Neurocrine Biosciences, Inc. (NBIX) Q4 2014 Earnings Report, Transcript and Summary

Good day, everyone and welcome to today’s program. At this time, all participants are in a listen-only mode. [Operator Instructions] Please note, this call maybe recorded. I will be standing by if you need any assistance. And it’s now my pleasure to turn the conference over to President and CEO, Kevin Gorman. You may begin.

Thank you very much and thank you for everyone joining us here on our Q4 earnings call. I am joined here as usual with Tim Coughlin, our CFO and Chris O’Brien, our Chief Medical Officer. Jane Sorensen, our Head of IR is here. And before we get started, Jane could you please read our Safe Harbor statement?

Yes, good afternoon. I want to remind you of Neurocrine’s Safe Harbor caution. Certain statements made in the course of this conference call that state the company’s or management’s intentions, hopes, beliefs, expectations or predictions of the future are forward-looking statements, which are subject to risks and uncertainties. Information concerning factors that could cause actual results to differ materially from those contained in or implied by the forward-looking statements is contained in the company’s SEC filings, including but not limited to the company’s Annual Report on Form 10-K. Copies of these filings may be obtained by visiting the Investor Relations page on the company’s website at neurocrine.com. Any forward-looking statements are made only as of today’s date and we undertake no obligation to update these forward-looking statements to reflect subsequent events or circumstances. Kevin?

Thank you, Jane. Before we get started, just a couple of words. I am looking forward to a year that’s really impressive in Neurocrine’s history with the amount of data that we are going to be coming out with. Seven different clinical trials we will be reading out this year. Eight, if you count the trial that AbbVie reported out at the beginning of the year. We did a lot of work last year, particularly in Q4 getting ready for such a data rich year this year. So, with that, I am going to turn it over to Tim, where he can go through the financials, then after that, Chris will go through our clinical programs. Tim?

Okay, thank you Kevin and good afternoon everyone. As Kevin mentioned, the past quarter has been very busy for the company with the initiation of the Kinect 3 study in tardive dyskinesia and the public launch of our CRF antagonist in congenital adrenal hyperplasia. This increase in activity was evidenced in our operating expenses with a 25% increase in R&D expense from the prior quarter. Our financial guidance shared with the investors and with the investment community at the beginning of the year was to end the year with over $230 million in cash investments and receivables coupled with a net loss of less than $61 million. We met both of these items ending 2014 with approximately $232 million in the bank and net loss of $60.5 million or $0.81 per share. Our net operating cash burn for 2014 was approximately $47 million. Our GAAP net loss for 2014 is $60.5 million compared to the previous year’s net loss of $46.1 million. Our net loss for the quarter was $19.4 million or $0.26 per share. This compares to a net loss of $10.6 million or $0.16 per share in the fourth quarter of 2013. The increase in net loss for both the quarter and the year ended December 31, 2014 resulted from increased clinical development activity, primarily related to NBI-98854, our VMAT2 inhibitor for tardive dyskinesia in Tourette’s syndrome as well as our CRF program in early stage pre-IND work. Additionally, our personnel-related expenses increased in 2014. We began 2014 with 81 full-time employees and ended the year with 94 full-time employees, almost all those additions were in research and development. Non-cash share-based compensation expense for 2014 was approximately $10.4 million. For 2015, our financial guidance is that we expect to have a gross cash burn of approximately $80 million to $85 million. This burn estimate is prior to any consideration of revenue, for example, milestones under our AbbVie agreement. The next milestone anticipated under the AbbVie agreement would be moving Elagolix into Phase 3 development for uterine fibroids. From an income statement perspective, we expect our operating expenses to increase to approximately $106 million to $111 million in 2015. This $40 million increase in expenses was due to three major factors. First, external development expense related to the Phase 3 clinical program for tardive dyskinesia is expected to increase this year by approximately $17 million to $20 million. Second, our CRF program for congenital adrenal hyperplasia will expand the two clinical trials this year, preclinical work as well as CMC work. The fully loaded costs of this program as well as some other earlier programs will increase R&D by approximately $10 million of the 2014 levels. Finally, share based compensation costs will increase by approximately $15 million this year. The increase in share based compensation expense is primarily driven by higher Black-Scholes valuations due to a higher strike price. Additionally, a portion of the increase is due to the potential vesting of certain performance restricted stock units which totaled $6 million. We have included this number in the guidance. The increase in Black-Scholes value related to options as well as the grant date fair value of restricted stock units is partially offset by a lower number of options restricted stock units that we plan to grant in 2015 versus 2014. The $25 million in anticipated share based compensation expense is also a major difference between our expected gross cash burn, again prior to any revenue and our projected GAAP expenses. So that concludes my prepared remarks on the financials. To conclude, our 10-K has been filed with the SEC today and I would be glad to entertain any questions during the Q&A session.

Thanks Tim. So Chris has quite a bit that we can go over, but my guess is he is going to save a lot of it for the Q&A session that he normally does, but we have a number of programs here obviously there is Elagolix, there is our VMAT2 program. And also as we have mentioned we anticipate in Q2 of this year that we are going to be filing IND and a new program completely new compound and indication, not much more to say about that other than that, but Chris. Chris O’Brien: Absolutely, thank you Kevin and good afternoon. Thanks for participating in the call this afternoon. I will start will Elagolix since that was the most recent news from AbbVie and I think everybody on the call is very aware of the details of that very nice efficacy and safety readout from the first of two Phase 3 pivotal trials in endometriosis and the second Phase 3 pivotal trial is currently underway. And as Kevin mentioned we anticipate from AbbVie a readout on the top line results of that at end of the year. AbbVie is doing a fantastic job conducting these massive studies. These are the largest endometriosis trials that have ever been conducted. And as we have seen with the limited data that’s available, the efficacy has been excellent across primary and secondary end points as well as a very nice safety profile. Obviously, women are continuing in the open label extension phase of both the Violet Petal study, the first Phase 3 as well as the Solstice study which is the second Phase 3 and that one is more of the mixed U.S. and international trial. Excellent work there on AbbVie’s part and I suspect we will have some questions during the Q&A, so I will hold off on more detail there. The fibroids program is also going well as the listeners are well aware, the Phase 2b study that’s currently underway is scheduled for completion of the second cohort and data readout later this year. That Phase 2b study will be the basis of kicking off an end of Phase 2 discussion with the FDA and presumably shortly there after if the results are indeed favorable, the start of a Phase 3 trial. Let me focus on the work that we are doing internally since the team is very busy with the VMAT and CAH programs as well as the new molecule for a new indication as we are preparing the documentation to file a new IND in Q2. So let’s start with the VMAT2 program, the main activity as Tim mentioned with the finances is the work on the Kinect 3 style – trial. Kinect 3 is the last placebo controlled registration trial that we are performing for this PD registration effort. The trial is going very well. We have sites open in North America that’s Canada, U.S. and Puerto Rico. The sites are recruiting very high quality subjects. We have been very pleased with the process that we have in place for screening these subjects and the quality of the patients and the quality of the videos that form the basis of the blinded central raters’ assessment of the dyskinesia. So, this is moving well. We are tracking exactly at timeline. We have talked about having the last patient randomized this summer and results from the Phase 3 trial in the fall. So, that’s going very well. We are pleased with the efforts from our investigators and the quality of what we have seen. And so far to-date obviously it’s blinded, but we are not seeing any kind of safety signal or concerns from the patients that have been randomized and you now have quite a few patients that have moved through 12 weeks of treatment. The second piece of the TD Phase 3 program is the open-label long-term safety study, so-called Kinect 4, and that study has been approved by the IRBs and we are getting ready to launch that trial in March. And so far we are very much on track with that program as well. In the next VMAT2 set of activities is in Tourette’s syndrome program and I think as we have discussed before on these calls and in our presentations, we have a clinical trial underway right now with both adolescents and young children with Tourette’s syndrome participating in a Phase 1b trial. That is they are treated for two weeks of continuous treatment and we are starting with low doses and working way to higher doses in this Phase 1b study. And the goal here is to assess safety and tolerability of NBI-98854 in children with tic disorder, with Tourette’s syndrome. And we are also looking at some efficacy markers although the study is neither designed nor powered to give us the efficacy report. We certainly will have data, pharmacodynamic data to look at, at the end of the trial, where we have the gold standard for tic studies, the Yale Global Tic Severity Scale as assessed by the investigators. We also have video assessment of tic severity using the RUSH video protocol and a number of other clinically relevant scales for this population. We will also have intensive pharmacokinetic data. We have obviously a lot of experience with PK data in adults with our compound and we have a model of exposure that we designed to give us information about what children should be exposed to with the given dose. Part of the effort in this Phase Ib trial is to help us confirm that in fact what they actually are exposed to is what our model predicts. And this will help us very much select the doses that we need for registration trials in Tourette’s syndrome. So, that’s going well. We are on track with that as expected. Our plan is to have results from the so-called T-Force trial in the fall. And if any of you have a chance yet to look, you can find out information about T-Force from the T-Force website and also on clinicaltrials.gov as well as the same thing is true for the Kinect 3 studies, there is a Kinect 3 website with additional information. So, that’s the VMAT2 program. I suspect we will have some time for Q&A on VMAT in a few minutes. Now, moving on to the congenital adrenal hyperplasia program, CAH, as mentioned in our presentations and in Tim’s comments, we started a public presentation about this program in December of this past year and that was with data from so-called 1501 study. This was a small pilot study in the women with congenital adrenal hyperplasia, a single-dose study designed to give us just very simple answer to a question, if you give me single dose of this drug, do you see some kind of pharmacodynamic effect on the biomarkers of interest. The study was not designed as an efficacy trial. It has obviously no information about chronic repeated dose exposure and it certainly doesn’t tell you about what happens in children with CAH, which ultimately are the target population, but we were very pleased with what we saw and also very pleased that the FDA told us they believe that these biomarkers are indeed the appropriate endpoints for this stage of clinical development. So that information allowed us to talk about the program publicly and invest money into the next trial. So, we have two as Tim mentioned, we have the first study is a single-dose trial in adolescents with CAH and that study is improved by the IRB and the sites are up and ready and they have started the screening process for this study. We will have top line results from this single-dose adolescent study in the fall. Immediately on the heels of this, we will startup the repeated dose study in young adults with CAH and this is a 2-week dosing trial looking at a range of doses to help us determining what doses we want to take into the pivotal registration trials and the data that we will use although we meet with the FDA about what Phase 3 looks like. And so this study is getting up and running and we will start dosing in Q2. We will have results from that study in the fall. I should mention that the primary investigator from the pilot study that was already completed, Dr. Auchus will be presenting that data at a special symposium that’s part of the upcoming Endocrine Society meetings to be held here in San Diego on March 5 at 11:30 AM and the program is about basically bench-to-bedside looking at the high performance pituitary adrenal therapies. And so Dr. Auchus will be presenting the data from the 1301 study. Very exciting times for us in this program and we are in the process of meeting with endocrinologist and pediatric endocrinologist both here in the U.S. and in Europe as we envision the expanded clinical program for CAH going forward. So, we talked about Elagolix. We have talked about a new IND with a new molecule for a new indication to be filed in Q2. We talked about the tardive dyskinesia program with Kinect 3 and Kinect 4. We have talked about the T4 study with Tourette’s syndrome and congenital and adrenal hyperplasia studies, the pilot study, the single-dose adolescent study and the repeated dose young adult study, obviously, a lot of activity. Very pleased with the progress and looking forward to a wealth of data reading out later this year. So, I will stop there and turn it back to Kevin and look forward to your questions.

Thank you, Chris. Actually, why don’t we open it up for Q&A right now?

Thank you. [Operator Instructions] We will take our first question from Robyn Karnauskas with Deutsche Bank. Your line is now open.

Hi, guys. Thanks for taking my question. So, I guess, first question you filed your 10-K and in it you have I am picking out some Irish subsidiaries wondering if you could comment on potential long-term tax rate of company? If you can’t give guidance maybe help us think about is it possible to get a better tax rate on Elagolix or is this something that might be relevant for your neuro products? And then the second question I just get this question a lot with Auspex data coming middle of the year. Can you just outline Chris for us like what QT evaluations you have done in your clinical trials for tardive dyskinesia and what gives you the comfort that there won’t be a signal? Thanks.

So, hey, Robyn, it’s Tim. Related to the Irish subsidiaries, we have set them up right at the end of December to take advantage of the grandfathering clause that’s out there as far as domicile and that is the reason we set up this year as far as the tax advantage – for potential tax advantage. We are still working through all that at this present time and it is for international strategy obviously to work our ways through that over the next couple of months and we will update the street once we get to that point. But right now, we are still going through the different valuations that have to happen prior to for example moving any intellectual property into those subsidiaries. Chris O’Brien: Okay. And Robyn to your question about QTC prolongation, so we have conducted a number of Phase 1 studies and obviously our Phase 2 and our Phase 3 work is ongoing. We haven’t seen any signals from arrhythmia or arrhythmia risk or QTC prolongation to-date. We will be discussing with the FDA what is it that they want to see for our NDA in light of kind of more formal QTC analyses. But we have a package of material currently available for the FDA. I don’t think we will have further detail to give you that until we finish some of our discussions with the FDA. The good news is that as part of our breakthrough therapy designation, we have excellent communication with the agency and we will be able to get these questions addressed in the near-term. I should also add that one of the things that we do as part of this program is try to address the quick question that’s most clinically important is can you give a drug like 854 to patients who are already receiving a combination of medications that have known potential to prolonged QTC drugs such as the antipsychotics for example in some of the SSRIs all of those have – and AEDs, some of them have – there is potential to prolonged QTC. So we have done a very careful job of documenting all of this concomitant medication use in conjunction with a wide range of doses of our study compound 854. And we have analyzed that data to-date we have seen no evidence for kind of any interaction or prolongation of QTC in those subjects. And that will be a very important part of our NDA because psychiatrist and neurologist who would prescribe 854 want to know that they can use this drug safely in conjunction with the underlying psychiatric medication. So that'll be an important part of the package.

That’s really helpful. And if I can have a follow-up if possible, the uterine fibroid data is coming out and in the past with Elagolix and Endo there was a series of Phase 2s and you had to work through them, I am just trying to figure out there is not a lot in my opinion for uterine fibroid in stock, what is the biggest risk with this Phase 2 now that you know so much from the Phase 3 trial and it was exactly – you predicted exactly how it would read out, what is the biggest risk to the Phase 2 not being positive or on the safety side what are the things you are worried about? Thanks. Chris O’Brien: That’s a very good question because this is an interesting situation with Elagolix because we know Elagolix reduces menstrual bleeding and uterine bleeding. We know that’s true in endometriosis. As we have seen with our data that we did in our trial developed in our trials. But we have also seen that AbbVie ran a Phase 2a study in which they saw proof of concept which allowed them to start the Phase 2b study. Now although they didn’t release data, they said we found proof of concept and we moved into Phase 2b. So the end point and the only end point for uterine fibroids for the FDA is uterine bleeding and menstrual bleeding. And a reduction in uterine bleeding was the basis from them moving from Phase 2a to Phase 2b. The people at AbbVie formerly Abbott and TAP were the ones that helped work with the FDA over a period of many years to design and reach consensus with the FDA on what that primary end point is. In this case there is an objective and there is also a subjective way of measuring uterine bleeding and AbbVie has did it for both of those things. So I don’t think there is an efficacy risk here and particularly you can get a sense of that if you look at clinicaltrials.gov and you see what the Phase 2b study looks like. And you will see that they are studying doses in the cohorts of Elagolix that are – they are looking at a dose that they haven’t specified but one can assume that it’s higher than what we have studied in endometriosis because they are using a low dose oral contraceptive as so-called add-back. And the only reason you do that is if you suppress estrogen or estradiol so much that you begin to have impact on bone mineral density. So, if you use a low-dose of an oral contraceptive and approved add-back, you can mitigate that risk of impact on BMD. So, what you see when you look at clinicaltrials.gov is they are not really looking at Elagolix, they know Elagolix works. They are looking at which does of add-back is the best to take forward into Phase 3. And so, I think we don’t have a major efficacy risk here on uterine bleeding and the issue is do they have a dose they are comfortable with in conjunction with a dose of add-back that gives them the kind of safety profile they need going forward and the literature is replete with examples of low-dose add-back taking care of BMD risk even with profound suppression drugs like Lupron.

And Robyn, they are fortunate in that, you do have a very good biomarker here for bone risk and that is the estradiol and they have modeled that extensively and AbbVie does an amazing job of modeling. In addition, that’s why this study is six months in duration whereas the Phase 2a was three months in duration, because you want to be able to have that six-month delta between your baseline DXA scan and then a DXA scan that would be meaningful. So to reiterate what Chris said really this trial isn’t so much about Elagolix, this trial is just about perfecting the level of estradiol to get back to the patient so that you can have a long-term treatment.

Great, thanks so much. Great, thanks for taking so many questions. Thanks.

Thanks, Robyn.

We will take our next question from Brian Skorney with Robert W. Baird. Your line is now open.

Thanks. Good afternoon guys. I appreciate taking the questions. I guess starting on part 4, there has been a lot of discussions about pricing of e-matches considering you are going after TD as the first indication of Auspex potentially targeting a different one. Can you just maybe kind of walk through very high level your thoughts on how we should be thinking about the pricing on 854? And a follow-up on Elagolix in uterine fibroids, I wonder can you just maybe set expectations in terms of what exactly we should be looking for in terms of clinically meaningful endpoint in terms of uterine bleeding and would you anticipate that we might also see significant reduction in fibroid size based on some of the historical data with GNRH agonists? Thanks. Chris O’Brien: Let me take that second one first, Brian and then I will let Kevin address the first one. So, with uterine fibroids, a normal woman has around 40 milliliters of uterine bleeding per month. High uterine bleeding is set at a threshold by definition, heavy uterine bleeding as anything over 80 milliliters a month. These women who are in the uterine fibroid trials have a lot of bleeding in the 200-milliliter to 300-milliliter or more per month. So, they come in with a very high baseline. And the bottom line is with effective hormonal therapy like Elagolix, Lupron and other drugs you can shutdown uterine bleeding to very, very, very low levels. So, what you will see is you will see either, I don’t know how AbbVie is going to tell us the results, but you will see that there is a measurement of the amount of uterine bleeding and the percent of responders women who get to either no bleeding or below normal or back into the normal range, you may see it several different ways. We haven’t had the discussions yet with AbbVie about the detail that they will share cum top line results, but that’s Tim’s job to negotiate the press releases. You will see the data reported using the objective measurement this is the so-called alkaline hematin method of quantifying a uterine blood loss, which is very objective and meets the FDA requirements.

And Brian as to your first question, I mean, it is premature to be talking about pricing at this stage. We are just in the middle of the Phase 3 program. We have done some very qualitative preliminary pricing research and we will be embarking on the quantitative research, but as you pose it between ourselves and Auspex, I mean, Auspex is initially going out into an indication that is very much an orphan indication with just less than 4,000 patients in the Huntington’s chorea population that have chorea that wouldn’t necessitate an intervention like Auspex’s drug. We are going into as our initial indication tardive dyskinesia, which as you know, is at least 500,000 patients. So, those are two very different populations. And just as you said on a very high level, they would have two different levels of pricing associated with them, but until we are much closer to commercialization, I think that’s probably all I can really say about pricing.

Fair enough. Thanks, guys.

Thanks, Brian.

And we will take our next question from Charles Duncan with Piper Jaffray. Your line is now open.

Hi, guys. This is Roy in for Charles. Thanks for taking the question. Kind of in line with the last question, I guess on 854, do you guys have plans to study in Huntington’s chorea at this time? Does that depend on the Kinect 3 data? And do you have any thoughts on an approved second generation HC drug being used off-label in TD or vice-versa is device other scenario more likely? Thanks. Chris O’Brien: If I understand the question correctly, Roy, the first question is would we study 854 in Huntington’s disease? It’s obviously not an urgent unmet medical need. All the efforts that we have currently are focused on TD and TS is that something we might do down the road, certainly possible, but it’s not something that makes a lot of sense from a business point of view and the clinical point of view at the present time. Now, having said that, we do have – we have backup molecules for 854 that have shown some very nice attributes in our preclinical models and testing and these potentially we would consider bringing into the clinic for other indications. And as we have mentioned publicly before, would that be schizophrenia, would it be other movement disorders, all that remains to be sorted out, but we certainly potentially could go there. As to your question about what do I think about next generation Huntington’s drugs going into the market for Huntington’s, it depends if they confer an advantage over existing therapies, then I am saying people would like that. Clinicians are always happy to address a deficiency of current therapy.

So, I was asking more about off-label use, if something is approved for Huntington’s, do you see it being used in tardive or do you see the vice-versa, something is approved for tardive, do you see it being for Huntington…. Chris O’Brien: Well, that’s a – it’s a little bit difficult, because currently the approved drug, for example, for Huntington’s disease is distributed through a specialty pharmacy distribution system and has a REMS program in place. That said this drug is to be used to treat chorea associated with Huntington’s disease. And it’s priced as an orphan drug. And so you don’t see a lot of off-label use of an expensive drug for a larger population.

Okay, that makes sense. Do you guys have any sense of the earliest Kinect 4 can complete and then maybe the earliest NDA can be filed? Chris O’Brien: So, we have said publicly our goal is to file the NDA in 2016 and that’s still what we are working on.

Yes, we have to see – it’s too early to talk about enrollments in Kinect 4 at this point in time. So, once we have enrollment curve as we said with our Kinect 3 enrollment curve would be getting more precise with those dates.

Okay. And then couple of quick ones on CAH if I could, just in general how big you think the market opportunity could be and how is that disease currently treated? Thanks. Chris O’Brien: So, it’s an orphan disease. There are about 30,000 patients with classic CAH in the country in the U.S. and half of those are females. And so it’s the women with CAH particularly the young women the girls, adolescents with CAH that’s the major unmet medical need. So, us, cut 30,000 in half, it’s 15,000 and then you say maybe your addressable population is 10,000 subjects. So, we think that’s the market opportunity there.

Current therapies? Chris O’Brien: The current therapies, there is no current therapy for the excess of androgens other than using very high doses of hydrocortisone. The hydrocortisone is used to replace the absent cortisol in these patients, since they don’t make cortisol. You can use even higher doses excessive super physiologic exposures to cortisol to try to shutdown the HPA access. But that results in an additional pile of unwanted side effects and makes management very difficult. These patients get obesity, diabetes, bone mineral density abnormalities and other problems. So there are no therapies that do what we are proposing to do.

Very good. Thank you.

Thanks Roy.

And we will take our next question from Ian Somaiya with Nomura. Your line is now open.

Thanks. Just had a couple of questions, first was just housekeeping, can you just update us on the regulatory timelines for the endometriosis indication for Elagolix U.S. and Europe and I just had a couple of follow-ups?

Yes. Hi, Ian, we don’t know really much at all about what’s going on in Europe with that be in the program, that we have not had any role or visibility into. With the way the program is proceeding right now as AbbVie is doing a great job I would see that it would be towards the very end of ’16 potentially for filing they have still talked about ’17 as being a commercialization target.

Okay and just a question…

And that would be – just to be clear that would be with endometriosis. Alright, uterine fibroids we would have to wait to see the start of Phase 3 and the pace on that.

Okay. And just a question for Chris on the Tourette’s Phase 1 trial, any – you are clearly studying a range of doses on that trial just curious any thoughts on I mean how the dosing in Tourette’s might compare to that in TD and just from a larger market perspective maybe a question for Kevin that you want to tackle it, just how sure we think about what the pricing dynamic would be between – in Tourette’s and TD?

I will take the pricing dynamic in there. I mean, number one for us as we look at it we will be coming out in TD first. And we will have a price that’s set there that will allow for broad adoption throughout the TD population. We then be coming out into the Tourette population, had it been the opposite I think we probably would have had higher pricing into the Tourette’s population. And then see what we could carryover in TD at least right now without any data or work in front of me I would say that the pricing is going to be similar between the two populations that we will have. Chris O’Brien: The doses I mean I mentioned our PK model before and so far looking at PK data from the Phase 1 study things are pretty much in line with that. The doses will range from quite a bit lower obviously in small children a skinny 6-year-old is going to require pretty small dose up to a fairly robust 18-year-old is going to require a dose like any other adult. And we believe that the exposure necessary to suppress tics is very similar to the exposure necessary to reduce dyskinesia. So I think you will see two or three doses available that start below and go up to the TD dose. One twist I would add is we likely would consider the availability of a pediatric friendly formulation for the young kids that don’t do well with capsules. But we will see that work is ongoing. So we will see and what the market research tells us is appropriate for this population.

And just one maybe a follow-up based on your answer, just to break the therapy designation does it enables you to have initial discussions with the FDA regarding what the next steps should be or could be for Tourette’s, now can you move into Phase 3 trials? Chris O’Brien: The breakthrough designation was given for this molecule 854 for tardive dyskinesia. It doesn’t apply to Tourette. The Tourette has the separate IND.

I fully appreciate that just as you just discussing safety for the molecule does it maybe inform in anyway in terms of what the FDA would be amendable to in terms of next steps in Tourette? Chris O’Brien: Sure, sure. I mean, just in a loose way about what are their general safety concerns about this kind of molecule, yes, but as a specific level for Tourette’s, we won’t have our next discussion with them until we get this Phase 1b data in hand.

Okay, thank you very much. Chris O’Brien: You’re welcome.

We will take our next question from Phil Nadeau with Cowen & Company. Your line is now open.

Good afternoon. Thanks for taking my questions. Chris, first one to you on the Phase 3 release for Elagolix or in the Phase 3 release for Elagolix, have you included the sentence that there were dose-dependent increases in bone effects? I haven’t heard your opinion of that sentence and what that could ultimately mean. I guess, what I am specifically wondering is tremendous what the FDA has requested you to see from a safety study and what type of bone effects do you think would begin to either give the update pause or begin to decrease the clinical differentiation of Elagolix versus Lupron and the other agents out there? Chris O’Brien: Sure. Thanks, Phil. That’s a good question. So, let me start kind of in reverse order. So, we know for drugs like Lupron, if you treat a group of women for 6 months, there is a reduction in bone mineral density as measured by DXA scan with a mean change for the population in that 6% range in the data it varies between 4% and 8% and up to 10% or the year. So, mean change is big. Now, you get a distribution around that mean. So, you have outliers and women with a clinically significant bone loss that it’s very common with Lupron. So, what we would expect with Elagolix is that the mean changes are very small and the distribution around the mean change is such that you don’t have outliers’ women with clinically significant BMD reduction. Now, you say well, what does that mean? Clinically significant BMD loss in a 30-year-old woman with endometriosis is you are talking 5%, 8%, 10% reduction in BMD. Remember the precision of a DXA scan is plus or minus 3%. So, when we reported our panel trial, the 6-month treatment with 150 milligrams per day, the mean change for the group was less than 0.5% and we didn’t have outliers. You don’t see women with 5%, 8%, 10% BMD reduction on an individual subject basis. So what AbbVie told you in their press release is that the data they have seen is that it was comparable to previous trials meaning the 150 milligram dose and that for doses that were not reported on in the past, i.e., the 200 milligram b.i.d. dose with that dose related change in BMD, not a surprise when you get increased reduction in estradiol [Technical Difficulty]

On the Tourette’s study, could you give us some idea of what is a clinically meaningful change in global severity of tics? Chris O’Brien: Sure. There is a really nice paper published recently, where that very question was analyzed the Yale Global Tic Severity Scale. Patients typically come in with baseline scores in the kind of the low 20% range. And a clinically meaningful change was considered to be about a 4 point change if they come in at that level of severity.

Okay. So it would be like a 25%ish change wherever they start on the spectrum which is…. Chris O’Brien: Yes, 20%, 30% in that range depending on the study and who is conducting the study, how severe they were on baseline, absolutely.

Okay. And then just one more for me on congenital adrenal hyperplasia, can you give us some idea of what a likely Phase 3 endpoint would be, first of all, would it be clinical or biomarker, and if it’s clinical, what would that be? Chris O’Brien: And so I wish I had the answer for you. I will know that after our end of Phase 2 discussions next year, but what my goal is that this is what’s called a regulatory language of some Part H meaning that you get approval based on clinically accepted biomarkers. Now, the biomarkers that clinicians use to manage these patients are the androgens that are collected and those are the things that we are measuring like 17-hydroxy progesterone or 17OHP. So ideally we did get this orphan drug approved on the basis of these biomarkers, these clinically validated and accepted biomarkers. And then post approval, consistent with what a sub part H is, have clinical follow-up data to collaborate what we are seeing in these trials. Because those kind of things are if you start treating young kids at are a very young age, what is their growth velocity and how is that compared to standard of care. So this is clinical data collected on height over a period of many years. That’s not appropriate end point for an orphan indication like this, but that’s a kind of thing clinically that would be interesting to see. I don’t know what the FDA is going to – this is the division of metabolism and endocrine products. They understand CAH very well. They understand these biomarkers. So that’s what our hope will be going into this, but I have to update you after we have those meetings.

That’s very helpful. Thanks for taking my questions.

[Operator Instructions] We will take our next question from the line of Thomas Wei with Jefferies. Your line is now open.

Thanks. Just I had a couple of questions, one is on the breakthrough status for 854 and just wanted to see if you have been able to since last time you spoke any sort of feedback from the agency on how they think about the class black box warning for this class of drugs. And is it possible for you to – is it a possibility that you think that removed or is that something that we should just assume is on the label? Chris O’Brien: Hi Thomas, thank you. So the warning that’s on the label for the only two – VMAT2 drugs that have been approved for human use, Reserpine and tetrabenazine are related to suicidal ideation. And we haven’t had the chance to have that discussion in the context of breakthrough therapy at present. But it’s a lot of history to overcome. And we know from the FDA’s actions to-date that many, many drugs have the same black box warning of suicidal ideation. For example all of the anti-epilepsy drugs the AEDs have a class label for suicidality even though as Dr. Temple and others have argued that doesn’t make a lot of sense, that nonetheless is that’s where we are at. And I think it’s a tough hurdle to overcome. Do we hope that we will have clinical data from our long-term trials, let’s say while this may be a class risk we don’t see evidence of suicidal ideation being worsened in this population. I hope that’s what we can do. These are patients with really challenging psychiatric and medical problems. And they have a background rate of suicidal ideation that’s very real. About 40% to 50% of the patients that actually enrolled in our trials have a history of suicidal ideation and even suicidal attempts at some point in the past. So we know this is real. And our goal is that we have done such a good job of selecting the appropriate doses with our highly selective compound that we actually have a good safety signal and the hope that data rules the day.

My second question was just as you are starting to get a critical mass of patients into the trial any thing that you can tell based on these new centers and the screening process that looks different from the prior studies or different relative to how you thought the patient population might look in terms of baseline demographics? Chris O’Brien: No, they are the same.

That’s helpful. And then my last question was just given the competitive dynamic, people are now looking at your drug, Auspex’s drug, the two different trials that are being run in the same indication. And I am getting some questions around the titration or lack care of, that’s one of the differences between the two programs. And so it would be helpful if you could remind us you had a titration scheme in the successful study that allow people to get to whatever dose they wanted to get to and Auspex is employing something that seems quite similar to done in their Phase 3 trial, but you have gone forward fixed dosing based on your PK modeling, can you give us some comfort that that better approach and that people won’t need flexibility of doses in the market? Chris O’Brien: Well, I think those are two interesting but very different questions needing flexibility again the need for titration are slightly different, so let me see if I can touch on that. In the Kinect 2 trial that we – where we had step wise dosing that was not done because I need a titration. That was done because that was the first trial I had ever done in patients with mood disorder and tardive dyskinesia. So they had a history of depression or bipolar disorder. And at least historically people have raised the hypotetical concern that a VMAT2 inhibitor in this population might be riskier. And so we designed – when we designed the 1202 study back in almost 4 years ago now, we had that consideration in mind and we were running that trial – we started that almost just months after we started the 1201 study. And so we didn’t know what dose ultimately would be the best dose. And so we designed that trial. We didn’t need to titrate. We don’t think we need to based on the nature of our compound. And in fact when we met with the FDA at the end of Phase 2 meeting, they clearly understood that and they said that they wanted to see a fixed dose pivotal trial and we are happy to do that, because we think fixed dose is good. So that we don’t need to titrate our drug for efficacy, but they also agreed that they wanted to see a lower dose and a higher dose and we had very beautiful exposure response data that told us quite clearly that you can capture a certain proportion of patients with a low dose and you capture the rest of the patients with a higher dose. And that going up any higher doesn’t give you additional benefit and so that’s how we ended up with 40 milligram and the 80 milligram dose in the Kinect 3 trial. So we don’t think you need to titrate our growth. And we think it’s a very simple one today start everybody on 40 milligram and if they are not a responder you can always put them on 80 milligram that’s a very easy program to do clinicians like that.

Thanks.

And it appears we have no further questions at this time. I will now turn the program back over to President and CEO, Kevin Gorman for any closing remarks.

Thank you very much. I think as you have heard here we got all of our programs moving swiftly forward. And as I said before this was going to be a very exciting year with all of the clinical trials readouts not including the first Phase 3 readout in endometriosis, we have seven more trials to readout this year. I find that especially impressive seeing this how this covers six different indications and we are doing this with four different compounds. So between ourselves and our partner AbbVie I am really looking forward to a wealth of good data as the year goes on. We are going to have an opportunity to talk about this data as it comes out at multiple conferences that we will be presenting at. Starting with Tim is presenting at the Leerink conference on Wednesday of this week as long as if you can make it out there with the weather those of you in the East Coast are having. So throughout the year we are looking forward to talking to each of you and all the questions that you have for us. Thank you very much.

This does conclude today’s program. You may now disconnect. Thank you and have a great day.