Not much to the BL, at this point. Might gain traction..here, read this>> esammee typed it up>>>
January 12, 2011
2:30 pm PT/5:30 pm ET
J.P. Morgan Annual Healthcare Conference
San Francisco, CA
jpmorgan.metameetings.com
Good afternoon. I'm Karen Jay from the biotech team at JP Morgan. It's my pleasure to introduce Geron Corporation. The breakout will be in the Olympic Room just down the hall and to the left. And with that, here is CEO Tom Okarma.
DR. OKARMA: Thank you. Good afternoon, and thank you all for coming today. Any forward looking statements that I make today are made pursuant to the Safe Harbor provision of the ‘95 Act.
Well, those of you who know the company know that Geron is developing three product franchises, each of which is emanating from the company's core competence in telomerase biology, the winner of the 2009 Nobel prize.
So in the cancer portfolio we target telomerase. A Phase II stage telomerase inhibitor drug and a Phase II stage telomerase-targeted dendritic cell vaccine. There's a new entry here on our oncology franchise, **GRN 1005 which we recently inlicensed** from a company in Montreal - AngioChem. And this is a molecule that we ****think will impact another major unmet medical need in oncology, namely, CNS brain metastases****, and we'll introduce this compound to you today.
On embryonic stem cells, the telomerase role is to immortalize and allow for the in–indefinite expansion of the starting material of our product manufacturing which is the undifferentiated embryonic stem cell, and we'll go briefly through the four or five products that we're developing based on that technology. And then, lastly, the third leg of our of our stool is also based on telomerase and is a newer, emerging story: the notion that telomere health and--an integrated, normally functioning telomere or end of the chromosome is important to prevent systemic fibrosis, and there's a very interesting proof of principle of this notion that was recently published from the DePinho lab at the Dana Farber in December's issue of Nature. So we'll talk a little bit about our product offering here, which is an orally active small molecule activator of telomerase which we think has utility perhaps in IPF.
So in terms of telomerase and cancer, you all know that it's one of the six hallmarks of cancers. All cancers obligatorily express telomerase. It's a universal and critical and specific target. The new information, very relevant to imetelstat, though, is that telomerase is also a validated target of the cancer stem cell, which I'll turn to in a moment.
And, thirdly, if you take a large biopsy of a tumor, unlike other tumor markers which are variably expressed in the different tumor cells in the biopsy, all of the tumor biopsy cells are positive for telomerase. The telomerase inhibitor, shown here, has a lot of bells and whistles of molecular pharmacology that I won't bore you with today, but remember that in the ‘90s, telomerase was the cancer target of the year and most major pharmaceutical companies were trying to find molecules that would specifically and potently inhibit telomerase and they all failed. What we had to do was to engineer a pretty complicated molecule, a 13 meter lipidated oligonucleotide that you could think of as 13 small molecules glued together that lies down in the active cleft of telomerase which is why it's potent and specific. And the chemistry that we invented and the lipidation - putting the lipid on one end - is what gives this oligonucleotide the bioavailability of a small molecule. It is not an antisense, it's a direct competitive inhibitor of the enzyme.
So the cancer stem cell story. You know that this is one of the hottest areas in cancer molecular biology, and ****we now have published in 9 out of 9 cases that imetelstat attacks the cancer stem cell. We press released this week a new publication on glioma and neuroblastoma, so without exception neural tumors, melanoma, breast, pancreatic, lung, prostate and myeloma cancer stem cells are all inhibited by this drug****. So imetelstat is the only clinically developing telomerase inhibitor drug that, that hits both the mature cancer cell as well as the cancer stem cell. So this is a compound now in Phase II development; we have **four ongoing Phase II trials**. And the Phase II program is based upon an extensive six Phase I trial program in which we treated over 180 patients in 22 US medical centers studying this drug as single agent, in combination and in patients with different kinds of liquid and solid tumors. So we've learned how to use this drug clinically, alone and in combination and in a variety of clinical settings.
Our second cancer program targeting telomerase is a vaccine and this was presented at the ASH meeting in December of last year. This slide shows the protocol. This is a patient specific vaccine which is manufactured over a 10 week period. Patients then get 6 weekly sub q injections, a month rest, 6 bi-weekly injections, and then one injection a month until the patient progresses or the vaccine is used up. We had a very interesting presentation at ASH, and this is the bottom line of it: We've actually ***almost doubled the disease free survival rate of high risk AML patients at 12 months***. The historical control values are about 45 percent; the observed value in our study was 81 percent disease free survival. These clinical remissions are robust because they are always in all cases accompanied by molecular remission. So all of the patients in clinical remission are also negative for WT1, the molecular marker in bone marrow. And in the overall study we had 55 percent of the patients responding immunologically to the vaccine.
So this data and the data from a prior published study in prostate cancer have driven our rationale to pursue the development of the second generation vaccine that is telomerase targeted, based on dendritic cells, but no longer patient specific. Vac2 is a embryonic cell based dendritic cell vaccine which has many features that we like. It's not dependent upon any particular patient, therefore is not impacted by the patient's disease, patient's genetics or patient's prior therapy. This is a frozen, off-the-shelf version of Vac1 so there's no delay in manufacturing - it's ready for off-the-shelf use. **We are now in advanced discussions with a non-US agency that we hope will develop clinically this program for us off of our balance sheet** and you'll hear more about that later this year.
The new entry on our oncology portfolio is the **1005 molecule,** a molecule that we like a lot and we hope will significantly impact the huge problem in cancer medicine which is cancer metastasis to the brain. This shows the structure of the compound; it is a synthetic peptide invented by our–the company, AngioChem, in Canada, to which is covalently bound three molecules of Taxol. Um, the company has demonstrated activity of this compound in two Phase I/II studies done in the United States, one in metastatic brain cancer which I'll describe, and the second in glioblastoma which for time I, I won't. The, the **drug clearly penetrates the brain**. That was demonstrated directly in the glioblastoma study where tissues of the--both the malignancy and the normal brain were removed surgically and the drug was measured.
The drug gets in the brain by means of binding to the LRP1 receptor which is the most prolific transporter of natural reagents across the blood brain barrier. The surprise, however, shown in these slides, is that, in addition to very significant reductions in the brain mets in the brain compartment, we also saw significant responses in the periphery -- in the lung, metastatic disease to the lung, and metastatic disease to the liver. And you probably can't see this from where you are sitting, but many of these individual patients are starred, and all of those starred patients are prior taxane failures. So in fact the response to this drug in prior taxane failures was 33 percent. The intracranial response rate is somewhere between 24 and 42 percent, which is a very encouraging response given the low single digit responses that are now known for tenazolamide and lapatinib. So this is a drug that works both in the brain and outside the brain. There is very little neurotoxicity centrally. Dose limiting tox was nutrapenia, just like Taxol, and it works in prior taxane failures.
This obviously is a very high unmet medical need -- there are over 100,000 patients in the US per year that present with cancer that metastasizes to the brain. So we are now developing, along with our investigators and consultants, the clinical development plan, and this is subject to a lot of fine tuning. What we plan to do is institute at the end of this year two Phase II studies, one in non small cell lung mets to the brain, a second in breast cancer mets to the brain. We have not yet decided upon inclusion, exclusion, primary endpoints, subpopulations, but the point of our endeavor will be by the end of 2012 to have defined -- confirmed, first of all, the response rate demonstrated by AngioChem, and second, to identify the subpopulations that we think are most likely to respond. So possible outcomes at the end of 2012 are -- we could talk to the agency about an accelerated approval; that, of course, will be data driven. More likely we'll extend the Phase II study and potentially even apply on the basis of a Phase II; or thirdly, again data driven, begin two global Phase III randomized studies comparing--adding our drug to either lapatinib for breast cancer or tenazolamide for lung cancer. So stay tuned for our confirmation of how we will go about developing this drug, but, clearly the addition of this compound really matures Geron's oncology franchise and enhances the investment thesis in Geron oncology. And recall that both the lung and the breast cancer studies of imetelstat and the first data set on 1005 all come out at around the end of 2012. So that will be an important milestone for the company.
Turning now to our embryonic stem cell program briefly. Let me first remind you that we started this field. We invested and funded the three academic centers in the United States that successfully derived human embryonic stem cells. Accordingly, we've had the time and the energy to develop all sorts of infrastructure and technologies that are useful for all of the embryonic stem cell based products – feeder free defined culture; and a co-invention with Corning Glass, the Synthemax surface which is now commercially available to which we have exclusive rights for our therapeutic cells; scalable depletion technology to remove from the final product contaminating cells; we are currently manufacturing under GLP–GMP; and we **have proof of principle of a micro carrier culture which is how we will scale up the manufacturing from flat [planer] surfaces to bioreactors**. All of the products in, in this group of programs for Geron are manufactured in the same way that monoclonal antibodies and recombinant products are manufactured using GMP master and working cell banks. That's how we reduce cost, increase lot size and ensure product quality.
So the first program out the box is now in **clinical trials for acute spinal cord injury. It's called OPC1.** We derived this cell - it's a glial progenitor - for the purpose of remyelinating the de-myelinated axons in human spinal cord injury. That's the prime pathology–it's not cutting of the axons. And we've demonstrated to the agency and our investigators that these cells when injected into spinal cord injured rats really remyelinate the injury. That results in a sustained and significant improvement in locomotion. What we didn't know, though, at the onset was the other activities that this cell pres--possesses which is critical for potential line extensions. These **cells are mitotic** so they expand numerically after they are injected; they migrate as they integrate into, into the tissue that we inject them in; they produce dozens of neurotrophins which are proteins that are useful to help neurons survive stress; and, thirdly, they induce new blusel--blood vessel formation. So in our way of thinking the glial progenitor cell is really the nursemaid of the central nervous system, and we think in addition to applications in spinal cord injury where the mechanism is remyelination we have **line extension opportunities in multiple sclerosis, thrombotic stroke, Alzheimer's and the leukodystrophies,** and we have ongoing academic collaborations now with KOLs in these fields using our cells in their animal models.
So we have three sites in the US now screening patients. The first patient entered this trial in October. We are studying a small number - 6 to 8 patients - with complete ASIA A thoracic injuries. These are patients that are completely paralyzed from the waist down. We inject a small number of cells - two times 10 to the 6th - and we inject them within two weeks of the injury. They're immune suppressed temporarily with low dose tacrolimus. Clearly the primary endpoint is safety, but there are a whole battery of instruments that are applied month by month by month, including nine repeat MRIs in the first year after injection to document toxicity, if any, and certainly any therapeutic effect.
Now the clinical development plan for this program is schematized here. We want to leverage this first cohort in complete thoracics as aggressively as we can. So the second set of cohorts will expand in terms of dose, move from thoracics to cervical, and begin looking at other spinal cord indications like secondary progressive MS or neuromyelitis optica, and, as our collaborations generate proof of principle for line extensions, we then move into the brain for MS, stroke, Alzheimer's or leukodystrophies. So this is a program that will build upon the current cohort which is why we expect to have 6 to 8 US sites screening and recruiting patients for this program.
We've made a lot of wonderful progress in **cardiomyocytes**. We now have three animal models in which we show engraftment of these human cells after an infarction that results in improved cardiovascular dynamics and surprisingly we show an anti-arrhythmic effect of these cells. In the guinea pig model after putting these human cells into the infarct ***not only does the animal not get arrhythmias, but we can't even induce an arrhythmia ***because of the improvement in conduction through the infarct that these engrafting cells generate. Now these cardiomyocytes are normal in all respects, including their sensitivity to calcium and erb channel and dual channel blockers. They have the same change in membrane depolarization that our heart cells do were we on these same drugs. Therefore, they can be used as sensitive human screens for cardio tox, and that's the first collaborative program with our partner, GE Healthcare, so the human ES derived cardiomyocytes have been launched by GE in October of last year for cardio tox screening.
Our **diabetes program now has proof of principle in animals**. So we inject the islet cells made from human ES cells into the kidney capsule, wait a month or so for them to mature, give the animal streptozotocin at time zero. The control animals rapidly become floridly hyperglycemic. Animals that contain the human islets are maintained at normal gylcemic for at least a month.
The sleeper of our program in embryonic stem cells is the chondrocytes. We are observing spectacular joint regeneration in both small animals and now we think in large animals, in sheep. And the cartilage that is generated by a single injection of these human cells is completely normal articular cartilage. It has all of the right configurations on the surface layer and deeper down, and it restores completely the tide mark - the junction between subchondral bone and cartilage. This has never been observed before in any form of joint regeneration.
Just quickly in the last moment or two, our **telomerase activator program.** This is a orally active, proprietary to Geron, small molecule that upregulates telomerase in so-called telomerase competent cells – which are really adult stem cells. One of the models we're showing utility is the bleomycin induced pulmonary fibrosis model. So you see on the top, three weeks after a single injection of bleomycin, the alveoli are completely collapsed, they're full of collagen, and there's an exudative immune infiltrate. In contrast, in a dose response way, if we accompany the bleomycin with the or--the 510 drug, we substantially improve or prevent the deterioration histologically and, more importantly, that's accompanied by reduced deterioration in lung compliance and airway resistance in the animals receiving bleomycin. So it's the first small animal model that we may have an indication for this drug in IPF.
Our **patents** are strong. Imetelstat is proprietary to Geron until 2026. The new compound 1005 runs to 2025. And we have a dominant IP position on embryonic stem cells, as well as complete global freedom to operate.
So, news flow. My last slide. 2011 will be a pretty busy year. In imetelstat, first half of this year we'll be announcing our investigator sponsored trials, and there'll be additional publications on the activity of this drug against cancer stem cells. We hope to have some top line data second half of this year on the two smaller Phase IIs, in myeloma and essential thrombocythemia. We plan to initiate the Phase II brain met study for our new inlicensed compound 1005. And we have, expect that the agency decision for the funding of the clinical development of our second generation dendritic cell vaccine based on embryonic stem cells. In the stem cell program, we expect to have some news about the clinical trial first half of this year, with more extensive followup second half of the year. We have applied for a substantial funding support from Prop 71 and we expect to hear that notification first half of the year, and by end of this year we'll have the proof of principle from our academic collaborators for line extensions of this same product into much larger medical opportunities.
A major milestone for the cardiomyocytes is first half of this year when we unveil the results of a very large large pig study where we will show, hopefully, engraftment, the induction of new host blood vessels in the graft, confirm improvement in cardiac output by both ECHO and MRI, and these animals will be telemetered for arrhythmias. So we hope to wrap up the preclinical efficacy study first half of this year. We will have publications on our islet studies in small animals as well as in our chondrocyte program, and by the second half of this year we expect to unveil the results of the ongoing sheep study in the UK where we hope to demonstrate the same kind of cartilage reconstruction that I showed you in the rats a few moments ago.
And then lastly in telomerase activation we've pushed the button for our IND enabling studies and we will have a go - no go decision on that IND submission by end of the year.
So, a lot of news on all of the programs. We have clearly bolstered the oncology program with the addition of 1005, and we are now executing on the potential discovery that we have invented - a telomerase inhibitor which will substantially move the outcome of patients with cancer. Our embryonic stem cell program is really cooking on all cylinders. We do expect to have some safety data to share with you in the spinal cord trial and we are looking toward the second IND submission in a couple of years which will be cardiomyocytes.
So thank you very much for your attention and it's a pleasure to speak with you today. |
