Dendreon (Nasdaq: DNDN) October 06, 2008 interim IMPACT phase 3 study results conference call transcript with analyst question and answer session:
MITCHELL GOLD (Dendreon CEO and President) Prepared Remarks
GOLD: Hello everyone and thank you for joining us to discuss the results from the planned interim analysis of our phase 3 IMPACT clinical trial.
Before we discuss the results, let me remind you about the design of this study. The IMPACT trial is a randomized, double-blind placebo-controlled phase 3 study, which enrolled 512 men with metastatic androgen-independent prostate cancer. The primary endpoint of the trial is overall survival. The statistical plan was designed using the integrated results from our two previous phase 3 studies, 9901 and 9902a.
The interim analysis was performed by an independent data monitoring committee (IDMC). The IDMC reported no safety concerns and recommended that the study continue to its final analysis.
While we remain blinded to the data, the committee reported to Dendreon a 20% reduction in the risk of death in the Provenge arm relative to placebo, a hazard ratio of .80. Alternatively this hazard ratio can be expressed as 1.25, representing a 25% increase in the risk of death in the placebo arm relative to Provenge.
At the final analysis, which is anticipated in the middle of 2009, if the study demonstrates approximately a 22% reduction in the risk of death based on 304 events, the company would expect the study to meet its primary endpoint of overall survival.
While we would have liked to received results that would have allowed us to amend our BLA (Biologics License Application) at this time, as we’ve said before, the final analysis, by design, has a higher probability for success.
Here are a few key considerations as we look forward to the final analysis from IMPACT. At the time of the data cutoff for the interim analysis, which occurred in May of this year, the median follow-up time in the IMPACT study was approximately 24 months (or 2 years). As we reported today, we observed a 20% reduction in the risk of death in the Provenge arm, a hazard ratio of .80.
Now if we look at the integrated analyses of 9901 and 9902a, at a similar follow-up time of 24 months, we observed a 22% reduction in the risk of death, a hazard ratio of .78. Therefore, these results are consistent with those from our previously completed phase 3 studies of Provenge in this patient population at a similar follow-up time.
As you may recall, the final analysis from our integrated studies showed approximately a 33% reduction in the risk of death, a hazard ratio of .67, supporting the hypothesis that there is a delayed treatment effect with Provenge, which tends to get larger over time.
Given that the results reported today are consistent with those seen in our previous integrated analyses, at a similar follow-up time, we are looking forward to the final analysis of the IMPACT study next year.
Prostate cancer is without question a difficult disease to treat, with only one product in the past twenty years that has been approved by the FDA that has shown an improvement in overall survival. Before we conclude, I would like to thank the hundreds of men who have participated in the IMPACT study. In the ten plus years that Provenge has been under investigation for patients with advanced prostate cancer, more than 800 men have participated in clinical studies. These men have demonstrated a courage in their participation in our clinical trials and have contributed to, what we hope, will be an advancement in medical care for prostate cancer patients.
At this time (4:58 mark) I’ll turn the call back over to the operator, who will open the phones for Q&A:
(Q&A instructions….)
Questions from MARK MONANE of Needham & Company (5:51 mark)
MONANE: Good morning and thank you for reviewing the results with us this morning, early in the morning for you in Seattle.
MITCHELL GOLD: Good morning Mark
MONANE: Um question for you, the hazard-ratio that you reported, is that an adjusted log-rank analysis? I remember you talked about adjusting for certain factors. Maybe you can go over those factors and answer that question first.
GOLD: I’ll let Mark Frohlich (Dendreon’s Chief Medical Officer) take that one
MARK FROHLICH: The analysis was an adjusted cox model, which we adjust for the prognostic factors, PSA and LDH.
MONANE: Ok that was helpful and then in follow-up, I guess the question is; Will the final analysis now be representative of the interim analysis and of course, those patients, the patients that are alive, will continue to contribute data points to the trial and the patients that are dead will not, but the question is: in the trial recruitment, the patients that were recruited later in the study, can you tell us if those were similar to the patients that were recruited earlier in the study? Is there any reason to believe that those patients would be different?
GOLD: No I think, what we’ve said in the past and what we know is we’ve conducted a Halabi analysis on the total patient population from the IMPACT study and compared it to that from both 9901 and 9902a and we see that the patient population is very similar to what we saw in 9901 as well as the integrated analyses. So the Halabi Model shows that the baseline demographics are consistent with what we’ve seen in our other previous studies.
MONANE: And when you say that with the 22% reduction in risk, you are talking about a hazard ratio of 0.78? Is that how we should interpret it?
GOLD: That’s correct
MONANE: And at that point, when you say “meet the primary outcome”, you’re saying that the p-value would be less than .05 with the hazard ratio not eclipsing 1?
GOLD: Uh, we meet the level of the statistical significance that’s described in the statistical analysis plan for the final analysis…yes.
MONANE: And we can assume then today, that the data that you reported did not meet…that…that… endpoint? Is that a fair assumption?
GOLD: That is correct. It did not meet the pre-specified criteria to allow us to amend our BLA. That being said, I think what we can take away from the data that we received on the interim analysis, is that it is very consistent with what we saw on the integrated analyses of 9901 and 9902a and that in those studies we saw that the treatment effect tended to increase over time.
I guess another caveat to that is not only in the integrated analyses but both in 9901 and in 9902a, we saw the treatment effect increase over time.
MONANE: Have any patients been lost to follow-up? Do you have data points on all the patients going forward?
GOLD: Uh, you know, right now it’s difficult for us to say but there has been very few patients lost to follow-up, it’s not 100% as we had in 9901 but it’s very close.
Questions from JOEL SENDEK of Lazard Capital Markets (9:02 mark)
SENDEK: Can you tell us what the p-value was at the interim analysis?
GOLD: You know Joel, as we’ve said in the past, we keep the details of the statistical analysis plan, we look at that as proprietary to the company but what I can say is that the final number of events, 304 events, and we’ve preserved a substantial amount of the alpha for the final analyses.
SENDEK: Ok that’s my second question. Which is, what is that (meaning the alpha figure)?
GOLD: And let me just emphasize, as Mark just mentioned to me, the company did not receive a p-value from the IDMC for the interim analysis.
SENDEK: Ok and how about, can you tell us what the alpha spend is at this point? To know what the statistics you’ll need at the final analysis will be?
GOLD: What we can say is that we’ve preserved a substantial amount of the alpha for the final.
SENDEK: So, but in the answer to Mark’s (Monane’s) question, you said that you’d need a .05 but presumably it would be less than .05, right?
GOLD: No, Mark said .05. We never said .05 but I think probably the best way to look at it Joel, is to look at the sentence where we say “if we meet a 22% reduction in the risk of death in the final analysis, that we would expect to achieve the statistical hurdle”
SENDEK: And presumably what you’re saying this morning is you just missed it. You know, if the interim were .78 as opposed to .8, you would of stopped the trial?
GOLD: You know, all I can tell you is that we did not meet the pre-specified criteria for stopping and amending our BLA. But I think going forward, we see that we need a 22% reduction, we’re at 20% today, and historically we’ve seen an increase in treatment effect over time in our clinical studies, so we look forward to the analysis that we’re going to see next year.
SENDEK: If it’s (the interim results) kind of in-line with what you thought but you missed the interim, I’m wondering did you make a mistake when you kind of came up with your interim statistical analysis plan? You know, because there is a disconnect there, in my mind. I’m just wondering if you could explain.
FROHLICH (we believe): The power was….the study was powered on the final results of…the integrated results of “01” and “02a”, which was risk-reduction of 33%…and so the interim analysis has less power than the final analysis by design so we still feel reasonably comfortable with our projections for the final analysis.
Questions from DAVID MILLER of Biotech Stock Research (11:43 mark)
MILLER: The interim would have had to have a much lower hazard ratio than .22 to be successful, correct?
GOLD: Well “much” is a descriptive term….
MILLER (interrupting):…would have to have a “lower than” (referring to the HR of the interim study results goal)
GOLD (continuing): would have to have had a lower hazard ratio than we observed today for us to meet the pre-specified criteria for stopping.
MILLER: Right, but you had said that if the hazard ratio…I’m sorry…if you had a 22% (reduction in the) risk of death…or a .78 hazard ratio…that will be sufficient to get a success at the final analysis, correct?
GOLD: That’s correct. So two things to take into consideration: one is, the treatment effect and the other is the increasing number of events.
MILLER: Right, right, but if had shot the hazard ratio of .78 today, because of p-value spend and things like that, that have to do with the interim, (then) it would not have been successful?
GOLD: We have not talked about that specifically, i.e. ”What would we have needed at the interim to be successful” but I think what would we have wanted to give the investment community color on going forward, is that if we shot a 20% reduction in the risk of death today and based on how much alpha we preserved for the final, we’d need to meet a 22% reduction in the risk of death.
MILLER: Can any of the patients on the control arm roll over now or are they all past that point?
GOLD: The patients that are in the control arm can still roll over if they want and the rollover rate to the frozen version of the product (Sipuleucel-F), has been consistent with what we’ve seen in our previous phase 3 studies.
MILLER: The first sum number of patients into the trial had a lower Gleason score by trial enrollment and you have said that “in our previous trials”, or in the previous trials, that the hazard ratio improved. How would you…can you talk a little bit about how you would respond to the question or to a charge that while this data kinda shows the healthier patients… the patients later on in the trial, just by definition…by Gleason score…were sicker… therefore it’s unlikely they (the patients) would see the same (relative-risk of death?) improvement as the trial goes forward…as they did in the previous data?
GOLD: What I would emphasize first off, is that the patient population as a whole in IMPACT is based on Halabi. Very similar to what we saw in 9901. And then second, what I would point you to, and I know that you are familiar with this poster, is the poster that Eric Small presented at ASCO Prostate cancer meeting a couple years back, where he actually showed that the biggest percentage differences in survival were in patients with the highest Gleason scores…and I think one of the take-home messages is that the survival benefit that we’re seeing is independent of Gleason scores.
MILLER: And then my last question is, given that there is this clear tail effect…and that the data looks better the longer out you go….are you worried now or do you have any second-thoughts about moving that final analysis forward?
FROHLICH (we believe): So the final analysis is pre-specified under a special protocol assessment that happened at 304 events, so we can’t change that at this time but as I noted before, we feel comfortable that the trial was powered for an overall treatment reduction of 31% (15:25 mark) (I believe he meant 33% though), which is consistent with what we saw in our prior phase 3 studies and integrated analysis
GOLD: And David, what I wanted to emphasize and I don’t know if you picked it up in my prepared comments, the data cut-off date for the interim analysis actually occurred in May of this year.
MILLER: Yeah I did pick that up. You guys made an amendment that essentially accelerated that final analysis from sometime in 2010 to…I assume it’s still second-half…are we still second half of next year for the final?
FROHLICH: We said middle of this year.
GOLD: Excuse me, we said middle of 2009
MILLER: So you accelerated that from sometime in 2010. Given that there is a tail-effect, are you having second thoughts about doing that?
GOLD: No, because I think…you know what we see is that we shot a 20% reduction in the risk of death today, with a mean follow-up of 24 months…very similar to what we saw in the previous phase 3 studies…and if that occurred in May and the final is going to occur sometime in the middle, I think we are pretty comfortable….if the treatment effects repeat itself (compared to the previous studies) and it tends to increase over time…and in fact, as it did in 9901 and 9902a and the integrated analyses…then I think we’re comfortable with that.
MILLER: I just want to make sure I understood your answer to Mark’s first question, so this is the adjusted cox hazard-ratio?
GOLD: Correct.
MILLER: Ok great. Thanks. I’ll jump back into the queue
GOLD: And David…the last thing to that is…when we gave you the .78 number at 24 months for the integrated analysis, that’s also on an adjusted cox as well.
Questions from WILLIAM HO of Banc of America Securities (17:13 mark)
HO: Hi guys, thanks for taking my question. I just wanted…was hoping you guys could discuss for a little bit about the recent failures that some of the other companies have had in this area of immunotherapy and what perhaps makes you different and increases your confidence of success next year?
GOLD: Without getting into the specifics of other studies out there, I think in general, prostate cancer has been a very difficult disease to treat, and we’ve seen several studies as of late reported out that have actually shown a negative treatment effect on overall survival. So I think we are very encouraged by the results that we’ve seen today at the interim analysis showing a 20% reduction in the risk of death.
I can’t speculate as to why those studies have failed and we’ve seen the data that we’ve seen today but I think there are some inherent differences that I should highlight: first, we use a recombinant protein as our antigen delivery cassette and that recombinant protein technology I do think is a key piece of why we are able to generate a substantial immune response against the antigen delivery cassette. Second, we use an ex-vivo process to load up the dendritic cells and as a result, we take it out of the immunosuppressive environment that exists in-vivo within the cancer patient (and???) are able to activate the dendritic cells, and we give it a very large number of activated antigen-presenting cells back to the patient. So I think there’s probably a whole host of factors that may be contributing…I don’t think there’s anything that we can conclude right now but I think we are encouraged by the results that we’ve seen today….particularly by some of the results that we’ve seen from other studies come out over the last year or so.
Questions from RENI BENJAMIN of Rodman & Renshaw (18:59 mark)
BENJAMIN: Can you just let me know if a futility analysis was part of this interim analysis as well and if so, what would have been required to stop the trial with this futility?
GOLD: Sure, as we’ve said in the past, there was no futility analysis as part of this interim analysis.
BENJAMIN: Ok and then, the hazard ratios that were reported…it seems it’s in a different manner than how it was reported in the past…is there a reason why there was a switch here?
GOLD: You know I think, there is a lot of debate I think in the scientific literature about what is the best way to report these hazard ratios…I think we’re seeing the way that we reported it today as one that is becoming an increasing trend in the literature and we just felt it was important to go to that trend. When we look forward to publishing the data that is consistent with what the scientific community thinks.
BENJAMIN: Ok, and then I guess a final question, based on the rate that you’re seeing right now, the impression (???) rates that you’re seeing right now, is there any chance that your final analysis comes in even earlier than what you are predicting now?
GOLD: You know, I think right now as we said in our prepared comments, we are comfortable with projecting it out into the middle of 2009.
Questions from AARON RINGS of Wachovia Securities (20:20 mark)
RINGS: Thanks for taking my question. The first question I had is that I was wondering if you could provide us with the confidence interval for the 24-month hazard ratio that you provided us, .78
GOLD: I don’t have that right now Aaron
RINGS: Ok, with data cutoff being in May, can you just walk us through basically what needed to occur between data cutoff and now and was it expected to take five months to gather the data just for the review or were there other things that were affecting the ability for the data safety monitoring board to get together and review that data?
FROHLICH: Just to clarify, we had to clean the entire set of database and not just the survival (information) but obviously all the safety information that are required to actually file a BLA should the interim have been positive. So that’s the amount of time at more than eighty clinical sites to bring all the data in, clean it, and actually lock the database.
RINGS: OK, thanks for that clarification.
Follow-up questions from MARK MONANE (21:33 mark)
MONANE: In the previous dataset we saw some long survivors, a certain percentage of people that were still alive three years later. Can you tell us anything about that at this point in time with the new dataset?
GOLD: No, we’re blinded to the data Mark, so we have no additional data on, say for example, the shape of the curves, or long-term survivors, etc.
MONANE: How about the standard deviation of the trial? Obviously that’s going to be important in statistical analysis. Can you describe that today or can you tell us if that was consistent with what you saw with the previous 9901 analysis?
GOLD: Mark, everything we received from the independent data monitoring committee was included in the press release today.
MONANE: OK, very good. I know that the company published some information about the role of a booster shot and the utility in a trial that you did in some Provenge patients. Can you talk about that in data a little bit more and did any patients get the opportunity to get a booster? I know it would probably be a frozen booster. Was that opportunity given to patients in this trial?
GOLD: So the boosting data that we’ve shown is in the P-11 study, and that’s in an earlier stage prostate cancer population. No patients in 9901, 9902a, or IMPACT have been eligible for a booster but we’re happy to talk about the concept of boosting if you’d like.
MONANE: So no patients in this trial got a booster. Is that correct?
GOLD: That is correct.
MONANE: Ok, that was what I was concerned with. And basically, last question is, did the company have any expectations of this interim analysis? Are you happy with this analysis? Are you disappointed with this analysis? What have you really learned from this analysis in terms of Provenge development going forward and thinking about it as a part of the company?
GOLD: Oh, I think we are encouraged by the data that we received from the DSMC. I think consistency and reproducibility are one of the hallmarks of biological activity of any product and the ability to impact survival, particularly in a disease like late-stage prostate cancer, is potentially very meaningful. So the fact that we’re seeing data today, 20% reduction in the risk of death, that’s very consistent with what we’ve seen in our previous phase 3 studies and that’s very encouraging to the company.
As Greg and I said as we meet with the investment community, we always position the interim analysis as an opportunity to accelerate the regulatory pathway but that the final analysis, by design, has a higher probability of success.
The fact that we shot a 20% reduction in the risk of death today and the target that we’re shooting for in the middle of next year is a 22% reduction and that in our previous phase 3 studies, we’ve seen this increasing treatment effect over time, I think we’re looking forward to the results of the IMPACT study next year.
MONANE: Thanks for the added information
Follow-up question from DAVID MILLER (24:40 mark)
MILLER: You mentioned that…would you assume that there was going to be a faster clean of the data next time or would we be back to more like the five months that it was this time (from the time of the interim data lockdown in May to getting the results in October)
GOLD: You know, I don’t think we can speculate on that. Mark Fiend (SPELLING??) did a tremendous amount of work to get ready for this interim analysis. David, as he said he had to do a tremendous amount of cleaning of the database to get it ready for the IDMC. So I think it is difficult for us to speculate at this time how long it is going to take. We are going to do it as rapidly as possible.
MILLER: You wouldn’t have to repeat this (scrubbing the data) on at least any of the the patients that have died already, alright?
FROHLICH: That is correct.
MILLER: OK, so you theoretically have fewer patients?
OK I guess maybe not… to answer my own questions here.
Are you going to meet with the FDA with these data?
GOLD: This data has already been discussed with the FDA
MILLER: OK…and anything you can characterize from their comments on it?
GOLD: No, I don’t think there is anything meaningful for us to disclose other than the fact that we are encouraged by the data and we did not meet the pre-specified criteria for us to be able to amend our application on it so we look forward to the final data.
MITCHELL GOLD final remarks (26:06 mark)
GOLD: We look forward to the final results of the IMPACT study in the middle of next year. In the meantime, we’ll continue to update you on our latest phase 2 trials of Provenge and the other products in our pipeline that we are excited about. Thanks again for participating in today’s call and have a great day.
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The accompanying interim IMPACT study results press release from Dendreon can be seen here:
investor.dendreon.com/releasedetail.cfm?ReleaseID=338495
The design of the IMPACT study can be seen below:
www.clinicaltrials.gov/ct2/show/NCT00065442?term=dendreon+provenge&rank=1
Copious amounts of information and data from Dendreon’s two previous phase 3 studies, d9901 and d9902a, can be seen below:
www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1-00-index.htm
