Wednesday, September 28, 2005 10:08:19 PM
DNDN-UBS Conference Call transcript and breakout session
Dendreon Corporation
2005 UBS Global Life Sciences Conference
September 27, 2005
Presentation by Dr. Mitchell Gold, CEO
Good morning, everyone. I would like to remind you that I will be making forward-looking statements during my presentation today and I would encourage you to look at our most recent SEC filings regarding the risk factors associated with these statements.
Just to give you a brief snapshot and overview of Dendreon. Dendreon’s a company that is squarely focussed in the field of oncology. Our most advanced clinical product is Provenge, which we plan to file a BLA on in 2006. But beyond that we have a very broad pipeline that encompasses other cancer immunotherapies, small molecules and monoclonal antibodies. Over the last year to 18 months we’ve really built our work force and centered around commercializing Provenge. So we’ve brought on manufacturing expertise as well as sales and marketing expertise.
We are fortunate that we have a strong balance sheet. We carry no debt. We ended the second quarter with just over $156 million in capital. We have strong collaborations with Genentech on our trp-p8 program as well as Abgenix and Dyax.
If you look at our pipeline today, our most advanced clinical program is Provenge, or APC 8015. It’s being studied in both late stage, or hormone refractory prostate cancer, as well as early stage, androgen dependent prostate cancer. And a majority of my presentation today is gonna focus on the clinical data and the regulatory pathway for Provenge.
Beyond Provenge we have APC8024, or Neuvenge. It targets the HER2-neu pathway and we’ve completed two Phase I studies in breast, ovarian and colorectal cancer. These are all patients that are HER2-neu positive. We have other antigen targets that we can encompass in our cancer immunotherapy platform. Two of those we in-licensed from Behr Diagnostics about three years ago. They include CEA and CA-9. CA-9 is highly relevant for renal cell carcinoma. CEA for lung, colon and ovarian cancer. The Trp-p8 program is one that we’ve made a lot of progress on over the last several years. In August of 2002 we entered into a $113 million co-development, co-promotion agreement with Genentech encompassing both small molecules as well as monoclonal antibodies. And we’ve made a lot of progress, particularly in the small molecule component, in that arrangement. I’ll go into that in a little bit more detail as well.
So our cancer immunotherapy platform is based on a proprietary technology that we have called an Antigen Delivery Cassette. And the Antigen Delivery Cassette really keeps two key principles in mind. First, that we select a well-validated and well-characterized target. In the case of Provenge, that target is Prostatic Acid Phosphatase and in the case of Neuvenge, the target’s HER2-neu. And second, that we manufacture this Antigen Delivery Cassette as a recombinant protein. So we don’t source antigen from a patient’s own tumor tissue, which we think has a lot of scalability commercial issues behind it, and we don’t source antigen from a patient from allogenaic cell lines. We make it in a very specific fashion as a recombinant protein and hence it’s very well characterized at the end of the day that we can get a very robust and reproducible immune response.
If you look at the continuum of prostate cancer, we see the initial label for Provenge in men with asymptomatic androgen independent prostate cancer. We see it really being as front line therapy, in front of Taxotere. Because of the favorable side effect profile of Provenge, we see it moving into earlier and earlier stages of prostate cancer. For example, men that have had PSA recurrence after primary therapy. And we’ve completed a number of Phase II studies that suggest that Provenge may have an effect in this patient population.
To that end, we have completed multiple studies in both late stage androgen independent prostate cancer as well as early stage androgen dependent prostate cancer. And I’m gonna review those for you now.
Let me remind you of a couple of key points. First of all, in oncology, survival is the gold standard clinical endpoint. It trumps all other endpoints. Progression is a surrogate endpoint. It is used to really determine, really measure whether there is a reasonable benefit of predicting benefit in a clinical endpoint such as survival. Survival is the gold standard endpoint. And as many physicians will say, you can’t fake that. So you’re either dead. Or you’re alive. In our statistical plan for both of our Phase III studies in late stage prostate cancer, 9901 and 9902A, we pre-specified survival in our analysis for our original protocol in September of 1999. It was prespecified in our statistical analysis plan. And I just took an excerpt from this plan for you to remind you how we highlighted it there. "Estimates of survival rate and progression." Progression was the primary endpoint of the study. "Three (?) frequencies at 6, 9, 12, 18, 24 and 36 months and median survival will be provided, based on Kaplan-Meier curves with corresponding conference intervals and a Cox proportional hazards model could be used to adjust for any prognostic imbalances in these studies." So survival clearly was something that we had thought of when we designed these studies early on.
Our first Phase III study, 9901, which will be the pivotal Phase III study to support the Biologics License Application of Provenge, was a study conducted in men...127 men, with metastatic, asymptomatic androgen independent prostate cancer. The men received three infusions of Provenge. These are short, typically 30-60-minute infusions. They received three of these over a one-month period. The primary endpoint, as I said, was median time to objective disease progression. The secondary endpoint was delay in the onset of pain. And survival was an endpoint as we’ve mentioned, which was respecified in our statistical plan in our clinical protocol.
These are the survival curves. Here you see Provenge in orange and placebo in green. And you see here very substantial prolongation in survival in men that received Provenge compared to men that received placebo. At the median, there was a 4.5 month improvement in survival in men that received Provenge compared to placebo. This was highly statistically significant, with a p-value of .01 and a hazard ratio of 1.7. A hazard ratio of 1.7 suggests that patients who received placebo have a 70% higher rate of dying than patients who received drug. When you look at the descriptive statistics here, the 4-1/2 month survival benefit is remarkable, particularly when you compare it to the existing standard of care, Taxotere, which is showing about a 2.5 month survival benefit and a hazard ratio of about 1.3. What’s most remarkable is how durable these forms of therapy can be. And you can see at the end of the study, three years after receiving Provenge, after their immune system’s been activated, the number of patients alive in the Provenge arm is almost three-fold higher, 34%, compared to 11%, of patients in the placebo arm. So the advantage of these forms of therapy is that while they may take a little bit of time to actually get ramped up, the durability of them, or what they can do long term, is very impressive.
When you look at time to progression. Again, Provenge in orange and placebo in green. We achieved a hazard ratio of 1.43, which suggests a 43% delay in time to disease progression in patients that received drug compared to placebo. And this approached, but did not reach, statistical significance. We shot a p-value of .061.
In order to ensure that there weren’t some alternate explanation that could result in a survival advantage, we looked to see if patients after they progressed, more patients in the Provenge arm had gotten chemotherapy. That could be one reason why they were living longer than men in the placebo arm. So we went back and checked all the chemotherapy that these men had gotten and in fact that wasn’t true. More men in the placebo arm actually got Taxotere-based chemotherapy than men in the Provenge arm. So that wasn’t an alternate explanation for the survival benefit that we were seeing. And we wanted to do this because the 9901 study was a relatively small study, so we needed to make sure that the survival data that we were seeing is very robust.
In addition, we wanted to make sure that there were no prognostic imbalances. For example, did we have healthier patients in the drug arm compared to the placebo arm? And that’s why we were seeing a survival benefit? And this is data that Eric Small presented at ASCO early on in the year. And after we took all these prognostic variables into account, the p-value actually got better. It went from .01 to .002. So there was no alternate explanation for the survival benefit that we had seen in the 9901 study.
What’s very compelling about these forms of treatment is their side-effect profile. Provenge is extremely well tolerated. The most common side effects are fevers and chills, usually of low grade and short duration. And they last for about 1-2 days, then they go away. And so the benefit to risk ratio of a product like Provenge is extremely high. And we think that benefit to risk ratio is going to be a key point as we move through the regulatory process for Provenge. It’s almost unprecedented in cancer studies.
The 9902A study was a companion study to the 9901 study. Just like 9901, it was a randomized, double blind, placebo-controlled study. It was slightly smaller and it enrolled 98men. And it was designed to be pooled with the 9901 study. Similar endpoints to the 9901 study as well.
The 9902A data...we’ve only released top-line data. We’re presenting the data at an upcoming scientific meeting. The 9902A data, a second, randomized, placebo-controlled Phase III study, supports the survival benefit that we saw in our first Phase III study, 9901, 9901 being the pivotal study. What we saw here is just like 9901. We had a 20% improvement in median survival for patients who were randomized to receive Provenge compared placebo. Just like 9901, at three years, there was a substantially higher percentage of men alive in the drug arm compared to the placebo arm. And when we performed a Cox multi-variate regression analysis, these data were statistically significant. They were not on the log rank test. And progression. Just like 9901, there was no benefit in delaying time to disease progression. I think what that tells you is that progression’s not a reliable surrogate marker for predicting clinical benefit, such as survival, with these forms of therapy. Because these therapies take a little while to ramp up.
As planned, these data were pooled and the pooled data essentially support what we saw in 9901 and 9902A. We’re seeing a very consistent survival benefit. Again a 23% increase in median survival. A higher percentage of men alive at 36 months in the drug arm compared to the placebo arm. This data was significant both by log rank as well as on Cox multi-variate regression analysis.
The key take-home message here is consistency across the three datasets.
So let’s make it simple. This has been a relatively complex story over the last several years. But it’s now, and I don’t think it’s rocket science, really, to understand where we’re going. OK? It’s a survival benefit, in the intent to treat population, that’s highly statistically significant. The data are robust. We can’t make the survival benefit go away. And we have an extremely high, perhaps even unprecedented benefit to risk ratio, given the side effect profile of this drug.
So we took this data and we compiled it in the form of a pre-BLA briefing document to the FDA and we asked them whether they agreed that the data from 9901 and 9902A were sufficient to support a BLA for Provenge. The proposed target indication in our briefing document was for men with asymptomatic, metastatic, androgen-independent prostate cancer. The clinical basis of our proposed BLA was an extremely high, highly favorable benefit to risk ratio, a significant unmet medical need for this patient population, with the only approved form of therapy having significant side effects, and providing a 2.4-month or 2.5-month survival benefit in this patient population. And contrast that to the data from the 9901 pivotal Phase III study where we showed a 4.5 -month survival benefit, a hazard ratio of 1.7 and a p-value of .01. A three-fold advantage in survival at 36 months for patients that got drug compared to placebo. And a very high benefit to risk ratio. The 9902A data and the pooled analysis also being supportive of the 9901 study. So that was the clinical basis of our proposed BLA.
In the BLA briefing document, the FDA responded that they believe that the 9901 in conjunction with the data obtained in study 9902A and, in the absence of significant toxicity, that that data was sufficient to serve as the clinical basis of our BLA filing for APC8015, or Provenge. In addition, they also agreed that efficacy data from other studies, such as P-11 and 9902B, would not be required as part of our submission package to the Agency and based on the successful outcome of this meeting, the Company plans to submit our BLA next year.
I think the recent ODAC-FDA activity is very favorable for the Dendreon BLA for Provenge. Tarceva and other products have shown that survival in the intent to treat population is received favorably by committees. The FDA views, as you saw from Dr. von Eschenbach’s comments late last week and early this week, are more focussed on treatments that are matched to specific patient therapies that have fewer side effects. And Provenge certainly meets that criteria. And the question that’s frequently asked, at every ODAC meeting of the panel is, "Do the benefits of this particular therapy outweigh the risks associated with it?" And we believe, given the data that I’ve just shared with you, that that answer will be affirmative for Provenge.
9902B is an ongoing Phase III study that’s being modified to enrol only men with minimally symptomatic androgen independent prostate cancer regardless of their Gleason score. It’ll enrol approximately 500 men. It’s currently enrolling at approximately 70 sites throughout the country. The endpoints are similar to the first two studies, survival and progression. Survival is now the primary endpoint. And it really allows physicians, as well as patients, to get access to Provenge as we move through the regulatory process on 9901 and 9902A. And, as I said earlier, the FDA has communicated to us that the 9902B study will not be required as part of our BLA submission package.
Let’s talk a little bit about what we’re doing in early state prostate cancer. The P-16 study is an NCI, National Cancer Institute, sponsored study looking at Provenge in combination with Avastin in men that have PSA recurrence after primary therapy. This enrolled approximately 26 patients. We looked at PSA doubling time. And here what you see is the median pre-treatment PSA doubling time in these men was 6.7 months. After treatment with Provenge and Avastin, you had about a 90% increase in your PSA doubling time. It went to 12.7 months. And that was highly statistically significant with a p-value of .004.
When we look at Provenge as a mono-therapy in a similar patient population, men with PSA recurrence after primary therapy, we see a similar effect. 71% of patients had a prolongation in their PSA doubling time. The median was about a 50+% increase in PSA doubling time. So clearly we’re seeing Provenge being able to move into earlier and earlier stages of prostate cancer.
We’ve now completed enrollment in a large Phase III study called P-11. It enrolled 170 men with early stage prostate cancer. We expect to get the PSA data from this study in the first half of next year. So it’s a near-term event for the organization.
So when you take all this data and you look at it across the continuum of prostate cancer, whether it’s late stage prostate cancer, where we’re showing a survival benefit, or early stage prostate cancer, where we’re showing a benefit on PSA doubling time, we have not seen a negative clinical indication of Provenge across the continuum of prostate cancer. And so we think clearly this drug is having a big effect on these men.
If you look at the market, right now the only approved therapy in men with asymptomatic AIPC is Taxotere. It’s a 2.4-month median survival benefit with a hazard ratio of 1.3. Certainly from an efficacy perspective....we have not done head to head trials comparing Provenge to Taxotere, but on the surface.... Clearly a 4.5-month survival benefit seems superior to a 2.4-month survival benefit. And a hazard ratio of 1.7 is superior to a hazard ratio of 1.3. What I think most compelling and why Provenge is gonna be frontline therapy is that the side effect profile of these two different forms of treatment are dramatically different. These are the Grade 3 and Grade 4 adverse events across both studies. You can see Taxotere has a significant amount of Grade 3 and Grade 4 adverse events where you only have a small number of Grade 3 and Grade 4 adverse events in the Provenge arm. Mostly fevers and chills. They’re of low grade and short duration. So this is very, very appealing to patients. And as you heard a lot of the patient advocacy groups say at a recent ODAC meeting, approximately 50% of patients would rather die of their disease than go into therapy like Taxotere, given its side effects. And most important is that with Provenge you get three infusions over a one-month period and you go on, you live your normal life. With Taxotere, every three weeks you get an infusion of Taxotere and the average course of therapy is 10 courses, so it’s 30 weeks.
When we conduct quantitative market research with both urologists and oncologists, who are the target market for Provenge, both the oncologists and urologists are highly energized about the arrival of Provenge to the market place. They see the survival data, as well as the side effect profile of Provenge, superior to that of the existing standard of care and as a result we anticipate penetration rates for Provenge to be in line with other blockbuster oncology products.
This is from a recent survey that we didn’t conduct. It was done at the international prostate cancer meeting in February. 69% of physicians said they’d be very likely or somewhat likely to use a product like Provenge once it’s available to them for men with hormone refractory prostate cancer.
The market for this patient population is extremely large. Prostate cancer is now the number one non-skin cancer in the world today. In the United States alone, there is in excess of 150,000 men with metastatic AIPC. Given the favorable side effect profile of Provenge, while our initial label will be in late stage AIPC, we see ourselves moving into earlier and earlier stages of disease. That market’s about three times as large. In the US it’s about 250,000 men. Globally it’s approaching 600,000 men. So these are extremely large oncology markets. Very small penetration rates in these markets and they have a big impact on sales figures at the end of the day.
So the platform, based on the Antigen Delivery Cassette technology, we believe, is expandable to other cancer phenotypes. Neuvenge is our best example of that. We took the Antigen Delivery Cassette, took out PAP, put in HER2-neu. We’ve completed two Phase I studies, we’re looking at safety and immune response. And what we see here. Is that when you compare the immune response against HER2-neu at baseline, compared to week 8, which is when we know the maximum immune response starts to kick in, you can see that we generated a Stimulation Index over baseline of about 25-fold greater than where it is at baseline. That’s huge. In an immune therapy study. Usually you see SI’s of may be 4, 5 or 6. Provenge is on the order of 20, 21. Here, with Neuvenge, it’s almost 25. And that was highly statistically significant with a p-value of 5 zeros and a 1.
So clearly the platform’s expandable into other antigens. We have to conduct formal Phase II studies here to see if this is gonna bring a clinical benefit such as Provenge brings to men with prostate cancer. And we’re really moving along that pathway currently.
I’ll talk a little bit about Trp-p8. Trp’s a gene that we discovered through our own in-house antigen discovery program. It’s been very high profile lately. Merck has a Trp program going on. Amgen has a Trp program going on. We own the Trp-p8 gene, which is the only Trp channel focussed on oncology. In August of 2002 we entered into a large collaboration with Genentech. The subject has been featured on both the cover of Nature as well as on Cell. And what we’ve found. And this was presented last week. Is Trp’s a trans-membrane voltage-gated ion channel. And if we can regulate it, either agonize it or antagonize it, we can inhibit the growth of tumor cells. And here you see different prostate cancer cell lines being inhibited through different lead candidates. And with the one that we’re really the most interested in, the brown one there, being 3211, we can basically result in 77% tumor growth inhibition. And that is highly statistically significant, with a p-value of three zeros and a 1. So we’re moving through the lead selection process now and we hope to select a lead by the end of this year. Then we’ll move that into pharmatox studies. This is a program that’s moving forward fairly aggressively. It’s early stage. But we think it provides a lot of promise to the organization. It’s something that most people don’t see within Dendreon today. It’s one of those hidden assets within the organization.
As I said earlier, strong balance sheet. No debt. If you look at the upcoming milestones for the organization, it will be the presentation of the 9902A data, which we believe supports the data seen in 9901; reporting the preliminary Phase III data on our early stage prostate cancer study, P-11; publication of the 9901 Phase III study in a peer-reviewed medical journal; and submission of our Provenge BLA. We plan on finalizing the protocol for the Neuvenge study in Phase II metastatic breast cancer; selecting a small molecule lead on the Trp program with Genentech; and advancing the monoclonals with Dyax and Abgenix.
So clearly from an investor perspective it is not easy to get behind first in class products. There’s a lot of ups and downs. This is a picture that I took from an article in Science in 1998. And it was really looking at the ups and downs of the monoclonal marketplace. And if you’d invested in Genentech at the right time. Roche did in 1991, took a 50% stake in Genentech for $2 billion, clearly that paid off for them. But if you had just looked at the products. And looked at the science. There’s a lot of skepticism on products like Rituxan and Avastin. If you looked at the science, you would have been able to really reap significant rewards on your investments in these first in class types of products. And what’s interesting about this graph is that they stopped it when Herceptin was shown to slow breast cancer in some patients. And they kind of guess that the graph is going up. They had no clue. At that point. That Avastin was right around the corner, and Erbitux was around the corner. And I think it’s the science that should really drive your investment decision. We believe the science at Dendreon is very strong and presents a compelling investment opportunity. In Phase III studies, it’s the first cancer immunotherapy to show a significant survival benefit, has a very high benefit to risk ratio. Given our recent discussions with the FDA, we have a first to market opportunity with this products. And there’s very strong physician interest in seeing a product like Provenge on the market to help patients with late stage prostate cancer. We’ve built a deep product pipeline behind Provenge, but Provenge is clearly the focus today. We have a discounted technology value. Given that we have $150 million in cash and a $400 million market cap, a $250 million technology value for these markets, I think, is something that we think is relatively small. And given our size and our technology and our platform, just like monoclonals did, we believe that we have the potential to fundamentally change the way that cancer is treated.
Thank you. And I’ll see you in the breakout room.
BREAKOUT SESSION NOTES from ackabaker on the DNDN Yahoo board
UBS notes
by:
ackabaker
09/27/05 03:55 pm
Msg: 135809 of 135830
Notes from conference breakout:
Room was more than half full (~35 people?)
I walked in a few minutes late (actually missed the main talk)
Discussion was surprisingly low-key considering the backdrop of UBS animosity
Q- do you know of any precedents where FDA ok'd a drug missing primary endpoint but met secondary?
Mitch- we learned from our pre-BLA meeting that we had been overly conservative about the primary endpoint- that TTP should not have been a major focus- Pazdur sees survival as clearly the basis for approval- our TTP result with a .06 p-value is definitely "supportive"- though we never could have gotten full approval on it
Q- When in 06 will you submit.. H1? H2?
Mitch- we're only saying 06 (smiling).
Q- Was the problem with TTP due to difficulties in measuring progressing?
Mitch- The measurement was time to first radiographic look(?), progression is difficult to characterize as it's a soft endpoint in prostate cancer- also the men just progress so rapidly
Q- What assumptions are you using with respect to Placebo crossovers?
Mitch- same as previous trials- about 75%
Q- Will the filing be based on asymptomatic disease?
Mitch- Yes- pre taxotere- i.e. frontline disease
Q- What's delaying BLA?
Mitch- As discussed in our recent cc- clinical data is done- CMC section is rate-limiting step- there are two components to manufacture- the recombinant protein and the patient's blood
Q- Burn rate??
Mitch- Haven't given 06 guidance yet- for 05 we guided to $90-100M but then guided to lower end of range in the last cc
Q- Will you sign a US partner?
Mitch- We don't want to, but if it makes sense in terms of having a partner with a very strong commercialization capability, we will.
Q- Do you have a QC program to look at patient's blood?
Mitch- Use standard operating procedures re QC specs- FDA said it's ok and won't need to do bridging studies as we go from contract centers to own facilities
Q- How did you keep the survival benefit even with cross-overs? Are you saying the survival benefit includes the crossover comparison? [People seemed stunned at this]
Mitch- Yes (chuckling)- let's just say it's best to get Provenge instead of not at all, but it's better to get it late instead of never. Most had progressed not due to symptomes but radiographically. It's best to give it early and with the side effect profile we don't think docs will hesitate to give it early.
There were a couple of other q's regarding commonly known facts that I didn't make note of.
Disclaimer- I have no involvement with ubs, only a professional history in the securities business and so attended strictly on that basis.
Dendreon Corporation
2005 UBS Global Life Sciences Conference
September 27, 2005
Presentation by Dr. Mitchell Gold, CEO
Good morning, everyone. I would like to remind you that I will be making forward-looking statements during my presentation today and I would encourage you to look at our most recent SEC filings regarding the risk factors associated with these statements.
Just to give you a brief snapshot and overview of Dendreon. Dendreon’s a company that is squarely focussed in the field of oncology. Our most advanced clinical product is Provenge, which we plan to file a BLA on in 2006. But beyond that we have a very broad pipeline that encompasses other cancer immunotherapies, small molecules and monoclonal antibodies. Over the last year to 18 months we’ve really built our work force and centered around commercializing Provenge. So we’ve brought on manufacturing expertise as well as sales and marketing expertise.
We are fortunate that we have a strong balance sheet. We carry no debt. We ended the second quarter with just over $156 million in capital. We have strong collaborations with Genentech on our trp-p8 program as well as Abgenix and Dyax.
If you look at our pipeline today, our most advanced clinical program is Provenge, or APC 8015. It’s being studied in both late stage, or hormone refractory prostate cancer, as well as early stage, androgen dependent prostate cancer. And a majority of my presentation today is gonna focus on the clinical data and the regulatory pathway for Provenge.
Beyond Provenge we have APC8024, or Neuvenge. It targets the HER2-neu pathway and we’ve completed two Phase I studies in breast, ovarian and colorectal cancer. These are all patients that are HER2-neu positive. We have other antigen targets that we can encompass in our cancer immunotherapy platform. Two of those we in-licensed from Behr Diagnostics about three years ago. They include CEA and CA-9. CA-9 is highly relevant for renal cell carcinoma. CEA for lung, colon and ovarian cancer. The Trp-p8 program is one that we’ve made a lot of progress on over the last several years. In August of 2002 we entered into a $113 million co-development, co-promotion agreement with Genentech encompassing both small molecules as well as monoclonal antibodies. And we’ve made a lot of progress, particularly in the small molecule component, in that arrangement. I’ll go into that in a little bit more detail as well.
So our cancer immunotherapy platform is based on a proprietary technology that we have called an Antigen Delivery Cassette. And the Antigen Delivery Cassette really keeps two key principles in mind. First, that we select a well-validated and well-characterized target. In the case of Provenge, that target is Prostatic Acid Phosphatase and in the case of Neuvenge, the target’s HER2-neu. And second, that we manufacture this Antigen Delivery Cassette as a recombinant protein. So we don’t source antigen from a patient’s own tumor tissue, which we think has a lot of scalability commercial issues behind it, and we don’t source antigen from a patient from allogenaic cell lines. We make it in a very specific fashion as a recombinant protein and hence it’s very well characterized at the end of the day that we can get a very robust and reproducible immune response.
If you look at the continuum of prostate cancer, we see the initial label for Provenge in men with asymptomatic androgen independent prostate cancer. We see it really being as front line therapy, in front of Taxotere. Because of the favorable side effect profile of Provenge, we see it moving into earlier and earlier stages of prostate cancer. For example, men that have had PSA recurrence after primary therapy. And we’ve completed a number of Phase II studies that suggest that Provenge may have an effect in this patient population.
To that end, we have completed multiple studies in both late stage androgen independent prostate cancer as well as early stage androgen dependent prostate cancer. And I’m gonna review those for you now.
Let me remind you of a couple of key points. First of all, in oncology, survival is the gold standard clinical endpoint. It trumps all other endpoints. Progression is a surrogate endpoint. It is used to really determine, really measure whether there is a reasonable benefit of predicting benefit in a clinical endpoint such as survival. Survival is the gold standard endpoint. And as many physicians will say, you can’t fake that. So you’re either dead. Or you’re alive. In our statistical plan for both of our Phase III studies in late stage prostate cancer, 9901 and 9902A, we pre-specified survival in our analysis for our original protocol in September of 1999. It was prespecified in our statistical analysis plan. And I just took an excerpt from this plan for you to remind you how we highlighted it there. "Estimates of survival rate and progression." Progression was the primary endpoint of the study. "Three (?) frequencies at 6, 9, 12, 18, 24 and 36 months and median survival will be provided, based on Kaplan-Meier curves with corresponding conference intervals and a Cox proportional hazards model could be used to adjust for any prognostic imbalances in these studies." So survival clearly was something that we had thought of when we designed these studies early on.
Our first Phase III study, 9901, which will be the pivotal Phase III study to support the Biologics License Application of Provenge, was a study conducted in men...127 men, with metastatic, asymptomatic androgen independent prostate cancer. The men received three infusions of Provenge. These are short, typically 30-60-minute infusions. They received three of these over a one-month period. The primary endpoint, as I said, was median time to objective disease progression. The secondary endpoint was delay in the onset of pain. And survival was an endpoint as we’ve mentioned, which was respecified in our statistical plan in our clinical protocol.
These are the survival curves. Here you see Provenge in orange and placebo in green. And you see here very substantial prolongation in survival in men that received Provenge compared to men that received placebo. At the median, there was a 4.5 month improvement in survival in men that received Provenge compared to placebo. This was highly statistically significant, with a p-value of .01 and a hazard ratio of 1.7. A hazard ratio of 1.7 suggests that patients who received placebo have a 70% higher rate of dying than patients who received drug. When you look at the descriptive statistics here, the 4-1/2 month survival benefit is remarkable, particularly when you compare it to the existing standard of care, Taxotere, which is showing about a 2.5 month survival benefit and a hazard ratio of about 1.3. What’s most remarkable is how durable these forms of therapy can be. And you can see at the end of the study, three years after receiving Provenge, after their immune system’s been activated, the number of patients alive in the Provenge arm is almost three-fold higher, 34%, compared to 11%, of patients in the placebo arm. So the advantage of these forms of therapy is that while they may take a little bit of time to actually get ramped up, the durability of them, or what they can do long term, is very impressive.
When you look at time to progression. Again, Provenge in orange and placebo in green. We achieved a hazard ratio of 1.43, which suggests a 43% delay in time to disease progression in patients that received drug compared to placebo. And this approached, but did not reach, statistical significance. We shot a p-value of .061.
In order to ensure that there weren’t some alternate explanation that could result in a survival advantage, we looked to see if patients after they progressed, more patients in the Provenge arm had gotten chemotherapy. That could be one reason why they were living longer than men in the placebo arm. So we went back and checked all the chemotherapy that these men had gotten and in fact that wasn’t true. More men in the placebo arm actually got Taxotere-based chemotherapy than men in the Provenge arm. So that wasn’t an alternate explanation for the survival benefit that we were seeing. And we wanted to do this because the 9901 study was a relatively small study, so we needed to make sure that the survival data that we were seeing is very robust.
In addition, we wanted to make sure that there were no prognostic imbalances. For example, did we have healthier patients in the drug arm compared to the placebo arm? And that’s why we were seeing a survival benefit? And this is data that Eric Small presented at ASCO early on in the year. And after we took all these prognostic variables into account, the p-value actually got better. It went from .01 to .002. So there was no alternate explanation for the survival benefit that we had seen in the 9901 study.
What’s very compelling about these forms of treatment is their side-effect profile. Provenge is extremely well tolerated. The most common side effects are fevers and chills, usually of low grade and short duration. And they last for about 1-2 days, then they go away. And so the benefit to risk ratio of a product like Provenge is extremely high. And we think that benefit to risk ratio is going to be a key point as we move through the regulatory process for Provenge. It’s almost unprecedented in cancer studies.
The 9902A study was a companion study to the 9901 study. Just like 9901, it was a randomized, double blind, placebo-controlled study. It was slightly smaller and it enrolled 98men. And it was designed to be pooled with the 9901 study. Similar endpoints to the 9901 study as well.
The 9902A data...we’ve only released top-line data. We’re presenting the data at an upcoming scientific meeting. The 9902A data, a second, randomized, placebo-controlled Phase III study, supports the survival benefit that we saw in our first Phase III study, 9901, 9901 being the pivotal study. What we saw here is just like 9901. We had a 20% improvement in median survival for patients who were randomized to receive Provenge compared placebo. Just like 9901, at three years, there was a substantially higher percentage of men alive in the drug arm compared to the placebo arm. And when we performed a Cox multi-variate regression analysis, these data were statistically significant. They were not on the log rank test. And progression. Just like 9901, there was no benefit in delaying time to disease progression. I think what that tells you is that progression’s not a reliable surrogate marker for predicting clinical benefit, such as survival, with these forms of therapy. Because these therapies take a little while to ramp up.
As planned, these data were pooled and the pooled data essentially support what we saw in 9901 and 9902A. We’re seeing a very consistent survival benefit. Again a 23% increase in median survival. A higher percentage of men alive at 36 months in the drug arm compared to the placebo arm. This data was significant both by log rank as well as on Cox multi-variate regression analysis.
The key take-home message here is consistency across the three datasets.
So let’s make it simple. This has been a relatively complex story over the last several years. But it’s now, and I don’t think it’s rocket science, really, to understand where we’re going. OK? It’s a survival benefit, in the intent to treat population, that’s highly statistically significant. The data are robust. We can’t make the survival benefit go away. And we have an extremely high, perhaps even unprecedented benefit to risk ratio, given the side effect profile of this drug.
So we took this data and we compiled it in the form of a pre-BLA briefing document to the FDA and we asked them whether they agreed that the data from 9901 and 9902A were sufficient to support a BLA for Provenge. The proposed target indication in our briefing document was for men with asymptomatic, metastatic, androgen-independent prostate cancer. The clinical basis of our proposed BLA was an extremely high, highly favorable benefit to risk ratio, a significant unmet medical need for this patient population, with the only approved form of therapy having significant side effects, and providing a 2.4-month or 2.5-month survival benefit in this patient population. And contrast that to the data from the 9901 pivotal Phase III study where we showed a 4.5 -month survival benefit, a hazard ratio of 1.7 and a p-value of .01. A three-fold advantage in survival at 36 months for patients that got drug compared to placebo. And a very high benefit to risk ratio. The 9902A data and the pooled analysis also being supportive of the 9901 study. So that was the clinical basis of our proposed BLA.
In the BLA briefing document, the FDA responded that they believe that the 9901 in conjunction with the data obtained in study 9902A and, in the absence of significant toxicity, that that data was sufficient to serve as the clinical basis of our BLA filing for APC8015, or Provenge. In addition, they also agreed that efficacy data from other studies, such as P-11 and 9902B, would not be required as part of our submission package to the Agency and based on the successful outcome of this meeting, the Company plans to submit our BLA next year.
I think the recent ODAC-FDA activity is very favorable for the Dendreon BLA for Provenge. Tarceva and other products have shown that survival in the intent to treat population is received favorably by committees. The FDA views, as you saw from Dr. von Eschenbach’s comments late last week and early this week, are more focussed on treatments that are matched to specific patient therapies that have fewer side effects. And Provenge certainly meets that criteria. And the question that’s frequently asked, at every ODAC meeting of the panel is, "Do the benefits of this particular therapy outweigh the risks associated with it?" And we believe, given the data that I’ve just shared with you, that that answer will be affirmative for Provenge.
9902B is an ongoing Phase III study that’s being modified to enrol only men with minimally symptomatic androgen independent prostate cancer regardless of their Gleason score. It’ll enrol approximately 500 men. It’s currently enrolling at approximately 70 sites throughout the country. The endpoints are similar to the first two studies, survival and progression. Survival is now the primary endpoint. And it really allows physicians, as well as patients, to get access to Provenge as we move through the regulatory process on 9901 and 9902A. And, as I said earlier, the FDA has communicated to us that the 9902B study will not be required as part of our BLA submission package.
Let’s talk a little bit about what we’re doing in early state prostate cancer. The P-16 study is an NCI, National Cancer Institute, sponsored study looking at Provenge in combination with Avastin in men that have PSA recurrence after primary therapy. This enrolled approximately 26 patients. We looked at PSA doubling time. And here what you see is the median pre-treatment PSA doubling time in these men was 6.7 months. After treatment with Provenge and Avastin, you had about a 90% increase in your PSA doubling time. It went to 12.7 months. And that was highly statistically significant with a p-value of .004.
When we look at Provenge as a mono-therapy in a similar patient population, men with PSA recurrence after primary therapy, we see a similar effect. 71% of patients had a prolongation in their PSA doubling time. The median was about a 50+% increase in PSA doubling time. So clearly we’re seeing Provenge being able to move into earlier and earlier stages of prostate cancer.
We’ve now completed enrollment in a large Phase III study called P-11. It enrolled 170 men with early stage prostate cancer. We expect to get the PSA data from this study in the first half of next year. So it’s a near-term event for the organization.
So when you take all this data and you look at it across the continuum of prostate cancer, whether it’s late stage prostate cancer, where we’re showing a survival benefit, or early stage prostate cancer, where we’re showing a benefit on PSA doubling time, we have not seen a negative clinical indication of Provenge across the continuum of prostate cancer. And so we think clearly this drug is having a big effect on these men.
If you look at the market, right now the only approved therapy in men with asymptomatic AIPC is Taxotere. It’s a 2.4-month median survival benefit with a hazard ratio of 1.3. Certainly from an efficacy perspective....we have not done head to head trials comparing Provenge to Taxotere, but on the surface.... Clearly a 4.5-month survival benefit seems superior to a 2.4-month survival benefit. And a hazard ratio of 1.7 is superior to a hazard ratio of 1.3. What I think most compelling and why Provenge is gonna be frontline therapy is that the side effect profile of these two different forms of treatment are dramatically different. These are the Grade 3 and Grade 4 adverse events across both studies. You can see Taxotere has a significant amount of Grade 3 and Grade 4 adverse events where you only have a small number of Grade 3 and Grade 4 adverse events in the Provenge arm. Mostly fevers and chills. They’re of low grade and short duration. So this is very, very appealing to patients. And as you heard a lot of the patient advocacy groups say at a recent ODAC meeting, approximately 50% of patients would rather die of their disease than go into therapy like Taxotere, given its side effects. And most important is that with Provenge you get three infusions over a one-month period and you go on, you live your normal life. With Taxotere, every three weeks you get an infusion of Taxotere and the average course of therapy is 10 courses, so it’s 30 weeks.
When we conduct quantitative market research with both urologists and oncologists, who are the target market for Provenge, both the oncologists and urologists are highly energized about the arrival of Provenge to the market place. They see the survival data, as well as the side effect profile of Provenge, superior to that of the existing standard of care and as a result we anticipate penetration rates for Provenge to be in line with other blockbuster oncology products.
This is from a recent survey that we didn’t conduct. It was done at the international prostate cancer meeting in February. 69% of physicians said they’d be very likely or somewhat likely to use a product like Provenge once it’s available to them for men with hormone refractory prostate cancer.
The market for this patient population is extremely large. Prostate cancer is now the number one non-skin cancer in the world today. In the United States alone, there is in excess of 150,000 men with metastatic AIPC. Given the favorable side effect profile of Provenge, while our initial label will be in late stage AIPC, we see ourselves moving into earlier and earlier stages of disease. That market’s about three times as large. In the US it’s about 250,000 men. Globally it’s approaching 600,000 men. So these are extremely large oncology markets. Very small penetration rates in these markets and they have a big impact on sales figures at the end of the day.
So the platform, based on the Antigen Delivery Cassette technology, we believe, is expandable to other cancer phenotypes. Neuvenge is our best example of that. We took the Antigen Delivery Cassette, took out PAP, put in HER2-neu. We’ve completed two Phase I studies, we’re looking at safety and immune response. And what we see here. Is that when you compare the immune response against HER2-neu at baseline, compared to week 8, which is when we know the maximum immune response starts to kick in, you can see that we generated a Stimulation Index over baseline of about 25-fold greater than where it is at baseline. That’s huge. In an immune therapy study. Usually you see SI’s of may be 4, 5 or 6. Provenge is on the order of 20, 21. Here, with Neuvenge, it’s almost 25. And that was highly statistically significant with a p-value of 5 zeros and a 1.
So clearly the platform’s expandable into other antigens. We have to conduct formal Phase II studies here to see if this is gonna bring a clinical benefit such as Provenge brings to men with prostate cancer. And we’re really moving along that pathway currently.
I’ll talk a little bit about Trp-p8. Trp’s a gene that we discovered through our own in-house antigen discovery program. It’s been very high profile lately. Merck has a Trp program going on. Amgen has a Trp program going on. We own the Trp-p8 gene, which is the only Trp channel focussed on oncology. In August of 2002 we entered into a large collaboration with Genentech. The subject has been featured on both the cover of Nature as well as on Cell. And what we’ve found. And this was presented last week. Is Trp’s a trans-membrane voltage-gated ion channel. And if we can regulate it, either agonize it or antagonize it, we can inhibit the growth of tumor cells. And here you see different prostate cancer cell lines being inhibited through different lead candidates. And with the one that we’re really the most interested in, the brown one there, being 3211, we can basically result in 77% tumor growth inhibition. And that is highly statistically significant, with a p-value of three zeros and a 1. So we’re moving through the lead selection process now and we hope to select a lead by the end of this year. Then we’ll move that into pharmatox studies. This is a program that’s moving forward fairly aggressively. It’s early stage. But we think it provides a lot of promise to the organization. It’s something that most people don’t see within Dendreon today. It’s one of those hidden assets within the organization.
As I said earlier, strong balance sheet. No debt. If you look at the upcoming milestones for the organization, it will be the presentation of the 9902A data, which we believe supports the data seen in 9901; reporting the preliminary Phase III data on our early stage prostate cancer study, P-11; publication of the 9901 Phase III study in a peer-reviewed medical journal; and submission of our Provenge BLA. We plan on finalizing the protocol for the Neuvenge study in Phase II metastatic breast cancer; selecting a small molecule lead on the Trp program with Genentech; and advancing the monoclonals with Dyax and Abgenix.
So clearly from an investor perspective it is not easy to get behind first in class products. There’s a lot of ups and downs. This is a picture that I took from an article in Science in 1998. And it was really looking at the ups and downs of the monoclonal marketplace. And if you’d invested in Genentech at the right time. Roche did in 1991, took a 50% stake in Genentech for $2 billion, clearly that paid off for them. But if you had just looked at the products. And looked at the science. There’s a lot of skepticism on products like Rituxan and Avastin. If you looked at the science, you would have been able to really reap significant rewards on your investments in these first in class types of products. And what’s interesting about this graph is that they stopped it when Herceptin was shown to slow breast cancer in some patients. And they kind of guess that the graph is going up. They had no clue. At that point. That Avastin was right around the corner, and Erbitux was around the corner. And I think it’s the science that should really drive your investment decision. We believe the science at Dendreon is very strong and presents a compelling investment opportunity. In Phase III studies, it’s the first cancer immunotherapy to show a significant survival benefit, has a very high benefit to risk ratio. Given our recent discussions with the FDA, we have a first to market opportunity with this products. And there’s very strong physician interest in seeing a product like Provenge on the market to help patients with late stage prostate cancer. We’ve built a deep product pipeline behind Provenge, but Provenge is clearly the focus today. We have a discounted technology value. Given that we have $150 million in cash and a $400 million market cap, a $250 million technology value for these markets, I think, is something that we think is relatively small. And given our size and our technology and our platform, just like monoclonals did, we believe that we have the potential to fundamentally change the way that cancer is treated.
Thank you. And I’ll see you in the breakout room.
BREAKOUT SESSION NOTES from ackabaker on the DNDN Yahoo board
UBS notes
by:
ackabaker
09/27/05 03:55 pm
Msg: 135809 of 135830
Notes from conference breakout:
Room was more than half full (~35 people?)
I walked in a few minutes late (actually missed the main talk)
Discussion was surprisingly low-key considering the backdrop of UBS animosity
Q- do you know of any precedents where FDA ok'd a drug missing primary endpoint but met secondary?
Mitch- we learned from our pre-BLA meeting that we had been overly conservative about the primary endpoint- that TTP should not have been a major focus- Pazdur sees survival as clearly the basis for approval- our TTP result with a .06 p-value is definitely "supportive"- though we never could have gotten full approval on it
Q- When in 06 will you submit.. H1? H2?
Mitch- we're only saying 06 (smiling).
Q- Was the problem with TTP due to difficulties in measuring progressing?
Mitch- The measurement was time to first radiographic look(?), progression is difficult to characterize as it's a soft endpoint in prostate cancer- also the men just progress so rapidly
Q- What assumptions are you using with respect to Placebo crossovers?
Mitch- same as previous trials- about 75%
Q- Will the filing be based on asymptomatic disease?
Mitch- Yes- pre taxotere- i.e. frontline disease
Q- What's delaying BLA?
Mitch- As discussed in our recent cc- clinical data is done- CMC section is rate-limiting step- there are two components to manufacture- the recombinant protein and the patient's blood
Q- Burn rate??
Mitch- Haven't given 06 guidance yet- for 05 we guided to $90-100M but then guided to lower end of range in the last cc
Q- Will you sign a US partner?
Mitch- We don't want to, but if it makes sense in terms of having a partner with a very strong commercialization capability, we will.
Q- Do you have a QC program to look at patient's blood?
Mitch- Use standard operating procedures re QC specs- FDA said it's ok and won't need to do bridging studies as we go from contract centers to own facilities
Q- How did you keep the survival benefit even with cross-overs? Are you saying the survival benefit includes the crossover comparison? [People seemed stunned at this]
Mitch- Yes (chuckling)- let's just say it's best to get Provenge instead of not at all, but it's better to get it late instead of never. Most had progressed not due to symptomes but radiographically. It's best to give it early and with the side effect profile we don't think docs will hesitate to give it early.
There were a couple of other q's regarding commonly known facts that I didn't make note of.
Disclaimer- I have no involvement with ubs, only a professional history in the securities business and so attended strictly on that basis.
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