Questions I continue to have

[huntingonthebluffs]

Again, I am a novice on watching a drug move from a phase I CT through the processes to get to a NDA and eventually a marketable product. What we are observing is understandable to some in the know and / or with experience with the processes. For me and possibly others there is a lot that doesn’t make sense. I’m trying to keep a positive attitude but with each dose of new information many of us comeback with the same questions from a slightly more enlightened but perplexed perspective. Questions I continue to have are:

1. Given a majority of analysts, patients & their families and investors find the terminology and process difficult to understand and follow, it seems ImetelChat and SA have the primary role of providing answers for which I am grateful. However, I hope that the sponsors of a transformational drug have a role and responsibility to speak publicly at a fairly detailed level and in something less than extremely scientific terms on what is going on especially if the shortest path is not being pursued. In addition, I would hope that the EMA and FDA would encourage sponsors to speed the process in these instances versus just providing the tools for sponsors to act on at their sole discretion. Are they?

2. The math escapes me on why exactly it takes nearly two years to obtain 24 weeks of data on patients in the MF CT. I understand there is a ramp up of sites, logistics and deployment activities and vetting of patients but nearly 4 times more weeks to obtain the 24 week baseline? And would none of the CT prep be advanced on prior to starting the CT even though it was announced many months prior to starting?

3. It appears to me that the MF R/R CT is an effort to learn what they can while delaying the milestone payment as long as possible? I know that is cynical, I hope and probably am wrong about that. Certainly, it is less likely to duplicate the Phase I Mayo study. Seems the MF frontline would have been the most expeditious means of getting through the process to a marketable product. So what is the likely strategy here, are we just biding time here to get to the likely eventual combination strategy for using Imetelstat with other drugs to speed up the efficacy results and percentage of patients achieving positive results?

4. I know large companies can have a bureaucracy and extensive process to insure success and avoid future mistakes. It seems that drug sponsors with drugs showing solid safety and significant efficacy on treating deadly diseases would take the most expeditious path to marketing approval available to them versus the longest path to helping the patients with death sentences facing them. Why is this not the case with Imetelstat or is it?

5. Lastly, if everything is positive and progressing as expected with a transformational drug like Imetelstat, why do the sponsors provide less than positive or at least easily misunderstood feedback to investors and those anxiously in need of this product? Maybe the upcoming conferences and presentations will be a watershed. Obviously, acquisition positioning, competitive and product stable concerns are very important but is that all that matters to the sponsors or just what is going on here?

Thanks again to Fishermangents for this great site and insights, Biopearl and others with the knowledge and experience on what is likely happening with this transformational drug.

[irishtrader52]

These are such good questions and I can assure you that many friends at Mayo including me ask the same ones. I am also cynical enough now to suggest that Johnson could care less about the patients and this is the 'big pharma' game. That said, it is still working for John since April 13 and it seems the science is sound.

[Fishermangents]

Hunt, these are all valid questions. We are left with trying to interpret the scarse information provided by JnJ and Geron. Usually JnJ doesn't speak publicly about new drugs that are in an early testing phase (i.e. P1 and 2). Maybe they will let us know more when imet is in P3. I consider it as a kind of encouraging that they have now two abstracts on AML and CML, although this is all pre-clinical and not related to MF.

If you scrumble together the things we see I believe imet is going well behind the scenes. At the same time my feeling is that they use as much time as possible to really pin-point where imet's ultimate power lies. As I have said before: they (and Geron off course) are first movers in telomerase inhibition. They want to make sure that the first blow to the market is bulls eye. That will make them the global reference for telomerase inhibition. It also means that there is a lot at stake. Understanding the MOA in combination with molecular markers will reduce the risk on failures significantly. That takes time. I am not sure if and when imetelstat will get another chance if it somehow doesn't take of now.

The fact that telomerase inhibition has the potential of being an almost universal method to fight cancer does also create the problem of where to start. In order to keep competition at a distance there will be as little information as possible, while at the same time a strategy for the long term is being developed (off course only once imet is approved). Scarlet said during the last cc that JnJ is 'sponsoring numerous pre-clinical studies'. How many is numerous? We know about AML and CML. But what are the other studies about? Are there drugs in the JnJ pipeline that could be combined with imet? There are so many questions that we can't answer. But my believe is that there is much more going on than we can see. And the stakes are high. So some of your questions will probably remain unanswered until we see the masterplan unfolding. I expect that to partly happen once imet is in P3 and maybe in its full glory only after approval.

[Fishermangents]

Hunt, regarding your 3rd bullet about delaying the milestone payment: I can't hardly believe that delaying this payment outweighs the commercial importance of having imet approved as soon as possible. If imet goes well, they will need to pay this milstone anyway, leaving the only benefit being the interest over the amount they can keep longer on their account. Currently JnJ pays the whole imet development (production, trials, research and whatever they need to pay to Geron for milestones) from their own money on the bank. The sooner they can get revenues from the sales of imet the better, I would say. As I said in my previous comment, I believe they are extra cautious and probably want to give a kick in the face of the FDA by presenting convincing results. As announced, JnJ will present 24 wk interim data of IMerge to the FDA in Q2-17, including all the other data of the complete imetelstat program (source: latest Q3 cc). That includes the Mayo study, where the interim read out was moved foreward to meet the 24 wk interim of IMerge (see CT site). My impression is that they want to collect as much data as possible in order to make a quick move after presenting to the FDA and other regulatory offices (such as EMA). A frontline MF P3 trial will alow a broader and larger group of patients to participate. The trial sites seem to be all ligned up. Let's hope that that will be the immediate outcome of the Q2-17 24wk read out.

[Fishermangents]

Here is an article (thanks to 'telomerase' from SA) that provides an interesting angle on the current pharma industry and what should be changed in order to bring drugs faster to patients. I copied the whole comment, because otherwise it may disappear behind passwords. Although Trump is mentioned it is not a political piece, so let you not being distracted by that. Imetelstat is also mentioned in it.

My Turn: Maybe Trump’s FDA will help us cure cancer
By BILL WALKER, For the Monitor (Saturday, December 17, 2016)

Why is there still incurable cancer? Why do we still age just as fast as the king of Uruk in 1700 BC?
To you these may seem impertinent questions. Like the character in the Epic of Gilgamesh, you reply that “the gods kept life for themselves and gave death to mankind.” Well, bad-mouthing the gods is no substitute for telomerase-activator drugs. We still have pre-technological diseases because our medical care is pre-technological. Cells are just tiny computers, with far less usable memory than cell phones. (A human cell has about 2.8 gigabytes of DNA memory, but nearly all of it is taken up by junk, lentivirus leftovers like SINE and LINE elements, and other DNA malware. Only 1.5 percent of “your” DNA actually codes for proteins.)

We know how to read the DNA, how to insert genes (with the same lentiviruses that drove our evolution), how to take genes out (with CRISPR). When I worked in the Shay-Wright lab back in 2001, we could already immortalize human cells with telomerase. A couple years later we were putting dystrophin genes into muscle stem cells and curing muscular dystrophy. We were also shutting cancer cell growth down with imetelstat, a telomerase-inactivating RNA with a lipid tail to get it into cells. (Actually, techniques to weaken cancer for the kill go back to the 1930s Warburg Effect, a simple but sadly unpatentable dietary trick which enhances the effects of nearly every cancer drug).
So in the early 21st century, we had the technology to fix diseases from Alzheimer’s to Parkinson’s to macular degeneration (I was going to list all the glial-cell diseases, but you get the idea). We had the technology to give any cancer a run for its money (a combination of telomerase inhibition and Warburg Effect techniques just one of the many unused methods). And instead we spent our time bad-mouthing the gods, our money marching around Iraq, and let sick children die. Now it’s 2016 and biotechnology is still unavailable to the terminally ill. (For humans, that is. Adolfo Cambiaso has just won a polo tournament with a cloned army of horses. As long as you don’t use biotech to help sick children, no one gets in your way). Imetelstat is still locked up in Phase 2 trials, telomerase activator technology is only just now being proposed for trials, and muscular dystrophy patients are “safely” going to their long, agonizing deaths without viral-vector gene repairs.

You’re expecting me to blame the FDA for the slow progress. Actually, I’ll let Dr. Andrew C. von Eschenbach, former head of the FDA 2006-2009, do it for me. Because it is the FDA and Big Pharma’s fault, and everyone involved knows it full well. The FDA forces terminally ill people to use drugs that we know will kill them, instead of letting their doctors try Phase 2 or 3 medicines that might work. The FDA prevents U.S. patients from getting safe drugs that have been in use in Europe or Japan for decades (e.g., roxithromycin, the strep throat cure in most of the world). We can’t even get melatonin from a nurse to help us sleep off our agony in the hospital, since no one can afford to get a non-patented natural substance through the FDA process. The FDA, like all regulatory agencies, is captured by the industry that it “regulates.” But it’s a co-dependent relationship; the industry was also captured by the cartelization powers of the FDA. So massive amounts of resources are spent to keep drug prices high, old drugs in use and unpatentable natural substances (often the bodies’ own hormones) out of medical use entirely.

The solution is obvious: Give power back to doctors and patients. Let doctors decide what treatments to use, not Big Pharma. As Dr. Eschenbach suggested back in 2006, after a treatment passes Phase 1 safety testing, make it available to doctors, and keep track of the results.
Donald Trump’s picks for FDA chairman are rumored to support “progressive approval” (letting doctors choose treatments). Like the Wizard of Oz, Trump may not be a very good wizard, but he may let us get on with solving our own brain (at least the glial cells), heart and courage problems.
(Bill Walker of Plainfield worked in the Shay-Wright telomerase and Poeschla lentiviral-vector labs from 2001-2008.)

Link: http://www.concordmonitor.com/Will-Trum ... er-6916187

[Fishermangents]

More about Bill Walker (tx to 'GernOneShotLeftonGoal'from SA, 18 December 2016)

"The linked article states Bill Walker "worked in the Shay-Wright lab back in 2001". Jerry Shay and Woodring Wright have worked together as Ph. D Principle Investigators at the University of Texas Southwestern Medical Center focusing on the role of the telomeres and telomerase in aging and cancer for a couple of decades. They have worked with Geron and GRN163L/Imetelstat for just about as as long and both continue to work closely with Sergei Gryaznov, sharing the credits with Gryaznov for multiple publications as recently as 2015. The UT Southwestern website also says this: "One drug that blocks telomerase, Imetelstat or GRN163L, was developed by the biotechnology company Geron with help from Drs. Wright and Jerry Shay".
So Bill Walker is saying he worked in the Shay-Wright lab in 2001 and witnessed shutting cancer cell growth down with imetelstat."

[biopearl]

Hi everyone, Cheng ho (more correctly Zheng He, our smart Dartmouth scholar) has written a nice and interesting article and does have first hand experience from the Halcyon days of Geron. But at that time nothing could get translated into an effect clinical drug. Let s hope thats changed. Hunts points are important. The CT site is littered with negative imetelstat studies. The current MF trials now are past the 24 week period and Geron/ Janssen posses data material to the success or failure of this venture. Yet they say they have chosen to wait at least FOUR more months or longer for the reveal. So are they playing for time and really need 36 weeks? If the data is material, what is their obligation to release it? They sure didn't hesitate to have a Sunday surprise when the 4.7 dose arm was abandoned. Inscrutable!! I continue hope for some earlier data release if its strong. If they wait the full time into Q2 it is hard for me to see this as good since early cessation of study for efficacy would certainly make the splash they need. But we may not see it. It could be that the play for time allows for the MDS study data to be made public and be either synergistic or provide damage control for the MF study. 2016 aint over yet and if Scarlett is true to his work we may still see an AML study. Happy Holidays and a Prosperous New Year to all. bp

[Fishermangents]

Hi, Bio. Thanks for your post. It keeps a matter of guessing, because we don't know what is going behind the scenes. The AML and CML presentations at ASH are intriguing and suggest a direction JnJ is looking at next to MDS and MF. On the other hand, there may be plans in a total other direction which are kept secret to everybody (see recent CTO). Even if the current data are positive (only JnJ and hopefully Geron know) they may decide to wait for the announced Q2 2017 interim analysis. After that read-out they also have announced to present the data of the whole imetelstat program to the FDA. If they decide to stick to that plan we shouldn't expect them to release important data to the general public prior to that FDA meeting. My feeling says that it can't be silence until Q2 2014, but I can't come up with a best guess as to what news we may expect (maybe some kind fast track? Or AML? Or MF frontline?)

You speak about a Cheng Ho article: where can we find that? Can you send a link?

Thanks again for your contribution.

[biopearl]

Hi Fish, you have the article already! Its in this thread by Mr. (Dr?) Walker. bp

[Fishermangents]

Aha! I didn't make the connection. No it is clear. Tx

[sargasso]

Words I attempt to keep in mind while waiting for hard data from GERN:

"Throughout all my years of investing, I've found that the big money was never made in the buying or the selling. The big money was made in the waiting."

- Jesse Livermore

[biopearl]

Sargasso, in that case we should have been millionaires ten years ago.

[sargasso]

BP,

I understand what you are saying. You (and it would appear many other investors) have been in this stock a long time. I am relatively new to the stock.

Another four months (give or take) and we will hopefully have some answers. I am somewhat concerned that GERN/JNJ may have set the bar too high w/ regard to the current MF trial. Perhaps it would have been better to do a Frontline trial first?

But of course I do not know that. I am just speculating, ruminating.