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NPS Pharmaceuticals, Inc. (NASDAQ:NPSP)

Investor and Analyst Event Conference Call

December 06, 2013 08:30 AM ET

Executives

Francois Nader - President and CEO

Roger Garceau - EVP and Chief Medical Officer

Eric Pauwels - Chief Commercial Officer

Jeffrey Rothman - Staten University Hospital

Mary Frances Harmon - Head of Global Patient Advocacy

John Bilezikian - Columbia University

Luke Beshar - EVP and Chief Financial Officer

Analysts

Salveen Richter - Canaccord Genuity

Joe Schwartz - Leerink

Matt Palmer - Oppenheimer

Tazeen Ahmad - Bank of America

David Nierengarten - Wedbush Securities

Jim Molloy - Janney Montgomery

Francois Nader

All right good morning everyone. When you throw a party you never know who will show up, so I am happy with it. And it’s a pleasure to be here, truly a pleasure. For a couple of reasons, one as you probably know, NPS has been extremely active this year and we’re very proud, I’m very proud of the work that the team has done. And it’s the pleasure for me to share with you the work of the NPS team and what we’re able to achieve this year.

Thus more importantly this year was very important for us as well given what we had to offer the patients. At the end of the day this is what we’re here for. And this year has been phenomenal because we’re able to offer the Short Bowel Syndrome patients here in the U.S. Gattex. And as you know, we filed Natpara as well that hopefully will help patients suffering from hypoparathyroidism.

With this in mind, I’d like to go ahead and give you an overview of NPS today and where we’re heading, so you probably know by know that NPS is a pure play thyroid disease company. And this is our mission; this is our vision is really to change the lives of patients suffering from rare disease worldwide.

Give me a second to read the Safe Harbor statement. This slide is extremely important because this is what guides what we do here at NPS starting with our mission. And as I said, our mission is really to pioneer and deliver innovative therapies that transform the lives of patients with rare diseases worldwide. We have an ambition and our ambition is to become the premier global rare disease company. I think we're off to an excellent start, it’s a long journey, but I can tell you that we're enjoying every minute of it.

Basically the strategy is very simple, the strategy is to globally develop and commercialize innovative first in disease therapeutics. I’d like to spend just a second on the strategy because it says globally develop, NPS today is a global company. We have been in global development for many years. And we are now a global company not only in development, but also in commercialization with products approved in Europe and the presence that is expanding worldwide.

We're in the business of innovative treatments. We're not in the business of (inaudible) nothing wrong with that, but this is not our line of business. So as you’ll see it in our slides, we’d like to be always either first-in-class or best-in-class, that’s our niche. And as I said, focusing on the rare diseases, it’s R and D we are pretty open to different therapeutic areas. We currently are in endocrinology and in gastroenterology.

So what are the pillars of our activities at NPS? The first one up there is the fact that I believe we believe that we have commercially valuable assets. We’ll talk a little bit about Gattex today, even though it’s the Natpara day, but nevertheless we cannot avoid talking about our lead product.

Revestive as you know is Gattex, the trademark of Gattex in Europe already approved, and Eric will talk a bit later on about our international activities and how we are developing the market for Revestive ex-U.S. Interestingly enough we have a very long exclusivity both here in the U.S., but also rest of the world. So we have a not only a long journey, but a long runway to take these two products to their peak sales.

We have an attractive pipeline actually for a company our size that’s pretty interesting because our first product in our pipeline is Natpara. We filed Natpara October 23rd this year. And we are looking at filing Natpara in Europe next year. Natpara was filed as a VLA, very important because it will give us 12 year exclusivity. And it will be filed as an orphan indication in Europe with 10 year exclusivity. But also it’s interesting because since we started the Gattex program in adults, frankly our biggest supporters were the pediatric gastroenterologists given the dramatic consequences of short-bowel syndrome on kids.

So it was very important for us to start with the adult indication first, but quickly thereafter it is important for us to make sure that kids can have access to Gattex if indeed Gattex is the right product for them. And Roger will talk a little bit later on about our pediatric program that looks at kids between age 1 and 17, it will be a global program.

And we have a third product, so NPSP795. What I can tell you is we're planning to launch proof of concept for 795 mid-year 2014. So, during 2014 you will hear us talk more and more about this exciting asset. It fits really square into our missions, square into our vision, because 795 is a product that is indicated for autosomal dominant hypocalcemia or ADH. And ADH is a very, actually it's an ultra orphan indication, few thousand patients worldwide. But these patients are treated by endocrinologists and the condition itself had to do with a dysfunctional calcium-sensing receptor. So very much square into our endocrinology franchise and we will be able to overtime to elaborate Natpara in support of NPSP795.

The third area of importance to us is something that we initiated only few months back. It's interesting because only back in March, so about eight months ago now even actually. We regained the global rights for our two products Revestive and Natpara from our partner or ex-partner Takeda. And this was a changing transformative moment for NPS, because for the last 25 years, 26 years we were a U.S. based company and now overnight we became a global company. Trust me, easier said than done. But I'm very, very proud of the progress we made so far. And we will give you a glimpse of all the activities that took place over the last seven, eight months on the commercial front and on the development clinical front.

We have targeted where we will be and we came up with a number called 30 countries. Here also it means that not only we are covering Europe or most of Europe, but also we’ll be expanding to a very important country called Japan, which is onset of challenges and opportunities that will be also expanded to Latin America and in key countries like Brazil, Argentina to name a few.

And so this program if you will the internationalization is really taking I would say three approaches; one, is the traditional additional development work that we will need to do in countries like Japan for example for Revestive and Natpara. We will be filing Natpara in many of the international countries as well. But the second axis is the traditional commercialization that goes through pricing and reimbursement; having Revestive approved in Europe, the next step is exactly doing that ensuring that we get the right price and the right to reimbursement in Europe. But the third axis if you will of this international strategy is an ambition program, which is an excellent stream broad for us to initiate patients on Revestive actually in countries like Brazil and in countries like Turkey, but also in countries like France and Italy where through interrogation if you will or a waiver, we can have named patient program even though Revestive is approved in both Italy and France.

And the last pillar if you will of our investment thesis has to do with two things. I am very proud to say that we have a successful track record. I believe that everything we’ve promised, we delivered. We’re a company that meets its milestones. We say what we do and we do what we say. And I’m very proud of this particular aspect of NPS, because it’s very important for us to establish this relationship of trust and support.

At the same time, we work very hard on strengthening our balance sheet overtime and we finished last quarter with over $178 million in cash with a very healthy balance sheet. At the same time, also a product that is extremely important for us, has been extremely important for us, will continue to be extremely important for us, is a royalty stream that we are getting from Sensipar.

As a reminder, Sensipar is a product that we licensed to Amgen back in the date and we get about -- not about, we get 10% royalty on the worldwide sales of Sensipar. Sensipar is $1 billion product today; we get 10% that's $100 million. We negotiated an advance with Amgen and this was last year or the year before anyway, so we have an advance, which means that out of the $100 million we give them back 32, we keep the rest. And this will go until mid-2015, where we’ll retain the totality of the royalty stream. So that's a very important asset of NPS.

And last but certainly not least, as you all know, rare diseases is a very specific business. And it’s a steep learning curve, because it’s very different in development and commercialization from the traditional either development or the traditional commercialization.

We’re very blessed that NPS to have a not only a strong experienced team but also a strong experienced team in the rare disease business. And we have individuals within the organizations who have developed rare disease products and who have successfully launched the rare disease products. So with that we are very, very blessed, if you will, with the fact that we have the right team to support the company.

As I said, 2013 has been an exceptionally good year for NPS, starting with the successful launch of Gattex. And the slide reads that we are on track to achieve the 2013 guidance. Well, this is what the slide reads because we prepared the slides couple of days ago. I am very pleased to report that as of this morning, we have -- we met the lower-end of our guidance. So remember, our guidance was 275 to 325 patients on Gattex by the end of the year. We can check the lower-end of this range. And this is thanks to the unbelievable effort that our commercial team and our field based team did, led by Eric to get us to this point. So, we're very confident that we’ll meet our guidance on all different metrics by the end of the year.

We regained as I said, our ex-U.S. rights for Revestive and Natpara and positioned the company as a global commercial company. And we filed the Natpara BLA and we’ll spend most of the day today talking about Natpara and look forward to filing the EU MAA next year.

So, this is my formal presentation. I’d like to walk a little bit through what we will be doing today, this morning. We will start with the Gattex section, if you will and starting with the long-term Gattex data that were recently presented at ACG. Unfortunately Dr. Lauren Schwartz, being a very active physician, could not be with us this morning, she was called for an urgent medical matter and her priority obviously is taking care of her patients.

So “Roger volunteer” to be Lauren this morning and he will present a number of the slides that Dr. Schwartz was supposed to present. So Roger was kind enough to take over this part of the presentation. Eric Pauwels, our Chief Commercial Officer will provide a global commercial update on our progress with both Gattex and Revestive. After Eric’s presentation, we’ll have a short, underline short, Q&A session on Gattex and Revestive because we are anxious to move to Natpara and share with you quite a bit of information about Natpara.

So, if I look at the agenda here, Dr. Jeffrey Rothman who’s with us today will give us a broad overview of hypoparathyroidism and the role of the parathyroid hormone seen from a clinician’s perspective. For many years Dr. Rothman has been an attending physician at Staten University Hospital, he is also Clinical Associate Professor of medicine at the State University of New York, Brooklyn. As I said his specialty is endocrinology with very specific focus on calcium disorders and thyroid disease.

Dr. Rothman, and this is why his presentation is so critically important is the fact that Dr. Rothman is involved in the care of over 40 hypoparathyroidism patients. So Dr. Rothman can give you really the clinical perspective from someone who sees these patients day in, day out; and definitely looking forward to his presentation. He is also a key investigator in our PARADIGHM natural history that I just read. So welcome Dr. Rothman; we're very happy that you are with us today.

We'll talk a little bit about the burden of the disorder. And after we hear the clinical component and the physicians’ perspective, I think it will be very important to hear the patients’ perspective. And you will hear from Gail and Becky to hypoparathyroidism patients who are graciously accepted to be with us today and share their experience as patients living with this condition. And I'm sure that their perspective will be very insightful and position if you will the importance of finding a treatment for hypoparathyroidism versus what's available today.

This will be followed by Dr. Garceau, Roger Garceau, our Chief Medical Officer who will come back to talk about PARADOX and PARADIGHM, two very important studies that we have and we will continue to conduct with -- in hypoparathyroidism and with Natpara, talking about the burden of illness but also talking about the natural history of hypoparathyroidism.

Dr. John Bilezikian is known by most of you. Dr. Bilezikian is probably one of the world’s foremost experts in hypoparathyroidism. He is here at Columbia University. And frankly the risk of embarrassing and actually I am not embarrassing him because he is not here yet, his is on the train coming in. But it’s interesting to see how things start in our business. And I can tell that the Natpara hypoparathyroidism project started because Dr. Bilezikian thought it would be a good idea to have patient’s hypoparathyroidism on PTH. He asked us, if we would be kind enough to provide him with drugs, and we said sure. And at that time, you might recall the company was knee-deep in osteoporosis, so hypoparathyroidism was not anywhere to be seen.

And then one day Dr. Bilezikian called me and said let’s talk a little bit more because it seems that your product is working beautifully well in patients with hypoparathyroidism. Sat down and had a conversation with Dr. Bilezikian and frankly the rest is history. So pretty amazing how the initiative of one individual Dr. Bilezikian could kick off, a full treatment for a significant unmet medical need like hypoparathyroidism. And so we are delighted that John will be here with us today.

And then Eric will take the podium again. And Eric’s presentation will be very important because Eric will give you the whole enchilada about our plans for the successful commercialization of Natpara worldwide. So, we will talk quite a bit about what we are doing, what we have been doing and what we will be doing for the successful launch of Natpara here in the U.S. and ex-U.S. And then we will conclude the session this morning with a Q&A on Natpara that I will be more than happy to guide with my team and two experts will be with us throughout the morning.

With that in mind, I think it’s time for me to turn the microphone to Dr. Lauren Schwartz aka Dr. Roger Garceau. Thank you very much.

Roger Garceau

Actually it’s a pleasure to be here. It’s an honor actually to substitute for Lauren because Dr. Schwartz has been a key person and [asset] in our treatment of patients. And she is passionate about treating SBS patients. And so her understanding, her knowledge, I cannot even begin to [REPLACE], so I am poor substitute at this. Okay. But what I’ll still try to do is give you a little bit of the long-term data that we recently presented at ACG.

As you remember, STEPS was our pivotal study. And STEPS was a double-blind study and those two arms, teduglutide and placebo. There were also patients who were in the optimization phase in a closed enrolment. And those patients we’ve put into what’s called STEPS-2, which our long-term two year extension of STEPS. So there are three arms that go into STEPS.

And then we follow those patients for two additional years, so the teduglutide arm gets treated for 2.5 years and the other arms get treated for two years. And I would just want to -- there is a couple of points in terms of four when we look at the data that and it is important to put in perspective. All these data will be -- has been filed with the FDA and we’ll be filing it with the European authorities soon as well. So hopefully this will become part of our label as well.

So it’s two things, three things actually are important. One is when we look at the volume, when we signed STEPS there was continued decline of [care] and needs for these patients even at the end of six months. Now when you start looking at and we have some data already a year, but now when we look at all the way on to 2.5 years, what we see is the continued benefit of teduglutide with the mean decreases in volume, continuing over time. So this drug seems to take a long time, and continues to have benefit over time as we go forward.

The other thing that’s important is we saw days off and we continue to see an improvement in days off in the translation of an one day off to two days off to three days off, particularly in the teduglutide-teduglutide group. So what you’re seeing now is translation of that volume decrease to days off.

And more importantly we presented a little bit of this data at the AdCom as well, is that the end of the study pronounced to seeing 13 patients come off of PN out of the 88 enrolled. What that means is in the teduglutide-teduglutide group out of 30 patients who completed, 10 were completely off PN IV. I mean this is unbelievably dramatic, we didn’t expect -- I mean if you look at natural history maybe you’ll have one and these whole 88 patients would come off. So this is dramatic findings.

The other important thing when you look at this is not only do they come off, but they come off over a long time with patients coming off as late as almost 2.5 years of therapy. So the message really if we look at these patients, it’s continuing to decline over time with continuum opportunity to come off of PN IV.

The other thing that’s important when we look at demographics, the only thing that seems to be correlating with these patients was if you had really high volume, you’re likely to come off. So if you have 13 liters or less that’s where the all the patients came off. So the proportion of those patients is even higher.

When we look at safety, again, we have presented some of this data, it’s including in our label. When we look at the full data analysis, there is really nothing that we have seen that’s different than our product label. What we see is basically adverse events are common and this population is a sick population. We know that the most common AEs are still abdominal pain, catheter sepsis.

Now in the long-term what we see is episodes of weight loss. So when they get sick, when they have sepsis, when they get infectious and when they get viral infection, they lose weight and it comes back. So at the end of the study when we looked at clinical stability, and we looked the patients are lean, their weights were stable their cerebellums were stable. So over time, the assay experienced up and down at the course of this, but these patients are clinically nutritionally stable.

So we see a few discontinuations and again had about 25% discontinuation rate at the end of two years, but not unexpected in this population with the majority being related to adverse events. And you will note that the teduglutide-teduglutide group, the one that had to do, they have six months have less and the other ones, it seems that a lot of these discontinuations are early and they are lot of times due to the abdominal complaints.

So our product label seems to be very good in terms of what we have in the label today. There is nothing different in this trial when you look at the full extension. This is different than we have today.

So conclusion at this point is this is very impressive data, we filed with the FDA. So hopefully we’ll have it included with our label. We will be filing shortly in Europe, so we will include it in European label as well. We are really looking at the long-term safety and efficacy of this drug now and hopefully for the future.

With that I am going to turn it to Eric who will really talk about the commercial side of this picture.

Eric Pauwels

Thank you, Roger. The STEPS-2 data is truly exciting data and very important for the long-term value proposition. As Roger mentioned, one of the key things that we have is including that in the labeling, both in the U.S. and in EU. Well, I’m happy to provide a global update on Gattex and Revestive; so, I will be using both of those trade names interchangeably. And clearly we're very pleased so far with the launch progress in the U.S. In the U.S., Gattex is the first major advance in short-bowel syndrome in the last 40 years, same thing as well in the EMEA.

As most of you know, SBS is a very serious condition, it's very complex disorder and it is life-threatening. Clearly the body can no longer have enough nutrients and fluids. And GLP-2, Gattex is a proprietary analog; there is a naturally occurring peptide that’s involved in gastrointestinal rehabilitation. The product was approved in December of last year and we launched in February, so we've had about 9.5 months of experience so far.

If we look at the three main value drivers of Gattex and Revestive; clearly you have to maximize the U.S. opportunity for adult SBS. The U.S. remains our single largest market, as we said with about 3,000 to 5,000 patients. And we've got to continue to grow that business by expanding geographically in the adult indication. And I'll show you a little bit of some of the preliminary work we’re doing right now to develop and increase our current patient base through international markets.

Our final value driver is continuing to support the data and the label changes. As Roger mentioned, the STEPS-2 data is very critical for long-term use and then generating pediatric data as well for this high unmet need.

As of November 1st, we provided you information on the current prescriptions. We have about 452 prescriptions which equates to about 9% to 15% of the total market, nine months post launch. We have approximately 600 physicians who are REMs trained. And of those, about 80% of them have written about one prescription. So we have a lot of headroom here in terms of growth.

About 80% of those physicians who are healthcare providers are clearly squarely into the specialist arena and are treating short-bowel syndrome. They are gastroenterologists and surgeons. As we reported, in November we had 235 net patients on Gattex. However, it’s exciting news as Francois mentioned that we are now at the lower-end of our guidance in terms of net patients.

We reported that we have $11 million in net sales. There are compliance rates which are extremely favorable after nine months is around 86%. However, we know this is an injectable product for chronic long-term illness. And we expect long-term guidance to be somewhere around 70% to 80% compliance.

So squarely, we are in the -- our guidance is on track for net sales between $28 million and $32 million. 275 to 325 net patients on Gattex by the end of the year. And we are guiding to gross to net of approximately 8% to 12%.

So in terms of launch observation so far, it’s clear that the mechanism of action that Gattex has in GLP-2 is well understood. It’s not a very complicated stuff. It’s GLP-2 which increases the service area. They got helping patients absorb fluids and nutrition. So gastroenterologists get the concept and understand the underpinning of therapy. Our partnership with Home Infusion Companies in NPS Advantage had led you a number of very positive in early starts and has kept us in terms of compliance, high compliance rates very high and dropout rates very low with a lot of touch points for these patients very early, which is important to ensuring these key metrics. We've had broad reimbursement coverage so far. I think it’s clear that we are very pleased that we have gotten coverage from all the major private and government payers. And it really has not been an issue today.

Our Home Infusion partnership with our five specialty partners continues to be very fruitful. They have as you know somewhere between 20% and 40% of all the short-bowel patients that they are currently managing in their network. And we continue to find patients through their networks and provide clinical services that are needed.

And finally this is just a lot of positive and anecdotal feedback, Roger showed you some clinical data, but every week we get feedback from the field force concerning the clinical response of the drug including patients who have seen not only profound reductions, but also patients who have been weaned off.

And some of you might recognize Debra who is at the FDA advisory committee. She is a patient who was involved in our clinical studies and now is our commercial patient, so she has been Gattex suspect for more than three years and she was involved in the teduglutide-teduglutide group, the TED group.

As you know this is a complex disorder and it requires a whole group of healthcare providers to really touch the patients. So we set up for Debra and every single patient as a service program to ensure that when prescriptions come in that we provide them the benefits investigation reimbursement support before the prescription is then sent to the specialty pharmacy. So that area of burden to the patient and physician has been effectively removed and/or simplified.

And when the product is dispensed one thing that is very important is that we ensure coordinated clinical services, because we're bringing a disruptive therapy to patients and we are asking them to change diet and also change and reduce parental nutrition. So it’s a quite a complex disease that also requires tight coordination of clinical services. Our in network partners are delivering those to their patients, as well as dispensing Gattex and PN. And when they’re outside of the network, our partners are simply distributing the product for Gattex and we're providing clinical services through the NPS Advantage coordinated nursing service program.

Patient efficacy is critically important there is if you will one specific group that’s dedicated to short-bowel. The majority of these patients reside in different areas because short-bowel syndrome is a condition of a condition so they can end up starting in Crohn’s and end up as a short-bowel patient that’s still in the Crohn’s group. But we focus on a number of different activities including developing education materials, enhancing digital process, patient meetings, patient [ambassador] type meetings that we currently have and clearly faster and strong relationship in terms of educating and increasing the awareness of short-bowel.

So moving on to the international opportunity for Revestive, as Francois said, we've been very, very busy. International was an important inflection point for the organization. And we've been busy establishing our headquarters, establishing our regional offices both [Ireland] and in London.

The Revestive EU marketing authorization was completed and transferred in October. We have now an international product call center that’s live with over 11 languages and so people would be able to -- they are calling in now asking about product increase and that’s live. We have finalized our core value dossier which is our central dossier with all the data now including the one Roger had presented on the long-term. And we are working to prepare the local dossiers that are critical for pricing and reimbursement in Germany, France and the UK.

We have presence already in more than seven countries and we are staffing, where major efforts of staffing right now internally are going on the progressing in all these key markets where we are going to be sequencing the launch, as well as name patient sales.

We are looking to target about five countries in 2014 for commercial cells and probably about half dozen more for name patient sales. Those countries that we’ve had commercially which we define as pricing and reimbursement would be Germany, UK, Denmark, Norway and Austria. So we expect those to launch and sequence pricing and reimbursement so that when other countries in Europe reference they will be able to see those markets.

Now first and of course very important to the long-term value proposition is the Revestive STEPS-2 data which will be filed with the EU as a marketing authorization variation and that’s planned in first quarter of next year.

We also have a number of other countries outside of the European Union that we’ll be targeting including Canada and Switzerland. These are -- while geographically they are both either big or very small, they represent important opportunities for us in terms of Revestive overall.

The opportunity as we’ve gone through few market research, through surveys and as well as looking at the epidemiology data, we squarely are in and working with our specialty infusion partners in United States, which clearly in 3,000 to 5,000 patients in the United States. There are approximately 3,000 to 6,000 patients in the European Union. And rest of the world which includes Japan, Latin America, Canada, we are in somewhere between 2,500 to 6,000 patients meaning that the opportunity overall is about 8,500 to 17,000 patients in 30 countries. Those 30 countries we targeted, because those are the countries that represent the majority of where orphan sales exist and importantly where reimbursement exist for higher cost orphan drugs.

The core value dossier is extremely important because the first sequencing of the value proposition has to be presented in Europe. And we know that Europe is becoming more and more conservative and stringent. So demonstrating the value proposition around disease, burden of illness, unmet need and the pharmacoeconomic value if you will which Revestive actually does provide. It’s not a 100% cost additive to the system, it actually works in various ways to help reduce the burden, but also reduce direct and indirect costs.

The country-specific dossiers are being targeted in the first half and I'll get into this specific timing of those on a country basis. And then we will be sequencing as I mentioned those five countries that will be critical for pricing and reimbursement. The exception will be France, where the negotiation in price usually takes between 9 and 12 months that I'll get to it in a minute in terms of what we will do in that -- in the time where we're actually negotiating price. So these are two key countries for us. We’ll be sequencing the launch accordingly. So of course Germany is the largest orphan market in EU.

We have a number of clinical investigators who have been involved in a number of pivotal studies already and are managing patients who are currently on drug. And we have a number of meetings with them already. The population in Germany is fairly well covered under government applied healthcare plans. The analog process or when we actually filed that will occur in the first quarter of 2014 as we are completing the local dossier. And we are expecting the commercial launch with pricing and reimbursement in the first half of 2014.

With regards to the UK, UK is actually interesting market because PN is reimbursed essentially through the NHS and a lot of services for SBS because there are few patients and they are high cost of the system and most of the cost including surgical transplant and medications essentially funded through NHS. It is a highly specialized and specialist driven market. So there are few centers that actually do the reception and the majority of those centers are where we had clinical investigators involved in the trial and we have patients in the UK currently that are being managed with teduglutide.

There is a well organized patient efficacy group already and we are working to solidify relationships with them. And there is already -- like the U.S. there is an established home healthcare, there are established home healthcare companies that deliver PN and provide clinical services at home.

So the UK model is very similar actually to the U.S. model in many ways. We expect the commercial launch to occur in the first half of 2014. We are still not sure about the nice strategy whether it will be reviewed next year or not, but clearly PN and other products are centrally reimbursed which is certain in the national commissioning groups and that’s the target at which we will prepare our dossiers and our arguments.

France is a critical market as well, in many ways, not just for patients, but also for pricing and reimbursement because France is a country that is referenced by most of Southern Europe and even outside the U.S. So from a patient care perspective and coverage, the national plan actual ensures equal access and diagnosis for therapies for rare disease. And there is a mechanism, either say through the d'ATU or what we call, Derogation D’Achat, which is a mechanism to allow for early access and named-patient sales, while you are in the process of going through pricing and reimbursement negotiations. These are typically reserved for drugs that have high unmet needs and where there are life frightening conditions. So, we actually do need that criterion.

We anticipate -- we've already identified numbers of patients and we are anticipating named-patient sales in the early part of 2014 to begin. And our dossier for the committed trust balance and such are currently in process of development. They will support the value preposition including what Roger presented the long term data.

This process hopefully will get us a very high ASMR rate. And through ASMR pricing reimbursement and transparency, that process can take anywhere between 9 months to 12 months. And there is really not generally, no favorability for any standard drugs or orphan drugs; this is a kind of set process that you have to go through.

We have clinical investigators in France. And importantly SBS is highly centralized in terms of the treatment. So there are handful of centers that really touch and see most of these patients and the nutritionary centers that manage the PI.

And as I mentioned, we have already market development activities and presence where we're identifying patients to go through Derogation D’Achat.

Turkey is very important. While Turkey is not a part of the EU yet, Turkey is extremely important in terms of its overall growth. And clearly, we've targeted because it has a well defined mechanism for early access essentially by -- TEB is basically central pharmacy group that actually can order products for life threatening conditions that are not available or registered in Turkey. So, we've begun the process of identifying patients. And the opportunity is highly centralized in three key cities in Turkey where academic hospitals do resections, treat patients and also send patients home with PN. So PN is actually dispensed in the hospital setting. And our market development activities have been in place now for a number of -- a couple of months already and we've identified patients and we’ll begin to see named-patient sales in early 2014.

Our largest market in Latin America: well, as Francois mentioned, we’ll be targeting a couple of key markets. Argentina and Colombia have named-patient sales but Brazil represents the single largest opportunity. And constitutionally, patients who are residents or citizens are allowed to have access to products and medicines constitutionally; and if the product is not available, they can import the product on a named-patient basis. So there are mechanisms particularly for ultra-orphan and orphan drugs.

We have again a presence already in Sao Paulo where we're currently doing a lot of market development and patient identification. And we've identified patients already. This is a process that takes a much longer period of time because there are judicial requirements as well to go through an interpret access, and that can take somewhere upto about nine months or more. But once patient is on drug, then the governments will order the product. There is very favorable guidelines already written in Brazil on how to treat SBS patients. And importantly GLP-2 which is teduglutide as already mentioned, even though it’s not approved as a particular analog that’s very favorable.

And finally Japan, Japan is the second single largest market in the world and very important for ultra-orphan drugs. 100% of the population is currently covered through national healthcare systems. And we expect actually and most ultra orphan drugs do expect premium pricing over the U.S. It’s very concentrated opportunity, really four-five key sites do most of the adult surgeries in Japan. And we have, as you know, in Japan it’s very hierarchy driven, so there in those sites there are experts who are not only transplant surgeons but also adult GI who take care of those patients. There is -- surprisingly there is already an established SBS patient efficacy group and they are already beginning, they are quite active and just starting up.

We -- academically the drug lag which is products that have actually been approved in the U.S. for life running conditions, the academic institution has already filed with MHLW for drug lag which brings about further credibility to advance the product development. And in the first half of next year, we are looking to file orphan designation which would be very important, would give us 10 years of exclusivity in Japan.

And product development including clinical and regulatory is clearly an area that we are defining and working with our internal groups and our KOLs.

I'll hand it back to Francois.

Francois Nader

Thank you much Eric. And well I'd like to invite our CFO, Luke Beshar as well as Roger and Eric to take few questions if you have on Gattex.

Question-and-Answer Session

Unidentified Company Representative

In mark about 10 minutes to have a short Q&A on Gattex before switching to Natpara. Any questions? Salveen, I think there is a microphone that is heading your way.

Salveen Richter - Canaccord Genuity

Thank you. You have mentioned in the past that your long term compliance and dropout rates will be achieved when a patient’s been on drug for about 6 months to 12 months, just wondering with the STEPS 2 data, as you have shown those to physicians and expected to get on the label. Will that extend the time point at which they reach that long term rate or do you expect an improvement there?

Francois Nader

Roger?

Roger Garceau

The STEPS data, we’ve shown it to some physicians. I mean they are impressed. But the trials are a little bit artificial to try to take keep patients in, but if we look at compliance over two years, it was very good. So in real life, we don't expect it to be there. And when we talk about how long it's going to take us to hit that compliance rate of or persistence rate of 70%, 80%. We are telling physicians and patients that you really need to think about treatment for a full year, before you think about that this drug is probably not working for you. Okay. Because what we saw even at the end of the STEPS is that some patients who “not responded to 20% by a year were responding.” Okay. So you've got to give them enough money.

Salveen Richter - Canaccord Genuity

Okay. And just a quick follow up.

Francois Nader

Sure.

Salveen Richter - Canaccord Genuity

You’ve mentioned seasonality maybe affecting Gattex uptake in the holidays; did you see anything around Thanksgiving?

Francois Nader

Well, it’s too early to say. But again, I would like to see everyone go through, so we have a full, if you will, view of the seasonality we are not there yet, prescriptions as we go -- as we know, goes through ebb and flow, haven’t seen anything unusual.

Salveen Richter - Canaccord Genuity

Okay, thank you. Yeah.

Unidentified Analyst

Hi. I just wanted to follow up on your 9% to 15% market penetration rate so far; how is that tracking versus your internal expectations? And then also use of that 80% of prescribers so far have just written one script. Dou think that’s because they just want to see how the drug performs in a patient or do you think that they might be having some trouble identifying the right type of patient?

Francois Nader

Eric?

Eric Pauwels

Yeah, I think to answer your question, 9% to 15% is exceeding our current expectations. I think overall we are very, very pleased with the current uptake in terms of prescriptions. To answer your second question about 80%, the feedback that we’ve gotten from the field force is that majority if not all these patients have more patients behind, so it’s a sequencing thing, they are trying the product and they are looking for the clinical response and looking at a sort of a benchmark for experience.

Unidentified Analyst

And just one quick more follow up.

Francois Nader

Sure.

Unidentified Analyst

Do you think that you could be expanding the number of partners that you have to distribute that tax in your term?

Eric Pauwels

So, we are always evaluating the current partnerships that we have as well as looking to how things will expand. As you know, this area is consolidating, it’s always moving, there has been another couple of acquisitions that have happened recently. And so we are always - it’s not something that is closed, but by the end of this year we’ll actually be evaluating our current performance and looking towards opening it up if required.

Francois Nader

Good. Thank you, Eric.

Joe Schwartz - Leerink

Thank you, Joe Schwartz at Leerink. I was wondering if you could talk about the profile of those first patients that are going on Gattex since SBS can be pretty heterogeneous. And what are you doing to ensure that the physicians have a good experience with those since there are so many different physicians? And then relative to that, can you talk about your physician phasing MSL infrastructure and other companies have decided to build that out in advance of future growth at this stage in launch recently? I was wondering if that infrastructure is sufficient now.

Francois Nader

Yeah. I’ll ask Eric to take the first part of your question and Roger to take the MSL part. Eric?

Eric Pauwels

Yeah Joe, your question around who are physicians selecting in terms of sequencing the patients, it’s really quite all over the place. And we've seen younger patients; we've seen more severe patients, high volumes at PN. So the word around heterogeneity is correct. There is a broad base of patients that are currently being tried and tested if you will with Gattex. So what we’re trying to do is not select specifically or try to look at a cohort of specific patients since we've had a broad variety of them that have come in. We've tried to take them one-by-one and look at that. Our NPS Advantage and our whole set up as I showed earlier is really set up to handle each patient that comes in. So in managing the referrals all the way to Rx and ensuring that the clinical services are coordinated very, very early with high touch points is critically important whether it’s a young patient or an older one.

Roger Garceau

The question with the MSL is important because not only do we have sales that's going in, but there is eight MSLs out there just for Gattex and we’re hiring additional MSLs and we’re in the process right now putting those on board to Natpara in anticipation preparing that market as well. But there is a high interface as well because as the physicians see the data and looking at long-term from the sales force through the MSLs and for medical information; it’s a good flow of information. But one other question is how do we treat the patients et cetera. So, there actually has been some very good communication, how do we think about the right patient needs.

Francois Nader

Thanks Roger. Joe, you have the follow-up question?

Joe Schwartz - Leerink

Yeah, actually real quick. The discontinuation rate, do you expect that to differ between those patients that are treated in network and out of network? I think there are more patients being treated out of network than maybe some of us expected?

Francois Nader

Probably can this question. I am thinking because we don’t think of discontinuation whether it’s within or outside of network. I don’t believe so, Joe. I mean time will say, but I don’t believe that that will be the case.

Joe Schwartz - Leerink

Sure, thanks.

Matt Palmer - Oppenheimer

Thank you, Matt Palmer for Oppenheimer in for Boris Peaker. I wanted to ask about the STEPS-2 data, the difference between the treatment-to-treatment and the placebo-to-treatment; looks like the volume reductions of 24 months are bit different. And I was wondering if you could explain why we see that?

Francois Nader

Sure, Roger?

Roger Garceau

So you have to see where the baseline was first. So the baseline for this teduglutide-to-teduglutide group is way back in the beginning of when it started teduglutide, which is the beginning of STEPS. So it’s starts at 12.9 and goes down to 4.9. And so that’s the volume decrease. The placebo group, don’t forget, had a titration and they lost about 2.4 liters at the end of placebo time. And then they have a further reduction on top of that. So what you see the difference is from the start of teduglutide for all three groups.

Now, the direct rollover group is a small number, so it’s hard to say what’s in there. The other thing that’s important to understand is that in STEPS you had much more frequent monitoring and visits. So at STEPS-2 you only have -- after the first three months, you only have every three month visit. So the ability to reduce after the first three months of STEPS-2 is much less. So there is a whole bunch of different dynamics in there. So if you add the placebo response and basically the STEPS-2 data for the placebo group it gives you better feel, but it’s a much larger reduction, if you look the way they actually started at the beginning of STEPS. Okay?

Matt Palmer - Oppenheimer

Thank you. And maybe just on the European pricing strategy, can you comment on whether or not the historic price for the active ingredient will have any bearing on the pricing?

Eric Pauwels

With regard -- I just want to clarify your question. Is it historic pricing for teduglutide?

Matt Palmer - Oppenheimer

Yes.

Eric Pauwels

Well, currently the only pricing that’s currently available to reference will be the U.S. price at this point in time. So historically when Europe actually goes through to, this is very exciting, it’s very closed system in Europe. They don’t actually look to the U.S. for price referencing. They are going to look at what innovative treatments are available for SBS within the European Union that they can actually reference. So that’s one of the reasons why we are sequencing Germany, UK, Nordics and those markets because currently price does not exist. They will be the first ones where we have established price.

Francois Nader

Okay. My light is blinking here which signals the end of the Q&A session. So, thank you for your questions, thank you guys. And it’s my pleasure to invite Dr. Rothman to the podium to give us the clinical overview of hypoparathyroidism. Dr. Rothman?

Jeffrey Rothman

Good morning. Let some people take some seats. Thanks very much to NPS for inviting me today. What I hope we will able to do in a very brief time is to provide you with some information about basic normal parathyroid function, the problems of parathyroid hormone deficiency and the available therapies and its problems.

So, I think all of us understand that that in normals calcium is tightly maintained within a normal range. And this is absolutely necessary because human beings depend on normal calcium for normal neuromuscular function, cardiac contractility and the like. Hypoparathyroidism is relatively uncommon and certainly in the simple sense due to the deficient or absent parathyroid hormone or its action.

Patients who have untreated hypoparathyroidism have a particular constellation of problems. As you would guess, low serum calcium, but in addition high serum phosphate levels, low-to-absent PTH levels, relatively high urinary calcium excretion. So that for any given level of serum calcium, there is relatively more calcium in the urine in individuals who lack parathyroid hormone and there is a difficulty in activating vitamin D and creating a hormone from a vitamin and that is 125 dihydroxyvitamin D.

Why does this happen? It happens mostly because of surgical problems either because of thyroidectomy most commonly or because of parathyroid surgery in which inadvertently parathyroid glands are removed where their blood supply is compromised. This can happen acutely, immediately following surgery with some frequency and the estimates very widely, but maybe approach 50%, this is [transient]. However, unfortunately some patients develop chronic hypopara. And this is rare in less than 5% of the time.

Outside the scope, a little bit of today’s talk are other causes of hypoparathyroidism, they are fairly extensive, they are fortunately rare and the leader in that category is autoimmune hyperparathyroidism which can occurs an isolated event or as syndromic event with other endocrine organ cell as well. I cannot dwell on this one. There are other infiltrated disorders, external beam radiation on occasion can do this, but these are all pretty rare.

So PTH is an 84 amino acid protein released by parathyroid glands, and absolutely necessary to maintain normal calcium and phosphate homeostasis. And as mentioned, serum calcium is maintained and tightly maintained in each individual within a very narrow range.

The target organs for PHT are the skeleton, kidney and gut. And we can kind of try to review this in one big picture. In normals, the parathyroid glands have on their surface a calcium sensing receptor on a surface of cells which acts kind of as a calciostat, so that each of us has within us a normal set point for serum calcium. If we fall below that set point this triggers within the parathyroid cells to release a parathyroid hormone, which acts on several major target organs, the major ones shown on the slide are the skeleton, kidney and intestine.

In gut, parathyroid hormone does not directly work, but works through the actions of activated vitamin D and it stimulates the activity of this activation in the kidney mainly by stimulating one alpha hydroxylase that creates an active hormone from a vitamin. So 125 dihydroxyvitamin D works on the blood to stimulate calcium and phosphate absorption from dietary and supplement sources and get that circulation parathyroid hormones absolutely vital through normal bone reabsorption and normal bone remodelling, so that the action of parathyroid hormone in the simple sense in bone is deliver a calcium and phosphorus anti-circulation as well.

The actions in kidney are somewhat more complex PTH stimulates calcium reabsorption back into circulation again to raise calcium, but has a very powerful affect to cause phosphate, in addition of phosphate reabsorption and phosphaturia and this kind of balances out the phosphate that is entered into circulation from both GI absorption and bone resorption. So that the net result of all of this is [normal] serum calcium and maintain of normal serum phosphate this feeds back to parathyroids and maintains normal homeostasis.

In the absence of parathyroid hormone we have problems. And shown by these target organs, we don’t adequately absorb dietary calcium or phosphate, this is true whether it’s in the form of supplement, or in the form of dietary calcium, bone turnover slows dramatically, there is an ability to rapidly localize calcium and in the aggregate an increase in bone density overtime and this is true in both compacular and cortical compartments of bone.

In the kidney calcium is not adequately reabsorbed and because there is an absence of PTH, so for any given level of serum calcium there will be more calcium lost in the urine this becomes a management problem, as we’ll see later, phosphate tends to be resolved. So we have this characteristic combination of low serum calcium and high serum phosphorus, hypocalcemia, hyperphosphatemia.

And to have a little bit on bone, bone is obviously a major reservoir for serum calcium and PTH is necessary for normal bone homeostasis. Patients with hypoparathyroidism have markedly decrease rates of bone remodeling and bone remodeling is a necessary part of good bone health. We have to be able to repair micro damage, micro cracks that occur in bone and in the absence of PTH this process is reduced. This is measurable and this will come up in trials data by measuring markets of bone turnover which are dramatically reduced in general in patients with hypoparathyroidism.

So this is the last endocrine-deficiency disorder where we don’t replace a hormone. If you have hypoparathyroidism we give you thyroid hormone if you lack testosterone or estrogen you can get that growth hormone and alike, but we don’t at this point in the United States or around the world use parathyroid hormone on label to replace parathyroid hormone deficiency.

So what we do is we use activated vitamin D and calcium to force calcium in essence calcium at phosphate reabsorption from the gut into circulation to maintain adequate levels of serum calcium. This is a problem. It’s a clinical challenge for all of us who treat hypoparathyroidism because it’s imperfect, it’s rather a blunt instrument and although we can often maintain reasonably normal calcium levels there are episodes in the course of the life of these patients where they periodically will either be inadequately treated either because they have some GI difficulty and can’t take or absorb their supplements and vitamins or episodes where we overshoot and they become hypecalcemic both have consequences. In the acute setting hypocalcemia is a frequent reason for emergency room visits for patients with hypoparathyroidism. They may develop symptomatic muscle cramping even tad knee, or angiospasm, seizures and generally feel often require urgent care with intravenous calcium supplements.

Chronically the problems are little bit different; we’re always walking a line between high, low and somewhere in the middle. Our target because of this obligate lose of calcium in urine is never to fully replace calcium levels to mid normal range but rather let it creep just into normal from the low side. Because if we fully supplement these patients and create fully normal calcium levels they will have obligate lose of calcium in the urine, hypercalciuria the potential for kidney stones overtime and because their phosphates tend to be high a high serum calcium phosphate product can cause deposition of calcium phosphate salts, in self tissue this is irreversible what it happens so it can cause permanent kidney damage by having over enthusiastic treatment. Sometimes even with good therapy some patients have residually high urinary calcium levels and we have to have it dossier direct which reduces calcium loss in the urine but creates its own problems in terms of sodium and potassium management.

So the potential complications of our management approach what we have available to us is the potential for hypercalcemia and hypercalciuria, this is related to large doses of calcium and vitamin D. And the potential for kidney stone formation nephrocalcinosis and permanent renal dysfunction as the consequence of therapy. Because PTH is not available to cross phosphatemia, these patients tend to have higher phosphate levels than we would like them to. And the combination of high calcium when it occurs in phosphate can close calcium phosphate at position. There are problems related directly to the use of [biocides] which are an ancillary problem in the management income these patients.

So we have an incomplete balance between partial simple management and long term complications. And the short term clinical focus for treating the patients is to treat their symptoms. And if symptoms are those mainly of hypocalcemia. So we can with our therapies reduce the risks of paresthesias, muscle cramps, twitching seizures and arrhythmias imperfectly but we can do it.

We have potential long term clinical consequences of our therapy in the form of incomplete symptom control and some of this are not going to be fixed at over what we do. The burden that these patients have in terms of their quality of life issues, neuropsychiatric issues are considerable and we'll hear more about that as we go along this morning. But we do not correct that with our therapy.

Potential exist for both hypocalcemia and hyperphosphatemia in these patients, hypercalciuria as discussed the consequence of that maybe in nephrocalcinosis and kidney stone, soft tissue calcification and even renal failure. There is an outstanding clinical need, because what we do does not fully restore mineral homeostasis to normal, it's an imperfect therapy. And bone is not really fixed at all.

We can correct serum calcium but we lead patients with a low turnover state and high bone density which may not be healthy bone in at least one reason paper from Brazil potential for fracture in these patients although bone density is high.

So hypopara is relatively rare complex endocrine disorder. With low levels of PTH hypocalcemia and hyperphosphatemia our current management is quite limited to symptomatic control of low calcium that was easing calcium and activated by [MD], the therapy is incomplete. It’s a balance between of partial symptom management and the prevention of long term contemplations and clearly cries out for better therapy.

Thank you very much for your attention and thanks for having me here today. Now it’s my pleasure to introducing Mary Frances Harmon who is the Head of Global Patient Advocacy for NPS, the title of the talk is a day in the life of hypoparathyroid patient. Go ahead Frances.

Mary Frances Harmon

Thank you. Gail and Becky have joined us here today. And both are living with hypoparathyroidism and they are actually currently taking that product through our clinical program. And they have come to the disorder from different etiologies, Gail is idiographic, they don’t know what caused her disorder, but yet Becky is post surgical and this is result of other recent surgery. Their symptoms and their journey, they are little bit different. And what we want to do is take a few minutes, little bit time we have had and it’s how to help provide you with a glimpse of what is like to really live with hypoparathyroidism.

So Gail can you describe for the audience, what your journey looks like by your symptoms realized when you first started to experience and how you arrived at the diagnosis?

Unidentified Company Representative

I first started just turns this about two years ago now. And it’s started with tingling in my hands and kind of like when your foot (inaudible) and it starts waking up. And overtime it became more and more intense and the duration was longer. I finally realized that something was really wrong when I was starting on a highway and my hand went into pat-knee, which means it’s a muscle cramping and clamping and I drive sticking, I couldn’t shift my car. I went to a doctor and they didn’t know what was wrong with me, they did a number of tests, they did blood tests, they did neurological tests, but it was, it took me looking on the internet actually to outcome to test me before institute.

Mary Frances Harmon

Okay. And Becky your surgery, how did you come to the diagnosis?

Unidentified Company Representative

I had two surgeries in 2005, date apart, for thyroid cancer, the first surgery when I came out of, when we have the surgeon said that they had remove one of my thyroids and they took second one out and chopped it in tiny piece of your about size [rice caught in silver], very small and you are hoping the blood flow would return and I would be what they call stand and in time my parathyroid function would recover. I went home the next day and six hours later they called back and said they didn’t cut all the cancer that I had to come back to the hospital have the second surgery. So they reopened me up and we’re not really clear, what happen to the second side that was just a small trauma at the surgeries or what, but I ended up without parathyroid function. A third the time what they did was they gave me calcium through like a tongue type thing, I was taking it every four hours about four tablets and they felt that over time that my parathyroid function will kick in and my calcium levels would come back up and it did not.

Mary Frances Harmon

Yeah. What it describes the symptoms that then that you were experiencing before your diagnosis that really helped you get to discovering that it was a permanent condition and what drove that.

Unidentified Company Representative

Well basically before the surgeries I was normal like everyone else and I was thrown into essentially a three year period and when I came home from the hospital I had (inaudible) all of this helps because I was constantly eating that they were not putting me on calcium per se. Within about two months I was having the same type of reaction that she was tingling around the mouth, tetany on the arms legs, muscle contraction, so you can’t straighten up your legs, you can't stand up on your feet. And one night I went to bed and I had severe shoulder pain on both sides and I thought (inaudible) and comfortable, I would be okay and I wasn’t, I got out and I (inaudible) having muscle pain from having the surgeries what have and that didn’t help. And I got out of bed and thought if I walk that would help and I collapsed and I went into (inaudible) which is 1,000 foot airway (inaudible) and I slipped the (inaudible) on my which I got later on my EKG and was having cardiac, something like a heart attack. By the time -- what they had me do on the middle of the night is eat calcium every 15 minutes and if I didn’t get better over a period of time, come into hospital and that’s when they discovered that my calciums were extremely low.

Mary Frances Harmon

Today associated with the hypoparathyroidism?

Unidentified Company Representative

No, not at that point.

Mary Frances Harmon

How did you get to that discovery?

Unidentified Company Representative

My [surgeons] were in June, the heart issue was in August and October, I flew to Denver to the Phycor Conference which is the Thyroid Cancer Survivors Conference and the doctors can speak to the patients about coming therapy and we have there and they said this isn’t the thyroid, there is something else going on you need to get home and see an interchronologist. So I returned sacramental and cannot get referral to the surgeon and was able to finally get a referral to my internal medicine person, she wasn’t taking your patients until February. So at that time I didn’t known what’s going on so I waited until February having these trimmers and issues and when I got in to see her, the first thing she did were a blood test called PTH and that’s when we discovered hypothyroid.

Mary Frances Harmon

So Gail, once you were diagnosed then how did they manage your symptoms what did you do to control them?

Unidentified Company Representative

Well initially my primary care physician referred me to an endocrinologist too and then it asked of that that she didn’t know anything about hypoparathyroidism but (inaudible) going to learn and she had maintained calcium in the form of chocolate (inaudible) and calcitriol And it was a kind of experimental phase that we went through to see what would work for me. I took anywhere 1.5 to 6 grams of calcium a day a number of different types of dosages of the calcitriol. And unfortunately she left the practice. So I saw double doctors after that I called doctor shopping it’s very difficult to find a physicians that really understands hypoparathyroidism. And actually just gave up and started treating myself.

Mary Frances Harmon

And Becky, how about you what the things that you did to control your symptoms once you got the diagnosis?

Unidentified Company Representative

Once I got the diagnosis the endocrinologist whether I took out a prescription pad just for not and put down, which you thought I need to take. And then just said if you need more with the symptoms you can pass more calcium and it includes also on gastroenterologist prescription drug helps you with calcium and I self treated for five years.

Mary Frances Harmon

And what types of dosages were you taking continuously?

Unidentified Company Representative

I was taking between 4,800 and 6,000 milligrams of calcium a day. And that was causing severe back pain in my kidneys and when I would urinate it looks like a powdered milk and from calcium for not absorbing it.

Mary Frances Harmon

Well. And you were also sharing a story with me last night. Which I think it could be interesting around your chest x-ray for something could be needed so.

Unidentified Company Representative

I had a violent infection or something I get a chest x-ray and extremely low and something that’s (inaudible) said don’t get dressed we will be right back and he says, did you have barium enema and I said no. And so he left and about two minutes later he are you sure you didn't have barium enema and I said I would remember that or a barium study. And so the third time I said just go and get the doctor and so the doctor came in the radiologist. And he says what's there something in your gut and I said it's calcium. I take so much calcium that you are not ready or so you just build up a lot of calcium and it's actually reflecting in the x-ray.

Mary Frances Harmon

So once you are diagnosed and Gail, once diagnostic know it's hypoparathyroidism you are managing as best you can with symptoms. Tell me what it was like, help us describe what it was like to live with it.

Unidentified Company Representative

I think we have a hardest things about it is the unpredictability. You can feel fine one day and then the next day you can get up in the morning thinking everything fine and then all the sudden your calcium permits and you have what we call the calcium crash. You can't determine why it happened, we can't anything to prevent that, and it can really impact your life, I know that when my calcium runs really low I have what we call brain - and had the cognitive impairment and I move the ability to speak which is kind of frightening it affects your muscles and it creates incredible fatigue and it’s difficult to manage. There is not one type to follow approach and what you took yesterday isn’t necessarily going to work today.

Mary Frances Harmon

And what just like I mentioned across, so can you just describe fatigue as I know is different for everybody what it is like for you when a crash comes on?

Unidentified Company Representative

So when I start feeling a calcium crash, it starts in-tingling in my hand and then it approach to my face when I start feeling numbness in-tingling around my face, I know I am in big trouble, my head goes numb, my eyes go numbs, do you every consider feeling your eye ball and so you don’t feel your eye balls. It’s a frightening physically demanding and fatiguing event.

Mary Frances Harmon

And are you able to abort (inaudible) it a bit?

Unidentified Company Representative

When I start experiencing crash, I will start taking large doses of calcium every 20 to 30 minute I will take a gram until I start feeling some reduction in symptoms and that can take several hours that responses like to take a pill and you feel better, it can take three to five hours to feel better. And afterwards you are so (inaudible) I will come home and sleep for 18 hours. I mean literally I am not able to move. And it’s a residual fact I will feel for the next several days.

Mary Frances Harmon

And how is that for you Becky, what is your experience?

Unidentified Company Representative

Mine’s similar to that a little bit. I start with the tingling and then (inaudible) around my nose and my hands and feet start trembling, and then I contract and when I contract I feel I can contract sideways that you can barely. And then it goes up my legs and arms and actually bad it can get into my arm [airway] and I do the same things as she does prior to be on PTH, would just pop calcium. The thing is as you take the calcium, the calcium level might come up and that to take some of the symptoms away but you are really affected for about three days, even if you put yourself under control or you think you’re normal, you’re so wiped out. And the pain from all the spasms that you’ve had at least three days, I am feeling it, and I’m saying with you, I am just sleep, and you’re in a dead sleep (inaudible).

Mary Frances Harmon

Can you predict what trigger the crash?

Unidentified Company Representative

Absolutely not.

Unidentified Company Representative

No.

Mary Frances Harmon

So you both on Natpara?

Unidentified Company Representative

Yes.

Mary Frances Harmon

And you’ve been in the clinical trials, so maybe you can each describe to the audience how that’s changed your management of this condition.

Unidentified Company Representative

Well, I was really nervous about starting that clinical trial, (inaudible) needles and injections [scared] me, but after a day or two I figured it out, and it doesn’t bother me and I felt normal. I can’t emphasize that how wonderful normal feels, it’s something that you don’t appreciate, if you just moving your life everyday without a medical condition. So at the (inaudible) needed, it completely changed my life. It has needed so that I live a normal life again by doing injection in the morning and for the most part I am good to go, it’s (inaudible).

Mary Frances Harmon

And how have you adjusted your calcium?

Unidentified Company Representative

I now take no calcium at all. I take test trial depending on where my levels are, I still run [lower] times but nothing like before being on PTH and the elimination of having to take all those pills is just incredible.

Mary Frances Harmon

And how about you Becky?

Unidentified Company Representative

When I started PTH, I was in a double-blind study and I went home after the first injection and I called the doctor I’m on it. So, he don’t know that and I don’t have it, -- tell him yet, I’m on it. It turned my life around. I stopped the thing when I stopped the (inaudible) and contractions. The brain fog is unbelievable. I thought -- before the PTH, I thought I was getting all (inaudible) I was 47 when I had the surgeries. And I've been telling the story that I was sitting in the living room and I was telling him to get a little [white thing] and he said [white thing] as it the little [white thing] he said do you mean the dog? I said yes and I didn’t know how to say dog, and he says you know the doc’s name I couldn’t remember the dog’s name and the dog was about nine years old at the time. And so he got the dog and having sit with me and I said you know I have to (inaudible) for the rest of my life, I don’t know if I can do this. And not really understanding the disease at that time I felt maybe this is Alzheimer too. Once I started on the PTH, I am fine. I can read, I can go to gym, I can travel, I can live pretty much normal life.

Unidentified Company Representative

I don’t know about you but I found it really -- it changed my outlook. I mean I thought more positive living with hypoparathyroidism, it’s depressing. And it’s -- you kind of feel like there always was a weight on your shoulders. And I just thought kind of lifting that weight and re-positivity about life. I don’t know, it’s hard to describe.

Unidentified Company Representative

And this disease, it’s not just hard on us, it is hard on our spouse’s and our families because they see what we're going through and they know what were [lying.] And it’s -- I look to their eyes thinking at times it’s kind of been very hard.

Francois Nader

Yeah. Well thank you, thank you both for sharing your journey and your story. Hopefully it’s helped to provide some additional insight. I believe we are going to take a 10 min break and when we come back, Dr. Roger Garceau will share with you some of the findings from PAPADOX and also describe the upcoming natural history study of PARADIGHM. Thank you.

Roger Garceau

Good morning. I invite everybody to have a seat and we will get back with the rest of the program. A little bit -- a lot more about Natpara and the role Natpara will play. We are very fortunate to hear from a couple of patients. And these patients we think about as are they typical or are they what we see. And you have heard about the disconnect between patients, symptoms and sometimes what the physicians see.

Well, what we did as part of the company is tried to explore a little bit about the patients’ attitudes and responses about where they are at for their current disease. This is actually presented already at the Endo Society earlier this year by Bart Clarke from the Mayo Clinic. And it was really -- this study was conducted in cooperation with clinical experts with hypoparathyroidism and more importantly with patients themselves.

The objective as you heard about, it seems to be a delink between a patient’s experience and what they are telling us and you hear some stories and what physicians sometimes tell us about how they perceive patients and what families et cetera perceive. So what we did is we said let's look at an internet survey or some sort of study to say can we get a better feel for what's actually going on with these patients in a much larger population. Again as an orphan disease, it's hard to collect a lot of population. We are fortunate to have two experts in the audience who actually have probably the largest collections in United States with the tow docs that heard today -- you will hear today.

So, it's important for us to understand what are the symptoms they experience and this is while on treatment. These are patients who are actually on (inaudible). So, they are being treated for symptoms, but you'll see what the reality is.

So, what we did is we prepared a whole bunch for questions, put together as I said with different experts and basically invited everybody who has hypoparathyroidism to participate. If you are adult in United States, they are going to buy it. Invitations were sent out through, the hypoparathyroidism associations, their membership saying please tell us what's going on with you?

Basically the only thing we excluded if they have a disease that really a nit a hypoparathyroidism. What we then did is the symptoms, they were asked (inaudible) the symptoms, about 38 symptoms. Okay, we were then ask to say it’s over the last 12 months, what were those symptoms you experienced and these symptoms were broken into three general categories, physical, cognitive and emotional.

We also then looked at as the disease and rate itself, are you mild, moderate, sever, and also with the symptoms that you have, rate down from one mild to seven to sever. And then we did some statistics in terms of where the average ranges are pree to the groupings et cetera. I will show you some of those results.

What’s impressive here is that we sent out about 2,000 surveys, and we actually had about 20% complete response. We’ve been analyzing it. We’ve done internet survey and my experience is extremely high. So this is a very good response. More importantly, when you look at demographics of the responders, what we see here is the mean age of 49.4, just give you some comparison, and the [replace] file was 47, and you will hear from Eric, it’s very much in line with what the market research tells us.

We look at etiology okay, mostly post surgical, 80%; in our trails, it was 74; male versus female, it’s about 80% female here on the clinical trial, it’s 78%. So, and Eric will show you similar data for the market research. So the demographics of people who responded to the survey are indeed the people in the studies and are deemed the people that we are seeing in the market research data out there.

So let’s take a look now in terms of what symptoms actually have health severities they have. Across the top, what you see is while the patients are on calcium and vitamin D, how the rating is held. So, about 80% are saying that they have been in the moderate to severe range. And what does that mean? When we look at symptom burden, how it interferes with their own life, and you’ve heard some of the very much illustrated better than I can. The issue is around ER business, the issues around having to go to the hospital and being admitted for disease. When you look at patients reporting mild to moderate, the mild patients have an average of nine symptoms. 11% report that interferes with the life every day, these are patients with (inaudible) they weight themselves as mild.

If you look at the sever ones, okay, experience is well over half of the symptoms they experience. And more importantly almost three quarters reported the significant interference with their life every day, right. Looking at ER visits, even the mild ones have a couple, days in hospital are more. And what you’re going to see is the impact on their lives is just not in terms of having go to hospital, but it’s much, much more broad.

Symptoms themselves, when we look at how long people flash symptoms, but we saw that these symptoms asked lasted on an average of 13 hours per day. That's basically thinking about they have symptoms all day long from what many of these patients.

When we look at the physical symptoms, so we’ll start looking at this one, what we see is at least 70% have muscle pain and cramping, another almost over 80% tuck-up the teeth, and you’ve heard it very clearly today that the tiredness they’re feeling; it’s not just an hour or two, it’s all day long, Other things like tetany, joint pain, headache. You see a lot of complaints in these folks. You also see issues around, and you heard it again earlier, this brain fog, this inability to think and concentrate, being almost three quarters of these patients self reporting, okay.

Memory loss, forgetfulness, these are not uncommon occurrences. What you heard today from these two ladies are not uncommon. And more importantly, when you look at the effect on them, the co-morbidity effects on anxiety and depression, what they feel like, and other co-morbidities, this is the disease that affects their lives and affects not just them, but their families which you heard.

We also look at and Dr. Rothman talked a little bit about, having these patients on what the balance is, looking at long term co-morbidities. When we look these patients what else do they have, we see that 70% have other co-morbidities, cardiac (inaudible) kidney sounds are common, other things like bone disorder seizures.

We also see a lot of ER visits. And you see the more sever patients have more, which is to be expected but even the mild ones, you’re still seeing significant days of hospitals and ER visits occurring for these patients.

Now we start looking at how can they work every day and again you've heard a little bit from our two guests. But 85% of these patients say that it helped -- they are really prevented from just doing normal activities. Again, these patients, just doing little things like working around the house or going out and do yard work or just driving long distance, just take normal maintenance and care is difficult for many, many of these patients.

It not only affects the patients, and you heard, it affects the relationship with others and it affects their ability to sleep, how they feel about themselves but also in terms of how do I interact with my friends, how does it affect my family, my kids, my husband and my spouse or whatever. It’s really a significant issue in terms of how you do that. These folks also don’t understand when you talk about these vague symptoms. I don’t feel good, I’m tired, my brain doesn’t work, it’s hard to explain because one has to experience it. Folks don’t understand what does it mean to feel a patient with hypoparathyroidism.

The other impact we see is you've heard the ability to work and one out of five of these patients have to change their [clinical] status. And don’t forget this is a disease of middle age, these are working women, these are people who are productive and all of a sudden one out of five have to either stop working or change working, half of those actually have to permanently stop because of the disease, huge impact on them. And when they’re working, you’re also seeing impact even there. What you see is 80% are saying that I impact productivity, I miss days, I can’t work at my full potential. You can imagine as the ladies spoke, ability if I can’t think right and I am tired, how can you be productive. So impact not just for themselves but on their family, on their work and basically their whole day.

So I just want to put in the conclusion that despite taking the calcium and vitamin D, these patients self reported a high burden of illness, a large spectrum of symptoms that lasts on an average of 13 hours a day. The average patient has 16 symptoms with the severe ones being on an average of 19 or more. You see acute episodes and you’ve heard them describe it earlier of the hypercalcemia, sometimes requiring emergency room visits and hospitalizations. We see really a large effect of this on a multi dimensional basis. It’s more than just symptoms, it’s a feeling of the well being, it’s the impact on depression, it’s the impact on their families, impact on the work, employment. These are all significant effects that hypoparathyroidism has on these patients and as heard from today, these patients are asking for help.

So what else do we need to know? You heard from the patients; we know little bit from the studies but we don’t know a whole bunch in a large population; this is orphan disease. What is the real natural history of this, how can I predict what’s going to happen when? Large collections of patents are small. I mean, Dr. Rothman has 40, I think, Dr. Bilezikian probably has I don’t know 70, 80, 90. That’s a very, very large, most physicians don’t have that many. So what you see is how do I help physician understand what is the progression, what is the impact of hypercalcemia, what is the impact on the (inaudible) So what we’ve done with the help of multiple access, including these two gentlemen is really started patient registry, looking at the long term fact that what's going to happen with these disease -- these patients over the long term. So PARADIGHM is the registry to do that, it’s to open that dialog with physicians to help them understand what's going to happen.

PARADIGHM has started, we’re actually enrolling patients and our goal is to enroll at least 900 patients worldwide. Recruitment will take a little -- we think it will take about seven years and we’d like to follow these patients for a minimum ten years. Hopefully, this will give us a better understanding of what's happened to these now and eventually when hoping that product is approved, Natpara effect on these patients as well.

So, we have a lot of questions about the natural history and also the long term effects, treatment with Natpara more importantly but long term effect of no treatment or treatment only with calcium.

With that, so we have ways to go. But with that I have it's very great honor to do something which is to introduce Dr. Bilezikian. I’ve known John for a few years. I got to beat this because it's like -- it’s overwhelming when I look at his CV and background. Dr. Bilezikian is -- actually Dorothy L. and Daniel H. Silberberg Professor of Medicine and Professor of Pharmacology at the College of Physicians & Surgeons Columbia. He is also a Chief for the Division of Endocrinology and Director of Metabolic Bone Unit at Columbia. He received his undergraduate training at Harvard and his medical training at College of Surgeons and Physicians. He is a member of multiple societies including the Endocrine Society, the American Federation of Clinical Research, The American Association of Clinical Endocrinologists, the American College of Endocrinology itself has designated him a Master. He served as Editor-in-Chief of the Journal of Clinical Endocrinology and Metabolism. He is currently the Senior Associate Editor of the Journal of Bone and Mineral Research. I believe he has five, I believe books out there including Editor in Chief for the Parathyroids. He’s been on I can name enough panels and he’s been actually served as Chair of NIH Consensus Development Panel on Optimal Calcium Intake and Co-Chair over the last two NIH workshops on our primary hypoparathyroidism.

He distinguished recipient of at least six prestigious awards that I can count including the Distinguished Physician Award by the Endocrine Society. His publications which number over 575 speak to this active academic achievements. His pilot work really formed the basis of us being here today and I really thanks John for all he’s done for patients and what he will do in the future.

And with that I will turn it over to John.

John Bilezikian

It’s hard to know what to say after that. The common thing is to say I wish my mother were here. But I will tell a story about my mother. Every year the after Thanksgiving, I have a luncheon with my great school friends who I still kept in contact with, and one of my friends just a week ago said, do you remember that your mother used to say that the first words that came out of your mouth were PTH. So that’s a talk I am sure, that it’s really been a pleasure to be involved in the evolution of our understanding of the parathyroid hormone disorders.

I started as everybody starts in this field with the problem of too much parathyroid hormone. That is a bad disease to primarily have a parathyroidism. And then I didn’t abandon that we still have a very active investigator program in primary hypoparathyroidism, but we [morphed] into the other disease that is too little parathyroid hormone, and that's bad too. And I am firmly convinced that it’s the goldilocks principle. You need just enough PTH to have the quality of life that PTH allows us to have. And hypoparathyroidism unfortunately is an example of the other end of that spectrum, too little PTH is bad.

So what I’m going to do in the next 20 minutes or so is to review for you the REPLACE study which is the definitive clinical trial that was sponsored by NPS. And then give you a taste of some of our own research also held by NPS’ support, the FDA where I have an orphan products grant and also the NIH and try to do give you a flavor of where we are now.

The REPLACE study was just published in Lancet, Lancet’s sub journal that’s new, Diabetes & Endocrinology, where we’re very proud to be in one of its inaugural issues. And this is the results, the initial definitive study of PTH 1-84 in hypoparathyroidism.

And let me give you just a broad stroke, so what we intended to do in this study. An endpoint that was really I would say setting the bar fairly high that is how did we defined responsivity after the 24 weeks of PTH 1-84 with a placebo control. And the endpoint as shown in this slide was greater than a 50% reduction in oral calcium requirements greater than a 50% reduction in the active vitamin D that they were taking and also maintaining their serum calcium greater than their baseline wherever that was. And also of course not excessive that is within the normal limits.

So as Roger implied, we’ll not show you those tables of the randomization, but the randomization was very successful. The placebo and the PTH 1-84 groups were very comparable in every way you can imagine in terms of their biochemistry, ideology their calcium and vitamin D needs. They were also comparable in terms of their bone turnover markers; Dr. Rothman has suggested and is as [true] that this is a low bone turnover disease, and I'll allude to this in a moment. But they had low bone turnover as defined by bone turnover markers.

And their bone density, this is probably one of the rare examples, where having high bone density is not good. And I'll try to illustrate that in a moment. But these individuals typical of hypoparathyroidism have a low turnover disease they accrue bone and they don’t turnover bone. So what bone they have is a lot, but is not very good because it probably is hyper mature.

So here are the data, and I will let you look at it for a moment. I think Roger you were so excited when you called me and we got today, you gave me the P-value was point and then nine zeros. And clearly you can see the difference. The groups that received PTH 1-84, 53.3% responded according to the criteria that are shown again at the bottom. And with regard to the placebo group virtually no one, one or two down to 2.3. So that was a very start success as defined by the primary endpoint of this study.

Now there was a secondary endpoint of the study and that is shown here. And that is, what percentage of individuals would achieve independence? That is, they wouldn’t need, didn’t have to take any of [Rocaltrol] or active vitamin D. And that their oral calcium dose was less than 500 milligrams. And again you can see the major difference the group that received PTH 1-84, 43% met that endpoint while a very small percentage of the placebo group met that endpoint.

Now here are some other interesting data that help to amplify the data I’ve just shown you. And this slide shows what was the reduction in the percent of their average oral calcium dose, and I don’t think I even have to tell which is the treatment arm, but obviously it’s a treatment arm where the percentage is dropping rather dramatically in the initial weeks of the treatment, while the placebo group shown in the open symbols did not show any reduction in their need for oral calcium.

And similarly this slide shows the reduction in the percent reduction in their average vitamin D group, their treatment arm, of course it’s in the dark symbols. The placebo group did drop partly that was part of the protocol they were immediately tried on lower doses. So they did have an initial drop, but they could not fall any further, in fact there was a trend upward in the placebo group overtime.

The illusion to phosphate is not insignificant as Dr. Rothman suggested. These patients tend to have a high normal or even an elevated phosphate. And that is a problem not acutely, but if you are running a high calcium phosphate product for years and years and years as these patients do when they are being given such high amounts of calcium and vitamin D. That turns into a net stable situation where a calcium phosphate can easily be deposited into soft tissue such as the brain, such as the kidney and not a welcome scenario as you look on the long term potential complications at calcium and vitamin D therapy in hypopara. So it is noteworthy that parathyroid hormone as a phosphate direct hormone was associated in this trial with a reduction in the mean phosphate level. And again, you can see how the two groups are separated very quickly, the group receiving PTH 1-84 shows a mark reduction in phosphorus without any change in the placebo group.

So, reflecting this lack of PTH and hypoparathyroidism, I wanted to now return to this issue of bone markers. Bone turnover markers in the blood and we have a number of markers that measure or reflect bone formation, we have markers that reflect bone reabsorption. And in hypopara both formation and reabsorption markers tend to be in a lower range of normal. There is better evidence actually with regard to bone turnover in hypoparathyroidism as seen by the iliac crest bone biopsy that dramatically illustrates what I'm talking about.

And again when bone turnover is reduced, bone doesn't -- calcium isn't lost from bone it, but it goes into bone, stays in bone and we have a situation of hypomineralized, hypermature and probably unhealthy bone. So one of the therapeutic goals of PTH 1-84 would be to restore bone remodeling, remodeling being the process by which we rid of old bone in micro packets and replace it with new more resilient bone.

So here is a very dramatic example not from the clinical trial from our own work in which you can see the difference on the left this is normal, this is fluorescent label using tetracycline, tetracycline being having an affinity for bone and also for resting with that beautiful yellow color. You can see the double label that reflects the two courses of tetracycline separated by 10 days. And that’s a normal amount of bone that has accrued over that in the period of time.

I would like to you show me if, because I can’t see it. On the right is the typical tetracycline uptake in subject with hypopara. This is a representative biopsy, but they look this way. Basically you don’t see anything. There is almost no tetracycline uptake again illustrating that bone turnover is extremely low in hypoparathyroidism.

So what is the story with PTH 1-84, how does it affect bone turnover markers? And as you can see in this tech slide, certainly they went up as you would expect without any change in the placebo group. And that again is a very important statement because we are helping to restore healthy bone remodeling and that should lead to better bone.

Well, how do we see better bone density, of course all of us know about bone marrow density [Dexter] Technology has been with us since 1986 and as time pass on of our valuation of the older postmenopausal women and also men as a diagnostic way to determine whether someone has actually osteoporosis or not.

Low bone density is associated with high fracture risk. A high bone density is not necessarily associated with the reduction in fracture risk. And as I mentioned before, in hypoparathyroidism bone mineral density tends to be high for the reasons that I mentioned.

And just showed you a dramatic MicroCT picture and I’m showing you another one perhaps even more dramatic. This is trabecular bone by the way. So this MicroCT bone biopsy has stripped away the cortex. But on the right, if I didn’t tell you that, you will say that's cortical bone. So what has happened is without parathyroid hormone that trabecular, a very important resilience of bone that makes up our lumbar spine and half of our hip, turns into cortical bone as it were.

And I would [submit] to you and by doing finite element modelling that massive bone that piece of concrete if you will is not very good. So we would like to do something about that, in fact we would like to reduce bone density. That seems a bit odd, but I would like to see bone density go down as a therapeutic endpoint using PTH 1-84 in hypoparathyroidism. So there is one of the target goals here, can we have an effect on bone density.

And changes in bone density we’re seeing in the -- again, sorry that's for the REPLACE trial. In the hip, total hip and the femoral neck there was a reduction significantly from baseline in those who received PTH 1-84. The lumbar spine didn’t change and the distal third radius didn’t change. Remember this is a very short study, 24 week study, you’ll surprise if you see anything with regards to depth and metric differences. The placebo group as you might expect didn’t change at all.

Safety of course is very important and the data regarding safety and tolerability have been presented in several different meetings. The treatment was very well tolerated during this period of time and there were no doubts one serious AE-related hypercalcemia that was considered treatment-related.

With regard to AEs, and I don’t have to tell this audience what the different between an SAE and an AE is. Well conducted clinical trial there should be almost a 100% adverse event because something is going to happen in life. I had a [sniffle] doctor, that’s an AE. I started -- doctor yesterday, that’s an AE.

So there should be a lot of AEs and there were both in the placebo and the treatment arm. And the spectrum of AEs did reflect the underlying disease pathophysiology. As you would expect these patients are not always completely a symptomatic with drug, they have paresthesias, muscle spasm and [headache] and occasionally hypercalcemia, but of course much less the case.

So with regard to this REPLACE study, the majority of patients met the rather strict criteria for that primary endpoint responding with a reduction in calcium and vitamin D needs. And also the REPLACE study, I would say does suggest to me that this is a very effective approach to the treatment of hypoparathyroidism. Patients were able to maintain those reduced levels of calcium and vitamin D. And again, I think that this drug is not only helping to regulate smoothly calcium in the blood, but it’s having fairly important defects on skeletal health as well.

Now I’d like to touch upon two studies that came from my group. These studies have been published as part of my team, and I’d like to give a nod to Jim [Sliney] who is one of the major figures in the Hypoparathyroidism Association and has been with me for over 10 years, devoting I would say his heart and soul to this disease. And this is one of the first [bits] of data that give us some long-term information about the use of PTH 1-84 in hypopara and these are the four year data.

We had in this study 54 subjects. They were initially treated with 100 micrograms. This is an open label study it was not controlled with the placebo group. But we had a fair number of subjects who reached that 4 year time point that doesn’t mean the other ones won’t reach, and we just said by the time we decided to put our data together, 27 had reached it.

And we measured bone turnover markers, we measured bone density. And in data that I cannot or will not show you today, we have actually done some very sophisticated studies including extreme CT and we are about to be doing bone biopsies that will give us some really neat data in the long-term management of hypoparathyroidism with PTH 1-84.

And as I alluded to before, one would expect bone turnover markers to increase and they did rather quickly and reached the peak as I will show you. And then they settled down to a level that was more typical of normal people. So they don’t go up and up and up. They go up and they come down, but they don’t come down to their baseline. They come down to a normal person’s baseline.

In addition there were declines in bone density. And here are the bone density results. Now the decline I mentioned was seen primarily in the distal radius. It is curious that the lumbar spine in our hands did go up. And before you say this is bad, I don’t think this is bad. And when I get the micro structure data I will probably prove to you that the bone density is going up, but it’s also changing the quality of bone.

So this isn't just more bad bone, this is actually good bone accruing and being shown best in the lumbar spine where bone density changes most rapidly in connection with PTH or any other therapy that we have available in the context of osteoporosis.

Here are the bone turnover markers; and again I won't spell out specifically, they are down the left and the right there are the CTX and the bone reabsorption markers, on the left, you see the bone formation markers. It really doesn't matter, which one is which. The point I'm trying to make is that they go up and they go down, some will go up more, some go up less, they has to do with what the markers are reflecting.

But the important point I would make is that they don't go up and stay up because I wouldn't want bone turnover markers to be triple and stay up there because I'm not sure that’s a good thing, but they don't. They go up and they come down in the new baseline is again I just suggested before is higher than the patient’s own baseline and more typical of what we were expecting new parathyroid subjects.

So with regard to this, this is really either for the first data that give us a real sense of time dependency with PTH 1-84. Bone turnover markers behaved as I would hope they would behave. We need more information about bone density and we are getting that. But I think the micro structural data that are forthcoming will help to assure us that the accrual of bone if there is accrual of bone is actually good bone and not that bad bone that is typical from hypoparathyroidism.

I know all of you are interested in quality of life and the testimonials you heard, one has to be careful about testimonials. But if you hear them over and over and over again then you’ll begin to wonder maybe this drug is affecting quality of life, but it would be nice to have some metrics.

And I am going to share with you now another [takeaway] that my group just published in JCM. I study not the REPLACE study, but we did take a look at quality of life. And we used the patient’s own data as their control. So this was not placebo-controlled, this was a before and after using the SF-36 Scale, and some of you may be familiar with the SF-36 Scale which actually very conveniently allows us to measure four physical and four mental domains relative to what is a normal bar and the normal bar is I am going to show you is a 50, so doesn’t matter whether it’s just a scale. But most people in this room, most of you will probably score 50. If you guys are really feeling good today, you might be scoring 60 or 70. If you are not feeling so good today, you might measure 30 or 40.

So here it is. Here is the bar, 50 you see in the physical component and here are cohorts of 19 subjects who filled up this SF-36 question there. And all of them are not feeling too good. None of them have even come close to what would be a population norm for this SF-36 scale.

And in the context of treatment on the left you see the [raw] score improvement and on the right you see by [By-T] score improvement. And so in virtually every domain, although a few were not significant, but in virtually every domain there is a significant improvement particularly if you look at this By-T score, this is the mental health domain so we had similar data for the physical domains. And I think this helps to support the notion that we heard from Becky and Gail this morning that changes their life. And I was mentioning to Bob and a few other people at the break that one of the things that scrapped into our study is a neurosis. Doctor, are you going to stop this drug, because I don’t promise drug forever, don’t have drug forever? So we were in that two year cycle and they say, I can’t stand the idea of life without this drug.

So I think there are data forthcoming and along with a biochemical densitometry and these very important end points of management that are suggesting that along with these parameters that have been statistically shown to the case that there may be an improvement in physical and mental functioning.

So this is just a check list, just a sense I don’t watch to, the check list of check list, didn’t say that for sure, sure; but clearly I think we can say that this drug is not only improving serum calcium, but maintaining serum calcium in a much neither way, it’s promoting calcium reabsorption that is a function of PTH, it is reducing the serum phosphate, another function of PTH and very importantly it’s reducing that calcium phosphate product. It is helping the body to activate its own vitamin D system because PTH simulates of 1 alpha-hydroxylase thereby allowing the kidney to make 125 in these spaces with hypoparathyroidism, bound turnover his behaving as we would help it to behave to be a more likely to be normal bone quality, where gaining more information that that is improved and the last point which we will be gaining more data on in the months to come is that this drug is very likely in my opinion to improve the quality of life.

So this has been a snapshot of where we are now and I hope these new data and then some of the old data I've shown well be helpful as you think about this exciting new option in patients with hypoparathyroidism. So thank you very much.

Francois Nader

Thank you Dr. Bilezikian, for this clinical overview of very important research that you conducted in this bad condition. So let me try to position where we are, we talked earlier today about hypoparathyroidism as a condition and doctor often guided us through hypoparathyroidism clinical aspects. We also heard from two patients about a day or a week and the life of a hypoparathyroidism patient and the challenges that they face day-in day-out and remember the uncertainty which is frightening when they don’t know how next day will be and all the consequences of this uncertainty.

Roger gave us an overview of the burden of illness, the characterization and where we're going from here establishing probably the largest worldwide patient registry in hypoparathyroidism and last but certainly not least Dr. Bilezikian, gave us a factual data on REPLACE and the other studies that he’s conducting in this again rare condition.

So with that positioning I think the next step is to tell you where we're going from here and then why at NPS we're so excited with the opportunity of taking Natpara worldwide. This is a great opportunity for the company more importantly we believe it’s a great opportunity for the patients, who will hopefully in the next year or so start getting Natpara and transforming their lives.

For that I would ask Eric Pauwels to come up and give us the market potential for Natpara as we see it today.

Eric Pauwels

So thank you Francois. And also I mentioned we are very excited with regards to the opportunity of hypoparathyroidism and especially as it relates to Natpara. Just some important and key messages around the opportunity; clearly hypoparathyroidism is a rare disease, but it’s not an ultra rare disease it serves a fairly large population, wouldn’t call it sort of large orphan and it wouldn’t be an ultra orphan but clearly it has a population and it’s not it’s an area that’s clearly underserved. We conducted extensive market research. And as you know doing prevalence for instance work in rare disease can be very challenging. But in this case we have conducted extensive research plus we have incorporated some outside research from the literature to do an extensive analysis to define that opportunity. And to hopefully categorize as well with the patient journeys and our target audience.

We have conducted a recent burden of illness study which was the first of its kind and Roger went through that in great detail and it also helps us understand if you will the segmentation of the patient, it’s very important to know that the backing from the [gates] of the world represent a certain portion of what happens through their journey of hypoparathyroidism, but it is a long journey.

We try to characterize what that as in the opportunity. One thing that’s squarely around that we’ve heard from today consistently is that this is the last sort of classic endocrinology disorder that doesn't have replacement therapy. And therefore, endocrinologists are clearly in the center in the focal point of treating this disease and it's not uncommon here or globally. We believe as well that Natpara is innovation, it will be the first and only product that would be approved worldwide for hypoparathyroidism. And we believe we will be having an ability to achieve what I'd call orphan drug pricing.

And finally we have a number of market development activities that are underway. We have infrastructure in place both marketing and also field based infrastructures in the U.S. and developing those internationally. So if we look at the overall opportunity, we're very excited about that opportunity and right now from a number of different sources in market research globally that have been conducted across different countries. There is approximately a 180,000 chronic hypoparathyroidism patients and we expect over that 12 year period about a 4.5% growth in these targeted geographies. These geographies included the U.S. where we did research. We did research in EU five countries and Japan and Latin America.

These are the patients if you will that in some way shape or form may have a need for long term physiological replacement therapy for PTH. When you look at the overall numbers and if we cascade that down by geography, there is no major surprise the U.S. has little over a third, the EU if you look at has about a third as well and if you categorize Brazil, categorize Japan, you can see as well that there is about another third and it's classic in terms of its distribution. What's important is to understand the etiology and it's very closely characterized as well as to what we've seen in the clinical studies and in the PARADOX data and other sources that we've seen as we have done -- as we have conducted market research, either through claims analysis or through track pulse. About 75 or three quarters of the patients are surgery, their etiology is surgical orient. So hypoparathyroidism has caused -- and about 25% autoimmune or other disorders idiopathic disorders as we saw in the patients.

If we characterize the spectrum and what’s very important is to understand that we have been discussing that even in the PARADOX study that it seems to be really nice need buckets of both mild moderate and severe. And that’s not quite the case as we have gone through the market research, we clearly understand that there is a large spectrum between what patients are controlled and which ones are not control and patients who are uncontrolled who we might tend to label as mild are those who have very limited symptom of etiology, they might have a few symptoms and might it take either a load or one or two calcium tablets a day and they are happy, defined, they are control.

When you start to move along this spectrum these patients who are highly symptomatic, who can have 6, 10, 12, 15 types of symptoms and for hours a day up to 12-15 hours a day and are uncontrolled it tend to be more on the moderate severe side. But rather than categorize them in sort of need buckets and these three buckets, we want to categorize them more as controlled and uncontrolled. And what we see across this spectrum of highly symptomatic usually when you cross into that red zone, it’s you not only have these neurological symptoms it is physical emotional cognate symptoms but there are also some of the psychosomatic symptoms that are very -- sleep disturbances. So in a term of segmenting the opportunity and this is where would be the addressable population and what the segment -- we would target initially globally would be those patients who are considered highly symptomatic, who are actually not well controlled on current therapy. And right now that's approximately 40% of that total global population, which would be the ones who will seek treatment first, will be the ones who would be highly motivated for treatment or comply with, who have high compliance rates.

Our secondary strategy would be to go after those patients who have long-term physiological replacement needs, but yet they maybe so mild that an injection once a day or taking PTH may not necessarily be an option.

I think both patients described each one of these very, very well. Hypoparathyroidism is a multi-factorial disorder. It’s very complicated in terms of management. And there is no therapy, there is no PTH replacement therapy approved anywhere in world today. And comorbidities can rate very, very high. You can see that most of this Roger presented because the top part was PARADOX, but one of things that strikes us is 80% of the waking hours of symptoms these are patients who have symptoms sometimes during the full day. 13 to 15 hours a day, they are symptomatic the way our patients describe, what Becky and Gail described.

A literature that's been published and Dr. Bilezikian presented some of this. Literature across the spectrum publishes that these comorbidities are very, very significant compared to normal population. In some cases we can see 5 to 17 times in terms of real complications, 4 times increase in seizers, a third more in terms of increased ER visits basal ganglia classification in fractures, very significant in terms of impact on quality of life and that ties in nicely what Dr. Bilezikian presented.

Our research show that the journey usually starts in two different ways. I mean we're over simplifying it in this case, but as you saw from both of our patients here one was surgical and the other was non-surgical. Following that surgery, there are four patterns that can mostly end up if you go back to the endocrinologists. So about 70% of those patients go back to the endos for treatment, about a third of those are either primary care physicians or surgeons or nephrologists as some of these patients end up with different specialties.

With that, the treatment PARADIGHM is either controlled and the only available therapy is right now are calcium and vitamin D which the majority of patients are taking we’re off-label care PARADIGHM.

With the research we've done across those markets, we clearly have found that there is about 10,000 endocrinologists. Of course as I said, these are the main prescribers of the product where 70% of the patients are going to reside. About 4,700 are in the U.S. now this is mostly all practicing which include diabetes and others, we’ll get to how they segment in a little bit. And internationally in those key markets which we select there is about another 5,300 endocrinologists. We really treat these patients.

We’ve done some research with payers. This is on a scale of 1 to 7 and we’ve asked them to characterize the clinical burden of illness. We’ve asked them to look at various cost associated with the disease, the clinical management and also to compare this with other analogs that are in the orphan space either self administered, biologics or analogs. And what is -- how would they characterize if you will the perceived unmet need? And as you can see there is certain, there is variances and [nuances] by country, but we clearly see that that payers do see that there is a high unmet need for hypoparathyroidism.

In terms of characterizing the potential of the product and how we develop the value proposition and also in terms of how we would think about our pricing structure because we have conducted payer research. If we look at burden of illness this is a very, very symptomatic group. And so if you look at the uncontrolled group, there are significant comorbidities and there is very poor quality of life. The unmet need, while there is no treatment available for these patients and this would the first and only patient product which is the last endocrinology disorder, a replacement therapy.

Innovation, well this is a biologic product and it replicates what the parathyroid hormone can’t do or does for them. It will be the first and only treatment. And finally there are costs associated with these patients. We looked at the employment history, changing of jobs, efficacy or efficiency within the time that they are spending, the cost associated with hospitalization, cost associated with bouncing around looking for endocrinologist, other endocrinologist in treating. So there is direct and indirect cost associated when we develop that value proposition. And of course as an innovative product where there is no therapy to really reference, there is this premium associated with rare diseases and that's the premium we would attached to.

So we've done research across different markets, and while we're not guiding to a specific number, can give you that the preliminary research does support a band or a range within other rare disease categories. And if you look at multiple sclerosis analogs on lower-end where PKU or chronic iron overload analogs that range right now we show relative in elasticity depending on the country and the payer. We have a lot more research to do as we get closer to the actual label in the U.S. and the label in Europe. We'll be continually doing work with payers to assess not only the value proposition, but also the willingness to pay.

Natpara in terms of its global rollout, we're building on the international foundation that we're currently building right now. We anticipate of course, we hope to have approval in the U.S. by the end of 2014. Shortly after that we’ll begin global named-patient sales, probably about 6 to 7 countries of which we could begin that process especially after the U.S. approval. We would file in the EU next year and we would hope to launch in the EU and sequence a number of the same countries that we've targeted for Revestive and sequence a price where we can get price and reimbursement pretty much in those same countries in Northern Europe and then negotiate pricing reimbursement in Southern Europe.

We could begin -- as we are garnering named-patient sales in some of the countries, we would look to see how we would position registration in Latin America in other markets. And of course we would be defining our clinical and regulatory strategy for Japan.

So in terms of the U.S. market if we drill down a little bit in terms of U.S., we conducted, we had seven studies some of them you’re familiar with which included chart polls, which included claims analysis and database and some primary research. And what we did is we actually went through that entire analysis randomonic (inaudible) and ended up if you will with a very tight confidence interval for the midpoint that would estimate about 53,000 patients. This is not [addressable], this is the overall estimate of prevalence.

And if we look at that expected growth, we would say about 4.5% of compounded annual growth primarily driven by the increase in number of thyroid disease surgeries that are taking place. And also as any orphan category, once you introduce a product that is new and innovative, diagnosis, awareness and education also increases in the idiopathic segment as well. So we will see that increase over a period of time.

In terms of targeting, we have identified 4,700 practicing endocrinologists. And we’ve profiled, of that our goal is to profile the 2,600 accounts or centers of which these 4,700 reside in, because they reside either in academic institutions or group practices or in different areas. So our goal is to ensure that we profile these accounts and focus on disease state awareness.

In addition to that there are 600 profiling experts. These are the ones who are, who have actually raised their head and in [essence] said, we are the specialists within these diseases and we’ll be focusing to understand a little bit more about referral patterns and of course disease state awareness. And there is approximately 133 teaching institutions or academic institutions that have published their programs which are credited by AMA. So these are our targets that we’ll be able to solidify relationships as we have currently infrastructure in place or as we build the infrastructure to the launch.

In terms of adoption process, it’s clear that our key opinion leaders and experts are the ones who are going to understand the disease and the ideology and the treatments and we’ll be targeting them in the early stage of the launch and if you will average practicing endocrinologist as well over a period of time. And we believe that again the main focus will be to highlight the benefits of the product, but also to categorize disease state awareness around what is the definition of uncontrolled patient, the symptomatic nature of the disease and potential treatment of purchase.

We’ll be deploying over the course of the year what I would call a field-based team, we have MSLs as well and as we expand the infrastructure. The team will be focusing on [influencers], there is probably about around 100 or so. And I mentioned a number of prescribers in those centers. So we’ll be doing disease state work, as well as profiling. And we have already our key account directors that are in place right now that we hired for Gattex. We're calling a pretty much on the same insurance companies as well. And we’ll be working with payers to understand if you will their perspective on reimbursement.

We are currently working very closely with a number of the key efficacy groups. In this case we actually have a dedicated group within Hypoparathyroidism Association that is fully dedicated to the disorder and the disease and has more than a 4,000 members from constituent and growing. We're working with Light of Life Foundation as well and [Trika] as Becky mentioned, Trika being a very important efficacy group. Within that we're developing a number of key initiatives to bring about awareness and engage and I'll get to those in a minute.

And since 2011 we've been working on messaging if you will what is the disease, what’s the mode of the disease, what are the symptoms and causes of this disease, how you go about diagnosing it? It probably essentially will be called blocking and tackling. As we become more sophisticated through our digital presence right now, we've created a number of different venues where we are actively engaged in working with efficacy groups, as well as with our digital presence to hypoparathyroidism.com to share patient stories and provide if you will further information so that patients can engage in discussions to know that they’re not alone.

So social media, efficacy has been playing a critical role. We have if you will a central database in which we are collecting unique names of patients of which we will be continuing to sort of engage in the United States with educational activity.

As we deploy the field force and we get closer and closer to the launch, there will be milestones that will continue to develop. We’ll continue to enhance and support our position with patient efficacy and extend that current audience base and move from disease state awareness obviously to promotion as we launch the product.

And then finally I would say that we’ve built NPS Advantage initially for Gattex. We know it’s working extremely well, we understand the critical nature and high touch point of ensuring that every patient is supported throughout the process from RX all the way to dispense the clinical services. And therefore we will expand and scale NPS Advantage to the necessary needs as we anticipate the launch demand.

We clearly will be not going through the same process as we’ve done with Gattex. So specialty and infusion partners are not required in this particular. It will be much more of a classic or traditional specialty pharmacy network that will supply the product directly to the patient, but we’ll continue to work with each one of these patients to ensure that there is burden free access reimbursement support. If clinical services are required we’ll coordinate nursing services and in general ensure that there is long-term compliance and adherence to the product.

So with that, I will wrap up and just say that NPS is certainly committed to these patients and that we’re well underway right now to preparing the market for successful 2014.

Francois Nader

Thank you, Eric. And I'd like to invite up here Dr. Rothman, Dr. Bilezikian, Dr. Garceau and Luke. I’ll try to squeeze in everyone here. And this is the Q&A session. So, we are all here trying to address the questions that you might have. We have a microphone and let's do it.

Unidentified Analyst

I’m (inaudible) I'm on Geoff Meacham's team at JP Morgan. In the market research data you showed from our math, it's approximately 40% uncontrolled to controlled, in your view, is that consistent across all the regions or perhaps different in the U.S.? And I'd also like to get Dr. Bilezikian and Dr. Rothman’s view on that data and if that's in line with their perception of the marketplace?

Francois Nader

Okay. Let's start with Eric maybe, 40% Eric U.S. and global.

Eric Pauwels

Yeah. The market research has consistently shown that those numbers are pretty consistent with the exception of Japan. And that seems to be more for [hopeful] reasons. For a variety of reasons patients don't complain about symptoms as much in Japan. But otherwise in other countries it's fairly consistent.

Francois Nader

Dr. Rothman, Dr. Bilezikian if they can address their experience as well.

Jeffrey Rothman

It's just I can tell is there clearly are patients who are reasonably stable and a very significant subset of patients clinically who require a lot of attention, a lot of care.

John Bilezikian

Yeah, I would agree. We tend to have a skewed population because where we close centers. So I would -- we are more 75% I would say that would be moderate to severe, but we are probably seeing more symptomatic than a typical physician would see. But I think that the information Eric provided is consistent with what we say.

Unidentified Analyst

Thank you.

Tazeen Ahmad - Bank of America

Hi, Tazeen Ahmad from Bank of America. I just had a couple of questions for Eric. Do you plan on using any of your Gattex sales reps to promote Natpara. As you look ahead, how many Natpara alone sales reps do you think you will need in the U.S. and what kind of infrastructure are you going to need ex-U.S.?

Francois Nader

Eric?

Eric Pauwels

So with regards to the infrastructure, at this time we haven’t completed the field force sizing so it should be completed early next year, so I have better idea to give you an idea whether we will be leveraging the Gattex sales force or not. We clearly are leveraging other components which are including our key account directors and MSLs. I think the infrastructure in general is going to be fairly much in the orphan space, which means this isn’t going to be a large specialty place, not a large pharma, large specialty place. As I mentioned to you there is 4,200 physicians, 2,600 targets, so we would anticipate a fairly small targeted field force and leveraging the current infrastructure that we have.

Tazeen Ahmad - Bank of America

Okay. And then just a question on pricing, you were previously been educating that a good illustrative example would be for by using MS oral drug pricing, now it looks like that’s probably on the lower-end of your expectations, I guess what in your market research gives you confidence that you can charge a price that would be potentially higher than that?

Eric Pauwels

Well, I think first of all, all the research that we've shown supports the value proposition innovation. So first, it is about a drug that actually targets the physiological replacement. It targets if you will the unmet need and a clinical burden is well understood by payers. So if you look at the rankings, we asked physicians, sorry we asked the payers and we also did ask physicians to categorize other analogs that were self-administered, orphan drugs, highly symptomatic than others and we came up, and they came up spontaneously with those. So we’re clearly I think in that range at this point in time. And we believe that we’ll be able to clearly build the on the value proposition from the data you’ve seen today.

Tazeen Ahmad - Bank of America

Okay. And then the last question is for the EU for Natpara, where do you stand on, I guess you’re moving the approval that was there before for osteoporosis so that you can clear the way to file for HPT?

Francois Nader

Yeah. So, you are absolutely correct. Preotact, which is PTH 1-84 was approved in Europe for osteoporosis, so we’re staging the progress as follows. We will withdraw Preotact from the markets and we’ll do it really in two ways very important. So from a regulatory perspective we withdraw the part, but also we’d be withdrawing the reference pricing in each one of the countries, very important.

Okay. Then we will file Natpara in hypoparathyroidism, so it will be a new filing, new MAA market authorization filing that will be followed then by the price again reimbursement process. Interestingly enough the reference pricing will not be there because there are no references left in the market. So think of it as two different tracks, one is a regulatory track and the second is the pricing and reimbursement track.

John Bilezikian

I just wanted to say, we do actually have market authorization in Europe now for Natpara for Preotact.

Francois Nader

Yeah, sure.

Unidentified Analyst

Thanks. Just for Dr. Rothman and Dr. Bilezikian, I’m just curious how long do you think you’ll keep patients on drug here and how much of the effort is going to be patient driven? You presented some interesting thoughts on quality of life metric? And then for Luke with the ramp up that we're going to see for Natpara launch, as well as the EU launch for Gattex basically. How do you think about SG&A as we look out to next year?

Francois Nader

Good question. Dr. Rothman?

Jeffrey Rothman

If I understood that, the question is how long keeping on.…

Unidentified Analyst

[Duration] of therapy?

Jeffrey Rothman

I view this is as long-term chronic replacement therapy without a duration, kept forever.

John Bilezikian

And I think in terms of who drives what, we've mentioned the hypoparathyroidism association. I foresee this will be heavily patient driven we would guess around already gotten around and this organization has solely dedicated to this disease. So I actually think that that there will be a lot of uptake from patients coming to the market that way.

Jeffrey Rothman

And anecdotally in the trials you can’t get them off.

Francois Nader

Thank you. Luke, SG&A?

Luke Beshar

Yeah. Our operating expenses, a great question. Our view next year we haven’t guided, we won’t until the first quarter of 2014. But 2014 is going to be a year of investment. International infrastructure is substantial, undertaking were frankly starting from a clean sheet of paper with essentially no feet underground or infrastructure in the rest of the world. We will be investing heavily in Natpara pre-commercial activities from a market readiness, market access, field force sizing, ultimately hiring the field sales force and then most notably including the commercial volumes that we will be producing pre approval which we will to expense. We’ll have two open registries next year, two registries for the full year for Gattex and Natpara and then on the R&D side, we’ll have two trials up and running through the year for both the Gattex pediatrics as well as the initiation of 795.

So all of that sort of sums through operating expenses are certainly going to go up significantly next year. the good news is that from a cash and capitalization point of view we have more adequate capital to be able to fund that. Not only do we have cash in the balance sheet of $178 million but the Gattex U.S. launch is now starting to strive and that the cash flows from that are going to be substantial and be able to partially underwrite that. And then the Sensipar royalties. So, from a capitalization point of view, we’re very good, and we are very good stead and we continue to have more an adequate capital to support and drive the long-term growth of the business. Does that help?

Unidentified Analyst

Thank you.

Francois Nader

Thank you. Joe?

Joe Schwartz - Leerink

Thank you. Joe Schwartz at Leerink. I was wondering if you could talk a little bit about the choice of the primary endpoint for Natpara, the reduction in two other drugs that are the stand of care and yet you’ve showed very impressive reductions in hypercalcemic events and increases in serum calcium which is very important to the physicians that care for these patients. So could you talk about -- which of those -- do you think that latter two pieces will likely be on the label and be something that you can promote?

Francois Nader

Okay, multiple questions. Let me start with the primary end point. I can say I was there. We met with the FDA. And frankly we approached the FDA with a couple or 2, 3 different options related to primary end point, because there are no precedence. So we had to come up with something meaningful. It was clear that FDA and us actually wanted something tangible, alright. And the tangibility here, this is the word. I started with maintaining normal calcemia. We did not want the maintenance of normal calcemia to be at the expense if you will of an increase or even the same level of calcium and vitamin D.

Alright, so it had to do -- something had to give and we picked up the 50% reduction. What made this primary endpoint as Dr. Bilezikian alluded to earlier, more difficult, it is a triple primary end point; it's an end. So normal calcemia and reduction of calcium by 50% and vitamin D by 50%. This was followed by a number of interactions with the FDA related to the protocol and a number of interactions we had with them since then.

Now when it comes to label, we filed the BLA and certainly we have our ideas as to how the label will look like. They labeling as you know is an extremely important step in the approval process, but it is in negotiation with the FDA. What I can tell you is we have very, very solid clinically efficacy data, but we have also very solid safety data. Remember that we have the Natpara hypoparathyroidism safety data. We have the Preotact post marketing safety data in osteoporosis and we have for those of you who remember, the PREOS safety data as well. So we presented the FDA with a very significant safety package if you will to support the Natpara approval.

Joe Schwartz - Leerink

And Forteo has a black box warning for potential carcinogenicity, do you expect there to be any difference with Natpara?

Francois Nader

Again the way we presented Natpara given the solid safety data that we have was without this particular black box. Again, this is a negotiation with the FDA and we will see where they land, but I could [defend] here to say based on the recent publication that even though there was this potential risk, fortunately the risk did not materialize for PTH.

Joe Schwartz - Leerink

Thanks.

Francois Nader

Sure.

Unidentified Analyst

Doctors Bilezikian and Rothman, can you comment on utility and I guess relevance of PTH 1 to 34 for hypoparathyroidism?

Unidentified Company Representative

Sure. The question is the potential utility of PTH 1 to 34. There are studies using PTH 1 to 34, those studies come primarily from NIH. Karen Winer has done some really nice work. And I simply said it works but then the other comment is, you have to use it much more frequently. PTH 1 to 34 is a much shorter half life than PTH 1 to 84. So practically it presents the challenge. In Dr. Winer’s study, the patients needed to take two to three injections a day for control.

So yes, it works but I don’t see PTH 1 to 34 is doing even close to equivalent in terms of patient convenience or acceptability.

Unidentified Analyst

Agreed. And it has a different purpose in the marketplace, where in a place where short exposure to PTH is necessary to treat osteoporosis that is inappropriate in treating hypopara?

Unidentified Company Representative

Just one additional comment, don’t forget that Natpara comes in four dose strengths. Forteo is one dosing strength at 20 microgram produces roughly the equivalent to the 100 micrograms of our Natpara. So and many of these patients will need much less Natpara in terms of forward dosing, so you are really using a single dose for a patient population that needs titration.

Unidentified Analyst

Okay. Thank you.

David Nierengarten - Wedbush Securities

David Nierengarten form Wedbush Securities. So, something struck me from what Gail said earlier about Dr. shopping. And we all know not every doctor is Dr. Bilezikian. Do you have any feeling for how many doctors uncontrolled patient might see over several years at being effective with the disease and kind of the patients progressed before, she or he could maybe find an endocrinologist who’s knowledge is enough about the disease to work with the patient and controlling it?

Francois Nader

I’d like maybe Dr. Bilezikian and Dr. Rothman to share your experience as to when do you see these patients and how do they end up in your practice?

John Bilezikian

That’s very good question. Actually we -- there was a survey gone and maybe NPS was part of it; the average endocrinologist in this country, if you ask how many patients with hypoparathyroidism do you have in your practice, I think the average number is one. So yeah, patients do have to shop, because your typical endocrinologist doesn’t have any experience. Now how much do they have to shop? It seems like they don’t have to shop for a high defined means. Again I have to refer to the Hypoparathyroidism Association because they have -- they know where in a country we have maybe 10 centers that are really pretty well known. So, I can’t answer to your question is to how much shopping they have to do. But I would have to say that they do have to shop, and if they make the right cause, it probably isn’t longer before they find an expert.

Francois Nader

Dr. Rothman?

Jeffrey Rothman

So, actually we're fairly well know in our community. They generally have seen two or three primary care physicians who have been helping very much and eventually wind up with this.

Unidentified Company Representative

And the PARADOX study also supported that now anywhere between five to six times patients as Gail described, particularly with regards to idiopathic because there is less known about disorder there versus surgical but the data at PARADOX however around 5 to 6.

Unidentified Analyst

Hi, thanks. This is somewhat related question to that. But I was wondering if anyone up there has done any work looking at either the concordance or discordance between a physician’s view of how a patient is doing in terms of degree of satisfaction and level of care versus the patient’s view of the same thing and whether there is a high degree of concordance or discordance among the patient versus doctors’ view how the patient is doing as on their current therapy? Thanks.

Francois Nader

Eric, would you like to address because you are kind of a neutral party, we have physicians here we have patients over there.

Eric Pauwels

Well, I think in the whole PARADOX study in first place, the survey was conducted for exactly that reason because we think there is the disconnect between the way patients actually see themselves in the disease and way physicians actually see it. So the simple answer is we saw a very -- through the survey, we saw that there was a doctor shopping but also just an unknown amount of understanding around the disorder not only from the doctor but also from the patient’s family. So there are elements of discordance if you will across the board between care givers, family and physician. And so this heightens the need for education and awareness but I think doctors, Dr. Bilezikian would be able to comment as well on that.

John Bilezikian

Well, I don’t know if I can. I mean we try to be honest, it’s in an imperfect situation now. My goal is not only to keep our eye on the hospital and keep them from having these crashes, the fact that they are not in the hospital and don’t have crashes, doesn’t mean that they are well controlled. And listening to patients, they muddle through. So I am not satisfied by saying well Gee! we’ve got them on calcium and D and it’s okay what else do we worry about and get that message to the patient. I don’t like to think that way. So but I can’t answer your question specifically. I think it’s obviously patients and physician specific, and I think a conscientious position if you ask that kind of question, it would be better concordance than you might imagine.

Francois Nader

So, questions. Yes.

Unidentified Analyst

Thank you. Could you just talk please about the normal (inaudible) variation of parathyroid in normal patient and when you use the replacement; are the levels relevant or you just titrate into numbers? And I am asking because I am thinking about the question about potential black box or other issues.

Unidentified Company Representative

Yeah. That's an interesting question. And we didn't talk about this beforehand. The reason I say is because we have been thinking very hard about this question about (inaudible) and it's very complicated. Parathyroid hormone like most hormones have a tonic secretory rate, have a circadian dynamic usually highest in the morning and lowest in the late afternoon. And then this what this calls so stochastic [pulse utility], random burst of hormone not just PTH its growth hormone and as well insulin and is also food dependent.

So, but we don't actually know the nature of that circadian dynamics. There have been literally four papers in the world's literature and there is nothing basically known about [pulse utility], there is two papers. So actually one of the things I'd like to study, in fact we are starting to study it to get a handle on that question, is there another generation of therapy. This will be a huge step, so once a day treatment at different doses. But if we learn more about the real intensive variability at PTH, then there might be ways to answer your question. But right now, we know there is circadian dynamics, we know there is [pulse utility], but we don't really understand what that means for PTH.

Unidentified Analyst

And so how do the levels compare in replaced patients versus area under the curve for normal or whatever the reasonable way?

Francois Nader

Yeah. There is something known about that Roger. Yeah.

Roger Garceau

This is where we don't know, we look at peak levels and the peak levels and in the curve. So peak levels are probably in the order of 250, 300, so normal levels are 50 STE range. But again we don't understand as Dr. Bilezikian said, we don't understand what the impact is of that versus area under curve. We know that calcemic response is not relative to the peak, but it’s somehow related to the slope, maybe related to the curve. And we don’t understand enough of the physiology of what’s happened. We know we have PKs on board for at least 12 hours and calcemic response lasts for over 24, that is why you see effect on phosphate, you can see the effect on calcemic response.

So, they are not fully linked, and we do know that this is given in the time because we actually blunted the peak a little bit and pushed out the curve and seems to get a better sustained duration of calcemic response. So this is one of the reason why this is given in that time. So it is a whole bunch of physiology yet to be understood about parathyroid hormone and what is the optimal, what we have is a drug that you heard as can have potential huge effects today and can for the majority of patients, probably will be very good treatment for them.

Unidentified Analyst

Thanks for the answer.

Jim Molloy - Janney Montgomery

Thank you very much, Jim Molloy from Janney Montgomery. I had a quick question, any updates on the potential panel on your discussions with FDA? And then just little more on (inaudible) [Bank of America] on pricing an orphan indication, 300,000 is probably outside the range, but have you given any updates on where you think it might come in?

Unidentified Company Representative

So for the pane, it’s difficult for us to say, if the FDA will decide to have one or not but what I can tell you is we are preparing for one, just in case, we’d certainly know after the product is approved, so we had a communication with FDA on day 60 and day 74. We filed on October 23rd, so the first feedback from the FDA will be on December 23rd just before Christmas and 74 will be January 6, I believe. So by then we’ll know if we have a panel or not, but we are prepared to be there.

Related to your second question, I think I mean maybe restating what Eric said, we’re certainly not guiding on pricing, but think of it, or at least this is the pricing strategy that we’re thinking about. We think of prevalence first, so this is -- you referred to 300,000 which is Gattex, 3.,000 to 5,000 patients, here the number is 53, so 53,000, so quite higher. Then we look at the condition itself with the unmet medical need, with the burden of illness, with the direct indirect cost, the quality of life.

And the last element frankly is the pricing assessment that we’re taking very seriously, conducting additional pricing studies looking at analogs. But at the end of the day, we need to make sure that the price that we will determine will meet couple of criterias on; it will meet the criteria that is the most relevant to this particular product, but as we did it with Gattex, which is very important, we don’t want a financial burden to be a hindrance for patients to be on Natpara.

And that's all I can say for the moment. The work is ongoing related to pricing; it’s a very important question. We have a little bit of time; we have about as that less than a year to make up our mind, but we’re taking this question very seriously.

Jim Molloy - Janney Montgomery

Thank you for taking the question.

Francois Nader

Sure.

Unidentified Analyst

Great. The third genetic component to the ideology here with these patients and then from both doctors, how do you define uncontrolled versus controlled, that just be curious basically which patients you’ll be putting on drug?

Unidentified Company Representative

Well there are genetic causes of hypopara as shown in the aggregate patient as opposed to surgical patient. Some are isolated autoimmune which may or may not be genetic, there less common issues to their genetic mutations including chromosome 22 which causes George syndrome which includes hypopara. There are families with chromosomal recessive poly endocrine disorders that include hypopara. So, it’s a fairly diverse if strictly talk about parathyroid hormone deficiency.

Unidentified Company Representative

And our experience -- there are diverse genetics and obviously the big grab, the autoimmune versus these post surgical clinically is very hard to tell the difference. You’ve asked who uncontrolled, controlled; it doesn’t sort out by ideology and there is no good answer. It doesn’t even sort out to is there zero parathyroid hormone in the blood versus two picograms grams per ml, a little smidgen. That doesn’t even work. So we really don’t know how to just sort of interact as to who can be put into these buckets if you want to put them in those buckets.

Unidentified Company Representative

The other somewhat unanswered question is why are some patients easier to manage than others. I have no idea, we were talking to someone a degree about whether some of them have recovered a little bit of their parathyroid hormone function and we haven’t really measured as they’re involved in ongoing treatment. But clearly there is the diversity of patients; it’s very hard to say who’s going to be more controlled than others and who is easier to manage.

Francois Nader

Thank you. Okay. Well, let me conclude the session by saying few words. First, as I started by saying early this morning, we are building a global commercial organization focused in the space of rare diseases. I think we’re off to an excellent start with a Gattex launch that is successful by virtually every metric. As I said this morning as well, we are at 75 patients which on drug which is the lower end of the spectrum and we still have few weeks to go. I am very excited about the prospects of Natpara globally; this is truly an unmet medical need. And I believe that Natpara based on everything we’ve seen so far will certainly be, if approved, an excellent agent to treating hypoparathyroidism and its diversity.

We’re also continuing to build the organization as Luke alluded to with the Gattex pediatric and 795 and we’ll talk about both later on. Last but certainly not least, we are ambitious about our international expansion, 30 countries as I said is easier said than done, but as we’ve always done it, we are very methodical, we’ll do it one country at a time or two countries at a time but we are following a plan. And we want to maximize what we do without opening the flood gates. So, it’s a very, very thoughtful methodical dogmatic approach in many ways while being pragmatic and seizing the opportunities as they come across.

I would like to take this also this opportunity to thank you for being here with us. I hope that you learned few things. We are certainly available for questions; you know where to find us. Like to take also a second to thank Dr. Bilezikian and Dr. Rothman for their contribution to hypoparathyroidism, contribution to Natpara and thank you again for being here today. I would like to thank my team. I have the best team in the world with NPS. Frankly they work in front of the scene, but many of them are working behind the scene to make this happen. And I'm very blessed by having really one of the best teams in the industry.

Last, I know I saw actually many of you taking notes, which is great but we have handouts outside. So you can pick up one and it will be -- also we have a PDF download via the webcast link on our website. And I know it's about 12 noon. And guess what, we'll feed you as well. So we have box lunches outside.

So, with that I will conclude this meeting. Thank you again for being here and sharing with us our success and our future. Have a good day.

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