Lexicon's CEO Presents at Wedbush PacGrow 2012 Life Sciences Management Access Conference (Transcript)

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Lexicon Pharmaceuticals, Inc. (NASDAQ:LXRX) Wedbush PacGrow 2012 Life Sciences Management Access Conference Transcript August 14, 2012 10:55 AM ET


Dr. Arthur Sands - President and CEO


Liana Moussatos - Wedbush

Liana Moussatos - Wedbush

I guess we'll get started. I'm Liana Moussatos from Wedbush. Welcome to our Third Annual LS MAC Conference. Right now we have Dr. Arthur Sands, CEO of Lexicon Pharmaceuticals, who'll give us a corporate update. Dr. Sands?

Dr. Arthur Sands

Thank you, Leigh Ann. It's a pleasure to be with you today. I will be making certain forward-looking statements and so I'd like to refer you to our filings with the SEC regarding risk factors that affect our business and our pipeline. So, it's been a very exciting and very busy summer for Lexicon as we've received our data from our LX4211 Phase 2b trial in diabetes. And I'll spend most of the session today describing the data from that trial. But I'll also put in context of our broader development plan for LX4211 as we get ready to move into Phase 3 with that compound.

Now all the compounds of Lexicon derive from our genetics engine. Our mission for those of you who don't know is we're dedicated to developing truly breakthrough therapies for disease that are all targeted in nature that as we use genetics and gene knockout technology to define the target, and so all of our programs are genetically defined as targets. And then we have a medicinal chemistry group that develops small molecules for those targets. So our entire pipeline has been developed within this research engine with genetics at the beginning and then getting to small molecule development.

So that's from the source of all these compounds in development. As you can see, we have quite an extensive and growing pipeline. Again, I'll spend most of the time on our diabetes programs and then I'll only describe briefly, have time for our serotonin programs and carcinoid syndrome and IBS at the end.

So let's turn to diabetes then. 4211, this is a very unique compound. It's the first-in-class agent in that it blocks both SGLT1 and 2. These are the two key transporters in the body that handle glucose. So it affects the glucose load in the body. And SGLT1 target is the primary transporter in the GI tract and this is I think brings us 4211 the unique attributes that I'll describe.

SGLT2 is a better known target. It's under development at a number of companies. It's the main transporter in the kidney and it controls the rate of glucose, the reabsorption from the urine back into the blood. But together we have found these transporters work in a coordinated fashion really to regulate the glucose -- overall glucose load in the body. And by blocking them, we can reduce that load.

In the GI tract, you reduce the amount of glucose that comes into the body and also trigger other beneficial mechanisms including Glip 1 and then with SGLT2, you can actually offload more glucose into the urine.

Now the industry has really, as I said, mostly focused on SGLT2 as you can see by this column to the right, a number of large companies with their partners. And the reason they avoided SGLT1 in the beginning is there was a theoretical concern that blocking that target might cause GI side effects. Indeed, there are humans lacking SGLT1 and a complete lack of the target does lead to a glucose-galactose malabsorption syndrome. And so that put off researchers from that target.

Now what we learned is we develop compounds that could hit SGLT2 or hit both that pharmacologic inhibition did not create that side effect profile, and that was a very important observation that we made first in our mice and our knockout mice and then using our compound that allowed us to have a therapeutic window of the advantages of SGLT1 without the disadvantages of the theoretical concerns.

So that created a unique space for us and for our compound LX 4211. It profiled better in our preclinical models than the SGLT2 selective compounds we had and it continues to perform better, and we think now is profiling better in humans in clinical trials. So that's the evolution, the genesis of us of being here with a unique dual inhibitor.

So our development strategy then. First and foremost, of course in diabetes you have to establish your agent has very robust glycemic control. It's a competitive space. There are a lot of agents out there, a lot of well established still patented agents, but also very old agents that actually do provide some level of benefit. So you have to demonstrate benefit on top of those. And ideally with a new mechanism of action, something that offers a new benefit to patients. And I think that our dual mechanism does offer that.

SGLT1 mechanism, as we've been the only one to really explore this so far in the clinic, also provides certain additional benefits in glycemic control, specifically potent postprandial or after meal time glycemic control. That spike in glucose after meals which is a very important and somewhat convey to a certain amount of -- ultimately morbidity of diabetes is that spike right after meals. SGLT1 on the GI tract allows us to blunt that and I'll show you some data we have to that effect.

Secondly, we have demonstrated in our program consistent metabolic benefits that now a diabetes agent can't just control blood sugar, it has to control other things as well; body weight, blood pressure ideally and this translating then to long-term benefits and cardiovascular risks and these of course are the trials that are required in Phase 3. So that's part of our core strategy here.

And then lastly, these are agents that are going to be ultimately delivered to potentially millions of patients, and so of course they have to have a very, very safe profile. So we focused extensively on safety. In this SGLT category that is the transporters, there's been issues with genitourinary tract infections. We think 4211 has a potential to show low infection rates overall, lower than competitors which we hope to show on our Phase 3 program.

And this again has to do with the dual mechanism, which results in less glucose being excreted through the kidney because of course we use both the GI tract and the kidney to regulate glucose. And we think we're not going to see GI tolerability events. We think we've seen enough data from enough patients now to know that we're within a therapeutic window in SGLT1 that doesn't produce those side effects.

So the differentiation is key, along the way. What does SGLT1 give us? On this slide, it summarize that; reduces glucose absorption from the GI tract, that's an important postprandial glucose effect; stimulates Glip 1 secretion and other beneficial peptides from the GI tract which is PYY, which is an appetite control hormone, Glip 1 of course being a drug in and of itself. We now know of its mechanism by which this occurs.

But importantly, because we're on this pathway, we can synergize with DPP-4 inhibitors, and I'll show you some data from our initial single dose studies with sitagliptin, Januvia to show an important synergy because of course so much of diabetes care is combination therapy, so who can you team up with in order to treat the disease more effectively.

From the SGLT2 inhibition, we do put glucose into the urine but we think 4211 puts less glucose in the urine and we're going to show that through time. We already have some initial data to that effect. This we think translates ultimately to a safer profile for the urinary tract infection issue.

But also this -- it translates in the last point here to being able to go into renally impaired patients, so -- since diabetes is of course the leading cause of kidney failure and up to 30% to 40% of diabetics have some degree of renal impairment. This is a very important population to go into.

The SGLT2 selective compounds, because they rely only on the kidney mechanism, really have not shown so far adequate benefit here in this population. We think this will be open to us, to a very substantial fraction of diabetes patients.

Then lastly we have a pilot study that's initiated in type 1 diabetes. So the theory here, I'll only touch on it at the end, but it would allow dramatic reduction in insulin use is our hope and that that reduced insulin use would actually lead to better glycemic control overall for the type 1 diabetic and then long-term lower morbidity and mortality associated with it.

Okay, the [two-way] study -- I'm going to show you, this is the first study we did in patients. We've shown extensively this data, but I want to focus on the postprandial data from this [two-way] study. Just to remind you this is an in-patient study over 28 days. Here you're looking at fasting plasma glucose. Patients come in at the beginning of the study. We wash them out of their metformin and then start dosing with -- either of two doses; 150 milligrams or 300 milligrams once a day of LX4211. As you can see a very rapid decrease in our fasting plasma glucose readings right way with both those groups.

This is a postprandial data from this controlled study. (Inaudible) as shown on the left here, just shows you before dosing all the dose groups look the same. This is the postprandial excursion after you eat. Diabetics of course have a very high excursion, up 200 points. But then both those groups show a very nice postprandial effect.

Now this has not been shown with SGLT2 selective compounds. So we think again this is a one effect -- SGLT1 effect and we think it will ultimately be unique for our compound. This is looking at the area under those curves I just showed you over the course of that study. Here's day two, so even by day two, we're having postprandial effects. We actually know we have it on the first dose, which makes sense because (Inaudible) on board and block the transporters in the GI tract and then throughout the study we see nice effects on postprandial glucose. So differentiation in terms of postprandial glucose, we think we're achieving that with our SGLT2 mechanism.

Now, turning to combination studies, the one study that we did with sitagliptin DPP-4 inhibitor, this is a single-dose study in 18 patients. It was blinded and triple cross-over design for all patient, seek either our drug alone, sitagliptin alone, or then the combination. And then you can pair all the results on a highly controlled setting. So jumping into the results then, here GLP-1, active GLP-1 and in this orange color in the middle is sitagliptin, we know it raises GLP-1, that's how it works. It inhibits the enzymes DPP-4 that breaks down GLP-1. Here's LX4211, we know that we also raise GLP-1, but together we saw an additive, and we know in animals a synergistic effect actually raising GLP-1. So we enhance the secretion of total GLP-1, if I were to show you that the total GLP-1 made by the body of those (Inaudible) for 4211, they're way up here.

So the total GLP-1 accretive is very high but when we also augment with the DPP-4 inhibitor, the amount of active GLP-1 that is available to act in diabetes. And these are in – this was done in diabetic patients. The effect of that is lower postprandial glucose, here is 4211 and these are the glucose bumps from breakfast here on the left, lunch and dinner, you can see we affect postprandial glucose better than sitagliptin it appears at breakfast about the same at Lunch they looked a little bit better than after dinner but together the two drugs actually have the lowest postprandial glucose curve.

This study was very important to us because, of course, sitagliptin is an established diabetic agent we know, it works in diabetics, it's sales are upwards of $5 billion a year and we know we are moving in this essentially single dose head to head in combination study we're moving these important parameters in a similar fashion, in a complementary fashion to this established drug.

And actually in some dimensions, I think better here is insulin, here's 4221 in blue again, lower insulin level secreted because we don't need insulin to actually regulate blood glucose. So that means the pancreas doesn't work as hard. So actually achieved better glucose control with lower insulin, that's what's exciting about this type of agent.

Here's sitagliptin, it does use insulin in fact that's one of the mechanism, so its higher. And then together we'd lessen the need for insulin. So consistent results there in this combination study, I spent some time on that because this is going g to be part of our phase three program, it will be combination study with DPP-4 inhibitors, we think that's going to be important part of the phase 3 and unique to our program, we're really not seeing that done by the SGLT2 inhibitors, because since they don't affect GLP-1 they wouldn't have a direct synergy effect. Now they may combine but we think we'll have an advantage because of our synergistic effect.

Okay, let's turn to the new data that we got this summer, this is the phase IIb beta from the study outlined here this is in 299 patients we had 5 treatment arms and the dosing we went with 75 milligrams once a day, 200 milligrams once a day, 200 milligrams twice a day before breakfast and dinner and then 400 milligrams once a day, all the once a day doses are just before breakfast. These dose levels were selective, these are tablets solid dose form, these were selected based on a 2a data which was a liquid, when we moved to the tablet we had to increase the dose strength a little bit because of the [Pk] study, [bio influence] we completed so. We think we are in the right spot here for the tablet strength.

Busy slide, but just look at this one line her on hemoglobin A1C, this is the base line characteristics, they're all eight, let's say which is obviously our goal was to be somewhere between 7 and 10.5 and the different groups are stratified here randomized relatively equally, the 400 milligram group add up, they came in at about 8.0 and 7.92 so were good stratification, also important, roughly equal number of females to males, may be slightly more females in the study.

So here are the main top line results for the primary endpoint hemoglobin A1c result. We can see in green here placebo at 0.09, so not much of a reduction. There are counsels on diet, so there typically is some reduction in the placebo group.

But then if you go down here, a nice dose response, 75 milligrams in gold, blue 200 milligrams once a day, BID here in red, and then the 400 milligrams achieving a 0.95% reduction in hemoglobin A1c. So for some perspective on the SGLT2 competing compounds and they're roughly equivalent to 12-week studies.

They achieve about a 0.7% placebo corrected or 0.67% that was up 0.7% was Canna. We're at 0.86 placebo-corrected. So we look better on this initial study. We think we can build on these results. We think it's definitely moving in the right direction. This curve looks encouraging and with greater time, typically we would expect to see a greater effect.

This is fasting plasma glucose, very rapid effect both of adult groups 200 BID and 400 look similar here in this parameter. And this is an interesting find. Now this is top line data and we're going to get our full dataset here, in the next few weeks of urine glucose reading. So it's just as important for this mechanism.

This is looking at the amount of glucose per unit of creatinine in a gram to gram ratio. So you are able to control for urine volume by this method. And you can see these two -- these three dose groups look very similar at about 39, 37 or so grams of glucose per gram of creatinine.

Now the actual T2 selective compounds, they check in at about 50 to 60. So they have a higher rate of glucose excretion. Not only that, you can see all these doses look pretty similar. Now recall though if I flip back here a couple of slides, the hemoglobin A1c in blue, there is a -- the 200 milligram dose group, when we went up to 400, we got a nice 0.4 additional increase in hemoglobin A1c effect, so a much more benefit, but really no more glucose being put on the urine.

And so we take this as the SGLT1 effect and the fact that the GI tract is helping too. And that you can achieve then a better glycemic control with less glucose having to be pumped out through the kidneys. So that I think we're going to be hitting that analysis quite a bit as we go through our Phase 3 program. We saw weight loss across all our dose groups. I'll tell you right now, don't read too much into the 200 milligram dose appearing to be more.

We had one outlier there that apparently lost -- it was recorded of losing 47 kilograms. We do not think that's physically possible and we're going to check those -- we are checking those records for accuracy. But I think they are going to end up roughly equivalent, probably about 2 kilograms of weight loss, which is consistent with what Canna has been reporting over extended periods of time. They've followed them out longer. So we think we're in the same ballpark in terms of weight loss. This is going to be a very attractive feature for this class in general.

Blood pressure reduction, statistically significant reductions in both systolic and diastolic blood pressure and I didn't point it out at the baseline characteristics, but these folks were fairly well-controlled when they came in about 122 over 78 or 80 in their baseline. So to give this kind of effect in people that are well controlled is an additional benefit. We are going to – next analysis of this, look at those who were hypertensive and see if we get a larger effect. But this is very encouraging. This is consistent with the SGLT2 selective compounds, largely thought to be mechanistically related to the diuretic effect and the sodium effect transmitted through the kidney. This is diastolic blood pressure reduction, that's one.

Turning to safety; we've gone over the safety tables, and quite some detail when we had a conference call here, so I just put a summary table here to capture the main story here. The overall adverse event rate across this bar, you can see placebo at 66.7%, the high dose (Inaudible) at 57.6%, all hovering about the same. So were either the same as placebo or less than placebo in terms of overall, an event rate. We were encouraged by this.

Then looking at GI disorders, again, basically the same, we are not seeing really any differences between those groups, and as we look at all the categories of GI events, diarrhea, I think we have five cases of diarrhea in the 400 milligram group and four in the placebo group over the three months. So really, no signal there in GI, that was a very important issue, and something that we needed to prove by the way, if you recall, given the theories.

General tract infections, looks like we have low rates, urinary tract, these are mainly vaginal yeast infections. Urinary tract infections referring to the bladder. Really no signal there. This looks favorable so far, compared to the SGLT2 selective compounds, but because these rates are in general, fairly low. It's going to take larger studies to make a point of that. But there is something we will track closely in Phase III. Then discontinuation rate, you can see very low overall. So very well tolerated, we are encouraged by the safety profile.

To summarize then this 2B study. Obviously, this is a gating factor for us, in terms of making decisions about this program, with regard to advancement of Phase III, we believe that this program is ready to go into Phase III. It is also important for us, with regard to partnership discussions, because of course, we are going to be looking for partner to go into Phase III with on this. What we have got here though, is an agent that has significant and robust reductions in hemoglobin A1c on the background metformin therapy, which is a standard of care. We think we achieved this with less glucose in the urine, ultimately we think that will translate to a more favorable safety profile. We saw significant reductions in body weight and blood pressure, ultimately that, we think will translate into a cardiovascular benefit, which again is key for this drug, and the safety profile looks good.

What else are we doing? Well, we are getting ready, as we get ready for Phase III, where we are looking at renal impairment and a pilot study, again, we think one of the unique benefit there. This is a seven day study and 20 patients, with moderate to severe renal impairment, and what we are looking for those results in the first half of next year, and we think that will help them form Phase III program.

A study I am actually very excited about, and we are working quite a bit on this with private foundation in Type I diabetes. This is in 30 patients, we are picking the study off, probably being about four centers, 30 days of therapy with 4211, and the primary endpoint is reducing insulin use. So the theory here is that, [near time] insulin use could be significantly reduced, the need for it, in Type I diabetes. Most Type I diabetics are taking five injections a day, usually something in breakfast or whatever, in meal, and then at dinner, and maybe two basal injections. So four to five injections a day, or they are on the pump, which they have to regulate as well.

The question here would be, could we get some significant reduction in that daytime insulin use. Obviously, Type I diabetic is going to continue to need basal insulin use. But we are going to find out how much insulin use we can reduce. Why is that good? Well, insulin alone is an issue for Type I diabetics. It's a sort of blunt instrument to control blood sugar. It's associated obviously with hypoglycemia, low blood sugar events. The less insulin need, could translate to lower hypoglycemic events, and also better overall control of these peaks and valleys, which is damaging through time to the microvascular (inaudible) and even the macrovascular (Inaudible).

Insulin is also associated with weight gain, significant weight gain through time. It's a growth factor, and so we think that weight reduction is actually desirable here in adults. So this will be tried in adults with Type I diabetics, and we will see how it does.

Phase III strategy for Type II, I am not going to go through the whole program, but we are working on the planning stages of this. We have six studies outlined. But the goals are here, define the efficacy with increased duration of treatment, so the shortest study in the Phase III program is six months, and it will go from six months, and some that are a year, and then two years of following patients. I mentioned, we will do combination ARMs with DPP-4 Inhibitors, I think those will be very exciting to track. Then renal impairment, we will have a focus study on renal impairment. Then we will have a very large cardiovascular study, which should be about 6,000 patients, with Type II diabetes, who are at high risk for cardiovascular events, and we hope to show first and initial part of that, no increase in cardiovascular risk, which is the – would enable filing for this drug. Then following those patients further, we hope to show benefit, that is a decrease in cardiovascular risk, as we would go further out with this program. Our goal is to start Phase III in the first half of 2013.

So, I think – I hope that the program that we are building here, is all designed to establish a highly differentiated profile, and what is obviously a very major medical market. I think most biotechnology companies don't have an opportunity to enter a market like this, it is something that we know, our partner could help us in, and I think we are going to be in good position to have a partner to do this. We have opportunities in Type II diabetes itself, but also the subsectors of Type II diabetes, renal impairment, and then Type I diabetes, which should be very unique. Again, the only dual inhibitor, and I think it has hit on some of these other points.

Well, that's diabetes. You can see it has taken most of our time to summarize most of this talk. Just a few minutes then left for our serotonin programs, that I'd like to touch on. This is – actually will be our first Phase III study. We are hoping to initiate this in the third quarter, I guess that's this quarter. So [let's look at] adult rate for carcinoid syndrome, this is a GI tumor that oversecretes serotonin and other neuroendocrine peptides. It's a neuroendocrine tumor and we have fast tracked status from the FDA for this, and also orphan status from the EMA and now we have orphan status from the FDA as well.

We are also pursuing this in ulcerative colitis, because we are seeing in our Phase II studies in carcinoid syndrome, a beneficial effect on treating the GI symptomology for the highly disturbed GI track. So we have reduced bowel movement numbers in diarrhea, which is the hallmark of this severe tumor syndrome. Now most of the competition here is focused on somatostatin analogues. These are injectable peptide therapies that have been out there for about 20 or 30 years. In carcinoid syndrome, it's hard to get the exact numbers, it's a relatively small market compared to diabetes, but probably around $500 million or so a year of these somatostatin analogues sold at carcinoid syndrome. They have a bottom market and Novartis is the biggest company there. They address acromegaly as well, and a number of other indications, taking the somatostatin analog, north of $1 billion a year.

So, we think that as the only oral agent entering this space, we can offer additional benefit to those who fail on the somatostatin analogues. Ultimately, the tumor progresses and all the patients fail. And so, we think it will be a significant opportunity for Lexicon.

We've seen – we would see proof-of-concepts in our Phase 2 study in the US, which was a placebo-controlled, blind study. In this quarter, we should get the results from our European study, which is an open-label study, a 12-week time period. That will be important because our Phase 3 program, which was described here, is a 12-week treatment period.

So basically we'll have done a trial in Phase 2 that really will mimic the same patient population and treatment period and close in terms of dosing, but we do know that doses are honing on. We are going to have 250 milligrams three times a day or 500 milligrams three times a day. This indication obviously couldn't be more different than diabetes. This is a total trial of 100 patients. So obviously, a very different and highly manageable trial. So this is something Lexicon is taking forward on its own and we think we can develop this program through 2 approval.

I did mention that we are also in 60 patients with this drug in ulcerative colitis. This is a 60-patient trial in US and Europe and we should have results in the first half of 2013. I won't go into the [thesis] here, but how serotonin and toning, down serotonin dialing that down could benefit these patients, but we have excellent preclinical data that encouraged us that this might be a larger market opportunity for this drug and it was certainly worth a proof-of-concept trial, which is ongoing.

So to sum up then, I think Lexicon is at a very interesting stage of its own development as a corporation from genomics 15 years ago identifying those targets, developing small molecules and address those. Now we have three programs that could make this Phase 3 transition here in a 2012 to 2013 timeframe. So these are important value creating events for us. I have spoken about 4211 for diabetes and telotristat for carcinoid syndrome. We've had all the regulatory interactions that we need to have for carcinoid syndrome otherwise, so that one is ahead diabetes. We are requesting those and we will be having those meetings in the fall to set up the Phase 3.

But what I won't have time talking about is 1033, which is a very interesting compound. Just a word on that, it's locally acting serotonin synthesis inhibitor. We are currently running a 360 patient trial. It's a very large trial, four weeks trial in IBS-d with our real version of IBS. This is a space where there is very little for patients. This is a program where we have a biomarker we are tracking and we actually have a companion diagnostic and we think it could be a very unique offering for patients in this category. So we will have results there in the first quarter of 2013.

So these three programs I think are really the leading edge in creating substantial value for us. This is our milestones over the next 12 months. We will have data events from our Phase 1 programs in RA and glaucoma shortly. I mentioned the open-label study in carcinoid. This is all in Q3. And then launches on the bottom here, we have our carcinoid launch Phase 3 at the end of the third quarter and then the diabetes launch scheduled for the first half.

We ended the half in strong financial position. We have cash and investments of $231 million. I mentioned along the way I think our business model, which is for these large primary care indications and I think indeed for most of our portfolio we will see partners in order to really help pay for the advance development and the more expensive phases of development and ultimately catalyze the commercialization. However, there are certain indications where we will look for Lexicon to take the lead there and to develop our own products.

So with that, I will stop and thank you. I think I took up most of time and we can take questions. Thank you very much. Couple of minutes. Sure, question.

Question-and-Answer Session

Unidentified Analyst

Is SGLT1 and 2 inhibition essentially flat across patients?

Dr. Arthur Sands

The question is, is SGLT1 and 2 inhibition essentially flat across patients? If your microphone is on, could you explain what do you mean by that?

Unidentified Analyst

I mean the percent inhibition, which is wind up being a biomarker drug over this week and give it to everybody?

Dr. Arthur Sands

Okay. No, it looks it was. We have not seen – we haven't really done a formal respondent and non-respondent analysis to look and see if there is any way to distinguish those, but this looks to be putting generally applicable mechanism to patients and we've seen that with BMS' development of SGLT2 and canagliflozin, J&J. So it looks like a pretty general mechanism.

We are highly potent. I didn't go into the in vitro potencies that were like 30 nanomolar against SGLT1 and our drug has high residence time in the GI track which is where the target is or 2 nanomolar against SGLT2 in the kidney. And of course, we go through the bloodstream to hit that. So we hit, we know we hit both, we've done extensive work and handling models and it looks like this is going to be a very general mechanism for the broad population. We've actually had excellent results in healthy normal volunteers as well and no hypoglycemia even in normal volunteers. So it looks like a pretty versatile mechanism. It's a good question. One in the back.

Unidentified Analyst

(Inaudible) weight loss. And so, are you getting, I am surprised if you are getting higher GLP-4 levels, you're not really seeing a better effect on weight loss? And the second question is this, is the cancer signal, is that now clearly an off-target effect or is this something to worry about?

Dr. Arthur Sands

So the first question on weight loss, the injectable GLPs, if you look at the trial results, they produce about the same level of weight loss as we are seeing here. You look at about the 1.5 to 2 kilograms of weight loss in those defined time periods. So I think weight loss, I think will be fairly comparable between the injectable GLPs and some of these oral, new oral agents. Now you have to look additive studies et cetera, et cetera but they do look I think from what I have seen fairly comparable.

The second point on the question of – by the way on the weight loss, there is two mechanisms there I think with us, not only GLPs but also (inaudible).

Unidentified Analyst


Dr. Arthur Sands

I don't think we are any better. Listen this…

Unidentified Analyst



Dr. Arthur Sands

In this 12-week study, the question is, are we better? I am going to make that statement, but I think as we go out to six months and two years, these agents seem to be to have durability and the curve seem to keep coming down. So now hold that maybe we could end up better on the weight loss front.

The second question on the cancer signal, was a cancer signal seeing in DAPA, the dapagliflozin from BMS and urine and bladder cancers? And our belief is that's likely a detection bias, because there is greater frequency of urination, perhaps greater referral to urologist and greater defection of these cancers, which evolve over a long period of time. We can't go into all the onsets of that, but the results of hematuria, blood in the urine signal in six of those nine patients at baseline which is a red flag so to speak for bladder cancer.

So we are actually screening those out. And I think in the future of those patients need to be screened more carefully and followed up. So you eliminate that detection bias, that's my (inaudible). There is no mechanistic rationale for cancer growth signal.

Okay. Well thank you very much.

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