美國安進 (AMGN) 2003 Q3 法說會逐字稿

Good morning. My name is Pailie, and I will be your conference facilitator today. At this time, I would like to welcome everyone to the Onyx Pharmaceuticals Inc. clinical update conference call. All lines have been placed on mute to prevent any background noise. [operator instructions]

Thank you. Miss Wood, you may begin your conference.

Thank you. Good morning, I'm Julie Wood, VP and Investor Relations of Corporate Communications at Onyx Pharmaceuticals Inc, thank you for joining us today. During the call, management will review the status of our novel signal transfection inhibitor BAY 43-9006 that we're developing with Bayer. We'll discuss the initiation of the first Phase-III clinical trial for patients with advanced renal cancer as well as recently announced preliminary Phase-II data from the randomized discontinuation study. Please note that this call being held on October 27th, 2003, is the property of Onyx Pharmaceuticals Inc. Any redistribution, retransmission or re-broadcast of the call in any form without the express written consent of Onyx Pharmaceuticals Inc. is strictly prohibited.

Dr. Len Post, Onyx's Senior Vice-President, Research and Development will begin the call with an overview of the Phase III trial and summarize recent clinical developments. After that, Dr. Scott Freeman, our VP of Clinical Development, will review the interim Phase-II data that was presented by Dr. Markutain (ph) of the University of Chicago. Dr. Tain's presentation was delivered Saturday, October 25th at the signal delivered Saturday October 25th at the (inaudible) meeting held in Amsterdam. Finally, Hollings Renton, our CEO will make a few closing remarks before opening up the session for questions and answers with the management team. A quick word on logistics. Scott is not on site with us. So his ability to participate may be limited by the quality of his phone connection. We're hoping that his line will remain intact and that he will be able to fully participate throughout the call, including questions and answers. Please note that we will be making forward-looking statements during this teleconference that could include clinical and commercial projections.

Statements that are not historical fact are forward looking. References to what we expect, believe, intend to do, plan, estimate, or other statements referring to future events or results are intended to identify these statement as forward-looking statements. Forward-looking statements are inherently subject to risks and uncertainties. For a discussion of these risks and uncertainties, we refer you to our annual report on form 10K filed with the SEC on March 25th, 2003. Specifically the section entitled factors affecting operating results ` within management's discussion and analysis of financial condition and results of operation as well as to our quarterly reports on form 10Q. Also note that the forward-looking statements are based on our beliefs and assumptions as of today. These beliefs and assumptions may change as a result of future events or the passage of time, which would cause these forward-looking statements to be outdated and no longer our view. We indicate no duty to update these forward-looking statements. I would now like to turn the call over to Dr. Len Post.

Thank you, Julie. We appreciate this opportunity to provide an update on recent developments regarding our novel single transduction inhibitor BAY 43-9006.that we are co developing with our partner Bayer pharmaceuticals Corporation. To date over 800 patients with different types of cancers have been treated with this novel (inaudible) agent in a range of clinical tracts. In addition to the Phase I single agent study that was reported in ASCO in May of this year, we currently have two phase two clinical trials underway as single agent studies. We also are conducting 8 Phase I B trials in which BAY 43-9006 is being co administered with a range of standard Chemotherapeutic agents. Two of those combination trials, ones that were reported at ASCO in May, have moved into an extension phase treating only Mel gnome and pancreatic cancer patients. BAY 43-9006 is a potent orally active inhibitor of the enzyme Raf kinase. By inhibiting Raf kinase 9006 blocks the (inaudible) pathway cells which is an important mediator in tumor cell proliferation.

In addition, external researchers have demonstrated that Raf is involved in blood vessel formation, known as Angio genesis. It is believed that both Raf's signaling pathway in tumor cells and the Angio genesis, may play a role in kidney cancer. In this mechanism, along with the Phase II data make us believe that this agent has significant potential for the treatment of patients with advanced renal cancer. With Bayer, we look forward to testing this hypothesis in a pivotal stage 3 study. We will see more information on 9006's mechanism of action at the upcoming EORTC meeting in Boston November 17 through 21. As we announced on Saturday, Bayer and Onyx are beginning the first Phase III study of 9006 as a single agent in patients with advanced renal cell cancer. Just to remind everyone, the initiation of the Phase III study triggers a $15 million creditable milestone payment to Onyx from Bayer. Over the weekend we also reported that we have an agreement in place with the FDA regarding the phase-3 study in renal cancer.

This agreement is based upon a special protocol assessment or SPA. For those of you who are not familiar with an SPA, it's a written agreement between the agency and the sponsor related to a specific protocol that's intended to form the basis of a new drug application. We are very pleased with the collaborative nature of the discussions with the FDA and are fortunate to have the additional clarity provide by the SPA. With the SPA in place, the trials are beginning. To be eligible the patients must have advanced kidney cancer, have failed a prior therapy, and has progressive disease. At the time of study entry, the trial, which will include over 800 patients, will be conduct at more than 100 sites internationally, the primary end point would be overall survival, and with timed disease progression and response rate and important secondary endpoints. While this is the first Phase III trial, we anticipate over time a broader clinical development plan that will allow us to assess the utility of 9006 in a range of tumour types both as a single agent and in combination with chemotherapies.

Today we will review the preliminary results from the ongoing phase-2 randomized discontinuation trial focusing on a coveted patients with advance and progressive renal cell carcinoma that received 9006 as a single agent during the initial 12 weeks of study. This is the data that was presented by Dr. Retain last Saturday. Of the 41 available patients to date with advanced and progressive ream cell carcinoma who participated in the ongoing Phase II randomized discontinuation study, investigators scored 73% of 30 patients out of 41 as having tumour shrinkage or disease stabilization after their first 12 weeks on drug. I should explain, these 41 are a total of 73 renal cancer patients who are on the trial and these are the 41 that have reached the point where we have the data for the 12-week evaluation. The other 32 are earlier in their evaluation and we do not yet have the 12 week data on these other patients. We believe that this 73% rate of shrinkage or stabilization reflects the unique properties of this compound, that is they can both ` shrink tumors and stabilize disease. These were seriously ill patients who would not have been expected to stabilize when they entered the study and had previously failed at least one systemic treatment for their cancer. In addition, BAY 43-9006, which is orally administered on a daily basis, was well tolerated. So we are making progress toward our goal of developing an efficacious anti-cancer treatment with manageable toxicities. Now I would like to tush the call over to Dr. Scott Free man. Scott will review the Phase II results in greater detail.

Thanks, Len. I would like to start by describing the protocol for the Phase II randomized discontinuation trial. All patients received 400 milligrams of BAY 43-9006 orally twice a day during the first phase of the study. At the end of the initial 12-week run in period, patients were assessed. Patients whose tumors had shrunk 25% or more remained on drug as it would have been unethical to randomize these patients to placebo in the second phase.

Patients whose tumors had grown more than 25% were deemed to have progressed and exited the study. A third group of patients whose tumors had neither grown nor shrunk more than 25% was classified as having stable disease. It is this group of patients that entered the blinded randomized portion of the study with half continuing to receive 9006 and half receiving placebo. After an additional 12 weeks in the randomized portion of the study, patients are again assessed. At any time during the study, placebo patients who become progressive can cross over to treatment with 9006. This trial has a unique benefit and then enables investigators at the end of the randomized phase of the study to assess whether the test compound is causing disease stabilization however, the study's major benefit for us was to accelerate the clinical development of 9006 based on the early signals generated during the initial running period. Since the randomized discontinue design offered the opportunity to examine multiple tumor types in a single study, important open label data where both the physician and the patient know the patient is receiving 9006 is generated during the initial 12 weeks of the study. This is data that helped Bayer and Onyx prioritize the initial Phase III single agent indication in renal cell cancer.

Specifically, since renal cell cancer patients were advanced patients whose disease were progressing on study entry, we are not only, which patients had tumor shrinkages, but also which patients had their disease stabilized. More over, since the patients whose tumors shrink by more than 25% continue open label treatment, we get realtime data on the duration of this benefit. I would like to point out that the results from the second 12 week period in which patients were stable to see of blindly randomized to either 9006 or placebo has not yet been reported and will not be discussed today.

While there are many eligibility criteria, I want to highlight the ones we believe are key to interpreting the results. Renal cell parents are required to have failed at least one prior systemic treatment and have progressive disease at study entry. In 12 months, five sites accrued 430 patients in the U.S. and in the U.K. While the study included a number of tumor types the largest sub groups of cholerical cancer, renal cell cancer, Mel gnome A and cancers of undetermined origin.

At the current time, the study closed to all but patients with renal cell cancer. For the purposes of this summary, I'll concentrate my remarks on the cohort of 41 valuable patients with advanced renal cell carcinoma. Investigators saw encouraging anti tumor activity with 73% where 30 of the patients who completed the run in period and who were assessed that the 12 weeks evaluation point as having either tumor shrinkage in ACCESS OF 25% or stable disease. 7 patients were found to have progression of their tumors when evaluated 12 weeks and came off study. 4 patients discontinued treatment at some point during the first 12 weeks due to either disease progression or adverse event.

As a reminder, all the data we're discussing today are interim data from the open label portion of the study and all the results are investigated or reported after completion of the trial, all data generated during the study will be independently reviewed and reported in final form. While some of the specific patient data will change, we expect the general trends and conclusions to remain the same. The important value of these data is that a signal, the additional clinical study of 9006 with a large randomized control design is clearly warranted in renal cell cancer. Of the 30 patients I just mention who'd didn't progress after 12 week run in period, 18% or 44% had tumor shrinkages grater than 25% and remained on drug during the second phase of the study.

Of those, there were 6 patients or 15% with investigators scored tumor shrinkages of more than 50% and 12 patients or 29% were reported as having tumor shrinkages between 25% and 49%. An additional 12 patients or 29% were deemed stable according to the protocol and randomized. Only 11 patients of the 41 patients evaluated or 27% progressed or discontinued treatment. While we are pleased with the range of tumor shrinkages, we think it's just as critical to look closely at disease stabilization.

For a compound like 9006 we believe that lack of disease progression is also an important benefit to cancer patients particularly, as they entered the study with progressive disease. We want to remind that the randomized Phase III study getting underway is the next critical step in a assessing the impact of 900 on endpoints related to disease stabilization. Investigators generally found 9006 to be well tolerated in the 312 cancer patients that evaluated for safety. The majority of he drug related address event would just as mile from moderate, that is grade I or II and consistent with the earlier findings. Specific notable grade III toxicities were diarrhea, 9%, hand foot syndrome, 8%, and some hypertension, 5%.

In conditions of the class with the most common toxicity, these were managed in the clinic by either reducing dosage or in rare instances discontinuing the drug. In summary in our Phase II study to date, we see anti-tumor activity in 9006 with patients with advanced renal cancer. While the clinical assessment of this compound is still ongoing and the data are relatively early, Bayer and Onyx are encouraged by what independent clinicians have observed so far. The results have prompted us, together with Bayer, to begin a Phase III study in patients with the renal cancer.

Now I will turn the call over to Hollings for some closing comments.

Thanks, Scott and Len. While we are pleased with the continued progress in the clinical development of BAY 43-9006, we acknowledge that taking a drug through to registration is neither a quick nor an easy process. Together with Bayer, we are carefully analyzing the data as they become available. We are making decisions that we feel will accelerate clinical development while ensuring that we have a robust package of data to support our regulatory filings.

I would like to take this opportunity to publicly recognize our partner Bayer. In 12 short months, BAY 43-9006 has moved from the start of a Phase II trial to beginning a pivotal Phase III trial, and with an SPA in place. This is significant and rapid progress, which demonstrates Bayer's capabilities and commitment. To summarize, the Phase II randomized discontinuation trial achieved the primary goal of rapidly identifying the initial single agent Phase III indication. This study was not intended to be used as a registration study although it could be useful to support the Phase III registration study. Specifically, renal cell cancer stood out as the obvious strong choice for the first Phase III study with 73% of advanced and progressive patients experiencing tumor shrinkage of greater than 25% or disease stabilization. Safety data on 342 patients supports previous observations that BAY 43-9006 is well tolerated at 400 milligrams taken twice a day every day. With our partner, we are moving aggressively and we are excited to announce the initiation of a randomized Phase III trial with over 800 patients at sites around the world. We are pleased with the collaborative dialogue with the FDA that led to the SPA agreement and the added confidence that the design of this trial could lead to a registration.

The primary endpoint is to show a survival advantage. Key secondary endpoints are timed to tumor progression and response rate. We will not be providing more detail about the confidential discussions with the FDA concerning the design of this trial for either full or potential accelerated approval. While this is the first Phase III trial, we intend to expand the clinical development program to allow multiple possible paths to registration. In 20004, that could mean an additional Phase III trial or randomized Phase II trials. The final decisions regarding our plans, our contingent on the ongoing review of the clinical data as well as consultation with the regulatory authorities.

This is an exciting time for Onyx and Bayer as BAY 43-9006 is a novel and innovative compound with promising early clinical results. We believe the compound has the potential to help transform certain cancers into chronic diseases. We appreciate the participation of over 800 cancer patients to date and look forward to their participation in future trials. We envision a future where patients can successfully manage their disease by taking an oral medication and we look forward to keeping you informed as we work to make this vision a reality.

Thank you for your continued interest in Onyx and in BAY 43-9006. Now we would like to move into the Q and A session.

At this time I would like to remind everyone, if you would like to ask a question, press "*", then the number "1" on your telephone keypad. We'll pause for just a moment to compose the Q and A roster.

Your first question comes from Steve Harr with Morgan Stanley.

Good morning, guys. I had a couple of questions for you. First of all, just to go back to the randomized Phase II study, Dr. Retain and you both mentioned that the trial is still open for patients with renal cell cancer. Any thoughts yet as to how many patients you may eventually enroll in that study?

I'll take that one real quick, Steve. It is open for ongoing equipment of renal cell parents. We have not decided how many patients will be ultimately in this trial. We'll be looking at the data and making that decision as we go along.

And then, in terms of the randomized discontinuation data, first of all, when will we see that. And number two, if you do take an early look at this, does that affect either the blinding or the statistics or your regulatory strategy if you were to potentially use the renal cell portion of this study for filing with the FDA for an current approval.

Let me just hand out that off to Jeff.

What multiple times I guess is what I'm asking.

I guess the first thing to point out is that because of the number of patients with shrinkages, there aren't all that many randomized renal cancer patients on this trial. We only have of that first 41, 12 of them randomized, so there aren't very many patients there and, it's probably going to be and we haven't decided yet what is going to be presented at ASCO, but in that time frame we should have some information on the randomized patients. I think it's also restating again what Hollings said was that this trial wasn't designed as a registration trial. It was designed to give us ongoing data so that we could make the kind of realtime decisions we've made to plan Phase III trials. So with issues like blinding and un blinding, we really are hard to assess because that isn't part of the trial except for the randomized patients are on study.

And one last question before I move on. Then I want to ask a question on the new study. But related to the old one, are you planning to score these responses with an Iraq or independent radiology committee or leave them as investigators scored only.

No. There are various plans -- I think Scott had actually mentioned that we do plan an independent radiological review on these `. But what we have now are the investigator reads.

And then as you go into the Phase III study `, I know you're allowing a cross over, I'm sorry. You're allowing patients as they progressed to go on other therapies and while your data look as good or better than what we see from (inaudible) earlier this year. How do you -- have you included the thoughts of patients going on to (inaudible) or SU11248 or other therapies in your empowering of your study?

Well, it's not so much that we built into the protocol to allow patients to go on other therapies. That's just part of dealing with oncology patients. Once they're off study and they're progressing, they certainly -- you know, have the right to try other things. There aren't that things available for renal cancer patients, unfortunately. They may or may not qualify for other trials, and that will be really between the patients and the inclusion criteria of the other trials. It's something that is really not under our control.

If I could just make a comment on that. We do plan to capture follow-up for overall survival. We also captured follow up for treatment that patients receive. So that's something that we will be evaluating. Patients do have the right to go on to other therapies after they come off our study, if they wish. And with other emerging therapies, what's the important part is that patients in both groups, both the control group and the experimental group, receive the same therapy when they come off the study.

Very good. Thank you, guys.

Next question?

Your next question comes from Mark Schoenebaum with Piper Jaffray.

Hello, guys. Congratulations. Amsterdam is a great place to celebrate good news. Hope you're taking advantage of it. Couple questions. On the timing of the phase-III, if I had done my math right, you guys enrolled 72 patients in 12 months at five sites in Phase II that's about 1.2 patients per month per site. Assuming you could accelerate, that rome in 2 or 3 x you could be done in with Phase III and by my math. Is that I time line you're comfortable with?

We haven't put out any projections and won't until we get some experience with more sites on study. That would be a record pace. I think that's being optimist in terms of months. Certainly, probably years. A few years.

OK. Fair enough. And also, the -- I guess the other question -- I guess Steve actually answered a lot of my questions. The other question I had is the hypertension that you saw in the trial, do you have any comments on that? Do you think that that perhaps is signal to mechanism that may be targeting Veg F that we think hypertension appears to be linked with inhibiting Veg F?

Let me break that into two parts. May be Scott you can just talk about the clinically what the view of the physicians was and then maybe Len can discuss the relationship to mechanisms and in renal sound particular. Scott you want to start off?

I think Dr. Retain made a comment about data that Dr. Flairty had evaluated renal for cancer patients where he basically had communication from Dr. Flairty that hypertension or patients that seem to be having hypertension at as a side effect also may have been the ones that had more of the tumor shrinkages. I think at this point in time, we're evaluating that and that hasn't been data that's been analyzed or discussed by either Bayer or Onyx. That was basically a comment that was made by Dr. Retain on the conversation they had with Dr. Flairty. So at this point we're eve evaluating this data.

I think also clinically with this, although there is some hypertension, Dr. Retain did mention that it was manageable with anti-hypertensive agents. I think it is one of the more common or one of the notable side effects, that it seems like it is manageable. Len, you want to talk about -

I want to make a comment. I think that's a good point. The hypertension relationship they were talking about was not severe hypertension but with any hypertension, even grade I hypertension, which is the majority of the hypertension that we see.

Len, you want to talk about the mechanisms in what that might mean?

Sure. And I think what mark is referring to is that there have been some links with ` the Veg F inhibitors with hypertension as one of the effects that have been seen clinically. And this compound was discovered as a RAF kind inhibitor, of course, and sometimes it's easy to for forget how many pathways RAF is involved with, including the signaling with the Veg F receptor. So this by virtue of its raving inhibitory activity would be expected to block the Veg F activity. Now in addition, , Dr. retain referred to some early data that there is some kinase inhibitory activity of the compound so that it may have a more direct effect and end up with the same result. That's data that we're going to be presenting in -- at EORTC that quite a bit of data has been generated by Bayer and all of that will be presented in detail at EORTC meeting in November.

Great. I know you probably have a lot of people in the queue but just two very quick house keeping questions. Can you set up expectations or tell us what we can expect of ASCO '04 and also comment on any other data from any cell tumors that were presented on Saturday? Thanks.

First of all, just talking about the expectations for ASCO, then I'll turn it over to Len and Scott to fill in a little bit of the other solid tumors that were presented. As we had indicated previously, the focus of the presentations for this meeting as well as the EORTC meeting for the Phase II date would be largely around, in particular the indication that was going into Phase III, which obviously we announced over the weekend. Looking ahead to next year, to next ASCO, which is in June in New Orleans, we would expect first of all importantly to have additional data on this randomized discontinuation including particular more follow-up on the renal cell patients. We have 12 week follow-up on the 41 patients that were described on this call and obviously there are not only more patients but more patients being treated, with a strong desire to look at the durability of both the responses that are open labeled as well as breaking the blinded portion of the randomized part of the study to get some sense of the duration. That's all date we're looking to get out there next ASCO. In addition, at this past ASCO, as Len mentioned, there were two combinations with chemotherapy that were reported out. And those two have gone into extensions using the highest combinable doses, which is full doses of all agents. In one case, it's a combination with taxel carbo for patients that have melanomas, and then the second is a combination with gemsideveen(ph) for patients with pancreatic cancer. So those extensions, portions of those protocol we believe, will probably be ready for presentation.

In addition, there are six other combinations with chemotherapy that have not yet been reported out there, so there may be some additional data on that as well. And then finally, we have been running in parallel to this randomized discontinuation study another single agent study, a Phase II study, more of a classical design in liver cancer patients. Again, we're looking at an open label fashion at the same dose, 400 milligrams twice a day for tumour responses and disease stabilization and duration. So, that data has not been reported out and will be subject to potential reporting out at next year's ASCO. Again, these are all things we and Bayer still have to work out, we still have to get the data, get abstracts, submit it and get ASCO to accept those abstracts, but that's the type of data that I think you'll see coming up.

So coming to your other portion of the question, may be Len you want to give a quick summary of the other patients in the study.

Yes, well because I should first say that we haven't analyzed in detail the other patients just because the priority has been to track down what we viewed as the signal that was relevant to taking us into Phase III. But Dr. Renton did put up one slide, with a couple of other summarizing what the other diseases were. And, you know, one of them was Mel gnome and that's been of interest for this compound all along because of the mutations in B-Raf in Mel gnome and there were no patients scored as responders of the 20 that were on the study that have been evaluated for their evaluation points so far but there were about a quarter of them, I say probably between 20% and 30%, and an exact number wasn't provided, that order of patients that had some disease stabilization and we'll of course be looking at those patients and analyzing that. Color Rectal cancer, which some of you know, that was the original target of this study was to take a close look at Color Rectal cancer and learned about discontinuation design of 92 patients that had reached the evaluation point. It was a small number of stabilizations, between 10% and 20% and a couple of responders and then there were some other patients that was just a bar label to other, Dr. Renton pointed out they've seen one responder each in pancreatic, Sarcoma and thyroid, out of a very small number of patients and each of those tumor types.

Yes, thanks for taking my questions.

and I just want to make one other comment on that. That Dr. Flary will have a post NCIARTC in November that will have some of his patients of renal cell cancer and Mel gnome a from the Ranbaxy's continuation trial.

Your next question comes from Philip Nadeau with SG Cowen.

Good morning, guys, congratulations on some good data. My first question is on meantime to progression. I realize you haven't yet reached meantime to progression but have you done any modeling to extend from the 73% to destabilization at 3 months to try figure out where meantime to progression will be?

I think the quickie answer is we have not. Partly obviously we are following some of the patients that are open label currently. So we're beginning to get some of that data. But the data that Dr. Retain showed, was only on 10 of those patients, so that's clearly a minority of the patients. And we have not reported out any of the data, nor have we got enough data to report out on those patients that have entered the randomized portion so I think it's too soon for to us draw any conclusions.

OK, and my second question is, follow-up to Steve's. You might have actually mentioned this in response to Steve's although I missed it. Your Phase III trial, does that preclude patients who have been on prior western therapy or is that western (Ph) of the arrangement vocation through lot were fail.

No, its specifically excludes that.

OK, fair enough. Those are all my questions. Thanks.

Your next question comes from Craig West with A.G. Edwards.

Good morning. This is actually Alex Hittle over here with Craig. Two questions both of which I think are fairly quick. One is on the dosing. The dosing, is that 400 milligrams twice a day for an 800 total or 400 total on the day?

That's 400 milligrams twice a day, so that makes a total of 800 milligrams each day. So a patient will take two 200 milligram tablets in the morning and two 200 milligram in the evening every day until they've progressed or have a toxicity that takes them off study.

OK, thanks. Second question is in the enrollment criteria, do the patients need to be progressing, are they progressing at a rate such that over the course of 12 weeks you would expect their tumors to grow an additional 25% s?

This isn't a randomized population, as you know. And also, since there's no control for the patients that are coming on, it's hard to be certain. However, the patients are progressing when they go on study and in general, you know, you would expect that patients would continue to progress, although renal cell cancer does have a hetero\general\Jen to it when there can be times that tumors are progressing for a month or two and then can stop. So I wouldn't say that I expect all of them to progress within 12 weeks, but certainly I would expect a significant number to be progressive on study and continue to progress. Especially, since this is a patient population that's failed at least one prior therapy and almost half of them had failed more than one therapy. Again, I want to caution you that it's not randomized so that without a control group, it's hard to know exactly what those patients would do.

I think the other thing maybe to add to that, I think you certainly would not have expected 18 of the patients to have a greater than a 25% shinkage and the way to really determine if the stable disease is being caused by the drug is out of the next 12-week phase where if they get through the randomization portion.

OK. Very good. Thank you.

Thanks a lot. Next question?

Your next question is from Bill Tanner with Leerink Swann.

Good morning, Bill.

Good morning. Thanks for taking the question. Just how the little bit more colors on perhaps when the company might articulate the Phase III plans in combination therapy if there are no go decisions and understanding that it sounds like at ASCO you'll be presenting data on looks like on Mel gnomea . And then seems like there are maybe some other prom promising date at in other kinds of cancer types, ovarian and sarcoma? Just curious when we might get a look at those data as well.

We are looking at data currently out of the Phase II single agent study in help hepatic cell or liver cancer in addition. As I mentioned, we had some pretty early signs of some activity although obviously we can't a attribute it to 9006 specifically until we do a randomized study when Dr. Flairty reported on 2 out of 10 responses at that time and 6 of 10 parents had stable disease with 4 showing signs of tumor necrosis. We're following those patients, but have begun on to add more patients to that study so I would expect more data on that study as well as the one in pancreatic parents. As you suggest, there have born other signs of activity in single agent study as and early signs in ovarian cancer cell. We are, with Bayer, look at what do we do next since we now have six other combinations underway that are in the Phase I B portion, and trying to decide, which ones might move into a next phase and we clearly haven't even tested everything from a single agent stand ninety we might be able to test. We've done quite a bit of screening, but I think there's more to be done. The bottom line is that I think for some of the studies already underway we're already generating data and we'll obviously look at other studies and make decisions as we go and as the data dictates.

OK. And then it seems like on the coal rectal, what's the thought on combining the compound with other types of chemotherapies to see if you get perhaps a better response there?

I think that's one of the options for us that has to be explored and discussed. Obviously there's been other agents that have shown active any in combination. So it's not something that we've made any final decisions about. It's part of what we're talking to Bayer about currently.

One final question perhaps for Len because he alluded to it. It sounds like probably we'll see in data biochemically at least at the EORTC meeting in Boston. This compound may in fact have broader specificity targeting other kinase activity of other proteins?

There will be some data like that at the EORTC meeting. Then we can have a more full discussion about what we know and what we think that means.

OK. Thanks.

Next question, please.

Your next question is from David Bouchey with C.E. Unterberg, Towbin.

Good morning. David. David?

Sorry. It was on mute. Good morning. Congratulations on some very promising data here. Most of my questions have been answered but is there one thing you can do for me perhaps can you give us a little bit more details on the kinds of biomarker studies we may see at EORTC.

let me want to quickly discuss which I mean there is an abstract that was submitted. There will be some presentations of data out of this randomized discontinuation trial. I think to say a lot more about that would be getting into the abstracts so I think we should leave at that but there will be some data discussed by Dr. Flairty.

and you know if you know that Dr. Flairty from his ASCO presentation, you know the kinds of things that they're interested in. At ASCO he reported things like the ASCO work effect and one of the patients but so that what was available at ASCO time, he's continued those lines of work and I think say any more with the pre impact of Flairty's presentation

And they also treated not only the melanoma patients, but mentioned at this last ASCO in combination, but on the single agent they were also clearly treating melanoma patients but also renal cell patients as well.

OK. Thank you.

Thanks, David. Next?

Your next question comes from Jay Marco (ph) with with T. Rowe Price.

Good morning.

Good morning. Thanks for taking my call. At first I want to congratulate you and Bayer for embracing a novel trial design actually gives you real information in multiple cancers and allows you to do the randomization within it. I have two questions about the Phase III trial design. One, are you allowing cross over, and two, are there any interim analyses built in to look at things like TTP before the trial completes and finds its survival endpoint?

On your first question, we are not allowing cross over, because that's important because survival of members is our primary endpoint and to preserve that endpoint, we're not going to allow cross over of the two arms. Your other question gets at something that we really haven't talked about yet. That gets into the details of what analyses we're going to do when. And I think as Hollings alluded to in his comments, we're certainly going to look for opportunities for accelerated approval, but I think it would be inappropriate to say more about the details of what might theoretically happen when.

All right. Thanks.

Thanks a lot, Jay.

Your next question comes from Wayne Rothanbotham (ph) with Grow Capital.

Hello, guys. A few quick questions. Dr. Flarity talked about on the call on Friday the durability responses over time get better and in other words, he was pretty clear in stating that he says MR's turning into PR's. Can you just comment a little bit about that? Do you agree with that statement? Do you expect to see some of these responses improving overtime as patients continue on drug and as you take more scans?

Again, we took a snapshot of this trial and reported that out so that's all we have to report to date. So I think that's what we want to do is to continue to follow not just, you know, a few patients but, not just the 41, we've already got 73 patients on study and we will certainly have more since we're adding more patients. But we clearly want to follow these patients to see how long either it takes for response, how long do they last, and on the patients that get randomized, what's the benefit from the drug during that period of time and we'll also look at the patients who get randomized to proceed those who get the opportunity to cross back over and go on to 9006 and see if there's any difference over time sequentially in terms of the behavious of the patients on that in the randomized portion. So, we'll be looking at that data. I think it's not something that we've reported out.

OK. On the 10 patients that were valuable or in the nonrandomized arm, meaning that they had 25% or greater tumor shrinkage, Dr. Retain reported that 8 out of 10 of them were still on drug post 18 weeks and that one had progressed at 24, I think it was and one at 36. Do these numbers include the actual 12 week run in period or did they exclude it, in other words, when we talk about one progressing at 24 weeks, is that 24 weeks plus 12 and the other at 36 weeks, is it 36 plus 12 or is it in all being on drug or still on drug and progression free at 18 weeks?

It's the cumulative total time on drug from the start of first treatment until the last time that they had a scan done. So basically, these are the patients that have gone past the first scan which is at the 12 week time frame, so the 18 weeks is 6 weeks further out and obviously 12 weeks further out and 18 weeks further out. So for those of you may be just, because I think some of the folks had seen the presentation or heard it, in that, in the 10 patients where there were analysis of those patients after 18 weeks, that's 10 out of the -- what was the number? The 18, right. That there was one patient -- well, I actually will go through all of it. There were two patients that had gone out after the 18 weeks, they were still on-going, there were five patients who had got into 24 weeks. 4 of the 5 were still ongoing. One had progressed and went off study and then there were 3 parents at 24 weeks. Two of them were ongoing and one had progressed -- sorry. 36 weeks rather. Sorry.

OK. And can you just explain to us why you're going to keep the Phase II ongoing and then continue to enroll patients while you're enrolling a Phase III as well? Because, in some ways, you would be competing with yourself in terms of patients. There must be a reason why you would keep this Phase II ongoing and enrolling patients despite the fact that you have an active Phase III.

Currently we haven't made a decision for how long to keep it open because as you suggest, our priority is to move this into the Phase III where we have an SPA in place already now with the FDA for using that trial for registration purposes. So it's really a question of what the data looks like and how long we want to keep it open ` recognizing that we do want to move this Phase III and we want to make sure that we are not drawing very many patients off of that. But I think we mentioned in this call this will be an international study with about 100 sites and this Phase II randomized discontinuation is only involved five sites but we do appreciate the potential competition for patients as one of the downsides. for keeping it open.

And lastly, do you know what is the percent; of the 41 patients that you reported on had clear cell type of Reno Carcinoma?

I don't think we've done that analysis yet, Wayne.

OK. Thank you.

Next question?

Your next question comes from Skip Klein (ph) with Gos.

Encouraging results. I just have a follow-up on the 41 that you had in the phase 2. How many of them had metastases on enrollment and what was the effect of the drug on the metastases?

Let's see. Len, did we know or Scott did we know how many had metastases?

Well 61% had prior nephrectomy. Therefore 39% didn't have prior nephrectomy. So at least 61% had metastatic disease. We don't know whether the ones with no prior nephrectomy, that is 39%, also had metastatic disease. So at least 61% had metastatic disease. In terms of the effects on metastatic versus ones that were local advanced, we haven't done that analysis.

So your analysis is really on the locally advanced because that's you what were monitoring?

No. This is on the whole population. Your question is -- I thought your question was how many had metastatic disease and what I'm saying is that at least 61% had metastatic disease since they had a prior nephrectomy.

OK. And those metastases are I forget in this disease are typically to the lung or the brain or both?

Lung, I think we had I think its (inaudible) let me see if I have that data quickly lung would be the main one.

Scott, just talk in general terms about where the Mets are.

In general, lymph nodes, lungs. Those would be the main places that the tumour would metastise.

But on the shrinkage or stable disease analysis, you're really just looking at the kidney? If I understand it correctly?

Total disease.

You look at total disease?

Of the patient, right.

So when you say something shrunk, you're looking at the met shrinking in the lung and the met shrinking in the lung and lymph node.

Exactly.

and then I guess the only other question is then you can talk about it, under the Spa, let's say your secondary end points are significant but the primary is just in the right direction but not seem to be significant. Is that adequate for following? .

I think again probably it's premature to talk about specifics. Although I would say generally the FDA if you're looking for full approval you'll be looking at the success or minimal success amongst some hurdle for the primary endpoint.

OK. I think I follow you there. So it's really the primary that is the main thing that that they focus on but they're not as rigorous as they used to be. Fair?

I think they focus on that for full approval purposes.

OK. Good. Thanks a lot.

Thanks, Skip. Next question?

The next question is from Lon Zipman with MPM capital.

Good morning. Congratulations on really innovative uses for study design here to accelerate development. Of the 10 patients that you were describing out of the 18, some of whom were out to 36 weeks now, just to confirm, that was of the 18 parents who remained on drug past 12 weeks?

That was a slide that Dr. Retain put up that involved 10 of the 18 patients that had greater than a 25% --

Right.

-- who you continued to follow after six weeks.

OK. Thanks for confirming that. And then on the Phase III study, could you briefly describe what would be used in that trial and what the control arm would be?

The dose is the same in all Phase II studies, that's 400 milligrams given twice a day every day. And the control arm in the study is placebo control.

Great. Thank you very much.

The next question is from Edmond Debller (ph) with Millennium Partners.

Good morning.

Good morning. For final clarification of the EORTC meeting, can you just go through the data points and summarize? I've heard there will be 80 patients in the renal cancer group. My question is how many are randomized, how many are not. And I guess you mentioned the -- what actions other presentation. Any more details you can give us on that will be appreciated.

As for what data will be at EORTC for this randomized continuation beyond the 41 that were reported out, we haven't completed the preparation for that. So there's a separate cutoff. Whether we have a lot more data or not I think it's too soon to predict. EORTC is only a few more weeks out so it will be a limited data.

But the speculation of 8 patients, is that excessive?

I think that's very unlikely at that meeting that we have those patients because there's only 73 that we're reporting on right now who have been enroll bud haven't made it the 12 week period of time. I doubt we'll have that data. There's a separate cutoff and I'm sure they won't all get to 12 week period of time

Can get me a sense of how many are randomized patients are they all randomized at this point?

No. If again all I think we can talk about today are the fact that we had a total of 41 patients that we reported out and of those 12 were randomized to date of the 41.

I think to complete the question, there will also be a preclinical work on bio-markers and then of course on that and then some clinical work on bio-markers by Dr. Flairty. So there will be three main posters there.

Yes, actually the pre-clinical work will be on mechanism as opposed to bio-markers and so we'll be talking about what other data does Bayer have showing that the compound inhibits other enzymes that are believed to be important in renal cancer and the clinical presentation is where you'll see some data on bio-markers.

Great. Thank you very much.

Ladies and gentlemen, we have reached the end of the allotted time for questions and answers. Are there any closing remarks

Yes. Let me just quickly say that again we appreciate the interest of the investment community, and again, we would like to compliment Bayer on this design and on how quickly they progressed to leading us to a very clear decision about the initial Phase III indication. And once again, with Bayer, we're generating a lot of data that I know people are interested in but we need to get the data, look at it, and report it out and we're going to have to limit our comments to those sets of data in the future. But again, stay tuned. We are obviously very excited about this product but we've just begun the Phase III, which is the critical stage and we do hope that the data that's been generated in earlier studies will also lead us to other paths toward registration. So again, thank you very much.

Thank you for participating in today's Onyx Pharmaceuticals Inc. clinical update conference call. This call will be available for replay beginning at 12:00 PM EST today till 9 PM EST on Thursday, November 27th, 2003. The conference ID number for the replay is 346-6835. Again, the conference ID number for the replay is 346-6835. The number to dial for the replay is 1-800-642-1687 or 706-645-9291. This concludes today's conference. You may now disconnect