Executives
Stanley Crooke - Chairman of the Board, President, Chief Executive Officer
Wade Walke - Executive Director Corp. Communications & Investor Relations
Lynne Parshall - Chief Operating Officer and Chief Financial Officer
Richard Geary - Senior Vice President of Development
Analysts
Jim Birchenough - BMO Capital
Stephen Willey - Stifel Nicolaus
Chad Messer - Needham & Company
Edward Tenthoff - Piper Jaffray
Charles Polsky - William Harris Investors
Isis Pharmaceuticals, Inc. (ISIS) Special Call October 18, 2012 7:30 PM ET
Operator
Good day, ladies and gentlemen and welcome to the Isis Pharmaceuticals' conference call to review the FDA advisory committee panel vote of KYNAMMRO. As a reminder, this call is being recorded for replay purposes.
I would now like to hand the call over to your host for today, Dr. Stanley Crooke, Chairman and CEO. Proceed, sir.
Stanley Crooke
Thank you. Good evening and thanks everyone for joining us on the call today. I will review the recommendations made by the FDA advisory committee panel and then we will open up the call for Q&A.
Joining me on the call are our Lynne Parshall, our Chief Operating Officer and CFO, Richard Geary, Senior Vice President of Development, Walter Singleton, Vice President, Development and Chief Medical Officer and Wade Walke, Executive Director of Corporate Communications & Investor Relations.
Wayde, would you please read our forward-looking language statement?
Wade Walke
Yes. Thanks, Stan. A reminder to everyone that this webcast includes forward-looking statement regarding the development activity in therapeutic and commercial potential on the safety of KYNAMRO. These statement describing Isis's goals, expectations, financial or other projections, intentions or beliefs including the planned commercialization of KYNAMRO in the forward-looking statement and should be considered an at-risk statement.
Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use of human therapeutics and in the endeavor of building a business around such drugs. Isis's forward-looking statements also involve assumptions that if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements.
Although Isis's forward-looking statement reflects the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' progress are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2011 and on its most recent quarterly report on Form 10-Q which are on file with the SEC. Copies of these and other documents are available from the company.
Now, I will turn the call back over to Stan.
Stanley Crooke
Thanks Wade. Let me begin by saying how pleased we are to have completed this next step in bringing KYNAMRO to the market for patients who are at extreme cardiovascular risk. I would like to thank the Genzyme and Isis regulatory teams for doing a great job with the submission.
We have aged patients, Christian, Catherine, Brad and Dave, whose compelling testimonies put a voice and a face to this devastating disease and the experts who joined us today and helped the team tremendously in preparation for the panel and of course the FDA and the panel itself for their thoughtful analysis. We are very encouraged by the committee's support for KYNAMRO at today's advisory committee meeting.
As the panel noted, there is significant need for new treatment options for patients with Homozygous FH. We continue to work with Genzyme on the next steps for KYNAMRO approval for Homozygous FH in the U.S. Finally, the regulatory process in Europe is progressing and we are on track to hear from them this year. Given that the European process is still in progress, of course, we cannot discuss it in any more detail today.
Given the work that lies ahead of us and the fact that we are very much still in the midst of the regulatory process, our comments today will be very brief. There is one issue that has caused confusion that I want to clarify. Cancer.
First, as you saw today, an analysis that actually compares incidence to exposure, a proper analysis, shows that the KYNAMRO and placebo groups did not differ in the incidence of cancer. Further, as Dr. Chadner said today, it's very unlikely that the advance cancers observed could have been caused by KYNAMRO.
Now let me deal with the animal carcinogenicity studies. Carcinogenicity studies involve administering large doses of a drug throughout the lifetime of an animal. As is standard within the industry, we work with independent and experienced contract research organizations who complete and interpret these complex results and they do that in the context of their broad experience in dealing with aged animals. Furthermore, as required, carcinogenicity studies are performed only after protocols are agreed and doses selected together with the FDA.
In the KYNAMRO studies, the conclusions from both carcinogenicity studies reached by the independent scientists who perform the studies were the same. All findings were incidental or unique to mice and not considered relevant. They concluded this after finding those statistically significant different from control animals using four separate statistical tests. A fifth, very sensitive statistical test of a mouse study showed an increase in adenocarcinomas that were deemed mouse specific and occurred only at the mid dose.
The conclusion of the primary and consulting pathologist was that that finding, and now I am quoting from the report itself, "was considered incidental and not test article related as it was not dose related and the increase was only slightly greater than the historic control rate". Of course, similar observations are made in many carcinogenicity studies for many drugs.
We were obviously very encouraged by these data and as such, when asked, our statements were based on the conclusions of this experienced independent group of scientists with which we agreed. The suggestion that Genzyme or Isis failed to be forthcoming is wrong. It is true that an FDA reviewer came to a different interpretation. Differences in interpretation of data particularly from such complex studies as these are a natural part of the scientific process.
With that I want to thank you for your interest and open the call up for questions-and-answer. Paris, can you set us up please?
Question-and-Answer Session
Operator
(Operator Instructions) Your first question comes from the line of Jim Birchenough with BMO Capital. Please proceed.
Jim Birchenough - BMO Capital
Congratulations on the outcome. A few questions just stemming from the panel and I am sensitive to what you can say but one of the topics was related to the lack of data with concurrent apheresis and so do you have a sense of what proportion of Homozygous FH patients don’t have access to apheresis because that seemed to be one of the areas of unmeet need the FDA panel seem to think about here?
Then I guess, the other part of it is, just as we think about the pipeline and what we have learned here with KYNAMRO, injection site reactions came up, flu-like symptoms and immune effects and some difference of opinion on pre-clinical cancer signal. So what can you tell us about efforts going forward to try and limit those effects and get a better level of understanding with FDA? Thanks.
Stanley Crooke
First, and Richard and Walter can amplify on this, the fraction of patients with Homozygous's severe FH that are able to obtain and tolerate apheresis is extremely low. As was pointed out several times during the last few days, apheresis itself is associated with significant issues, significant side effects and significant problems and as a consequence people who begin apheresis very often discontinue.
It is interesting, in that, we chose to do rigidly controlled Phase III trials with a placebo control and no dose adjustments allowed in response to ALTs or any other observations and we chose not to do an inter-patient dose escalation study in patients with apheresis because we felt that that wasn’t an appropriately controlled trial. I think every thing that we know about apheresis and KYNAMRO, as Dr. Moriarty said today, argues that KYNAMRO will be additive to apheresis and the studies are in progress to do that.
Anyone want to add to that answer?
Lynne Parshall
Stan, this is Lynne. I can just add a little bit of more granularity on the patient numbers. In the United States, there are two different group of patients. One, apheresis, that’s of the 12,000 to 15,000 patients in the United States who are eligible for apheresis. I apologize. I don’t have that number broken down, Jim, for Homozygous and it is a larger percentage of the Homozygous population than for the rest of those patients who are the severe Heterozygous.
But as you can see from those numbers, with 200 to 300, out of 12,000 to 15,000, it’s a very small fraction of patients but in the United States that are apheresed of the patients who are eligible today.
Richard Geary
And most of what they tell us is most of the patients who are being apheresed in the United States are actually Heterozygous FH patients. So, the best estimate I have heard comes from marrying the gallon who thinks its something like 10% of the Homozygous actually either are able to access a unit of close enough to a unit to use it or are able to tolerate it.
Stanley Crooke
Now, on to the technology questions. Lets deal with carcinogenicity first. Carcinogenicity studies are, as I said, enormously complex and they are subject to all sorts of differences in interpretation. The vast majority of carcinogenicity studies have significant observations, as did (inaudible) in their study and that’s natural because as these animals age and die, they develop all sorts of lesions.
So we believe that this carcinogenicity study very strongly supports the potential for other second generation antisense drugs to be used for a variety of indications. I think it is particularly encouraging given the fact that the mouse and the rat are the most sensitive species to the non-specific information that these agents produce.
Second, with regard to inflammatory processes, I think we have great news. We showed, and as we have reported for 20 plus years, antisense drugs are prone to producing pro-inflammatory effects that are of different levels and types depending on the species and the mouse and the rat are by far the most sensitive species. In the KYNAMRO study, what we did was that we evaluated and with detailed time courses after every single dose in the protocol that we call CS32 all of the systemic mediators of information that we could measure. In that study, we showed no significant change in any systemic inflammatory signal. So I think that’s great news.
With regard to the other potential issue on inflammation which is the antibodies, these assays, the antibodies that we saw were low TIGER, dated not after the safety of efficacy of KYNAMRO in any meaningful way. So we think again that’s good news.
Finally, in addition, tolerance. We have spoken for several years about all of the learnings that we have had as a result of giving KYNAMRO to patients who had no experience taking subcutaneous drugs and physicians who had no experience really giving them. We learned along the way that education and Isis make a big difference. Now we learned that as a result of our experience and over time our patients' tolerance for KYNAMRO improved.
We think that those learnings were applying to every other drug in our portfolio and if you look at, the experience that we had with KYNAMRO as a learning experience about how to handle subcutaneously administered drugs in these kinds of patient populations, I think you can see why we are very optimistic that the tolerance for our drugs will be much more acceptable as we move forward. Now, while we are at it, why don’t we deal with the discontinuations, because I think that what we have learned about that was perhaps lost a little bit today.
Richard, would you like to handle that one?
Richard Geary
Sure. So in our Phase III program, it was reported today and I think most you have known about the HoFH program for some time, that 82% of the patients actually completed that pivotal trial and then there was this long-term extension trial where quite a number of FH, both of our HeFH Phase IIIs and our HoFH were able to roll over this long-term extension and it was there in the long-term extension and many patients were not retained long-term. In part this was because of difficulties in the administration of this study. Early on, the HoFH patients were only given a one year consent to go into this and many of the sites got out of the study after the one year and still it at least appeared that we lost a lot of HoFH. In actuality, the HoFH that were able to consent for two years, we have more than 80% retained to the two years.
So when we spoke to the physicians at these high retention sites, particularly those that put their HoFH patients in the two year portion of this trial, we learned that and some of these are now their fourth year. They told us that the reason they were able to retain these patients is really due to frequent communications they have with the patients and their families and education of the patients in regard to the severity of the disease. So it's very much the relationship that they have with their patients. And I can tell you that all of these learnings are going into our patient and physician training which is at the core of the Genzyme program.
Stanley Crooke
Just to finally bring that to a close, we are taking advantage of all the things that we have learned in this process and for example we learned that if you do a long-term study in South Africa where people have to travel many, many scores of miles to get to the clinic, your dropout rate is going to be higher. Of course we also learned that while it's clinically, from a clinical trial perspective, the very best practice, in terms of quality of data, to allow no dose adjustments.
We know now that dose adjustments can be excepted and understood by people who have to evaluate these trials and so there are many things that we are capable of doing today that we chose not to do in the very first drug that we developed to this spot and all of those learnings are being applied everyday as well as additional learnings that we have had out of the regulatory process that perhaps we will talk about another day.
I think we have beaten that to the ground and I believe we can move onto the next question.
Operator
Your next question comes from the line of Stephen Willey with Stifel Nicolaus. Please proceed.
Stephen Willey - Stifel Nicolaus
Congratulations on the outcome today. Just a quick question, I guess, on focus. I know that studies being conducted under SPA right now but just in listening to the tone of the panelists today, it certainly sounded like they would want to see something in addition to LDL reduction data, in terms of being able to expand the label. So, I am just wondering, as you heard their feedback today, does that that then, maybe, put you and/or Genzyme in a position whereby you might want to amend the protocol? Maybe get some of that additional score out of data that seem to be asking for?
Stanley Crooke
Well, the SPA was negotiated with the FDA, recognizing that outcome studies are not possible in the severe patient population either. Carefully considering all of the options available for surrogate measurements of atherosclerosis and it was jointly concluded that it made much more sense to do a high quality experiment and we think that’s what we are doing and not attempt to ask those questions in this particular trial.
Richard, maybe you want to add to that?
Richard Geary
No, I think that’s exactly right. We did consider imaging but it's not an endpoint that’s acceptable to the regulators. I think there was a lot of speculation about what might be able to be done but experts have looked at this very carefully and for this particular trial which, again, has been agreed to with the FDA, its still LDL-C is the strongest surrogate.
Stephen Willey - Stifel Nicolaus
Okay, and I understand there is some debate as to the pro-inflammatory markers that are being turned on. Can you, maybe, just elaborate a little bit as with respect to how the 2.5 chemistry maybe a little bit different than the 2.0 that mipo incorporates with respect to some of these preclinical findings that we seem to be focusing on today?
Richard Geary
The preclinical findings, again, our judgment, and its not just our judgment, it’s the judgment of the contract house that did the work are the dose findings were incidental and not relevant human beings. So we think that’s really great news.
Don't forget that while we have only done one carcinogenicity study in with second generation antisense drugs, we have done many one year studies that have been submitted to regulatory agencies to support clinical trials in all sorts of diseases. So we have a great deal of justification of being confident that these animal observations are manageable and we have spent a lot of time understanding the mechanisms, understand species characteristics and having detailed explanations for people who want to invest the time to understand them.
So we feel very good about that. With regard to the clinic, I think the mipomersen data are really compelling. We did as thorough a study as can be done today looking for signs of inflammatory markers. That study was vetted by all of the major people involved or many of the major people involved in the questions of information and cardiovascular disease, including Paul Ridker who because of schedule couldn’t be at the meeting today and all of them, and the FDA were very comforted by the data that we had.
The third point is, as we have reported a couple of times, as we have continued to understand how to manage physicians and patients with mipomersen, the tolerance for KYNAMRO has steadily improved. As we showed you in the later parts of CS6, or the open label extension, so when you look at dropout rates and tolerance across all of the KYNAMRO experience, you are looking at a blend of a lot of early experiences and then later experiences which are much more positive.
Finally, I think we have mentioned it several times that we have continued to advance our screening process for generation two and we certainly are seeing improved tolerability in a variety of dimensions and greater potency out of our generation two drugs. Of course, the lower the dose, the better your tolerance because these are all local dose effects.
Now, with regard to generation two five, we think their properties are going to be similar to the very good performance that we are seeing today out of our latest group of generation two drugs with regard to these nuisance tolerance side effects.
I hope that answers your question.
Operator
Your next question comes from Chad Messer. Please proceed.
Chad Messer - Needham & Company
Hello, can you guys hear me okay?
Stanley Crooke
Yes, we can hear you.
Chad Messer - Needham & Company
All right, I apologize if drop out. I am actually on the train heading back from the FDA panel, heading back up to New York. Just one quick comment and then a quick question, if I may?
My comment is that having just sat through that panel, staring everyone else at Isis, I think that the panel was probably less concerned than I was worried that they might be about the carcinogenicity concerns raised by the FDA in the documents. So I commend the panel on taking that debate with sort of necessary perspective that you pointed out.
Question to you is this, so you have been through this panel with the FDA before. Even here, backed the decision by them, we are expecting to hear approval decision from the European authorities. How would you compare and maybe contrast a little way the process has gone in the U.S. versus in Europe for you guys? Thanks.
Stanley Crooke
Chad, I would be delighted to answer that but I just think it's not prudent while we are in the midst of the European and U.S. processes. Suffice to say that the European process is proceeding and we continue to be pleased with the progress.
Sorry, there is a great deal of noise.
Chad Messer - Needham & Company
(inaudible)
Stanley Crooke
Maybe, I think that’s probably on the phone on the train. So we probably ought to stop that and we will make this the last question. Next question.
Operator
Your next question comes from the line of Ed Tenthoff, Piper Jaffray. Please proceed.
Edward Tenthoff - Piper Jaffray
Great, thank you very much. My congratulations as well. I think the team did a great job on this. Two quick questions, if I may. Following up, firstly, can you confirm whether or not you guys were on the docket CHMP this month for review?
Second question is having to do with the size of the market. In the past you guys have discussed something as high as 3,000 patients in the U.S. and maybe as high as 18,000 patients in Europe with the severe Heterozygous label. Does the panel today cause you to rethink or change those estimates in terms of appropriate patient population at all?
Stanley Crooke
Lynne, why don’t you take that?
Lynne Parshall
Sure, Ed. Nothing about the panel today causes us to change our estimates either of the actual number of patients or the accessible number of patients. With regard to the CHMT docket, in the sense that we are in the middle of the regulatory process with Europe, its very different process from the U.S. It's proceeding at pace and so it's really not appropriate for us to give much more granularity on that right now.
Stanley Crooke
I think we will take one more question and then we have got a lot of work to done now and it’s a great kind of work to do, so we want to go and do it. So one more question and then we are going to call it in.
Operator
Your next question comes from the line of Charles Polsky. Please proceed.
Charles Polsky - William Harris Investors
Hi, Stan, congratulations on the positive panel. I missed the very beginning of this call. So if my question is redundant, I apologize. It seemed to me the part of the expert at the panel today, the toxicity concerns they had were a mixture of the mechanism of action of this particular drug and as one of the experts expressed his individual concern, that acting at the level of RNA was pro-inflammatory.
So the question is what read-through do you see from looking at the concerns that were raised today, looking through the rest of the pipeline and what do you think that does in terms of having to increase your calming concerns on the part of regulatory agencies that are not familiar with systemically administered antisense agents?
Stanley Crooke
Charlie, I did cover that earlier. So maybe I can just answer it very briefly and then I will be glad to talk with you by phone tomorrow. How about that?
Charles Polsky - William Harris Investors
That sounds great.
Stanley Crooke
So, my overall view is that this is great news for the technology. We have shown in careful studies that the inflammatory infection manner. We can't identify systemic mediators of inflammation despite the fact that we tried very hard. We have learned that tremendous amount of how to manage the nuisance side effects. The flu-like syndromes and the injection site reactions and we are already doing much better job of that.
We have learned a lot about what are acceptable clinical trial designs and how you are rewarded for very, very rigid clinical trial designs. Not too much. So all in all, we feel that the learnings from this have enabled us to do better and we are focused not more and so we are feeling very good about it. Maybe I will just leave it at that, if I may, and then I will be glad to talk to you by phone tomorrow.
Is that okay, Charlie? Any other comments from my colleagues?
Richard Geary
No.
Stanley Crooke
If there are no more questions and no more comments, I think the Isis people will get back to work and we want to thank you very much for your interest and support and we look forward to telling you a lot about exciting news from other drugs in our pipeline in the coming months.
Operator
Ladies and gentlemen, that concludes today's conference. Thank you for your participation. You may now disconnect. Have a wonderful day.
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