Well, good morning, good afternoon, and good evening, everyone, wherever you are in this world. Welcome to this session of Endo 2021. And I'm delighted to tell you that as of this morning, we have 7,283 scientific registrants here at our Endo 21, which is a wonderful representation of global endocrinology. And we now have session OR14, and we're going to be hearing some very exciting advances in pituitary treatments. And I'm delighted to ask our first speaker, Dr. Monica Gadela from the Universidade Federal Rio de Janeiro in Brazil, to start our program. So Monica, over to you. Thank you for the introduction. And thank you to the Endocrine Society for allowing me to present on behalf of my colleagues the results of the LINC4 study, a phase 3 study with an aprofront randomized double-blind placebo-controlled phase designed to assess efficacy and tolerability of oxalodostat in patients with Cushing's disease. Here are my disclosures. Cushing's disease is associated with significant clinical burden, impaired quality of life, and increased mortality. Oxalodostat, LCI-699, is a potent oral inhibitor of 11-beta-hydroxylase that is approved in the USA and Europe for the treatment of patients with Cushing's disease and endogenous Cushing's syndrome, respectively. In a phase 3 randomized withdrawal study, the LINC3, oxalodostat led to rapid and sustained reductions in mean UFC in most patients with Cushing's disease. Here we present results from the first phase 3 study of oxalodostat to include the initial 12-week randomized double-blind placebo-controlled period, as I mentioned, the LINC4. So adults with persistent recurrent or de novo Cushing's disease and mean UFC above 1.3 times the upper limit of normal were randomized in a proportion 2-to-1 to oxalodostat 2mg BID or matching placebo for a 12-week double-blind period. Dose titration every three weeks were made according efficacy and tolerability. The dose range 1mg TOD to 20mg BID. It's important to mention that decisions regarding dose titration were made by non-blinded independent endocrinologists. Then from week 12 until week 48, all patients receiving open-label oxalodostat 2mg BID. Patients receiving a lower dose continued in the same dose. Again, dose titration every three weeks were made according efficacy and tolerability. The dose range 1mg TOD to 30mg BID. From 48 weeks, patients could enter in an optional extension phase. How about the primary endpoint? It was the proportion of randomized patients with a complete response, I mean normal mean UFC, at week 12. The key secondary endpoint, proportion of patients who received oxalodostat, both randomization groups combined with normal mean UFC at week 36. So 73 patients were randomized, 48 patients in the LCI group and 25 patients in the placebo group. As expected, the vast majority of the patients were female and had been operated on. Regarding the median baseline mean UFC, it was 2.5 in this arm and 2.2 in this arm. Most patients completed the 12-week treatment, as you can see here, the vast majority did it. Only one patient discontinued due to an adverse event that was arthralgia. The same holds true for week 48. The vast majority again of the patients completed the 48 weeks of treatment, with only a few patients discontinued due to an adverse event. From now on in the graphs, oxalodostat will be shown in purple and placebo in green. So in this graph, it is depicted the proportion of randomized patients with a complete response at week 12. So as you can see here, 77% of the patients that received oxalodostat attained normal mean UFC, in comparison with only 8% of the patients that received placebo. So we can say that the study met its primary endpoint. In this graphic here is depicted the proportion of randomized patients with normal mean UFC up to week 12. 27% of LCI patients had normal UFC by week 2, with greater benefits of LCI from week 5 onwards. The median time to first control the response was 35 days for patients randomized to oxalodostat. This study also met its key secondary endpoint. Since 81% of the patients had normal mean UFC at week 36, the lower bound of the 95% confidence interval, as you can see here, 7%, exceeded the threshold for significant clinical benefit. Here is depicted additional secondary endpoints, the mean change in mean UFC from baseline. So here is the double blind phase, here the open label phase. In green, patients that at the double blind received placebo and then oxalodostat, and here the patients that started on oxalodostat and continue on oxalodostat. This increase here is because after week 12, as I mentioned before, all patients restarted on LCI 2mg BID. I'd like to emphasize that no patient randomized to oxalodostat experienced an escape event up to week 48. In line with improvements in cortisol levels, we also saw improvement in clinical parameters as blood pressure, weight, and waist circumference. In addition to that, we also observed improvement in quality of life through the Cushing Quality of Life Questionnaire and also through the BDI, the Back Depression Inventory. How about the diverse events? So during the randomized 12-week treatment period, were mostly EEs who were mild to moderate in severity and were manageable with dose adjustment or interruption and or additional therapy. Only one patient discontinued oxalodostat because of arthralgia, as I mentioned. In this table is depicted the AEs present in more than 20% of the patients during the overall study period, with a median duration of oxalodostat exposure of seven weeks. The most common AEs were arthralgia, decreased appetite, fatigue, and nausea. The AEs of special interest overall study period are depicted here. Most hypercortisol-related EEs were grade 1-2 and were manageable with dose interruption, adjustment, and concomitant medication. So in conclusion, a significantly greater proportion of patients achieved mean UFC normalization at week 12 with oxalodostat versus placebo, 77% versus 8%. Improvements in mean UFC were sustained. 81% of the patients had normal UFC at week 36. Rapid and sustained reductions in UFC were accompanied by improvements in clinical parameters of hypercortisol and quality of life. LCI was well-tolerated and had a manageable safety profile. Only a few patients discontinued treatment because of AEs. So the efficacy and safety data from the LINC4 study further enhanced the results of the LINC3 study by showing that LCI is a highly effective and well-tolerated treatment for patients with Cauchy's disease. Thank you very much for your attention. Thank you, Monica. That was a terrific presentation. One quick question is 45% of your patients had arthralgias. Do you have a mechanism for the arthralgias? If you don't have one, do you want to speculate on one? Thank you very much for the question, Dr. Melmed. We think that it is because of the cortisol withdrawal syndrome because usually these patients have arthralgia, nausea, fatigue. So we think that is due to withdrawal syndrome. Oh, okay. Then a question which several people have been asking and which was apparent from several of your slides. The abstract says that 8% of your placebos group achieved the primary endpoint and yet at week 8, 20% achieved primary endpoint. Do you view this as a drug placebo effect or is this just the natural background of the patient's Cushing's disease? How do you explain the high placebo effect? 20% of 25 patients is high. In the placebo group, the percentage that got UFC control is 80%. Actually, in the link 3, it was 29%, but in link 4 is only 8% and this 8% is composed by two patients. And we think that this is because probably those patients have very mild diseases. So they have like 1.31 or 2 UFC. And then when we reevaluated these patients over 12 weeks, they were in the normal range, but these were only two patients in the whole population. So very few patients in the control group got UFC normalization. But there were 20% at eight weeks, the placebo group? No, no, no, no. Only 80%. Oh, okay. Only 80%. So I think your answer sort of epitomizes the challenges which we're facing in that we have to do more than one UFC and it's a very difficult diagnosis to make. And these endpoints are very difficult to follow because of these fluctuations that you're clearly pointing out. It's important to mention, Dr. Melvin, that in this trial, it was done three measures and the mean was calculated based on these three measures and the patients had to have two high UFC out of these three. So it was not based on only one measure. Okay. Another question is, and this is the same question that's come up since the beginning of this class of drugs, is, can you tell us anything about the ACTH levels and the tumor size? Yes. This is not a property for ozelotrostat. It's a steroidogenic inhibitor class effect. We may see this with all these drugs. So ACTH may increase, tumor volume may increase, but we don't have, we didn't have in this trial, any clinical relevant increase, but this is not a particular find of ozelotrostat. It's expected to happen. Another question is, as you know, adrenal targeted drugs are now the vogue and over the last few years we have several available possibilities. How do you place this new drug in the context of all the others that we have available in terms of efficacy and side effects? Should this be the first? Should this be the second? Where do you place it in the context of the panorama of anti-adrenal therapies that we have available now? Yeah, I think that in terms of efficacy, it's superior. If we compare these to ketoconazole or even levocetaconazole, it's around 50%. With LCI ozelotrostat, we have around 8%. So in terms of efficacy, I think that's superior. And I think in terms of side effects, it's similar or even a bit better. So I think that is, in terms of efficacy, superior. One question about adrenal insufficiency, how do you treat it? And how do you, first of all, how do you treat it in the trial? And second of all, what do you recommend to clinicians to treat adrenal insufficiency with patients on this medication? So one thing that we learned from LINK4 to LINK5 is that we should uptritrate the dose a bit slower. In LINK3, it was uptritrate every two weeks. In LINK4, every three weeks. So we got less adrenal insufficiency. So slower, easier uptritration is the first one. And then the adrenal insufficiency, the diagnosis was made in clinical signs and symptoms. So we even or decrease the dose or stop the drug and start a glucocorticoid, depending on the case of the patient. Well, thank you very much. That was a terrific presentation and the terrific answers and a nice discussion. And thank you to all our questioners. And for those of you who didn't get your questions answered, I'm sure that Dr. Gadela will be available to answer your questions any time. You can call her or write her or email her and she'll be happy to answer, as will any of the other co-authors. So thank you very much. Moving on to the next presentation now, which is going to be presented by Dr. Lynette Nieman from the NIDDK in Bethesda in Maryland. Dr. Nieman, you're on. Thank you very much for that kind introduction. And on behalf of my co-authors, I'd like to thank the Endocrine Society and the organizers for inviting us to present our results today. I have no disclosures. As you all know, surgical resection is the optimal treatment for Cushing syndrome. However, medical treatment with metapyrone, a steroidogenesis inhibitor, is approved in Europe based on observational retrospective studies. Metapyrone may be used as a bridge to surgery when surgery is contraindicated or unsuccessful, when a tumor is occult, while awaiting the effects of radiation treatment, or based on patient preference. PROMPT is the first prospective study designed to confirm metapyrone efficacy and tolerability in Cushing syndrome patients. This was a single-arm open-label phase 3-4 multi-center European trial that was conducted in the country shown in dark blue on this map. The inclusion-exclusion criteria were as follows. We enrolled newly diagnosed adults with endogenous Cushing syndrome of any etiology except for advanced adrenal carcinoma, or those with recurrent or persistent Cushing's disease after transphenoidal surgery. Each patient also had a mean of three 24-hour urine-free cortisol levels that was at least 50 percent above the upper limit of normal, which was 165 nanomoles per day. Urine-free cortisol was measured by tandem mass spectrometry. This study was a two-part study. The first lasting 12 weeks was the core study, and this involved dose titration of metapyrone. The second part of the study was an extension study for patients who had a good decrease in their values at the end of the core study. Today I will be presenting results from the dose titration core study. I'd like to point out that the arrows shown here indicate the weeks at which the patients were evaluated for their response to metapyrone. The initial dose of the drug was titrated according to the severity of Cushing's syndrome, with patients with mild to moderate Cushing's syndrome, defined as a urine-free cortisol of less than five times the upper limit of normal, receiving an initial dose of 750 milligrams per day, while those with more severe Cushing's syndrome received an initial dose of 1500 milligrams per day. The dose was then further titrated according to biochemical and clinical symptoms. The urine-free cortisol was used as well as serum cortisol. If the urine cortisol was greater than the upper limit of normal, or the serum cortisol was greater than 12 micrograms per deciliter, the dose was increased by 250 to 500 milligrams in the mild to moderate group, and by 500 to 1000 milligrams in the severe group. By contrast, if the serum cortisol was less than 7 micrograms per deciliter, or there were certain signs and symptoms of adrenal insufficiency, the dose was decreased by the same amount in each of the two groups. Finally, the optimal dose was reached when the urine-free cortisol was within the normal range, or the serum cortisol was both greater than 7 and less than 12 micrograms per deciliter. The endpoints of the study are shown here. The primary endpoint was the proportion of complete responders, defined as those with mean urine-free cortisol less than the upper limit of normal. Secondary endpoints included the proportion of partial responders, defined as the mean urine-free cortisol decreased by at least 50%. We also evaluated the clinical symptoms of Cushing's syndrome, blood pressure, circulating lipids, glucose, insulin, and testosterone values. We assessed the quality of life, as well as safety parameters, adverse events, and tolerability. We timed the duration to eucortisolemia, to 50% reduction of mean UFC, and to an improvement in clinical and biochemical parameters. The patient population included 50 study enrollees, and there were three dropouts. One discontinued early in the study because of unrelated pneumonia and septic shock. Two underwent transvernodal surgery late in the study, despite improvement on metapyrrole, and were included in the modified intent-to-treat analysis. Within the intent-to-treat analysis group, 69% had hypertension, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median urine-free cortisol at the study start was 570 nanomoles per day, which is about three and a half times the upper limit of normal, and the range was from 290 to about 8400 nanomoles per day. This slide shows the demographics and clinical history of the 49 patients in the intent-to-treat group. They were aged 46.4 years. About 70% were women, and nearly 90% had Cushing's disease. The median time since the start of their symptoms ranged from 0.3 to nearly 22 years, with a median of 3.9 years. Five patients had previous pituitary irradiation, 30 had previous pituitary surgery, and of these, the median time since their surgery was 1.41 years, with a range of 0.1 to nearly 21 years. Here we show the change in median UFC over the 12 weeks of the study. You can see that by week 1, there was a median reduction of almost 50%. By week 12, the median reduction was 74%, and you can see that half of these patients had values below the upper limit of normal, shown as the pink dashed line. The final median metibropone dose was 1500 milligrams per day, with a range of 250 to 5500 milligrams. At 12 weeks, 81% of the participants were responders, 47% had a normal urine-free cortisol, and 33% had a decrease in urine-free cortisol of at least 50%. Of note, 22% of participants had normalization of late-night salivary cortisol. We also found metabolic and clinical parameters to be improved. The quality of life score improved by 10 points. 31 of the 47 patients had normalized or improved signs and symptoms of Cushing's syndrome. There was a change in the blood pressure of 4 to 5 millimeters in systolic and diastolic, respectively. Amongst the hypertension patients, 9 of the 32 had a decrease in the dose or number of medications, and 5 of the 32 had an increase in either the dose or the number of medications. Hemoglobin A1c remained relatively stable, cholesterol improved significantly, and testosterone increased in women. There were adverse events in 26 of the 50 patients. These were mild to moderate in almost all cases. Primarily, these were gastrointestinal, with nausea and decreased appetite. There were symptoms of adrenal insufficiency that were mild, such as fatigue, headache, and headache. In addition, 6% of the population had either peripheral edema, hypokalemia, and or new hypertension. Six patients had reversible adrenal insufficiency. A dose adjustment was required in seven patients because of these AEs, and a temporary dose interruption was required in the six patients with adrenal insufficiency. Despite the increase in testosterone, no patient complained of worsening acne or hirsutism. So, in summary, mean UFCs normalized in 47% and decreased more than 50% in one-third of the patients after 12 weeks of metopyrone treatment. Improvements were seen in clinical signs of hypercortisolism, associated comorbidities, and quality of life. Metopyrone was well-tolerated, with 26 of 50 patients experiencing at least one drug-related adverse event. These were mainly mild to moderate, and only six experienced adrenal insufficiency. The adverse events led to dose interruption or dose adjustments in 26% of patients. One patient discontinued because of a serious adverse event. In conclusion, this prospective study confirms that metopyrone is a rapid-onset, effective, and safe medical treatment for Cushing's Syndrome patients. Thank you very much. Thank you, Lynette. That was terrific, and especially for U.S. audiences who haven't had that experience, this is a very, very important study. So, thank you very much to you and your co-authors. I'm going to repeat the same question that I asked Monica earlier. We now have a whole host of available new options for anti-adrenal targeted therapy. Where do you place metopyrone based on your results? Well, I do think that one non-medical judgment on this is going to be the cost. So, certainly, I think everyone is very much looking forward to seeing what the pricing structure will be for the newly arriving drugs that we will have on market or have on the market. I do think that in contrast to the previous study where dose adjustments were given more often, we had a break from the fifth week to the twelfth where there's only one dose adjustment in the middle. And I do know the results of the ongoing continuation study, and I believe that shows that we do get some improvement in response rates, probably because of dose adjustments. So, I think that probably these drugs are relatively equivalent, a little more side effects in the link study than ours, better efficacy in that study, which may relate to symptoms of adrenal insufficiency. I would agree with the idea that this is probably, the arthralgias are probably a measure of decreased cortisol. Okay. We have a question here about compliance. This was quite an extensive study, many countries with lots of monitoring. How did you monitor compliance? How many missed doses were there? Were there geographic differences in compliance? You know, Cushing's patients are very difficult in terms of challenging a rigorous monitoring process. So, could you answer the question about compliance with the protocol? Yeah, I haven't broken down the issues about compliance by study site. I completely agree, not all patients are compliant, and this was assessed through pill counts. And I don't have off the top of my head, the percentage that were non-compliant. There is one person who actually had quite an increase in UFCs at one point and was likely not compliant with the study medications. Okay. And another question about safety. A lot of the AEs that you mentioned were reminiscent of background Cushing disease. Could you break out your AEs into responders versus non-responders? And in the true responders, was the AE profile different? Or can you attribute most of your AEs to underlying Cushing disease, like hypertension, for example? Right. Well, the new AE of hypertension only occurred in a minority of patients, 6%. But most of the AEs, to me, seem very much like adrenal insufficiency, on the way to adrenal insufficiency. The GI side effects, the arthralgias, the headache, the fatigue, all are very consistent with a decrease in cortisol production. So I would assume that this is actually reflecting the efficacy of the drug in some respects. I like the idea of looking at the correlation between responders and AEs, and we haven't done that. So thank you for that suggestion. We'll do that. But I think that this is an issue of dose titration, as well as the variability of UFCs that was mentioned earlier. Okay. And another very topical question, which has been asked for multiple neuroendocrine contexts now, any role for combination therapy? I love combination therapy, but when you're developing a drug, you use it as monotherapy. My patients with ectopic ACH secretion, oftentimes, if someone has UFCs greater than eight times normal, I think it's pretty hard to get these patients under control with a single agent. And when we look across all of these recent studies, there are very, very few patients with extremely high values. And in this particular study, the patients with the highest values, there were four who had extremely elevated UFCs, and three were not controlled. And one was nearly controlled, was barely a little bit above the upper limit of normal. And a final question, especially from the USA, is the drug available in the pharmacy? Can you prescribe it today? Yes, it's distributed in the United States through HRA Pharma. If you go to their website, they have a telephone number to the pharmacy that distributes it, and it is possible to get it. If you have a lot of trouble getting it, the best thing to do is to call them, because sometimes the faxes don't get looked at as quickly as you might hope. But I also am aware that some hospitals have a small stock in the hospital to initiate therapy quickly. Thank you very much, and apologies to all the multiple questions that weren't answered. We just don't have time. But again, Dr. Newman is available by email, by telephone, and I'm sure she will answer all your questions or to speak to any of her co-authors. So thank you again for a really terrific presentation. Thank you. We're going to move on right now to the next presentation, which is by Susan Sampson from the Mayo Clinic in Florida. And I just wish to disclose that I am a co-author on this paper as well. Susan, you're on. Hi, this is Susan Sampson, and on behalf of my co-authors, it is my pleasure to present the data from the one-year outcomes of the open-label extension of the Phase III Chiasma Optimal Study. This was a multicenter international trial which explored the efficacy and safety of oral octreotide capsules for the treatment of patients with acromegaly previously treated with injectable somatostatin receptor ligands. Here are my disclosures. Oral octreotide capsules were recently approved in the USA as a treatment option for patients with acromegaly who previously responded to and tolerated treatment with octreotide or lanreotide injections. Oral octreotide capsules are a novel formulation with transient permeability enhancer allowing octreotide to be absorbed systemically from the intestine into the circulation, achieving levels similar to octreotide subcutaneous injections as based on a Phase I study. We previously reported our oral octreotide capsule safety and efficacy in the 36-week Phase III Chiasma Optimal Pivotal Study as referenced at the bottom of the slide. The aim of this current analysis is to explore the long-term durability of the response to oral octreotide capsules for those who continued in the open-label extension for an additional 48 weeks. Just to remind the audience of the optimal trial design, this was a randomized double-blinded placebo-controlled study in 56 patients with acromegaly. Patients had to have proven active disease after surgery and had to be controlled with a mean screening IGF-1 of less than or equal to one times the upper limit of normal on injectable somatostatin receptor ligand therapy with octreotide or lanreotide. Patients were randomized to oral octreotide capsules or to placebo capsules with 28 patients per group. All patients were started on oral octreotide at 40 mg total daily dose and this could be titrated up to 80 mg daily at the investigator's discretion. Because this was a placebo-controlled trial, patients could revert to their previous injectable somatostatin receptor ligand shown as rescue injection here on this slide if they fit the predefined withdrawal criteria which is shown in the lower right panel. This was in order to regain disease control, period. It is important to note that no patients were lost to follow-up in this trial and it met all of its primary and secondary endpoints. After the 36-week double-blind placebo-controlled period, patients could enter the 48-week open label extension shown at the right side of the slide at 60 mg to be titrated up to 80 mg or down to 40 mg at investigator discretion based on IGF-1 levels and or safety and tolerability. To enter the open label extension, patients were eligible if they completed the double-blind placebo-controlled period on oral octreotide or placebo without reverting to injectable therapy or if they met the predefined withdrawal criteria and were followed through week 36 of the double-blind placebo-controlled period. Maintenance of response for this trial was an average of the IGF-1 at weeks 46 and 48 that was less than or equal to one times the upper limit of normal. Multiple imputation approach was used for analysis of maintenance of response. This slide shows the patient disposition for the open label extension. Of 28 patients in each arm, from the optimal trial, 20 from the placebo arm and 20 from the oral octreotide arm entered the extension. For those patients from the oral octreotide arm, 19 were on study drug at the end of the 36 weeks and 14 were responders. 18 of 20 or 90% completed the open label extension. For patients from the placebo arm, 9 were on study drug with 5 characterized as responders at the end of the double-blind placebo-controlled period. This means 6 had reverted to their injectable therapies. Of these, 14 patients completed the open label extension or 70%. All patients entered the extension at 60 mg daily with 27 patients titrated up to 80 mg and 3 patients lowered to 40 mg daily during the extension. Turning to the data, the mean IGF-1 levels at the start and end of the 48-week extension are shown in the right panel. Using multiple imputation, the patients from the oral octreotide group who completed the core trial on study drug and had not reverted to prior somatostatin receptor ligand therapy maintained a mean IGF-1 less than 1 times the upper limit of normal at 0.91 at the start of the extension and 0.90 at the end. 100% of the 14 oral octreotide responders completed the open label extension and 93% maintained the stringent response criteria. Notably, of 4 patients who entered the extension with an elevated IGF-1 of 1 to 1.3 times the upper limit of normal, 2 of those patients completed the extension with improved control to less than 1.0. From those who entered the extension from the placebo group and had not reverted to prior somatostatin receptor ligand therapy, the mean IGF-1 was 1.09 times the upper limit of normal at the start of the extension and then improved to 0.87 by the end of the 48-weeks. This slide shows the growth hormone response during the open label extension. This is shown in the right panel. Growth hormone was measured every 30 minutes for 2 hours to obtain the mean at the start of the extension and also at week 48. For those entering the extension on oral octreotide, the mean growth hormone was 0.45 ng per mL and was 0.40 at the end of the extension. For those entering from the placebo arm, the mean growth hormone was higher at 1.12 ng per mL and was 0.71 at the end of the extension. Overall, on oral octreotide, patients from the placebo and oral octreotide groups achieved a mean growth hormone less than 1 ng per mL at the end of the extension. Regarding safety events, 87.5% of patients experienced at least one treatment or emergent adverse event, but most were mild or moderate and assessed to be unrelated to study drug. The gastrointestinal side effects of nausea, diarrhea, and vomiting are known side effects of injectable somatostatin receptor ligands as well. No new safety concerns were noted with the prolonged exposure to oral octreotide capsules in the extension. While in the extension, the patients were started on a higher dose at 60 mg as compared to the 40 mg daily in the double-blind placebo control period. Therefore, there is interest in the tolerability of starting at the higher dose of 60 mg. Adverse event data from those patients who entered the open-label extension from the placebo arm, that is, those who had not previously been exposed to oral octreotide capsules, demonstrate a lower number of subjects with any treatment emergent adverse events at 57.9% compared to the rate of 96.4% during the double-blind placebo control period. Opinion-related adverse events also were lower at 31.6% for the 60 mg first exposure versus 40 mg in the double-blind placebo control period. In conclusion, the data from the 48-week open-label extension of the optimal trial showed that sustained maintenance of biochemical response to oral octreotide capsules was durable, with 93% of responders from the oral octreotide arm maintaining stringent IGF-1 control at 48 weeks. The safety profile is consistent with what we know about injectable somatostatin receptor ligands and disease burden, and no new safety signals were seen on long-term oral octreotide capsules. Drug-naive patients from the placebo arm who were initiated on the middle dose of 60 mg did not have higher incidence of adverse events compared to patients initiating drug at 40 mg. I want to thank you for your attention. Thank you, Susan, for that presentation. We have several questions here. So the first question is the 60 mg dose. Based on your data now, are you able to recommend the optimal dose for efficacy and safety to patients who are being administered this medication? I do think that the 60 mg starting dose in the open-label extension, for those who had previously been on placebo, does let us look a little more closely at how that dose works and how patients do safety-wise. We know that both the treatment-emergent adverse events and treatment-related were lower. It makes you look back at the original 303 trial and think about the adverse events we saw in the placebo versus the oral octreotide adverse events of special interest. Those are things like the symptoms of acromegaly that can worsen during a trial but are still recorded as an adverse event. Knowing that those are lower in oral octreotide in the 303 trial and thinking about doing a deeper dive into the safety data in this open-label extension will surely answer that question. Thank you. There is a question here about what is the role of oral octreotide in somatostatin receptor ligand in IE patients, i.e. as the first option when medical treatment is needed? What would you answer based on your experience with the trial? Well, we know that the current FDA label requires that our patients have responded to octreotide and lanreotide. And I think a lot of us who would use tumor characteristics or immunostaining that would teach us that this tumor would be responsive to octreotide would know that this medication will work in the same way. It's an oral form that is absorbed systemically just like if you injected octreotide. So I would expect that as primary therapy it would behave like injectable octreotide. But currently our label is that we need to have had a patient already on an injectable coming into the use of this medication. Thank you. There's a question here about was there any regression in tumor size or decrease in growth hormone production per se over time? So we did present the growth hormone data and I think it's very telling in both the core trial as well as the open label extension. And we do see that growth hormone decrease in the placebo group who came into the extension drug naive and decreased under the down to the mean. I think it was in the 0.4 range for the oral octreotide group and then 0.7 for the placebo group. So that's what we know about growth hormone. We do not have any data analysis yet on tumor size. Okay. Thank you. Then the final question is how many patients did not normalize their IGF-1 by the end of the extension and how many of these required rescue? So the extension didn't include a rescue phase. It was really that patients withdrew consent or had treatment failure. So we know that 90% of the patients on OOC and the DPC continued on and of the responders that ended the double blind placebo control trial, you know, 93% remained controlled and only one of 14 had an IGF-1 that was about 1.1 times the upper limit of normal. So 14 of 14 responders from the oral octreotide capsule group continued that response all the way through the 48 weeks. Okay. Well, thank you. I'm sorry we don't have more time. And again, please write your questions into Dr. Samson and she will be happy to respond or any of her co-authors. So thank you so much. And moving on now to our final presentation for this session, which is going to be presented by Dr. Bettina Winsler, who is coming to us from the University of Basel in Switzerland. Bettina, you are on now. So thank you for the introduction. In the following, I would like to present to you my study about glucagon-like peptide 1 receptor agonists and fluid intake in primary polydipsia. So these are my disclosures. So fluid intake is generally believed to be very healthy and in the lay press, you will find a lot of pictures like this and statements that fluid intake or water intake improves your well-being and promotes important health benefits. And of course, drinking is very important to keep your osmolality in a narrow range and your sodium level. However, if you do it excessively, as it is the case in primary polydipsia, it is no longer healthy or harmless. In fact, excessive fluid intake carries the risk of water intoxication and hyponatremia. And this is especially the case if water excretion is impaired. So in this table, you see data of 23 patients with primary polydipsia who presented at our hospital with profound hyponatremia. And you can see that all of them had different factors impairing water excretion. For example, low solute intake or a concomitant vasopressin stimulus, which may be due to medication, infection, stress, or acute psychosis. So in view of these consequences, the question is, how can we treat primary polydipsia? And to date, no medical treatment options are available for this treatment. And that brings me to the next slide and to the GLP-1, the glucagon-like peptide 1, which is, as you know, a gut hormone which is released in response to food intake and it has important effects in the body and it has also important central effects. It reduces appetite and food intake. And so I was wondering whether GLP-1 has also an effect on fluid intake. If you look at early studies investigating GLP-1 and food intake, you can see that fluid intake actually also decreases under a GLP-1 infusion, as shown here at different doses, which is actually quite a lot, minus 18%. And this reduction could just be due to the reduced food intake, but it could also be an independent effect. And in fact, neurons of nuclei of the larvina terminalis, which is a key brain structure in thirst sensing and water balance, express GLP-1 receptors. And these GLP-1 receptor-expressing neurons are believed to confer satiety during fluid intake. So the question of the study was to explore whether GLP-1 receptor agonists reduce fluid intake and thirst in patients with primary polydipsia. This was a randomized placebo-controlled double-blind cross-hours study. And all participants underwent a three-week treatment phase on placebo or dulapotide at a dose of 1.5 mg per week. After three weeks, the treatments were interchanged, and they had a second treatment phase. So at the end of each treatment phase, an evaluation visit took place at our study center, beginning at 8 o'clock in the morning until 4 o'clock in the afternoon. And the participants were offered two standardized meals, which they had to finish. And there was also a water dispenser, and they were invited to drink as much water as they wanted. The primary outcome of the study was the total fluid intake during this eight-hours evaluation visit. And other outcome measures were thirst perception, reported average daily fluid intake, voiding frequency, nocturia, and adverse events. In a subset of 15 patients and matched controls, we also performed an exploratory functional MRI study. And so the patients, they had two additional fMRI sessions and underwent a thirst rating task, which I'm going to explain in the following slides. And at the end, thirst perception and brain activation was compared between patients and their matched controls, between treatment arms, and also between the different stimuli, which were drinks and chair pictures. So here you see an example of the beverage pictures. So they were exposed to sets of pictures, to beverage pictures, or to control pictures, which were chairs. And at the end of each picture set, they were asked to score their thirst perception. So I'm now going to show you the results. So the median age of our 34 patients with paleopolydipsia was 29 years. We had more females than males, and many of them had a psychiatric disease. So the reported daily fluid intake at study entry was four and a half liters. So during the evaluation visit, or in the morning of the evaluation visit, we also measured sodium levels. And as you can see, sodium was not different between dulapotide and placebo. And importantly, also assessed gastrointestinal symptoms were not different between the two groups on the day of the evaluation visit. So this is the primary endpoint, the total fluid intake during these eight hours. And you can see here the values in yellow on dulapotide and blue placebo. And participants actually decreased their fluid intake by almost 500 milliliters, which corresponds to a relative reduction of 17%. On this figure, you see that two thirds of patients reduced their intake, which varied between minus 500 and minus 2,500 milliliter per day. We also assessed appetite and thirst perception at different time points of the evaluation visit. You see that patients were not hungry anymore after the meals. However, I think this is quite characteristic for patients with polydipsia, they still reported thirst perception during the whole evaluation visit. However, thirst perception was reduced on dulapotide in yellow compared to placebo in blue. And so these results were also consistent regarding all the other outcome measures. So patients reported decreased average fluid intake. So the average fluid intake was reduced by one and a half liter per day. They also reported a reduced swallowing frequency, so minus two admixtures per day. And finally, in the last figure, you see the percentage of patients reporting nocturia. And also here, patients on dulapotide reported less nocturia. So this is the result of the fMRI sub-study. In the middle, you see patients with primary polydipsia on placebo, so those had the highest thirst perception when exposed to drink or beverage pictures, but also when they were exposed to chair pictures, they were still higher than their matched controls. And here on the right hand side, you see that dulapotide reduced thirst perception in patients with primary polydipsia. Unfortunately, we were not able to detect differences in brain activity between patient groups or treatments, and this is most probably due to the limited number of the participants in this sub-study. So in conclusion, I have shown that GLP-1 receptor agonists, such as dulapotide, reduce fluid intake in patients with primary polydipsia. I have also shown that dulapotide reduces thirst perception in these patients compared to placebo, and GLP-1 receptor agonists might therefore be a novel treatment option in these patients. I would like to conclude and to thank all the study participants and all my colleagues who made this study possible, and I'm now very happy to take questions. Thank you very much. That was really a fascinating study for us and a lot of new information for us to digest. Thank you. A lot of questions. So the first one is, is the effect specific to Dulagretat, the drug you used, or is it a drug group effect, and why did you choose this specific drug rather than any of the other families? So thank you very much for this question, yeah. Well, I think it's rather a class effect, so I would suspect the same effects with any other GLP-1 receptor agonists, and maybe Dulagretat is quite a big molecule, and so the permeability from the blood to the brain barrier permeability is not quite clear in Dulagretat. So I even think that maybe if we would have chosen a smaller molecule as semaglutide or exenatide, it would even have had a better effect, but the reason why we chose Dulagretat was we wanted to take a once weekly medication, and so at that time we didn't have semaglutide, and if you use exenatide once weekly, it takes a long period to have a steady state, so it was more a question of feasibility. You know, as neuroendocrinologists, we're very interested in SIDH and following our patients after pituitary surgery. Do you think there's any role for agonists or antagonists in these clinical situations which are so common for us? I'm not sure. I think it's quite difficult to use this kind of drugs in an acute setting. As you know, gastrointestinal problems are quite common during the first days or weeks of treatment. I think it's maybe better to use it in a chronic situation or a chronic disease. So that's a very effective answer, but then what happens to hemoglobin A1C and blood sugars? These patients become hypoglycemic. No, actually, no, that was not a problem, it was not an issue. We also measured glucose and A1C, but as we also use CHP1 receptor agonists in obese patients without diabetes, that's not an issue, and also in these patients, they were not diabetic but we didn't have any problems with hypoglycemia. Oh, okay. So what is the effective dose that you're going to recommend based on your study that our listeners can try? Sorry? Can you repeat the dose? Oh, okay. So the dose. So we use the dose of 1.5 milligrams per week. Is that the optimal dose, do you think? I actually think if we go up with the dose, we could also expect like a bigger effect. It was just, I mean, it's a dose which the drug is approved for that dose at the moment, but with all the CHP1 receptor agonists, we have studies now showing that, you know, at bigger doses, we have more effects. So I would actually expect even a better effect than a higher dose. Okay. Well, thank you very much. This is a fascinating talk for us and terrific data. Thank you to all our speakers who had a wonderful session. We've all learned a lot and enjoy the rest of ENDO 2021.

glucagon-like peptide 1 receptor agonists

primary polydipsia

excessive fluid intake

fluid intake reduction

thirst perception

dulaglutide

GLP-1 receptor agonist

randomized controlled trial

placebo-controlled study

urinary frequency