is under review at this moment in PNAS)
Full interview: http://drkkd.com/sergei-gryaznov-the-interview/
