Amgen's Management Presents At Post-ASCO Conference (Transcript)

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Amgen Inc. (NASDAQ:AMGN)

Post-ASCO Conference Transcript

June 3, 2014 4:00 PM ET


Arvind Sood - Vice President, Investor Relations

Sean Harper - Executive Vice President, R&D

David Reese - Vice President, Translational Sciences and Therapeutic Area Head, Oncology Global Development

Pablo Cagnoni - President, Onyx Pharmaceuticals


Terence Flynn - Goldman Sachs

Yaron Werber - Citi

Salim Syed - ISI

John Chung - RBC Capital Markets

Howard Liang - Leerink Swann & Company

Matt Roden - UBS



My name is [Nicosia] (ph), and I will be your conference facilitator today for Amgen Post-ASCO Conference Call. All lines have been placed on mute to prevent any background noise. There will be a question-and-answer session at the conclusion of the last speakers’ prepared remarks. (Operator Instructions)

I would now like to introduce Arvind Sood, Vice President of Investor Relations. Mr. Sood, you may now begin.

Arvind Sood

Welcome, Nicosia, thank you. Good afternoon, everybody. So, let me be the first to welcome you to our post-ASCO conference call. We have presented data from several studies on both pipeline and marketed products at this meeting, which provides strong evidence of steps we are taking to advance the comprehensive therapeutic oncology portfolio.

So joining me today are Sean Harper, our Executive Vice President of R&D, who will provide a broad overview of our oncology portfolio. David Reese, who is our Vice President of Translational Sciences and also the Therapeutic Area Head for Oncology Global Development, will then discuss some highlights from our presentation at ASCO particularly in the immuno-oncology space. Also joining us today is Pablo Cagnoni, who is the President of Onyx Pharmaceuticals.

The presentation has been posted on our website. So with the customary reminder that we may make forward-looking statement, let’s get started, and I'll turn the call over to Sean. Sean?

Sean Harper

Thanks, Arvind. This first slide, which is slide #5, just gives an overview of what it is that we are doing these days in late-stage development and marketed product activity highlights in Amgen oncology. And to start-off, T-VEC is a very novel agent that we are beginning to become more and more interested in, as we look at the data that is emerging.

First, of course, we have the product in monotherapy Phase 3 results that we have seen the durable response results from last year. We do have at ASCO the overall survival analysis and Dave Reese will go through many of these results with you in some more detail.

But while we did miss the overall survival by a very narrow margin, the subgroup analysis within the study and the shape of the survival curve are actually very interesting and we think the product can have quite a bit of benefit in the particular patients who have more of the benefit than others within the spectrum of patients that we studied, so we will look at that.

Of course, in the big picture in the long-term, we see T-VEC is being a potential cornerstone in the monotherapy because of the ability to immunize individuals specifically to tumor antigens from their tumor.

At the same time that interventions such as checkpoint inhibition are taking place. And we did have some of the early data for combination; the first combination study we initiated in the earlier days was with ipilimumab, of course.

Here we are seeing the tolerability being really very good as one will predict because the safety profile of T-VEC is so benign, but also some hints about and additive or synergistic effects around combination.

And certainly, first principals, as well as our preclinical data suggest the potential for synergy. So we are very excited also to be initiating this year combination studies with PD-1 in addition, in the collaboration with Merck.

Blinatumomab, obviously represents the sort of tip of the iceberg of our BiTE platform that we obtain through the acquisition of Micromet. It’s a first-generation BiTE that we are looking at in Phase 2 in relapsed/refractory B-precursor ALL.

We believe these data are fairly compelling from a benefit risk perspective in patients who have run out of therapeutic options and we believe may service as the basis for initial registration in a number of markets.

We have many of BiTE programs in clinical development -- in preclinical development, I should say. Right now that have second and third-generation characteristics with respect to half-life biodistribution so and so, we remained very enthusiastic about this other area of immuno-oncology therapy.

Vectibix obviously is a marketed product, that’s been around for awhile. But we have some pretty interesting new data looking at particularly in Phase 2 head-to-head study in the first-line in colorectal cancer against bevacizumab, where there appeared to be a substantial transfer advantage to Vectibix in that setting and of course, Wild-Type RAS patients.

And we are getting better and better at being able to define the exact Wild-Type RAS population by excluding a variety of other mutations in the RAS family of genes and that extended biomarker analysis is also presented here at the meetings. It’s important all of this in the context of having just been granted first-line approval in United States, of course, in FOLFOX containing first-line colorectal cancer.

Rilotumumab and AMG 337 are our MET-inhibitor programs. Rilotumumab is an antibody that binds the antigen and AMG 334 block signaling through the receptor and AMG 334 block signaling through the receptor. We are focusing those programs in -- first in gastric cancer and exploring other tumor types as well.

And Trebananib as you know hit the PFS endpoint last year, we are waiting on the overall survival data in recurrent ovarian cancer which will be a fairly binary impact on the program and if it’s positive it will great, it’s a huge unmet need, if not that will probably represent the end of investment in Trebananib.

Kyprolis and oprozomib, of course, are really important new additions to our oncology portfolio. And at Onyx I know they were working very hard doing everything they could do to try to have data come, of course, to ASCO, but well this is largely out of our control, it is an event driven study. So that more likely these results will come in the relatively near future and we will share them with you as they emerge.

And finally, just not to forget about XGEVA, we have a couple of important studies that are going on with XGEVA, pursuing a multiple myeloma indication in the head-to-head comparison to zoledronic acid, as well as an adjuvant breast cancer study, which is quite an ambitious study trying to look at both unmet free survival, as well as whether we can have an overall impact on disease progression in breast cancer which has been hypothesis that’s been around for some time with respect to anti-resorptive therapies.

So, with that, I'd like to turn things over to David Reese to go through some of the details of the program.

David Reese

Thank you, Sean. If you turn to Slide 7 in your presentation, what I would like to start with are some of the key immuno-oncology dataset that we presented here at ASCO this year. The first of those were the primary overall survival data from OPTiM.

This was a key secondary endpoint of this pivotal Phase 3 trial. In addition, as Sean mentioned we presented the Phase 1B portion of a trial examining T-VEC in combination with ipilimumab in patients with advanced melanoma. Finally, we presented the results of a confirmatory open-label, large single-arm study of blinatumomab in patients with relapsed or refractory B-precursor ALL.

On Slide 8, you can see a pictorial representation of the mechanism of action of T-VEC. I'll review this very briefly and then move on to the actual data that we presented here at ASCO. T-VEC is an oncolytic virus that is injected directly into accessible tumor lesions. The virus has been engineered to express GM-CSF.

It replicates in tumors cells eventually lysing those tumor cells, releasing what we believe is a shower of tumor antigens. GM-CSF is designed to recruit dendritic cells to the local tumor microenvironment, ultimately leading to the activation of T-cells which can act locally at the site of injection and potentially migrate elsewhere generating a systemic immune response. We will show some data in just a minute that lead us to believe that in fact we are inducing a systemic immune response with T-VEC.

On Slide 9, this is our title slide from the primary overall survival data that were presented from OPTiM with T-VEC. These data were presented last evening here in Chicago at ASCO. And if you turn to the next slide, I'll simply remind you of the study design for the OPTiM Phase 3 trial.

This included patients with advanced melanoma who had injectable unresectable Stage IIIB or IIIC or stage IV melanoma. They were randomized in a two to one fashion to receive either intralesional injections of T-VEC every two weeks or subcutaneous GM-CSF every two weeks. The primary endpoint of the trial which we have previously reported was durable response rate, key secondary endpoints included overall survival and I’ll take you through some of those data in just a moment.

Turning to Slide 11, you can see the data from primary endpoint that we have previously presented in the bottom table. The key primary endpoint is durable response rate. The durable response rate, which was defined as a response lasting six months or longer and which had to initiate within 12 months of the start-up therapy with 16.3% in the T-VEC arm compared to 2.1% in the GM-CSF arm. This of course was highly statistically significant.

In addition, the overall response rate was 26% on the T-VEC arm compared to just under 6% on the GM-CSF arm. The complete response rate was nearly 11% with T-VEC in this particular trial.

Subsequent to the primary analysis on Slide 12, we performed an individual lesion level analysis. This is a complicated slide and I’d like to take you primarily through the left hand portion of it which I think contains some of the most important data of either individual lesions that are plotted and there are changes in size over time in the trial.

In the top left panel, you can see injected lesion and their change in size. Approximately 50% of injected lesions completely disappeared, meaning they have 100% decrease in size. Now from a biologic perspective and a clinical perspective, what we found of great interest were the following two panels on the left hand side of the slide, uninjected non-visceral lesions, 22% of those having 100% decrease in size and over a third more than a 50% reduction in size.

And then finally in the bottom panel, you can see that uninjected visceral lesions which are typically distant metastases, 9% of these became unmeasurable and 15% had a greater than or equal to 50% decrease in size. These two lower panels, we believe, provide evidence of a systemic immune response generated by T-VEC.

Slide 13 shows the overall survival data that were presented here at ASCO. This was a secondary endpoint. The trial was not powered for survival. As you can see, there was an increased overall survival median of 4.4 months in the T-VEC arm with the median overall survival of 23.3 months versus 18.9 months in the GM-CSF arm with a hazard ratio 0.79 and as Sean mentioned an unadjusted P value of 0.051.

The inset table on the Kaplan-Meier graph year is a representing landmark analysis looking at survival at fixed time period. And you can see that at 12, 24, 36 and 48 months, there was an improvement in survival on the T-VEC arm. The absolute difference in survival reached approximately 11% at 48 months.

We also conducted exploratory subgroup analysis for overall survival represented on Slide 14. As you can see, the effective T-VEC appeared to be most pronounced in patients with IIIB/C or Stage IVM1a disease with a 43% reduction in the risk of death in this patient population and a descriptive P value of 0.001. This effect of course was less pronounced in patients with more advanced Stage M1b or M1c disease. Although we should note that there were some patients in that group who appeared to achieve durable responses with T-VEC.

An additional exploratory analysis shown on Slide 15 examined outcome by line of therapy. In this instance, there appeared to be more pronounced effect in patients receiving T-VEC in the first line with a hazard ratio of 0.50 and a descriptive P value of less than 0.001. This effect again was pronounced in patients receiving T-VEC as second line or greater therapy.

In terms of safety, we show couple of the key safety tables on slide16. The most frequent adverse events are those consistent with the viral syndrome, including fatigue, chills and fever, are the only Grade 3 or higher adverse event reported in more than 2% of patients with cellulites. In general, we believe that T-VEC has a quite acceptable safety profile and this may allow us to be combined with other immunotherapies in a relatively safe fashion.

So in summary as we previously reported, T-VEC met its primary endpoint of durable response rate and there was a higher overall response rate in the OPTiM trial. We've seen responses in both injected and uninjected lesions including distant visceral lesions, suggesting the generation of a systemic immune response. And while the trial did not achieve statistical significance for overall survival, it closely approached it with a p-value of 0.051.

I’d like to turn now to some of the combination data with T-VEC that were presented here at ASCO. On slide 18, you can see the title of a study that was a Phase 1b multi-center trial, evaluating T-VEC in combination with ipilimumab in patients with untreated unresected advanced melanoma. This was largely a similar patient population to the one that had been treated in the OPTiM trial.

Slide 19 shows the study design of this trial. After enrollment, patients received two doses of intralesional T-VEC separated in time for by two weeks at the time of the third injection of T-VEC patients were studied on ipilimumab, adding three milligram per kilogram dose. They’ve received ipilimumab every three weeks according to its standard schedule for a total of up to four doses. Patients were then followed for safety and efficacy outcomes.

On slide 20, we show a waterfall plot of some of the primary efficacy data from this Phase 1b study of interest. 10 of the 18 assessable patients had a response rate of 56%, overall response rate and the complete response rate was 33%, with 6 of 18 patients achieving a complete response. As you can see in the waterfall plot, the majority of patients had some degree of tumor shrinkage in this trial.

In terms of safety, I think one of the key messages that we took away from the first 19 patients treated with this combination, was that there did not appear to be any enhanced toxicity with the combination of T-VEC and ipilimumab. And as you review this adverse event profile, you will see that it largely reflects what one would expect with the use of either single agent alone.

So in summary on slide 22, we saw a 56% response rate in the first 19 patients treated on the Phase 1b portion of this trial, with the 33% complete response rate and a 72% disease control rate overall. I have not shown data in this presentation, but we did present data suggesting systemic immune activation through measurement of CD8 T cells, which increased after treatment with T-VEC and then further increased with the addition of ipilimumab.

To date, there have been no dose limiting toxicities. And we've not seen any unexpected adverse events to this time. Based on these data, we have launched a randomized Phase 2 trial. Looking at this combination, that study is actively enrolling.

Let me turn now to blinatumomab on slide 23. Blinatumomab, I will remind you, is a BiTE antibody designed to engage T cells, activate T cells against CD19, a target antigen that is almost universally present on acute lymphoblastic leukemia or ALL cells.

On slide 24, you can see the title of the large Phase 2 single-arm trial that we presented here at ASCO. This was actually presented just a couple hours ago by Professor Topp in one of the final sessions at ASCO in 2014.

The next slide shows the study design of this confirmatory open label trial. Patients received two cycles of blinatumomab by continuous IV infusion and within evaluated for response for the primary endpoint, which was the complete response rate or complete response with partial hematologic recovery.

Those patients who were in complete response at that time were offered Hematopoietic stem cell transplantation. Had they not achieved the complete response, they could go on to receive up to three cycles of consolidation therapy with blinatumomab. Any patient achieving a complete response during that course of therapy was also potentially a candidate for stem cell transplantation. As in other trials with blinatumomab during the first cycle, there was one in week at a lower dose prior to escalation, two full doses of the drug.

The next slide shows the primary response data from this trial. I think the key points here would that be complete response, or CRh rate was 43% in this group of patients with advanced relatively difficult to treat ALL. Importantly, of those achieving a complete response or CRh, 40% were able to go on to receive the potentially curative therapy of Hematopoietic stem cell transplantation.

In addition, in 73 patients who were assessable for this endpoint, there was a minimal residual disease response also known as molecular remission. That is important because in a number of studies that's been associated with improved long-term outcome. Overall, we were pleased with the response data in this trial. We continued to follow a number of these patients, some of whom are in response now over two years after receiving therapy.

On the next slide is reported the broad adverse events that were observed in this study. As you can see, a large number of patients did experienced grade 3 or 4 adverse events that is quite common in trials of new agents in patients with relapsed or refractory ALL. The general spectrum of the adverse events reported here and that were observed were largely consistent with what one would expect in this patient population.

On the next slide, we do report neurologic adverse events. As you know, we have previously reported this with blinatumomab. In addition, it's been seen with some of the other anti-CD19 directive therapies. Importantly, of patients experiencing grade 3 or higher neurologic adverse events, the large majority had events that were reversible 24 patients. There were no fatal adverse events related to neurologic syndromes and in patients whose neurologic events were irreversible that was usually in the setting of an uncontrolled and progressive systemic disease.

So in conclusion, we believe the present study confirmed the significant single-agent antileukemia activity of blinatumomab in patients with Philadelphia chromosome-negative B-precursor relapsed/refractory ALL, with a complete response or CRH rate of 43%. I did not show the data although they were presented a few hours ago in the presentation suggesting that across all subgroups of patients that were analyzed complete responses were observed.

The adverse event profile was consistent with what we have previously reported with blinatumomab and fatal adverse events were only seen in patients who had uncontrolled ALL. We do have an ongoing randomized, open-label Phase 3 study of blinatumomab in this population that compares the use of blinatumomab with standard of care chemotherapy.

On slide 30, you see listed I won’t go through this in detail, but what is a relatively broad clinical development program for blinatumomab both in B-precursor ALL in adults, in pediatric patients, as well as a Phase 2 program in the few large B-cell lymphoma. We look forward to talking to you about these data sets as they begin to arrive.

Finally, I would like to spend just a moment talking about some of the panitumumab abstracts that we presented here at ASCO in a first-line metastatic colorectal cancer. We presented data on an extended RAS analysis and subsequent anti-EGFR or anti-VEGF treatment in PEAK, which was a large randomized Phase 2 study of FOLFOX chemotherapy with either panitumumab or bevacizumab. We also presented data regarding survival in patients with either KRAS or NRAS wild-type metastatic colorectal cancer and non-liver-limited disease, and finally additional data based on performance status.

I should note that when we talk about extended RAS analysis or RAS mutations in colorectal cancer, we mean patients who have no mutations in either KRAS or NRAS across all of the relevant exons that are examined.

Dr. Rivera presented data on the extended RAS analysis, entered a PEAK trial. PEAK again was a study in which 285 patients were randomized to receive FOLFOX chemotherapy and either panitumumab or bevacizumab.

And on slide 33, you can see some of the key results in terms of median overall survival. Looking at the wild-type KRAS population, median overall survival was 34.2 months with panitumumab versus 24.3 months with bevacizumab and those differences seem to be maintained if patients went on to receive the alternate agent in subsequent lines of therapy.

In the all RAS population with KRAS and NRAS mutations excluded, overall survival was 41.3 months in the panitumumab arm compared to approximately 29 months in the bevacizumab arm, but 41 months overall survival while it’s from Phase 2 study is one of the most impressive results has been seen in this disease. And I think we have seen over the years with this sort of biomarker and molecular selection continual improvement in outcomes in patients by being able to identify those sort of most stable to benefit from these drugs.

In summary, we think that we have an innovative oncology pipeline. We are quite happy with where our immuno platforms are positioned right now. We presented data on both T-VEC and blinatumomab. As we have mentioned in the last few days, we are preparing a filing package for T-VEC in 2014, with an intended submission this year with blinatumomab. We are discussing the potential of filing with regulatory authorities based on the current data sets.

Finally, I would remind you that a few days prior to ASCO we received extended indications for Vectibix, which is now approved in combination with FOLFOX chemotherapy for the first-line treatment of metastatic colorectal cancer.

With that, I will pause and turn over to Arvind.

Arvind Sood

Yes, okay. That’s great, Dave. Thank you. So also let’s go ahead and open it up for the Q&A session. I think we have plenty of time for questions.

Question-and-Answer Session


(Operator Instructions) And your first question comes from the line of Terence Flynn.

Terence Flynn - Goldman Sachs

Hi, thanks for taking the questions. Maybe first just broadly, coming out of ASCO obviously and increasing lot of focus on immunoncology and then the multiple of targets out there. I am just wondering what the companies interested in and maybe broadening your footprint beyond T-VEC and blinatumomab. And then the second question I had related to just latest views on the risk benefit profile of Kyprolis also coming out of ASCO. We saw some incremental once weekly data and I am assuming you met with some of your KOLs. So just wanted to see if there is any update there? Thank you.

Sean Harper

This is Sean. I will speak to your first question and then I will ask Pablo to respond about the Kyprolis question. I think we are interested in broadening the footprint. We have currently internal preclinical programs that are immunotherapy focused. Interestingly, things that we have been doing in the background even before this area became as hot as it is at the moment. But we also have been looking on the external side and actually are pursuing potential in licensing of some additional technology platforms in molecule-based approaches or immunotherapy. So we are looking to expand that focus and have actually taken some steps even in our discovery areas in our inflammation and oncology areas to combine much of the efforts that are going on in the discovery platform to bring an immunoncology kind of approach to bear.

And then Pablo perhaps you could respond to the Kyprolis question.

Pablo Cagnoni

Yes. Thank you, Sean. Let me make two comments. One is related to the weekly schedule. As you know the Champion data were presented at ASCO. We find the response rate with the weekly schedule very encouraging. We are in the process of accruing more patients to the Champion study in order to have a more robust data set with the single-agent weekly schedule Kyprolis, but so far we are very happy with the results we are seeing. And we are having internal discussion as to what the best way to expand the weekly Kyprolis program. So stay tuned because over the next few months we will initiate more studies.

The second question was related to risk benefit for Kyprolis, not only interactions with KOLs that we had at ASCO and other similar meetings, the overwhelming majority of clinicians that use Kyprolis continue to tell us that they have a favorable impression of the product that the risk benefit is favorable to patients and they have a good experience using the drugs in patients, a good experience receiving the drug. In addition, I want to emphasize that by now Kyprolis has been in the market close to two years. We have more than 10,000 patients treated. We have four Phase 3 trials enrolling, all of which are monitored by data monitoring committees. None of the data monitoring committees has requested any changes to the study designs and we have not observed any safety signals that are inconsistent with the label that we have. So we’ll continue with the development program and we will continue to share results as they manage.

Arvind Sood

[Nicosia] (ph) let’s take a next question please.


And your next question comes from the line of Yaron Werber.

Arvind Sood

Yeah. Yaron Werber. Yaron, go ahead.

Yaron Werber - Citi

Great. Hi, thank you. Two questions if you don’t mind. One, when you look at your PEAK data in the KRAS wild-type we showed a nice activity versus Avastin. Erbitux is a big ECOG study that was present showed on survival just the same sensible response as Avastin. Does that -- I know it’s a class trial. What do you think accounts for the difference or do you think potentially panitumumab is better agent? And then just if you don’t mind, just to probe a little bit, what you guys are waiting for to make a decision on T-VEC and blinatumomab in terms of filings? Thank you.

Sean Harper

So let me answer, I’m Sean, the second question. With T-VEC, we’re really not waiting on anything for decision to file. We have committed to file this year and we’re proceeding with that plan. With blinatumomab, we have a strong sense that the data set is supportive of the filing. But because it’s a single arm Phase 2 study, it requires a lot of collaborated discussion with regulators to be certain. That’s the appropriate thing to do.

But we’re certainly moving in that direction. And then David Reese, I’d like to hear comment on the question of the PEAK versus the cetuximab co-op study that was -- I’ve been looking at those data myself and wondering some more questions that wanted to share your perspective.

David Reese

Sure. Yeah. I’ll be happy too. So I think there are couple of things to point out. In the cooperative group trial, our patients could use as backbone chemotherapy either FOLFOX or FOLFIRI. So there was a mixture of backbones compared to FOLFOX alone in the PEAK study, which makes cross trial comparisons even more difficult than usual. The presenter Dr. Alan Venook did break out the results by chemotherapy regimen and in the FOLFOX cohort, which was about 75% or so of the overall sample size in the cooperative group trial.

There was more of the trend towards improvement with the use of cetuximab. In addition, they presented only the KRAS exon 2 data and indicated that they are examining at this time and will be presenting shortly data by the overall RAS analysis meaning KRAS and NRAS mutational status.

The discussion Dr. Tabernero shared some thoughts which I would agree with, which one would expect a further enhancement of the hazard ratio in the patients receiving FOLFOX space chemotherapy with Cetuximab in that trial.

I think, overall our perspective is this really starts to come together and suggest that consistent with our recent first-line approval, the use of an EGFr inhibitor panitumumab with oxaliplatin based chemotherapy is a good choice in the first line for patients with metastatic colorectal cancer.

Arvind Sood

[Nicosia] (ph) lets take our next question.


And your next question comes from the line of Mark Schoenebaum.

Sean Harper

Yeah. It’s Mark Schoenebaum from ISI. Mark, why don’t you go right ahead, please?

Salim Syed - ISI

Hey guys, this is actually Salim Syed in for Mark.

Sean Harper


Salim Syed - ISI

Thanks for taking my questions. So just two quick ones hopefully, again, on blinatumomab, when do you think, we should anticipate a decision with your file or not in 2014. And then on type four as, so there are few trials now outside of multiple myeloma. Just wanted to get your thoughts on type four as long-term outside of multiple myeloma, please? Thanks.

Sean Harper

So, again, it is Sean, I’ll take the blin question. I think, we have to have the discussions with the regulators. They are happening now kind of real time. I would expect that later in the year, we will be able to one of our earnings calls or other form. We’ll be able to share the outcome of that so that it would be clear this year. And with respect to the question around the multiple myeloma again, probably why don’t you feel that.

David Reese

Sure. Thank you, Sean. The Kyprolis development plan continues to be focused in myeloma. I think it’s important to stress that. We have some studies including investigator responsive trials in exploring the use of Kyprolis and other settings. And importantly, we've initiated a company sponsored trials. It’s the Phase 1 study, in combination with chemotherapy and also lung cancer.

We have some preliminary data from the small number of patients showing prolonged stable disease and one very interesting complete response in multiple lung cancer from an older study and we decided it was important to explore it further. So that study is ongoing currently. But our focus continues to be to accelerate the multi myeloma development of Kyprolis in order to complete the ongoing Phase 3 trials and continuing to move that plan forward.

Arvind Sood

And let’s take our next question. Yeah, go ahead.


And your next question comes from the line of Michael Yee.

John Chung - RBC Capital Markets

Hi, thanks. It’s actually John on for Michael. Can you guys hear me okay?

Sean Harper

Yeah, we can, go ahead.

John Chung - RBC Capital Markets

Yeah. So with regards to T-VEC with monotherapy with Phase 3 results, you have mentioned that you're committed following this five year-end. So with that, what gives you the confidence that the FDA will accept and approve this data, given the endpoint on survival. I see that you have given the sub-group analysis. So potentially limit the indication to those first line and earlier lines of therapy. Thank you?

Sean Harper

Yeah. Michael, I would say that we never have absolute certainty around being able to get an approval when we make a submission that we tried to have a pretty good dialogue with regulator or before we would submit. And the view that we have is that the primary endpoint of the study is the durable response rate, which is felt to be in itself clinically meaningful advantage to these patients.

In addition on a secondary endpoint, where we were not statistically powered, we missed essentially by one patient making statistical significance. And the agency is pretty thoughtful about those kinds of situations in general. So I think that when you look at the shape of the survival curve, when you look at what's driving the survival curve, which is durable responses, when you look at the safety profile of the product, all of it really leads you to believe that the product is providing a very good benefit risk for the appropriate patients.

As you point the effect appears to be not much more pronounced in patients who yet to develop a lot of visceral metastasis. And so I'm sure the data would be displayed in labeling to allow clinicians to see that. And I think that ultimately we’re taking kind of long-term view on this molecule, which is that this is just the beginning of its lifecycle. And the combination data will be very important but we see this as in and of itself at this point being an important therapeutic advance for patients who present with this kind of local regional disease.

Arvind Sood

Operator, next question.


And your next question comes from the line of Howard Liang.

Howard Liang - Leerink Swann & Company

Hi. Thanks very much. Just follow-up on the filing, is there, will the submission be only in the U.S. or post-U.S. and worldwide?

Sean Harper

Yeah. So we are in discussions globally on the product and would plan to submit in countries where we feel that, A, there is a reasonable probability of an approval based on this data and B, that there would be reasonable hope of getting reimbursement and kind of return on investment of actually making a commercial launch of the product. So that -- we will work that out as we go forward. Certainly, the biggest opportunity for the product will probably be in the United States at least in the short-term.


And your next question comes from the line Matt Roden.

Matt Roden - UBS

Hi. Great. Thanks. It’s Matt Roden with UBS. Thanks for taking the question. I have one on T-VEC. So, Sean, when you look at these subgroups where you suggested that benefit looks more pronounced in the stage III and stage IVM1a and then also in front-line? Is that direct the strategy you would take in your PD-1 combo studies in terms of patient selection? And then secondly, can you just remind us what the proportion of patients have injectable lesions in stage III and stage IV and whether not it differs? And then three, can you just remind us what the defendable patent life is on T-VEC? Thank you.

Sean Harper

Okay. Okay. And your first question just, as I wrote them down, I missed the first one now.

Arvind Sood

Hey, Matt. Are you still there, maybe you can just repeat the first question? Hey, Sean, I think, the question was about the T-VEC subgroup analysis, the benefits of stage III to IV of disease and how would that direct your patient select.

Sean Harper

Oh! Yes. Yes. In combination, no, it’s an excellent question, that’s why I didn’t want to loose it. Okay. So, yeah, let me comment on that, I think, that it’s an excellent question and what we are doing as we are taking the point of view that because we really, when you look at the checkpoint inhibitors in melanoma anyway, they are being used in kind of later stages of disease.

And we are seeing, and of courses, there is a desire by those agents to move earlier into disease and we are seeing most of are activity kind of an earlier disease, we’d like to see that T-VEC play a role in later stage disease and since we don't know what will happen during combination, the preclinical data and other data would suggest that there can be a very strong synergistic type of an effect.

So we are in fact exploring combinations across that spectrum of disease, with the view that we even though we may have seen minimal effect in the later stages, as monotherapy that does not preclude potentiation of the effect of a checkpoint inhibitor like a PD-1 antagonist in that sitting.

Likewise, that bringing a PD-1 antagonist forward in some of the earlier stage disease with T-VEC might be very exciting as well. So we are looking at the whole disease spectrum in combination. So that’s a very good question since we didn’t look at that long and hard and that’s where we landed.

The proportion of lesions that are in the different settings, you are asking question about what proportion of these patients have injectable lesions. By definition all of these patients are viewed at least subjectively right as unresectible and the vast preponderance of them have injectable lesions in this spectrum.

Occasionally, there are patients who just have visceral metastasis, for example, that would be difficult to get out and inject in some cases and other cases it might be quite doable. In the study -- in the OPTiM study patient had sometimes lymph node or subcutaneous nodules which were visualized by portable ultrasound and injected. So the answer is that across the spectrum the vast majority of these patients have disease that can be injected.

And finally on a patent question, I’m not prepared to provide an exact date on the patent, what I would comment on is, an agent like T-VEC is quite unusual, right. It is a vaccine kind of category. And as a consequence there is no generic or biosimilar pathway that exists for an agent like T-VEC. And as you probably know vaccine sometimes play pretty active role in portfolios of companies for decade. So it’s a bit of a different animal in that regard.

Arvind Sood

[Nicosia] (ph), do we have any other questions.


And you do have a follow-up question from the line of Howard Liang

Arvind Sood


Howard Liang - Leerink Swann & Company

Thanks for taking a follow-up. I just have a question on OPTiM, if you can comment on 12-weeks therapy, whether it was filed, I am not sure if I, I don’t know if I saw that in the presentation. Like also I was actually interested whether there is any information from that analysis on the potential interaction or synergy with the checkpoint inhibitor?

Sean Harper

So, I -- I am sorry, I had trouble catching your first part of your question?

David Reese

Okay. I can handle that one, Sean.

Sean Harper

Okay. Great.

David Reese

David Reese, in terms of subsequent therapies, it was relatively balanced between the arms in the OPTiM trial. So it’s our belief that that probably did not play a major role in affecting the overall survival outcome.

Arvind Sood

Great. Sean, do you want to make any closing comments.

Sean Harper

Well, mainly to thank people for their interest and attention and to just emphasis the fact that we remain very committed to our oncology activities. We feel that we actually began work in immunotherapy by the acquisition of assets like T-VEC and the BiTE platform sometime ago before the area become so hot.

And we are very committed to it is, I mentioned, all going all the way back to our discovery research efforts where we have really merged these kind of areas of strength that we’ve had at the company for many year in information research of course. It’s been a natural thing for us to bring that expertise together with our oncology research capability and to focus our business development efforts around that and there will be some further news in those -- along those lines as we move along in terms of bringing other capabilities to there.

We are also obviously very pleased to see the Vectibix approval in first-line and some of this is supportive data coming from PEAK and so on that should encourage the use of the product in the first-line setting. So thank you very much.

Arvind Sood

Great. Thanks, Sean. Thank you everybody for your participation and we will talk to you soon.


Ladies and gentleman, this does conclude today’s conference call. You may now disconnect.

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