George Farmer - Vice President of Corporate Development
Ying Huang - Barclays Capital, Research Division
Synta Pharmaceuticals Corp. (SNTA) Barclays Global Healthcare Conference March 12, 2013 3:45 PM ET
Ying Huang - Barclays Capital, Research Division
My name is Ying Huang. I'm the U.S. biotech analyst here at Barclays. So very pleased to introduce my next presenting company in biotech, which is Synta Pharmaceuticals. And then also I'm very pleased to introduce the speaker on behalf of Synta, George Farmer, who is the VP of Corporate Development at Synta. So with that, let me turn the podium to George.
Thanks very much, Ying. Ying and I have known each other a long time. I will be making some forward-looking statements. Please refer to our website and SEC filings for further detail.
Synta Pharmaceuticals was formed out of a joint venture between 2 Japanese companies back in 2002. Our CEO, Safi Bahcall, led a management-led buyout. Public went company -- the company went public in 2007. Brought 120 employees in Lexington, Massachusetts with a small molecule pipeline of a number of different drugs. And importantly, we own a 100% of the worldwide rights to our pipeline, which is shown here. I will spend all of my time today talking about our lead compound, ganetespib, which is an Hsp90 inhibitor, which is being evaluated in a broad GALAXY program of 2 randomized trials as well as other genetically-defined settings in ALK+ non-small cell lung cancer and metastatic breast cancer. And we have over 20 clinical trials ongoing with collaborators at cooperative groups in various institutions.
Ganetespib is a novel molecule that's highly targeted to a very specific protein, but has shown to have a very broad applicability and is very active across many different tumor types. We've treated over 600 patients with this drug in over 20 clinical trials and have seen very encouraging signs of activity, both as a single agent and in combination with other cancer drugs. We believe the drug is poised to serve some very large markets. And again, we own 100% of the worldwide rights.
The first indication that we see ganetespib ultimately being approved for is in non-small cell lung cancer in the second-line treatment setting, specifically for adenocarcinoma patients. We're estimating about 160,000 new cases of adenocarcinoma in the major territories. Assuming a modest penetration rate and pricing of current oncology drugs, we see the opportunity alone in second-line non-small cell lung cancer as being in excess of $2 billion a year.
Our GALAXY program is consisted of 2 randomized clinical trials, both effectively designed the same, evaluating ganetespib in combination with standard of care second-line chemotherapy. We reported interim analyses from this GALAXY-1 trial at September -- I'll touch on the results later on in the presentation -- and expect to have 6-month overall survival data at -- for presentation, hopefully, at ASCO, in the June time frame, then some other data points later on from GALAXY-1. In parallel, we're initiating the GALAXY-2 confirmatory Phase III trial which will ultimately be about 500 patients and we plan to have some data readouts from that study next year.
This is an illustration of our -- of a concept that came out of Forbes Magazine from an article on cancer drug development last year. Showing that there are about 500 different small molecule tyrosine kinase inhibitors in clinical development, preclinical development or have launched today. A lot of them go after the same targets, which have been validated in the clinic already and also in preclinical molecules. But this really just illustrates how there's a lot of copycats out there. A lot of people are chasing after the same targets with molecules that are not really very well differentiated in our view. What's special about ganetespib is while we are a targeted therapy, the target that we're going after is a very specific one. And by virtue of going after this very specific target that has multiple -- capable of multi-silence and multiple oncogenic pathways at once, we can achieve this activity in a very clean manner but having a very wide collection of specs. This is in contrast to the target therapeutics that are on the market like GLEEVEC, Herceptin and Tarceva, which are very -- have very specific targets and have very specific pathways; and in contrast to the dirtier TKIs and broad chemotherapies which have these wide effects on multiple pathways.
Hsp90, the target for ganetespib, is a chaperone protein, shown there in blue. And the chaperones in the cells are required for maintaining the integrity of a number of different client proteins that are involved in cell growth and tumorigenesis. A lot of those are listed down there on the left, some very familiar names and common targets by the pharmaceutical and biotech industry. When Hsp90 is inhibited by ganetespib, the client and the chaperone dissociate and the client's integrity effectively falls apart and is shunted into the proteasome pathway and degraded. So in contrast to kinase inhibitors, which effectively shut off the activity of a specific kinase, inhibition of Hsp90 ganetespib leads to the elimination of the kinase in the cell.
Here is an example of that, this is a western blot on the right, showing that ganetespib can have simultaneously -- simultaneous broad inhibitory activity on a number of different kinase -- kinases involved in tumorigenesis.
We see development of ganetespib in sort of a two-pronged approach. One is as a monotherapy in genetically defined diseases where the clients are well known and known to be important drivers of tumorigenesis. And the other is in combination with chemotherapeutic agents that are either targeted therapies or radiation, or we think that the addition of ganetespib is affecting -- is sensitizing the activities of these other treatment modalities and is inhibiting angiogenesis metastasis, mechanisms of DNA repair and resistance simultaneously, and enabling these other therapeutics to have more of a cytotoxic effect.
So like I said, in contrast to the kinase inhibitors, many of those listed there to their cognate targets, in contrast to these, where the kinase inhibitors bind to the active sites of these enzymes and turn them off, ganetespib is inhibiting Hsp90, removing the chaperone and eliminating these kinases from the cell. So think of the kinase inhibitor effectively as a punch to the face, or as ganetespib as a punch to the stomach.
Here's some examples of activity of ganetespib monotherapy in an ALK+ non-small cell lung cancer patient who had progressed on crizotinib after 1 year of treatment, came into one of our trials and exhibited a nice clinical effect there, comparing the baseline scan on the left to the one on the right. Here is an example of ganetespib activity in a patient with non-small cell lung cancer driven by mutated BRAF. This patient had been treated with a slew of other therapeutics, came onto our trial, and after week 16, showed extremely impressive partial response. This is an example of monotherapy ganetespib activity in a patient with HER2+ gastric cancer. And finally as monotherapy in triple negative breast cancer where we do not know what the client is, we've seen some very nice degrees of activity. This is 1 of 2 patients out of 4 that exhibit partial response to ganetespib. And you can see this particular patient had been hit with a number of different agents, some approved, some experimental, who came onto this clinical trial and showed some -- a nice benefit from ganetespib and actually also experienced some symptomatic improvement as well.
In ALK+ non-small cell lung cancer, where the drug has been studied most extensively as a monotherapy, we saw 4 out of 8 patients exhibit a partial response. Here is the duration of therapy from those partial responses shown in each one of these patients. The takeaway here is that these other chemotherapeutic agents, that all these patients experience in other targeted therapies as well, really did not do much for these patients. When they came onto our trial after being heavily pretreated, they got nice durable responses. That one patient on the top is actually out over 2 years now and continuing to benefit from ganetespib monotherapy.
In a combination study, we see ganetespib working very differently. Again, we see ganetespib potentially sensitizing tumors to the cytotoxic effects of a variety of different agents and having a broad effect on angiogenesis, metastasis, DNA repair and chemo resistance, and effectively changing the biology of the tumors, at the same time enabling these agents to have -- be much more cytotoxic.
This brings us to the -- back to the GALAXY program, which consists of 2 randomized clinical trials. The first one, the GALAXY-1 trial, is comparing standard of care docetaxel chemotherapy single-agent versus docetaxel plus ganetespib for treatment of second-line non-small cell lung cancer. We completed the initial target enrollment of 240 patients from this study last November. The design of this trial was based on an operationally adaptive design whereby we would find out what the right patient population should be to enroll and advance into a confirmatory Phase III trial. We accomplished that goal and have -- are in the process of initiating this Phase III trial, which will ultimately be 500 patients. We'll have readouts from this trial we expect in 2014.
This is interim analysis that we presented last September from the GALAXY-1 trial, in the first 172 patients enrolled. This is an intent to treat analysis of all the patients. And a couple of things that are worth pointing out. Number one, the curves are separating, which indicates that ganetespib is having an improvement on overall survival on these patients. Number two, the docetaxel arm shown in red is behaving exactly as would be expected. Patients are living on the order of 7 to 8 months. And also, a lot of these patients had been enrolled very early on in the trial and there's a lot more maturity of this data set to be required in order to give anyone any meaningful confidence that this trial is actually demonstrating an overall survival benefit with ganetespib. To get kind of a better insight as to how this trial may ultimately read out once the data is mature, a prespecified analysis of the first 7 -- of the first cohort of patients that had been enrolled for at least 6 months in this study. So all of these patients, all 77 of them shown in this slide, have been followed for at least 6 months. This analysis was completed around at the same time as the initial intent to treat analysis. And again, you can see a nice separation of the curves. Docetaxel's behaving as it should. But importantly, this data set is much more mature. A number of these patients have been followed out for a significant number of time to give us the statistics shown there on the lower left corner, showing a hazard ratio of 0.57, which is extremely impressive, and a p-value showing something close to very high statistical significance.
The adverse event profile that was shown at the September analysis is consistent with what we've seen with ganetespib. This drug is extremely well tolerated. Basically, diarrhea, shown there on the bottom, is the major adverse event that's associated with administration. Most of it is Grade 1, 2 and most of it can be managed very easily with over-the-counter medication.
So the GALAXY-1 trial was intended to de-risk the outcome of the confirmatory Phase III trial, which we've called GALAXY-2, and which we are currently initiating. And here are just some benchmarks that we've used in order to inform our investigators and investors about where we see GALAXY-2 ultimately going and how we are confident in the ultimate trial design.
So Avastin, Alimta, Taxotere, these are all major drugs approved for the treatment of lung cancer. Really never showed much treatment benefit at all. Avastin is probably the best one out there showing a hazard ratio of 0.8 translating to about a 20% treatment benefit. Alimta, approved in second-line, was approved really because it was more tolerable -- better tolerated than Taxotere. And Taxotere was approved on a 0.88 hazard ratio versus best supportive care. What we showed in the ITT and the 77 6-month follow-up patients who have hazard ratios of 0.7 and 0.56, respectively, is really quite a impressive. But we think that we can do even better than that. We identified a prespecified group of patients that showed a hazard ratio of about 0.4. And these are all patients that effectively can be described as normal progressing. They're all patients that have made it through front-line therapy that did quite well and had been living with their disease for at least 6 months prior to joining the trial. And this is a patient group, again, prespecified, that we are enriching for in our Phase III GALAXY trial.
Here's a Kaplan-Meier of that population showed last September. And you can see, again, extremely nice separation of the curves. Much wider than in the intent to treat and a p-value that is really quite respectful of 0.1 on a hazard ratio of 0.36. If this data holds up when we do subsequent analyses, this would represent probably one of the best hazard ratios in the entire oncology industry.
We're enriching for this patient population in the GALAXY-2 trial, the design is summarized here. 500 patients all with non-small cell lung cancer advanced disease with adenocarcinoma, this is the exact same population as in the GALAXY-1 trial. The only difference here is we're excluding these outright progressors, we're excluding those patients that just do not benefit from front-line therapy. We're using the same dose, the same schedule as in GALAXY-1, and the primary endpoint would be overall survival.
In order to see this treatment effect, if it's real, this 0.4 hazard ratio treatment effect size, our statisticians tell us that we only need about 120 patients to enroll on a Phase III trial. Since we're going after such a large market opportunity like non-small cell lung cancer and this is, in fact, a Phase III pivotal registration trial, we're doing a 500 patient study. And with 500 patients, again, if this treatment effect is real, we believe that we're significantly overpowered to see -- to capture the treatment effect in this study.
We have some preplanned interim analyses that are event-driven. Again, based on the treatment effect that we're seeing in GALAXY-1, if this translates to GALAXY-2, this slide basically illustrates that we could stop the trial early based on these interim analyses, which we expect will occur in the first half of 2014 based on our goal of completing enrollment in this trial this year.
The timelines that we've laid out are as follows: the GALAXY-1 trial, we -- again, we had reported this interim analysis last September on 172 patients. We completed enrollment in this trial in November on the first 240 patients of target enrollment. Ultimately, we'll have about 250 patients that completed enrollment in November. In May, they will all have reached their 6-month follow-up time point and we hope to present that data at ASCO in June. On 240 patients' worth of data, with 6 months follow-ups on each and every single one of them in a disease where patients typically live only 7 to 8 months, we believe that data set is going to be extremely informative one way or the other. We'll have final PFS data around the ESMO conference time frame, that's the end of September, early October and then 12 months follow-up data from that same 250-patient cohort around November of this year. In parallel, the GALAXY-2 trial goes on, we expect interim analyses from this trial in the first half of 2014. And again, this trial is enriched for those patients most likely -- that we believe are most likely will respond to ganetespib.
Little bit of science. We believe ganetespib is an anti-angiogenic agent by virtue of the data -- some of the data shown here. On the left is just a cell culture assay showing that we can reduce VEGF levels in cancer cells. VEGF is a key growth factor required for new blood vessel development. And in the center, this is data from actual patients, from a colorectal cancer trial going on at Emory. Here, these are pre- and post-biopsies of patients before and after treatment with ganetespib, and you can see that where -- that the drug is inhibiting levels of VEGF expression as well as expression of a factor called HIF-1alpha, which is induced by hypoxia, and is a very bad actor in tumorigenesis. HIF-1alpha, as shown there on the left, has received a lot of attention over the past 5 years. It's been known to be induced by low-oxygen conditions of tumors, aggressive tumors that grow out of control in low-oxygen environments just because blood vessel growth can't happen fast enough. HIF-1alpha turns on all those signals required for new blood vessel formation, but it also turns on a lot of other factors involved in tumorigenesis including invasion and metastasis and stem cell immortalization. Lots of literature has come out and a lot of these references can be found on our website.
This is some actual data taken from the GALAXY trial looking at patients with -- who have progressed as of the September analysis. There are 2 reasons for progression. One reason would be that an existing target lesion has grown by a certain percentage or there would be -- a patient could progress due to the appearance of a new lesion at a distant site, or a combination of both. If you look specifically at those patients that progressed due to the appearance of new lesions, you can see that ganetespib can reduce these -- the appearance of new lesions by about 1/3. So combining this data with the preclinical data that we've seen as well as other clinical data, this all lends to the hypothesis that we're really changing the biology of these tumors and having a potent effect on metastasis. And that could be a reason why these patients are living so long in the GALAXY trial so far.
Second-line lung cancer is a big opportunity. It's the one that the company is extremely focused on right now. Our main objective is to complete the GALAXY program, the first 2 trials of the GALAXY program, and file for approval with the regulatory agencies if the GALAXY-2 trial is positive. But we see some adjacent opportunities being quite big, certainly, in front-line lung cancer. Our advisers tell us, "Well, if you have such a wonderful and safe tolerable drug that's extending survival, why not move in to earlier lines of therapy?" We are in the planning stages of advancing ganetespib into front-line treatment settings as well as in metastatic breast and neo-adjuvant breast cancer treatment settings are 2 other areas where taxanes are used for treatment.
Adjacent indications would involve those that taxanes are also used like in prostate, ovarian, gastric, head and neck, and bladder cancer. All those are very large opportunities. And given that anything that comes out of lung cancer second-line setting could be regarded as proof of concept and ultimately support potential activity in these other treatment settings as well. And finally, we have lots of preclinical data showing that the drug is synergistic with other chemotherapeutic agents, other targeted agents, and also with radiotherapy, which is bigger than all of chemotherapy combined.
We have a number of investigator-sponsored trials that are going on. Those are listed here. We get a lot of questions about our ALK. The ALK trial that's going on at Memorial Sloan-Kettering Cancer Center in New York. This is looking at ganetespib in combination with the ALK-inhibitor crizotinib in patients with ALK+ non-small cell lung cancer.
These are our finances as of the third quarter last year. We had $55 million in cash. We did an equity raise in December. Burned about $14 million to $15 million a quarter last year. We'll be updating these numbers on Thursday on our year-end conference call.
So in summary, we believe we have a very potent chaperone inhibitor here that's been evaluated in over 600 patients in greater than 20 clinical trials with a very encouraging safety profile and that we have seen very encouraging signs of clinical activity in second-line small cell lung cancer. Again, just a proof of concept study, we think, a big indication outright but one that could support very broad potential of this drug in other indications going forward. And importantly, Synta owns 100% of the worldwide rights to this drug. We have said we would like to hold onto U.S. and European rights and are considering regional deals particularly in Asia.
And with that, we can move to the breakout room, in the Poinciana 2 room across the hall, I believe. Thanks.
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