Rhythm Pharmaceuticals, Inc.

good day and thank you for standing by welcome to the rhythm pharmaceuticals third quarter financial results conference call at this time all participants are in a listen-only mode after the speaker's presentation there will be a question and answer session to ask a question you will need to press star 1 on your telephone please be advised today's conference is being recorded if you require any further assistance please press star 0. i would now like to hand the conference over to your speaker today David Connolly with Rhythm Pharmaceuticals. Please go ahead.

Thank you, and good morning. I'm David Connolly, head of IR and corporate communications here at Rhythm Pharmaceuticals. For those of you participating via conference call, the accompanying slides can be accessed and controlled by going to the events section of the investors page on our website at ir.rhythmtx.com. This morning, we issued a press release that provides a third quarter 2021 Financial Results and Business Update, which is available on our website. As listed on slide two, with me today here in Boston for the conference call are David Meeker, Chair, President, and Chief Executive Officer of Rhythm, Linda Shapiro, our Chief Medical Officer, Jennifer Chen, Executive Vice President, Head of North America, and Hunter Smith, our Chief Financial Officer. With slide three, I'll remind you that this call contains Remarks concerning future expectations, plans, and prospects which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various factors, including those discussed in our most recent annual report on file with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David, who will begin on slide five.

Thank you, Dave, and good morning, everyone. We're very pleased to report another strong quarter of execution for Rhythm, and I'll remind you that we're building Rhythm piece by piece, gene by gene, and are, like I said, very pleased with the progress to date. The first slide is to highlight four areas of high focus for us. One is, of course, the commercial experience with Incivary. Second is looking forward to the anticipated Varded Beetle and Ahlstrom's launch in 2022. Third is to build out our global presence, working with healthcare systems, first and foremost in Europe, but we will increasingly look beyond there. And fourth, to continue to advance a robust clinical development program, which has the ability to meaningfully increase the addressable patient populations. Now, quarter three is a quarter with multiple highlights, again, with continued execution. First, the U.S. Incivry launch is progressing and meeting expectations. As we said, we expected to have tens of patients on treatment, and that view of the world has continued to hold. We're pleased with the net sales, clearing one million for the quarter. But more importantly, we're really happy about the learnings that we're beginning to accumulate from this initial commercial experience, which will lay the foundation for our subsequent Vardik beetle launch. And in the international markets, Europe specifically, reimbursement dossiers have been filed in major markets and some of the smaller markets as well. And we're in advanced discussions with the three major markets, Germany, France, and the UK. Second, as we advance toward BBS launch in mid-2022, as you know, the regulatory submissions have been filed in both the U.S. and Europe. In the U.S., we've fully hired a highly experienced field team, and Jennifer will provide you with more color around that. So a year ahead of anticipated launch, we feel like we are in a good place, so I'm looking forward to that event. Third, we had a very strong presence at medical meetings with 22 presentations at three major medical conferences. Positive data was presented from a variety of different clinical data sets with world-renowned KOLs presenting several annotated data. In a noteworthy category, we have our first data on health-related quality of life and additional data on hunger and weight scores across a number of different genetic diseases. Linda will provide a little more color on that in her presentation. And finally, the clinical development programs remain on track with M&A-favorite, pediatric, and early-stage trials advancing to first patient in, and I will provide a little more color on our testing program here in slide two. Before we get to that on the next slide, slide number seven, I just want to remind you there's an efficiency to rare disease community building. which we are taking advantage of. And in the rare disease setting, you often have a limited number of centers of excellence, a limited number of KOLs, and they serve multiple purposes. And so you can focus your efforts very much around these sites. Not only do they run the trials, serve as key opinion leaders, they're also the same physicians, healthcare providers, who diagnose and actually treat these patients. What we're doing is pursuing a hub-and-spoke model where that center of excellence, the clinical trial site, is at the center, and then we will work with a surrounding set of treaters, interested parties who are potential referral sites, referring into that site, and over time some will become their own center of excellence depending on the level of interest. Moving to slide eight, here's a brief update on our testing program. We've had several generations of our screening, genetic screening panel. In May, we went from a 40 gene panel that we reported out on to reporting out on an 80 gene panel. And that panel includes all the genes of interest to rhythm in terms of genes we believe are closely linked to the MC4 pathway. But it also includes a number of genes that would be of interest to the obesity treater at large, meaning other genes that might help inform what is the underlying driver of that patient's obesity. So what this pie graph shows is on the order of 55% of patients who present with a history of early onset obesity and hunger, are likely to test positive for one of the genes of interest, meaning a gene that would qualify that patient for entry into the Emanate trial or the Daybreak trial, which is an additional 31 genes we've yet to explore but have some reason to believe they may be related to the pathway, or be potentially eligible for commercial therapy within Sivri. Now, of note in that 55% are 1.96, almost 2% of the population who are biallelic for Bardot-Beetle or the ALMS-1 gene, which is the gene that is responsible for Ahlstrom's syndrome. So that percentage is a noteworthy percentage. There's much more to be learned. We don't know that all of those patients, that their genetic defect is driving their underlying obesity or that they will even go on to develop Bardot-Beetle, but it opens up a whole other avenue for better understanding this disease, and rhythm's gonna play a leading role in driving that exploration. With that, we'll move on to slide nine. Slide nine is just to remind you again that we do have a broad pipeline, and it underscores the fact that I think we have a legitimate pipeline in a product, and Linda will provide a little more color on our progress across this portfolio in her section. And with that, I'll turn it over to Linda.

Thank you, David. This is an exciting time for Rhythm as our efforts around Bartlett-Beutel syndrome are coming together on many fronts, putting us in a position to bring to patients the first-ever therapy to address the unmet needs of hyperphasia and severe obesity that affect the lives of patients and families living with this disease. Bartlett-Beutel syndrome, or BBS, is a clinical syndrome with many features, including severe obesity from an early age, and an insatiable hunger or hyperphasia, which impact the health and quality of life for patients, their families, and caregivers. There is currently no effective treatment, and we know from interviews and our work on health-related quality of life in patients and families with BBS that was presented this week for the first time, just how dire the need is to control hunger and to stop thinking about food all the time. This quarter, as David said, we are one step closer to delivering a transformative new treatment option to patients, having completed our regulatory submissions in the U.S. and E.U. SEP melanotide has demonstrated clinical efficacy and safety, as well as meaningful improvements for patients and their families, caregivers, and healthcare providers. And we look forward to reviewing some of these data today. Slide 13. The severe impact that BBS has on the lives of patients and families is significant, and we've made tremendous strides this quarter in documenting, qualifying, and quantifying this impact. But the patients, caregivers, and families clearly speak best for themselves, as their quotes on this slide from in-depth qualitative interviews that we conducted with patients with BBS and or their caregivers point to the stress and guilt of denying food to children with hyperphagia and point to how the worlds revolve around food, which limits their focus on anything else. Pause here for an opportunity for you to read through some of these quotes. During a company all-hands meeting, we heard last month from the mother of a child with Barda-Beetle syndrome, and her story reinforced our understanding of the impact BBS has on families. and underscored the unmet need that exists in this community. She told us about the significant weight gain evident by two years old that continued as off the charts rate of weight growth and the challenges she faced in school with weight gain, including physical as well as social difficulties. She told us it was very tough. These firsthand accounts reinforce our understanding of the impact BBS has on families. and underscore the unmet need that exists in this community. Slide 14. This quarter, we completed regulatory submissions for Bartlett-Beetle syndrome and Ahlstrom syndrome in both the United States as well as the European Union. In September, we submitted a supplemental new drug application to the FDA for Imsivir, the branded name of setmelanotide, for the treatment of obesity and control of hunger in adult and pediatric patients six years of age and older with BBS or Alzheimer's syndrome. We requested priority review from the FDA as part of the application. Based on FDA timelines, we will know in November if our supplemental NDA has been accepted with priority review. And if granted, that would mean a target FDA review period of six months from that date of acceptance. In October, we submitted a Type 2 variation application to the European Medicines Agency for IMSABRI for the treatment of obesity and control of hunger in adult and pediatric patients six years of age and older with BBS or Alzheimer's syndrome. The review timeline in Europe is calendar-based, and we would expect a decision from the European Commission in the second half of 2022. We are confident in these submissions as they are based on data from the pivotal Phase 3 trial in which setmelanotide achieved clinically meaningful and statistically significant reductions in body weight and in the unrelecting hunger associated with these syndromes. And these submissions include a series of comprehensive narratives from each individual patient, supporting our belief that Insufree has the potential to offer the first therapeutic option for the early onset, severe obesity, and unrelecting hunger that characterize these syndromes. On slide 15, here's a reminder of the trial design of our phase three trial, evaluating set melanotide therapy in patients with Bartlett-Beutel syndrome and Ahlstrom syndrome. This trial began with a one-to-one randomization in a double-blind placebo-controlled period of 14 weeks, as highlighted in the light blue area, and then progressed through a minimum of 52 weeks on set melanotide therapy. All patients were titrated on setmelanotide at the beginning of the open label portion and proceeded to complete at least 52 weeks on therapy for those who began on placebo and a total of 66 weeks on therapy for those who began on setmelanotide. Patients were evaluated for the primary and key secondary endpoints at 52 weeks on therapy as shown here in the red boxes. Slide 16. The data from the 14-week double-blind placebo control period are shown. Significant BMI reductions in patients with BBS on semilanitide therapy versus placebo. Patients in the placebo group had negligible weight loss or BMI reduction at 14 weeks compared to patients in the treatment group who reduced their BMI by an average of 4.3%. This translates to a statistically significant placebo-corrected set melanotide treatment effect of 3.8% BMI reduction in 14 weeks. On slide 17, as before previously, this trial achieved all primary and key secondary endpoints with statistically significant and clinically meaningful reductions in body weight and hunger at 52 weeks. These data on patients with BBS from the Phase III trial are presented this week at the Obesity Week Conference in a symposium by Dr. Robert Haas from the Marshfield Clinic, the leading BART at Betel Syndrome key opinion leader in the United States. As you can see, we saw clinically significant reductions in body mass index across all 31 patients with BBS in this trial, with a mean reduction of greater than 9% in both adults as well as children and adolescents at 52 weeks of therapy on set melanotide. On slide 18, set melanotide achieved clinically meaningful reductions in hyperphasia, that insatiable hunger that dramatically affects the lives of patients with Bartlett-Beetle syndrome and their families. As we saw, these data in both the initial 14-week double-blind period set here in the light blue blocks, and out to 52 weeks. At 14 weeks, these data showed that patients in the placebo group had a modest reduction in hunger scores compared to the nearly 35% reduction achieved by the treatment group. Interestingly, when we compare the data trends over 52 weeks, there is a clear separation of hunger during the double-blind placebo-controlled period, highlighted in the light blue box. followed by the placebo group reaching treatment levels rapidly after crossover to the open-label set melanotide treatment period with the white background. Also, after the placebo-controlled double-blind period at week 14, you can see a brief rebound of hunger when patients on set melanotide were re-titrated onto the drug. This speaks to the sensitivity of hunger in Bartlett-Beetle syndrome patients as well as the sensitivity of the set melanotide response. Slide 19. At the Obesity Week conference this week, we are also presenting the first ever health-related quality of life results to measure the impact of set melanotide therapy on patients with BBS. This is particularly important in this ultra-rare disease, as our research underscores the need to address the health-related quality of life burden experienced by patients. The data show after one year of treatment with set melanotide, 85% of patients reported clinically meaningful improvements in or preserved their non-impaired health-related quality of life status. For adult patients, changes to their impact of weight and quality of life score from baseline to 52 weeks were clinically meaningful with a mean increase of 12 points. For pediatric patients, we saw a clinically meaningful increase of the P's quality of life score from baseline to 52 weeks of 11.2 points. Clinically meaningful improvements in clinical outcomes such as body mass index and hunger also mirrored improvements in health-related quality of life. Importantly, at the patient level, improvements were sustained over the 52-week trial period. With slide 21, I'd like to shift gears from BPS to our robust clinical development programs to treat more patients with obesity and hyperphagia due to genetically impaired melanocortin-4 receptor pathways. I want to begin by touching on a recent publication that illustrates the severity of disease for patients with any ligus variants in several of our genes. Scentmelanotide's growing body evidence in these indications And then I'll summarize with a short update on our next wave of clinical trials. On slide 22, there's an article titled Implication of heterozygous variants in the genes of the leptin-melanocortin pathway in severe obesity by Dr. Sophie Courbage and the team in the lab of Dr. Karine Clement at Sorbonne University in Paris. It was published online this summer in the Journal of Clinical Endocrinology and Metabolism. This article details for the first time the phenotypes of patients with early onset severe obesity and hyperphagia through the heterozygous variants in the melanocortin-4 receptor pathway, including leptin receptor, POMC, and PCSK1 genes, comparatively to patients with homozygous or biallelic variants. Importantly, the comparison shows similarly severe obesity with similar early onset and severe hyperphagia all of which underscore the genetics and the effect of the impaired pathway, the burden of the rare genetic disease of obesity, and the need for therapy. This research underscores the effects of a genetically impaired MC4R pathway and the burden of rare genetic diseases of obesity and the need for therapy. On slide 23, in addition to Drs. Corbage and Cormans, we are grateful for the support of the world's leading key opinion leaders in genetic obesities. Between the European Society for Pediatric Endocrinology, the Obesity Medical Association, and the Obesity Society Congress this week, 22 presentations of set melanotide and uncovering rare obesity data have been presented by physicians, including Dr. Martin Wabisch of the University of Ulm, Dr. Peter Kuhnen of Humboldt University in Berlin, Dr. Jesus Arrente of the Autonomia University in Madrid, Dr. Sadaf Barouki from the University of Cambridge, Dr. Elizabeth Forsythe from the University College of London, and Dr. Robert Haas from Marshall Clinic, who I mentioned previously. We've covered nearly everything today except these efficacy results from complete top-line analyses of our Phase II basket study, which were presented at SB in September. These data show weight loss and hunger reduction at three months on therapy in patients with SRC1 or SH2B1 gene deficiencies. as well as a clear separation between patients who responded to set melanotide treatment at three months and those who did not. All these presentations are available on our website. Lastly, on slide 24, our clinical development programs are on track, most notably the Daybreak and MNH studies, which aim to address severe obesity and hyperphagia across 36 genes with strong or very strong relevance to the melanocortin-4 receptor pathway. Flight initiations are underway with investigator meetings planned for this month and next month, and first patients in participate in the fourth quarter. There's a tremendous amount of activity ongoing and a lot of excitement. And with that, I'll turn it over to Jennifer. Thank you.

Thank you, Linda. I start on slide 26. Our strategy of making MCFRI commercially available in the U.S. is meeting our expectations through these first two full quarters. As David said, in the third quarter, we reached $1 million in net sales, and we are pleased to report that patients are getting access to MCFRI with positive coverage decisions and reimbursement. We remain focused on HCP engagement and walking them through the process from start forms and authorizations, and if needed, support throughout the appeals process. Our corporate accounts and patient service teams, which are new this past quarter, are making a significant difference. And most importantly, in communications with patients on MCFRI, we are hearing positive feedback. An adult man who was constantly distracted by hunger for as long as he can remember now forgets to eat. And this next report really speaks to what we are providing. A mom who told us emcevery therapy resulted in weight loss and reduced her daughter's obsession and constant drive to eat. She was able to tell her 11-year-old daughter, see, this is not your fault. On slide 27, looking to BBS, Linda shared some details on how devastating BBS is for patients and families who have no approved therapy. As we have previously communicated, prize-winning supplements for BBS are 2,500 in the U.S. and the same in Europe. The community has come together around the need for a therapy, and relative to patients with biallelic POMC, PCSK1, or leprosy deficiencies, they are known to the healthcare system. We know there are more than 600 patients in the US-based CRIPS registry, and in the EU4 and the UK, we estimate there are a total of 1,500 diagnosed BBS patients. As we know from experience in rare disease, these initial prevalence estimates are usually low, and we consider them a starting point as we actively engage with the community to diagnose and find more. On slide 28, our U.S. commercial availability strategy for POMC, PCSK1, and leopard deficiency obesity enabled us to put the infrastructure in place that allows for access to MCIVRI now. It also lays the groundwork to set up for success for the BBS launch. Looking ahead, our near-term priorities are clear. Establish access via patient support and payer engagement, elevate the need to treat the hyperphagia and severe obesity that comes with BBS, and accelerate and facilitate diagnosis. Next slide. Through our patient support team, we are making direct contact with consented patients or their caregivers as HCPs prescribe MCIVRI for them. Our team provides comprehensive case management, offering education and coordination of treatment access activities to help identify and resolve barriers to therapy. We also provide support to prescribers as they navigate the prior authorization process to facilitate timely para-coverage. Our continued support and engagement at key milestones in the patient journey are designed to ensure adherence. Next slide. In addition to having high-touch patient services established now, we have fully hired, trained, and deployed in the field our team of BBS territory managers. They are a highly engaged and experienced team with more than 20 years of pharma sales experience on average, on top of rare disease and launch experience. And with experience in ophthalmology, nephrology, and endocrinology, we are seeing results. These territory managers are engaging physicians and focused on identifying BBS patients and expanding the care network for BBS patients. Their focus on physician engagement starts with ongoing engagement of top tier targets of approximately 125 ACPs with BBS patients in their care. In addition, we have tiered targets we believe are likely to have BBS patients that have been identified through machine learning as well as follow-up of ACPs with biallelic BBS genes identified through our URO program. Next slide. Armed with the full data from the Phase III BBS trial, we recently completed double-blinded qualitative primary market research with 30 U.S. ACPs who treat patients with Bartle-Beetle syndrome. It is clear that obesity is universally viewed as a serious health concern in individuals with BBS with no treatment options. When presented with the product profile of MCIVRI, 75% of them said they would prescribe setmelanotide as a first-line therapy for BBS patients to treat obesity. This is due to the mechanism of action, our expected age range of 6 plus, and weight loss efficacy. Moving to slide 32. And lastly, I just want to touch on the work of our area development managers who are charged with executing a targeted strategy to drive genetic testing of individuals with early onset severe obesity. This, of course, will help drive enrollment for Emanate and Daybreak. But also, we know this will help us find patients with biallelic POMC, PCSK1, or LEPR. And as David mentioned earlier, we are also finding ACPs with patients who have genetic variants associated with BBS who may or may not have a clinical diagnosis of BBS. In these cases, the ADMs will hand these ACPs to the BBS territory managers for follow-up. Hence, A very nice collaboration is seen amongst the field teams. I'd now like to turn the call over to Hunter to review our third quarter financial results.

Thank you, Jennifer. I'm on slide 34. During the third quarter, Rhythm reported product revenue net of $1 million. All revenue came from the United States. There were no revenues during the comparable quarter of 2020. Loss from operations was $44 million, an increase of $10 million over the comparable quarter in 2020 due to increases in both clinical trial activity as well as higher headcount in our research and development, commercial, and general administrative functions. Operating loss was offset by approximately $9 million tax benefit, reducing the tax provision we made in the first quarter due to our sale of the priority review voucher. Our share count was 50.2 million basic and diluted shares, and loss per common share was 70 cents, a decrease of 7 cents versus the third quarter of 2020. We concluded this quarter with cash, cash equivalents, and short-term investments of 328 million, which we believe to be sufficient to fund Rhythm's operations into the second half of 2023. And now I'll turn the mic back over to David so he can conclude. Thank you.

Thank you, Hunter. And hopefully, as I think you've heard, we had a really good quarter in quarter three. Linda highlighted the significant progress we've made across our clinical development programs and look forward to that continuing for the balance of before and into 2022. The large presence that we've had in medical meetings, and it's obviously important to share new data, and you've heard some of that, but it's also a critical component in increasing awareness and drawing further attention to the problem of rare genetic diseases of obesity. And as you heard from Jennifer, we are continuing to make good progress in preparing for a very meaningful opportunity, we believe, as a part of the fetal launch. And I have to say, in my years of experience working in the area of rare diseases and I think the team that has been built and is in the process of being built has experienced the same thing that I've worked with, and so we have a good challenge in front of us, but we certainly have the team and the capabilities who have the ability to execute on that. So the last slide is just, again, try to put in perspective rhythm and the opportunity in front of us. As we've talked about, the initial approval for POMC, PCSK1, and LEPR biallelic deficiencies We believe they're on the order of 600 to 2,500. The data around that, we're still learning and beginning to explore it. But over time, that number will grow. It starts small, and again, we're meeting expectations. Nothing's changed in our forecast or guidance there, if you will. But the opportunities ahead of us are much more significant. Barted beetle and alstroms, because as a syndrome, they are more easily identified, and therefore we start with a much larger number of patients who have been diagnosed based on their clinical presentation. We project on the order of 2,000 to 3,000, but this is a group where, again, based on past experience, epidemiology can often underestimate the number of patients that may be out there. The work that we're doing with the URO testing, the genetic screening, where patients are presenting with that history of early onset obesity and hunger, an odd insignificant number of them have genetic defects, biallelic defects, for Bartlett, Beadle, and Ahlstrom. And as I said, whether they will ultimately go on to full-blown presentation remains to be seen. But it does provide a bit of a window into perhaps this fact that, yeah, for sure there have to be more patients out there who have yet to come to diagnosis. So we'll continue to push on that. And finally, just to remind you, M&A trial, it's five sub-studies. And Each one of them will read out independently. They're independently powered, and any one of them offers a very meaningful increase over our current opportunity, and you can see the numbers projected here. So they're all 20,000 individuals, U.S.-only opportunities. And then the Daybreak Trial, which is a very efficient, as we've explained in the past, way of looking at the additional 31 genes we believe are linked to the pathway, and we should in a relatively... rapid way, I hope, you're going to get insights into a number of these genes as to whether they, in fact, are driving that underlying early severe obesity presentation. So with that, I'll turn it back to the operator and open it up for Q&A. Thank you.

Thank you. As a reminder, to ask a question, you will need to press the star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of Phil Nadeau with Cohen & Co. Your line is open.

Good morning. Thanks for taking our questions, and congrats on all the progress. Just a few from us. First, on the BBS Salesforce already being deployed, are there goals for the Salesforce in terms of number of HCPs contacted or number of BBS patients engaged by the time of the approval mid-year next year? Jennifer?

So the current BBS territory managers are provided with different targets. The first number of targets starts with the approximately 125 ACPs that were already within our sphere that have BBS patients. So the engagement of those initial physicians will remain a key target for them. In addition to that, as we outlined on the call, there's an opportunity in terms of disease educating a broader set of physicians who may have BBS patients. This includes follow-up of physicians who have biallelic patients through and discovered through our URO program. There are, in addition, we have been working through machine learning to also learn about the histories and journeys of patients who have BBS. And through these learnings, we are able to do more accurately identify ACPs who may have BBS patients within their care that can also be a target for follow-up. So they do have a tiered list of physicians that they are following up with already identified BBS patients, as well as potentially having BBS patients that they can educate and get to a clinical diagnosis.

Perfect. That's very helpful. And then second, on the quality of life data, what drove the improvements in quality of life for BBS patients? Was it the hyperphagia, specifically BMI changes, or some combination of the two?

Yeah, thanks, Linda.

Sure. That's a great question, and The way the questionnaires are designed, it does not drive down into that detail, but to your point, it likely is a combination of both and the weight. Specifically, the adult questionnaire, the impact of weight and quality of life is designed about weight, but there is a component where the hyperfacial could have improved the quality of life as well.

Perfect. And then last question. Sorry, go ahead.

No, I was just going to say about half of the hunger questionnaires could only be done by those patients who did not have cognitive impairment. And in the BBS world, there are some number of those. And so in that smaller subset where we could link the hunger to the quality of life benefit, it did mirror.

Perfect. Okay. Then last question for us. In terms of the M&A and daybreak trials, what's limiting to getting those first patients in the door? Is it finding the patients or are there other startup activities involved? particularly at the sites that are gating?

Yeah, great question. So we're going through the standard process of startup. So we're completely aligned to our timelines and on track. So there is no limitation per se. We're just following through the steps. We have actually a number of patients lined up at the site. So once we turn on the green light, they'll be ready to go and we anticipate them. quite a bolus in the beginning for those patients who are already lined up.

Perfect. Thanks for taking our questions, and congrats again on progress. Thank you.

Our next question comes from the line of Joseph Stringer from Needham & Company. Your line is open.

Hi. Good morning, everyone. Thanks for taking our questions. First one is just a general question on comparing the relative launches. for MCIVRI initial launch, POMC, LEPAR, versus Bari Vito and potential launch for Bari Vito and Alstroms. What are the – do you expect to sort of hit the ground running in terms of, you know, if the approval does come in second quarter of next year, would you be ready to sort of launch commercially – soon thereafter, or are there any gating factors around that? And the second question is around the potential contribution ex-U.S. versus U.S. in terms of sales for Barty Beetle and Alstrom's. It seems like the patients are a little bit, there's more identified patients ex-U.S. It seems like there's a maybe a little bit better infrastructure around patient ID and things like that, XUS. So just curious if you could compare and contrast U.S. versus XUS relative contributions to that. Thank you. Okay.

Jennifer, lead off.

Thanks for the question. So I think that there are for sure differences just in terms of the initial launch around MCFRI for the PPL indication. One of the biggest differences is just in terms of the teams that were in place to really start the process of educating and also interfacing with our customers. We didn't really have the teams in place for the initial launch, also based off of the a very low number of PPL biallelics that were also diagnosed. And our expectations in terms of sales, as outlined in the past, has been 10 in the first couple of years. Things are very different for the BBS launch. We have hired the team that will be in place to really position us for being able to hit the ground running once we get the approval within the BBS indication. And as was mentioned on this call as well, there are a significant more number of BBS patients because of the fact that they're syndromic and more easily identified that we would be able to expect to be able to get onto drug if we were to get approval next year. As it relates to patient numbers, I would say that in terms of Europe, they are more well-organized just in terms of genetics and getting patients who are suspected of genetic diseases to specific specialty centers to get genetically diagnosed. We also speak to the volume of patients that have been identified as BBS in Europe and for international versus the U.S., but I'm going to also shift it over to David to provide a bit of more color on that perspective.

Yeah, thanks, Amber. And, Joy, I think just to maybe add one more thing on the U.S. is we, unlike the first POMC, our world, where we had almost no patients in the U.S., a significant number of the patients in the development program did come from the U.S., and so they'll be available, and easier to transition. Second is that the product's in the channel, unlike the initial launch where there was the usual startup just getting the supply chain established and filled. So that's the U.S. Europe, as Jennifer said, is absolutely more, well, better organized, larger number of patients. We've talked about 1,500 patients being available across the EU4 in the U.K., meaning these are patients that are well-identified and sitting with us in centers of excellence. The gating factor for Europe, as we all know, is you work country by country in terms of getting reimbursement and establishing pricing. Access may come early in some country and may be quite delayed in the other. So the big issue there will be just the timing of reimbursement. I hadn't mentioned it, but we expect first sales on our first approved indication over there in the first half of 2022. Obviously, the BBS and AAS filing is running in parallel to the FDA filing, as Linda said.

Great. Thanks for taking our question. Okay. Thanks, Roy.

Again, to ask a question, you will need to press star 1 on your telephone. Our next question comes from the line of Corrine Jenkins with Goldman Sachs. Your line is open.

Yeah, good morning, everybody. I'm just curious as you've engaged in the various medical conferences you've attended this fall, what have you learned specifically from the community with respect to BBS, either on the clinical need or with respect to the physician's view of the set melanotide profile?

Thanks, Corrine. I think, you know, I'll lead off and then let Jennifer or Linda jump in. You know, what's really interesting to me is you do clinical trials, and they're driven by p-values and, you know, top-line data. But that doesn't really tell you the whole story, and I think it's become absolutely clear it doesn't tell us the whole story here for BBS and Allstrom's. And what's been most enlightening in the recent data sets have been the interviews. So we had exit interviews done, and that will be coming out as a publication in the not-too-distant future, and I think it's in one of the posters there. And if you look at the quotes, it's in the quote that I think you really begin to understand the devastating impact of this disease. I mean, you heard a couple today from both Linda and Jennifer. One that stands out in my mind, and I think it's in the poster if it's not in the publication, but a young child at the age of four who was taken away from his family because the family was viewed by the social services as overfeeding their child and essentially abusing their child, and it was put in a facility for a year and a half for something that was absolutely not his fault. So that's where the nuance is coming in. Jennifer did report out the market research data where physicians presented with the profile of this drug. Seventy-five percent of them said they were prescribed at first line, and I think In an area where disease awareness is relatively low and you're educating on both the disease at the same time you're educating on the drug, that's a pretty remarkable recognition, again, that this is an emerging area and the unmet need is absolutely clear. So I don't know if that helps, but that's the kind of thing that we're learning today that we didn't have last time we spoke.

Yeah, that's helpful. Go ahead.

I'll just quickly tag on and support that, whether it's through the market insights from physicians or patients or the interactions with physicians themselves. You know, the aspects of the obesity and hyperphasia, even in the syndromic indication, really pops up in terms of being one of the key priorities of addressing within this particular patient population, simply because of the impact that it has not only on the patient, but as well as the caregiver and family. So it is definitely a need out there where physicians are waiting to have something to be able to specifically address the needs of the patient population.

Thanks. And then as we think about the growth in the URO testing, can you help us understand whether that's primarily driven and how you expect it to be driven on the forward of new HTPs or just existing HTPs that are already doing testing, testing more and more patients.

In addition to the territory managers that are on ground, which are a team that's also supporting the ongoing efforts that were put in place through our MSL, We also have our ADMs, or Area Development Managers, and in terms of testing initiatives, as I outlined in the last earnings call, we have put in place efficiencies around our URO program that should make it easier for physicians to be able to order kits and tests and see the results. So the initial target will definitely be educating physicians who are already testing to see if there is interest in terms of increasing the volume through the efficiencies. But certainly they also have additional targets that are key just in terms of increasing awareness around RGDO in general, suspecting, and then testing as well.

And Karina, let me just add one other thing. There's a poster in the most recent posters that just went up on our website which speaks to our URO testing program, and we describe in there the number of kits that have been positioned, healthcare providers requesting kits, and the number of returns. So on the order of 1,400 healthcare providers have returned kits. So, you know, for me, that's just a fabulous starting point in terms of physicians, healthcare providers who are clearly indicating an interest, recognizing that genetics may be driving it. The vast majority, or the majority, if you will, are peds, endo, peds, and medical genetics. Again, all of this is in the poster. And the other piece, which in the top 10, you know, again, back to your question and Jennifer's answer, the high utilizers today are driving the bulk, and the real opportunity are those healthcare providers who sent in one test. They've signaled an interest. They've already done it once, and so the ability to scale from there is significant. is good. Um, and then last, um, I just want to, um, what's also really interesting in that poster since I'm talking about is the, the number of, uh, the age of the patients who are being tested and, you know, fully 20% are less than six years old and, another 30% are between, uh, the ages of 7 and 12. So 50% are children. And for a genetic disease, not a surprise. You know, you would expect these kids to be presenting early. The problem essentially arises at birth, and parents notice it and they seek help. So a lot to be learned there, but a lot, you know, like I said, I think we have a lot of optimism around the opportunity and the role that URL testing is going to play in this overall development.

Great. Thank you.

Next question.

There are 40 questions at this time. Now I turn the call back over to David Meeker.

Great. Well, thanks to all of you for tuning in this morning, and we look forward to talking again in three months' time at the fourth quarter update. With that, I'll say goodbye. Thanks, everyone.

This concludes today's conference call. Thank you for participating. You may now disconnect.