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In an earlier article we covered the fact that Geron (GERN) is a significantly changed company. Investors who have not detected this change in direction and business-savvy that accompanied the new management, are really commenting on a different company that has little if anything to do with the new Geron of a few months ago. Further, investors or writers who are still referring to GRN1005, GRNOPC, or GRNVAC, are lingering in an ancient era that I believe is no longer relevant.

GRN163L, or Imetelstat Sodium, is what Geron has decided is their medicine. As confusing and puzzling this was to the investment community, myself included, it is now making so much sense.

The puzzling changes started with the dumping (and this is the right expression here) of the human Embryonic Stem Cell (hESC) research and assets. Effectively, to a great demise in stock value, Geron decided to give away its long and pioneering history of stem cell research - down to laboratory notes. Geron shareholders will end up with about 5% of their GERN stock ownership as Asterias stock -- i.e. 50 shares of Asterias per 1000 of GERN. Yet, the most puzzling change was the halt of very promising studies of Imetelstat in several cancers, including the very impressive results of the essential thrombocythemia (ET) study in which the conclusion was

Treatment in 18 ET patients who had previously failed or were intolerant to conventional therapies resulted in 100% hematologic responses (88.9% CR)"

The statement from Geron's CEO, Dr. John Scarlett, prior to the American Society of Hematology (ASH) annual meeting as well as the leaked article from Mayo Clinic prior to the actual presentation of Dr. Tefferi's results, led me to further investigate Imetelstat. After all, I needed to know why Geron would put "all their eggs in one basket."

What the CEO said about Imetelstat was

"it's done things that no other drug has been able to do"

While the, now removed, Mayo Clinic article quoted Dr. Tefferi as saying

Some patients in our clinical trial taking imetelstat obtained dramatic responses and there have been some complete responses which is almost unheard of for drug therapy in this disease.

In his presentation at ASH, Dr. Tefferi did spell out what he meant in numbers and charts. The case he presented was convincing. Actually, from the slides that leaked -- and my apologies for not having actual slides to refer you to since these were not released -- we understand that this was a very well designed and managed study. If anything, Dr. Tefferi's stated objection to current MF treatments seems to have added to the discipline as opposed to people's fear of bias.

In Dr. Scarlett's presentation (which you can access from here), the excitement was absolutely there. Yet, the gruesome details he went through was indicative of that what is being presented is real and not a fluke. It is as if the company and the scientists want us to believe that this is real.

After all, what is evident from both presentations is that, at the Mayo Clinic and at Geron, there is some level of "awe" -- if I may use this word -- at what they are witnessing. In some sense, this study at a disease with no cure showed them that Imetelstat is a far more complex and potent drug than they have imagined it to be from data on the 370+ patients that were exposed to it to date.

So what is going on?

To start, let us take a casual tour of the science basics. It was observed that a large number of cancerous cells (90%) have something in common, regardless of the cancer, and that is, that the Telomeres is longer than it should be. Telomeres are part of the normal DNA sequence of the chromosomes and are located at the end of the sequence. As cells multiply, the length of the Telomeres shortens. Come in telomerase, which is the RNA responsible for restoring the Telomeres. As such, this telomerase activity causes the genetic code to be restored. Hence the observation, and the basis of the science is that if you block the RNA, which is absent from the healthy cells, you should affect the cancer. It sounds so straight forward and "mathematically logical" that I fell in love with it since I heard it, more than a decade and half ago!

GRN1005 was Geron's first attempt at blocking the telomerase action through what the company called an "opportunity to combine telomerase inhibitor with CNS-targeting peptides." As we have seen from previous trials, this was not as effective as was hoped. A new and novel concept was introduced by Geron through Imetelstat sodium, also known as GRN163L. It turns out that, and let me quote Dr. Scarlett from his above referenced presentation:

"But instead the company persevered and developed an oligo at the time of very un-favored approach I might add developed in oligo not as an anti sense but actually as a competitive inhibitors of the enzyme which has at its heart an RNA template which provides the complementary RNA to add on the nucleotide repeats at the ends of chromosomes that are called telomeres."

In short, Geron went, as the poem goes, "the road not taken" and I believe "that has made all the difference" -- quoting Robert Frost here. After all, what is becoming clear is that Imetelstat works in a way that nobody seems to fully understand. Yet, the medicine seems to work. In essence, the problem created for Geron due to what is trickling and our increasing understanding of Imetelstat is where to focus the dwindling resources to get the largest ROI in the shortest time!

Imetelstat has been tried on multiple cancers. That is, researchers were far more excited about Imetelstat than it seems the company itself and the general equity investors have realized. As a matter of fact, the National Cancer Institute lists 12 phase I and II studies at the time of this writing.

The first such exciting study, is a now discontinued study for brain cancer. It was found that Imetelstat can safely cross the blood-brain barrier. This 2010 in vitro/in vivo study states

Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway.

The human trial that followed led to inconclusive results and was halted. Similarly, the non-small cell lung cancer study was shelved. Yet, if you read some of the literature about the non-small cell lung cancer (NSCLC), you realize that Dr. Tefferi's stated excitement was shared elsewhere and for other cancers. In this NSCLC study, Imetelstat, for no known reason, inhibited metastasis. The actual quote:

In this study, we demonstrate that the anti-adhesive effects of GRN163L, which may also contribute to the antimetastatic properties of this compound, are related to the disruption of cytoskeletal proteins, resulting in alterations in cell architecture and the intracellular relocalization of cytoskeletal elements.

True, in-vivo studies or observations do not a medicine make. Yet, it is clear that this medicine works like no other.

As such, the question is: why did the company not make the effort to figure out the details, which companies with less exciting candidates followed up on and persevered? I think that my original article did answer this question: the company was far too obsessed with stem cells (hESC)! That is now over.

I believe the current strategy that the company is undertaking, by getting the medicine approved for a given disease, is sound. In this case, MF is a terrible disease that causes the spleen to become the size of a handbag. MF has no cure, and Jakafi, from Incyte (INCY), which sells for $84,000/patient/year, only addresses the symptoms.

Hence, providing a "cure" to MF is something that should be welcomed by doctors, patients, and the FDA alike. It might not be to the liking of the investment community that is heavily vested in Incyte, but it surely is the right approach from both business and humane points of view.

As stated by Geron's CEO in the Q&A session at ASH (above link), the plan is to hold a multi-center Phase-II study in the first half of 2014. Acquiring patients for a Phase-II can be a 6 month endeavor. Designing a randomized Phase-II and using it to launch (or combine it with) an effective Phase-III is possible. In short, it is a 12-18 month process to complete a well-designed Phase-II. This should be followed by a Phase-III, which if the Phase-II is designed with that in mind should be a 12 month process. FDA approval after that is a 6-12 month process, depending on whether the drug is "fast-tracked." As such, three years is not an unreasonable number. Jakafi went from Phase-I in May 2007, to NDA submission in June 2011, and then approval in November of 2011. Imetelstat is already more than a year down that path.

The next step to follow, when and if the FDA approval is attained, should be to test Imetelstat on the many different diseases that previous studies showed promise for. At that point, the company should have enough in their war-chest to undertake the studies, tolerate a possible failure, and work out the scientific details to make the medicine work.

A good approach would be to move from MF to ET, where there are already excellent Phase-II results. Then it would make sense to move into fixing the science for one of the inconclusive diseases, be it lung or brain cancer. In parallel, I would love to see Geron attack other leukemia diseases, as it is clear that they have two winners on that front, and AML studies have already showed very promising results.

Imetelstat seems, at this time, as the one telomerase inhibitor that is multifunctional and to be able to disrupt many of the mechanics of cancer, beyond any other medicine in that class, including the original candidates by Geron. Hence, my Aspirin analogy! After all, Aspirin, and its derivatives are invaluable for muscle pain, inflammations, arthritis, and blood clotting, among other things. Yet, we do not seem to fully understand how it all works.

In conclusion, I agree with Dr. Scarlett that it is a shame that "Liz Blackburn and Carol Greider had not yet received the Nobel Prize" and it is my hope that Geron will very shortly prove that the Nobel prize was well deserved long ago! I believe that Imetelstat is currently the best candidate to turn telomerase inhibition into an effective cancer cure.

Source: Geron: Is Imetelstat The 'Aspirin' Of Cancer?