Rhythm Pharmaceuticals, Inc.

Welcome to the Rhythm Pharmaceuticals first quarter 2022 earnings conference call. My name is Hilda and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session. During the question and answer session and at any time, if you have a question, please press 01 on your touchstone phone. I will now turn the call over to Mr. David Connolly, Investor Relations and Corporate Communications. You may begin.

Thank you, and good morning, everybody. I'm Dave Connolly, head of IR and corporate communications here at Rhythm Pharmaceuticals. For those of you participating via the 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 our first quarter 2022 financial results and business update, which is available on our website. And as listed on slide two, today here with me in Boston for the conference call are David Meeker, Chair, President, Chief Executive Officer of Rhythm, Jennifer Chen, Executive Vice President, Head of North America, Linda Shapiro, our Chief Medical Officer, Hunter Smith, our Chief Financial Officer, and Yann Mazzebro, Executive Vice President, Head of International, is on the phone joining us from France. With slide three, I'll remind you 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 important factors, including those discussed in our most recent annual or quarterly 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. Thank you for tuning in this morning, and we look forward to updating you on the progress we've made in quarter one. But before I do that, I'd like to start on slide five with a bit of an unusual start here. This is a cartoon of our biology. Many of you know this slide well. As we all know, it's been a particularly difficult moment in the markets generally, and it's been particularly difficult for small and mid-cap biotechnology companies. And I think at moments like these, it's worth looking at fundamentals. They're always important, but particularly so at these kind of moments. So I wanted to spend a couple minutes just reviewing Rhythm's fundamentals. So number one, there's a clear unmet medical need that we're pursuing here. Patients who have A genetic variant that impairs the MC4 pathway suffer from hyperphagia, decreased energy expenditure, and consequent early onset obesity, and all the comorbidities associated with that. Two, the biology is incredibly strong, as highlighted on this slide. It's been well studied. The pathway that we're pursuing, the MC4R pathway, the endogenous ligand, the alpha-MSH, which interacts with the MC4 receptor, When it engages, it decreases the appetite, increases energy expenditure, and you get a reduction in weight. And we've shown in, again, multiple trials that that's associated with other benefits as well. Third, we have a precision medicine, a solution to this problem. The set melanotide is an analog for alpha-MSH, and when it engages the receptor, you get all those benefits. And we are essentially a replacement therapy. It's very simple conceptually and biologically. And we're working in a world where other approaches to try to manage this problem have not been reliably successful. Bariatric surgery, you can get weight loss, but do you get it reliably and sustainably? And that's the same for other approaches to weight loss management. Forward de-risk. Most things fail in this industry, and we've been fortunate enough to get set melanotide through the regulatory process in both FDA and EMEA. We have an approved drug with Another one or two indications imminent coming up. And so from a risk standpoint, this is a company that's passed one of the very major hurdles that we all aspire to. Five, and it's not an endless list here. We know what we need to do commercially. We know what we need to do clinically. And we know what we need to do financially. And we have the team to do it. Now what you're gonna hear as we continue to update you, we're executing and as I said, I feel really good about the fundamentals that we're standing on. So with that, let's go to the quarter. So slide six, we're on track. Let's talk about the US first. We're very much looking forward to our Purdue for data on June 16th. We've used the time well as you can imagine. We've continued active patient identification and disease education efforts. Jennifer will highlight and provide a little more color around that effort. The current commercial opportunity is playing out exactly as we had hoped. We have tens of patients on therapy. We continue to learn more about the market access situation. We are able to educate payers, and those interactions are laying a strong foundation for a BBS launch. And really importantly, as we've highlighted in the past, we continue to get to interact with patients who have consented in to our patient services group, now called InTune, and that's hugely valuable insights as we think about how we can provide the best service for that patient, how we can help them manage through the early part of beginning a therapy like this, the daily administration, the early side effects and the like, that all can be significantly benefited by that strong interaction. The international markets are an incredibly important part of our whole story. I'll talk a little bit more about that in the next slides coming up. But suffice it to say that as we look at Europe, we've highlighted this many times, for all rare diseases, and it's certainly the case in the areas that we're working, Europe is better organized, Singapore healthcare system, Patients get referred, center of excellence gets set up. True KOLs, thought leaders emerge out of that. They have the opportunity to see many patients. They can do research. And so, again, the end result of that is as a starting point, there tend to be many more patients identified. And once you do get approval through the healthcare system for access, the process of then getting patients on to therapy is much more straightforward. And then in our third bucket, we have a broad clinical development program, and it's a thing. We put in a tremendous amount of work to get these trials up and running, and they're now running. M&A, Daybreak, the hypothalamic obesity trial, pediatrics, weeds, weekly formulation trials, all ongoing. We're generating a lot of data, and we're publishing that data, and we just had abstracts released at PEAS, Pediatric Endocrine Society, over the weekend, and we announced a on Monday, new additional abstracts, which will be presented at ENDO, and Linda will highlight those in more detail. And finally, as you know, we're very much looking forward to providing updates, the results on our hypokalamic study and our MC4R rescuable interim data, and that will happen mid-year. So next slide, number seven. So internationally, and as I said, We've highlighted that first commercial patients started in March in France and were underway in their early access program. And with that early access program, we're about a year ahead of where we would be if we did not have that in France. Germany all along has been a real education and a very positive development here. These products, weight loss drugs in general, are viewed as lifestyle products and restricted. We were able to get an exemption from Annex II. And that was just published in the past couple days in the National Gazette, so that's confirmed. Reimbursement dossier is now being submitted, and we look forward to having our first commercial patients in the next couple months in Germany. In the UK, a nice recommendation expected in June, and we will get it. This is not one where, you know, are we going to be approved and able to go forward in the UK? No, we're going to go forward. Final details to be worked out. But that, you know, we've progressed to that stage where we can be extremely confident. Similarly in Italy, final stages of price negotiation. Feel remarkably good about that. That's evolved perhaps even more favorably than we had hoped. Netherlands earlier, but active. And then Spain and Sweden were in the process of being associated. So We're working our way through Europe with a team of about 20 people, highly experienced, and Jan's on the phone. Again, if there's additional questions, we can go there. And so on the clinical side, as you know, we've updated our M&A and Daybreak strategies slightly, and Linda will dive into that in greater detail. But I'll just say up front, we feel that the adjustments we've made to emanate, we have a flat-out better trial with a higher probability of success. And I'll remind you that we're working in an area where we continue to learn. We continue to learn more about not just us, but us and our partners, the world at large, more about individual variants and allows us to think about classifying them, looking at ones that were in that boost category, but now maybe with a little better understanding you could categorize them as more likely to be toward the pathogenic, likely pathogenic end of the spectrum. And so as we've redesigned it, again, narrowing it down, focusing on those, it does give us that better trial. The numbers, so from a total market opportunity, the numbers have decreased, but I'll remind you here, so no change to the SH2B1, SRC1 numbers. And the heterozygous, POMC, and leptin receptor numbers at about 10,000 puts us at an aggregate opportunity, U.S. only, of 50,000 plus. And the HET, leptin, receptor, and POMC worlds will in fact be a less confusing commercial opportunity. These patients are better and more clearly defined based on their genetics and therefore will be easier to manage through the overall process. So that and that feel really good about where we are with M&A and Daybreak. So with that, I'll turn it over to Jennifer.

Thank you, David. So beginning on slide 11 here, we last shared details of our BBS commercial readiness efforts in February, and with PDUFA and launch coming June 16th, we aim today to provide some more details on the tremendous progress our teams have been making. As we outlined before, the estimated prevalence of BBS in the U.S. is 1,500 to 2,500 patients, and we know approximately 70% to 90% of these patients have obesity. We consider these patients in four distinct categories. The first are those that remain undiagnosed. Similar to other rare genetic diseases, the vast majority of patients remain under the care of HCPs who have not yet suspected or clinically diagnosed the patients. This remains a large opportunity. The second category are those patients under the care of HCPs who have suspected BBS but may not have yet definitively diagnosed them. Physicians may continue with additional evaluation before verifying a clinical diagnosis. In disease states where there is no approved therapy, there may be less urgency to come to a specific diagnosis. Having an approved therapy often aids awareness of the disease and some urgency towards making a diagnosis. In the last two segments of patients who have been diagnosed, the territory managers have validated more than 150 physicians who are managing over 350 BBS patients under their care. And we continue to find additional BBS patients through our efforts. Next slide. As we prepare for the upcoming potential approval of MCFRI, the priority focus of the territory managers remain on engaging with physicians with already identified BBS patients under their care. For this group, they all have a baseline understanding of BBS, but we are continuing to educate on the underlying impairment to MC4 pathway function and the impact of the resulting hyperphagia and severe obesity on patients. In addition to this group, our second set of priority physician targets remain our focus in terms of speeding the diagnosis of BBS. Here, our outreach, engagement, and educational efforts center on BBS disease state awareness, so physicians can suspect BBS and better understand the path to diagnosis. Rhythm is coming to know these physicians through our Uncovering Rare Obesity Genetic Testing Program. In the long term, URO may prove to be a rich source of BBS patient identification, as these patients have some degree of severe obesity in order to qualify for the test. If there is a hit for biallelic BBS, we are able to then work with the physician to consider a clinical diagnosis. We've talked in the past also about our machine learning approach. We have developed a targeted list of physicians associated with certain ICD-10 codes that are relevant to BBS. Next slide. The work of our territory managers also supports the building of care teams and broadening referral networks. As we know, BBS has a constellation of symptoms. While hyperphagia and obesity are among the most prevalent and pressing of the symptoms, we know patients with BBS suffer from retinal disease and vision loss, renal impairments, and other health-related issues. Therefore, a critical factor affecting optimal care of patients with BBS, where they suffer from various disease manifestations, is the accessibility of a multidisciplinary care network. The Marshfield Clinic in Wisconsin serves as a gold standard of holistic multidisciplinary care for BBS patients. This clinic started with Dr. Haas, an interested pediatric nephrologist, who connected with an ophthalmologist and expanded their network from there. Interestingly, we are seeing more and more of this type of approach. For example, this last quarter, one of our territory managers called on an inherited retinal disease specialist at a sizable health center here in the Northeast. This specialist had an interest in BBS and had diagnosed patients under his care. but he was really focused on the vision issues for these patients, not their obesity or hyperphagia. Our territory manager identified and connected with a nearby pediatrician with a focus on obesity and a pediatric cardiologist who had expressed interest in BBS and fostered introductions. These introductions have set in motion the development of a pediatric obesity clinic with a special focus on BBS. We know these connections are also happening in other parts of the nation. Building out these care teams is important. It helps gain traction in diagnosing patients earlier in their journey, and more importantly, it helps provide these patients with a more complete care team. Next slide. Just as Rhythm territory managers are working to help build our physician network and care teams, We have a separate customer engagement team designed to support patients along their journeys. As David mentioned, Rhythm in Tune is a patient support program designed to help overcome challenges and empower patients and caregivers by providing education and resources tailored to fit the unique needs of each patient. We match patient and caregivers with a dedicated patient education manager as a single point of contact for a personalized experience. We have really learned from our initial approval in patients with PALM-C PCSK1 leprosy mutations and have fine-tuned our support offerings in preparation for the BBS launch. For our initial approval, the main focus was on supporting patients through the reimbursement process. Now, as we finalize our preparations for the BBS launch, we have supplemented this support with proactive engagement of our customer service team to help patients go from prescription receipt, through reimbursement approval, to maintenance on therapy. And we have a robust action plan to stay in contact with patients and caregivers, whether by phone, video call, or even simple checking in emails throughout the course of therapy. Next slide. We are ready to launch on day one, June 16th or earlier. Upon approval, the teams are prepared to engage directly with prioritized physicians with identified BBS patients, along with consented BBS patients and caregivers. We have several healthcare providers as well as BBS patient and caregiver speaker programs planned, and we are ready to supplement these moving forward. In addition, we continue to maintain close relationships with patient advocacy organizations, which are looking forward to sharing the potential news of approval with their membership. We know there are patients awaiting for a BBS therapy, and we are ready to deliver. With that, let me hand it over to Linda Shapiro to provide a regulatory and clinical update.

Thank you, Jennifer. We're now on slide 16 to discuss a brief update on our regulatory progress. Our PDUPA goal date for Bartlett-Beetle and Alstrom syndrome is about six weeks away on June 16th, and label discussions are anticipated to begin in the coming weeks, leading to the final step. In Europe, we anticipate the CHMP will make its recommendation on our type two amendment for BBS this summer, with the full decision to come from the European Commission in the fall. And we do have a recent update to report that last week, the CHMP provided a positive opinion for a modification to the SNPC, the EU label, with recommendations to expand the use of Imsivir in patients with moderate and severe renal impairment and biallelic POMC, PCSK1, or leptin receptor deficiency. The final EC decision on this amendment is anticipated in July, and the same amendment modification request is being considered as part of the scheduled review for BBS. Now onto slide 17. I'll focus brief remarks on our several ongoing trials evaluating fentanyl anitide in rare genetic and now also acquired diseases of obesity. Before providing updates on MNA Daybreak and our phase two trial in acquired hypothalamic obesity, let me mention briefly our phase three weekly formulation switch trial and our phase three pediatrics trial for young children between the ages of two and less than six years. These trials are both important elements of our strategy, as we know very well that in BBS and genetic obesities, the hyperphagia and severe obesity begin very early in life and have a devastating effect on these patients and their families. We can bring set melanotide to these patients earlier in their lives and in a more convenient and user-friendly weekly dosing regimen. We believe it will make quite a difference for them and their caregivers and overall long-term treatment adherence. As a reminder, the pediatrics trial is a multi-center, multinational, one-year, open-label, Phase III trial enrolling patients with biallelic, POMC, PCSK1, or leptin receptor deficiency obesity, or a clinical diagnosis of BBS with genetic confirmation. As we announced last quarter, we enrolled our first patient in February. Phase III SWISH trial evaluates a weekly formulation of setmelanotide in comparison to the daily formulation. and patients six years and older with a rare genetic disease of obesity who are currently in our long-term extension trial and taking a stable dose of the daily formulation of set melanotide. First patients were dosed with the weekly formulation in January, and enrollment is progressing. Now we'll go into a little bit more detail on our hypothalamic obesity trial, Daybreak and Emanate, beginning with Emanate and slide 18. MN8 now includes four independent sub-studies evaluating set melanotide in patients with severe obesity due to one of four genetic subtypes. There remains a significant unmet need for people living with these rare genetic diseases of obesity that are unresponsive to other treatment interventions. These patients are living with hyperphasia, that pathological insatiable hunger, and severe obesity, which has a significant impact on all aspects of their lives. We are committed to bringing these patients a much-needed safe and effective therapy. As for many of them, we know lifestyle interventions of physical activity and nutrition changes do not work, nor do bariatric surgery or other pharmacotherapies, as they do not address the underlying impairment to the MC4R pathway that is the root cause of the hyperphagia and severe obesity. As we announced last month, we have implemented modifications to optimize both MNA and daybreak, focused on the rare patient populations which we believe have the highest likelihood of success. We initiated the trial with the first patient enrolled in April. Now onto slide 19. A little more detail on the design for this trial. M&A includes four independent sub-studies evaluating step melanotide compared to placebo over 52 weeks, patients six years of age and older with hyperphasia and obesity due to a heterozygous variant of the POMC PCSK1 genes, leptin receptor gene, SRC1 gene, and the SH2B1 gene. As we announced last month, the POMC PCSK1 and leptin receptor sub-studies, we are focusing enrollment on variants classified following the framework established by the American College of Medical Genetics as pathogenic and likely pathogenic, as initially planned. And we have modified to include a narrower sub-population of variants of uncertain significance, or GUS, Now only include the boost subset with variants that are suspected to be pathogenic and most likely to impair the MC4 pathway function. Based on this rationale and our phase two basket trial data, also most likely to respond to semlametide. Primary endpoint in this trial is the difference in mean percent change in BMI compared to placebo for each sub-study. And BMI is a well-suited measure for this patient population that includes both adults and children. This trial design allows for independent data readout, submission, and registration of each of the genes in sub-studies. Next slide. We also recently modified our phase two daybreak trial to focus initially on rare variants associated with 10 prioritized MC4R-relevant genes, which we and several key opinion leaders believe have the highest probability of response to set melanotype. For the remaining genes, we paused enrollment and we will evaluate expansion of Daybreak to these genes based on the early clinical data from the prioritized genes. Daybreak has an efficient design that allows for quickly achieving signals of proof of concept for each genetic cohort independently during an initial open-label run-in period. This could provide signals of potential efficacy in certain gene cohorts by the end of this year in patients who demonstrate a clinically meaningful response to set melanotide. This is then followed by a randomized placebo-controlled second stage. Daybreak enrollment began in January of this year. Hypothalamic obesity is a rare acquired form of obesity that develops following structural injury to the hypothalamic region of the brain that contains the MC4 pathway neurons responsible for controlling physiologic functions such as food intake, energy expenditure, and body weight regulation. This disease is most commonly associated with cranial pharyngioma, a rare brain tumor, or the associated treatment by surgery or radiation. Approximately half of patients with cranial pharyngioma experience rapid onset acute weight gain and hyperphagia shortly after tumor treatment. While treatment does exist to replace many of the hormones controlled by the pituitary gland that is also injured during tumor treatment, There are no safe and effective therapeutic options for the hyperphasia and obesity that result from injury to the hypothalamus, and this can be the most devastating and disruptive for patients and their families. The community around hypothalamic obesity is well established and well organized, with the Raymond A. Wood Foundation founded in 2016 to empower hypothalamic pituitary brain tumor survivors for improved quality of life by providing access to education, technology, and evolving treatments. In October 2021, this group hosted a patient listening session with the Food and Drug Administration where several patients and caregivers provided testimony on the insurmountable challenges of hypoglycemic obesity. I have a sample of quotes here. Upon returning home from the hospital, he foraged at night. Hyperphagia is the biggest cause of low quality of life. Within six months, I gained 30 pounds. It's clear there's a significant unmet need and this patient community is desperate for safe and effective therapy. Now to slide 22 for a brief review or a brief overview of our phase two trial in patients with hypoglycemic obesity. This is a phase two open label proof of concept trial evaluating set melanocytes in individuals with hypoglycemic obesity. Enrollment is complete with 18 patients aged six years or older in this open-label 16-week treatment period. We look forward to sharing preliminary data this summer, so please stay tuned. Back to slide 23. We have a busy spring planned when it comes to presentations at medical conferences. These presentations afford us an excellent opportunity to engage with top key opinion leaders in treating healthcare providers on rare genetic diseases of obesity and the severity of hyperphagia and obesity these patients and their families live with. Importantly, it also gives us the opportunity to discuss with them the efficacy and safety of set melanotide, and we are pleased to have tremendous support of leading key opinion leaders who are delivering these presentations. At the Pediatric Endocrine Society 2022 Virtual Annual Meeting this past weekend, we presented new data supporting the potential for set melanotide to treat the early onset obesity, hyperphasia, and metabolic impairments associated with Bartlett-Beetle syndrome. In addition, we announced cumulative safety data from across the set melanotide clinical development program, demonstrating that treatment is generally safe and well tolerated. And as we announced today, six abstracts of new data were accepted for presentations at the Endocrine Society Annual Meeting and Expo in June of this year. Highlights here will include one-year BMI data in SRC1, SH2B1, and heterozygous POMC PCSK1-11 receptor, along with longer-term data in BBS and biallelic POMC PCSK1-11 receptor. We're thrilled to have the support of an all-star cast of key opinion leaders, as listed on this slide. These conferences provide us with a great opportunity to communicate and disseminate data about set melanocytes and genetic diseases of obesity to support recruitment in our ongoing trials, as well as raise awareness and educate the healthcare community about POMC, PCSK1, left receptor, and BDS. With that, I'll turn the call over now.

Thank you, Dr. Shapiro. Turning to slide 25, as David mentioned at the start of the call, we're pleased to report product revenue of $1.5 million in the first quarter of 2022 as compared to approximately $35,000 in the first quarter of 2021. While sales during the quarter included our first sales from outside the U.S., sales volumes did not significantly affect the quarter's results given how late they occurred during the quarter and the limited number of initial prescriptions involved. Net sales in Q1 2022 were down sequentially versus Q4 2021. This decrease was largely due to a decrease in orders from our specialty pharmacy versus prior quarter. Files shipped from the SP to patients were largely unchanged. Cost of goods sold was $230,000 in Q1. The largest portion of this figure was amortization of sales milestones paid to Ipsen. Rhythm previously paid Ipsen a milestone of $5 million for the first U.S. sale and during Q1 paid a $4 million milestone covering the first sale in Europe. These milestones will be amortized quarterly. COGS also include the 5% royalty payable to Ipsen. Loss from operations was $52.7 million in the quarter, an increase of $18.3 million over the first quarter of 2021. R&D expense increased by $12.6 million to $32.5 million. The increase was primarily due to higher clinical trial expense involving the startup of our M&A Daybreak weekly formulation switch studies. In addition, Rhythm purchased $3.8 million of clinical supply material during the quarter. SG&A expense was $21.4 million in Q1, an increase of $6.9 million versus the first quarter of 2021. The increase was largely the result of increased headcount costs in our U.S. and international commercial organizations, as well as increased marketing spend. Consistent with the results in Q1, we expect our full year 2022 operating expenses to increase over 2021 due to increased clinical development activities. As is typical of large clinical trials, there are significant upfront costs during study startup. In addition, we anticipate higher commercialization activities related to the potential launch of an exhibit at BBS. in the U.S., as well as ongoing efforts across Europe. Our share count was 50.3 million basic and diluted shares, and loss per common share was $1.05. We concluded the quarter in a strong financial position with cash and cash equivalents and short-term investments of $241 million, which we believe will be sufficient to fund Rhythm's operations in the fourth quarter of 2023. And now I'll turn the call back over to David for concluding remarks. Thank you.

Thank you, Hunter. So I think, as you've all heard, we have a lot underway. In the box on the left, I think what's most noteworthy is we had a very daunting at one level task of getting all these clinical trials up and running, and they're all basically up and running. And so what we look forward to going forward, lots ahead. PDUFA date, EMEA approval, as you've heard, lots of data that we're reporting out, some of that in the first half. launching in Europe, started in France, Germany, UK, Italy, all to come. And we'll also be beginning that last de novo study as part of our weekly overall development plan in the second half. So again, very much looking forward to those events and a very important year for Rhythm. And we now welcome your questions. So with that operating, we can go to Q&A. Thank you.

Thank you. We will now begin the question and answer session. If you have a question, please press 01 on your touchstone phone. If you wish to be removed from the queue, please press 02. If you are using a speakerphone, you may need to pick up the handset first before pressing the numbers. Once again, if you have a question, please press 01 on your touchstone phone. And we have a question from Phil Nadeau from Cohen and Company. Please go ahead.

Hi, this is Lila on for Phil. Thank you so much for taking the question and congrats on the progress. Maybe really quickly on the phase two data expected in hypothalamic obesity. Can you maybe just give a brief overview of what you might consider proof of concept there and in terms of the proportion of patients that achieving a reduction in BMI, what would you need to see to progress development? Thank you.

Linda, you want to go?

Sure, so the endpoints are focused on changes in body weight, BMI, and other BMI-related measures in the pediatric population, as well as hunger and hyperphagia scores. I don't think at this time we can comment on what we would need to progress, but middle of the year, we will be announcing the data and plans, if appropriate, thereafter.

And the only thing I would add to that is The FDA has very clearly outlined that 5% threshold for weight loss BMI change is clinically significant. It's significant from a regulatory standpoint. Needless to say, we would need to see at least that. I also think we're looking to make a meaningful difference here. And so, as Linda said, when we evaluate that data, we'll not be looking to just barely clear the hurdle, so to speak. So again, I'd be looking for something north of that 5% kind of improvement.

That's very helpful. Thank you so much.

Thank you. Our next question comes from Derek Archula from Wells Fargo. Please go ahead.

Hey, good morning, guys, and congrats on the progress. Just a couple questions from us. Just first on the BBS launch, we'd love to just kind of get a sense of how you think the trajectory could go and if there's any good analogs you could point to Is this something where we expect more of a slow trickle or is there a bolus of patients given the outreach you've done? Second, I would ask just in terms of the Germany sales, I guess now that you're ramping or you're starting to sell there, how many patients have you actually identified in that country? Thanks.

I'll go to Jennifer first on the U.S. launch and then Jan, I'll turn to you for some comments on Germany.

Sure. Thanks for the question. I think in any rare disease, especially when there's no therapy available, it's difficult to really accurately project the trajectory of any launch. With that said, I think that the BBS launch will be completely different in terms of expectations versus what we saw with the PPL approval. We feel, first, very, very good in terms of the strong number of patients that have already been identified to date. I think, once again, in an area where there's no therapy available, the starting point and where we are is quite strong. With the territory managers in the field, we have also the corporate accounts team in place. As I outlined, rhythm and tune, actively setting expectations. And we have a team in place that is really quite anxious and ready to go in terms of the launch and helping to get patients on drug and stay on MCFRI. So we are very confident in terms of having a successful launch here. And there is a lot of excitement that we hear also from the community, from patients, caregivers, as well as physicians.

And any analogs that you think of? Maybe I'll just stop. I mean, you know, this is a challenge in the rare disease space. Obviously, there's some similarities in the sense that rare disease drugs priced at the price point they tend to be priced at, often working with physicians who have never written a prescription for a rare disease drug and never gone through the approval process, which is a bit more cumbersome than writing a prescription for your local CVS, obviously. So all that is part of it. But that said, there's not really a good analog for this, but I'll reinforce what Jennifer said. The starting point with the number of patients we've identified, the level of organization of that community at this point is incredibly positive. So I think in a relative sense, we feel good, very good about where we'll start. And that first six months, as you know, Derek, we try to guide people away from this idea that there's a specific expectation, whatever it is. I don't know if we're going to come out of the gate fast, whatever that means, or a bit more slowly. But over time, meaning the six to 12, 12 to 18-month period, that's the period where I would really look at to get a better sense for what this opportunity is going to look like. Oh, sorry, Jan, Germany.

Yes, so I will start maybe with Europe. So in Europe, EU4 plus UK, we have more than 100 patients already identified by PPL patients, and Germany represents roughly more than one-third of this number.

Got it.

Thanks.

So the bottom line is... Oh, go ahead.

Go ahead.

No, no.

I was just going to add one thing, reinforcing again that Europe is well-organized. Thank you.

Got it. And maybe just one follow-up, if I can squeeze it in. Just in terms of the U.S. and the moving parts around kind of paying a payer and reimbursement for BBS, I mean, I know I think you've had some discussions, but any update there in terms of just making sure the indication will get paid for? Thanks. Jennifer?

Yeah, so I think that this is like one of the areas where we have certainly learned from the initial CPL experience. I would start off and say that from a commercial payer perspective, we have had very strong reimbursement across the board, just in terms of coverage of MCFRI. There's a couple of different plans that have not made decisions, and there are opportunities for our corporate accounts team to just go ahead and educate and follow up as they move forward in terms of their dialogues with various different payers. From a Medicare perspective, because of the CMS statute on weight loss medications, we expect that we're not going to be successful in terms of coverage there at this point of time. I will outline that one piece to remember, though, is similar in terms of our biallelic PPL patient population and what we saw. The BBS patients that we've identified also because of our focus in terms of where we do disease education, they are primarily younger and more likely to have commercial and or Medicaid coverage. On the Medicaid side, what we're seeing is it is mixed. We certainly see states that are covering MCFRI. those that have also not yet made a decision, and those that have weight loss exclusions and decided not to cover MCFRI. And once again, I think that with a team on ground, the latter two buckets really are opportunities for our teams to go and educate and differentiate our target populations from the broad obesity population. I think in terms of expectations, we are not expecting to get 100% coverage across the board, but I do feel positive just in terms of our ability to change the current landscape. We are already seeing positive reception to our value story, and in fact, even in certain States that have outlined from a Medicaid perspective, they are excluding in SIPRI. We've been able to get patients through the process on drugs. So it's an evolving process where there's a lot of opportunities to still continue to dialogue and educate.

Thanks, Jennifer. Did we answer your question, Derek?

Yeah, all good. Thank you so much. Great. Congrats on the progress. Thanks. Thank you. Next question.

Thank you. The next question comes from from . Please go ahead.

Yeah, good morning. Thanks for taking my questions as well. I'll piggyback off of some of Derek's questions on BBS. Are you able to comment on whether you've already started engaging the FDA on labeling discussions for BBS? And secondly, when we think about the launch trajectory, I guess the slide with regards to 350 patients or more being identified, I think the commentary today was more than 150 physicians that take care of those identified patients. So how much of an overlap is there between those physicians that take care of BBS versus the biallelic PPL? Just wondering about the COVID impact. We've heard certain KOLs at institutions still restricting in-person sales rep meetings. And I've got a follow-up. Thanks.

I'll give that one to Jennifer. On the engagement with the FDA, as we've said previously, we expect that engagement at some point roughly a month or so ahead of time, and that's all we've had. There's no further update there.

To your question just in terms of ACP overlap, You know, for the PPL patient population in terms of the scripts, you know, the volume as outlined from an expectation perspective was low. However, you know, the majority of these physicians coming in were already in our rhythm CRM, so were patients or physicians that we were also already engaging with, hence there is some overlap. with the BBS physician pool, but there's also physicians that have not yet prescribed from a PPL perspective and, you know, we are actively engaging with as we move forward.

Great. Okay. Thanks for that. Oh, sorry, David. Thanks. Yeah. Okay. Well, so the other question is just shifting gears a little bit to Daybreak. Following the amendment, you spoke about how within the 10 sub studies or the genotypes that you're looking at, two are actually going to have some broader implications as it is part of 13 gene pathway network. So can you maybe talk a little bit about those two genes? What led you to identifying those two versus the other 11? And how much of a de-risking can we anticipate based on those two genes? with respect to sort of what their protein products do in that MC4R pathway?

Yes, that's a great question. Thank you very much. So, we came to identify the genes by working with the key opinion leaders who are experts in this field, as well as looking into our own preclinical data to identify those that are de-risked and most likely do have the greatest potential impact of impairing the pathway and therefore being responsive to set melanotype. So those two genes that are part of the SEMA3 family of genes, we're looking both at the Plexin A4 as well as the SEMA3G. So two different angles into that family. So we really do feel this will give us the greatest opportunity to be able to identify the impact that all of those associated genes have, as well as the impact that the other genes have, based on the science that does support that they do have a strong relevance to the MC4 pathway.

Okay. All right.

Well, thank you.

Yeah. Yeah. I guess I was just kind of curious, how much of a de-risking can we really anticipate, given that if it's part of a complex, for example, that functions as a single unit versus multiple different proteins being engaged at different portions of the pathway. I guess that's kind of what I was trying to get at, but we can certainly catch up offline or talk later after the data is out.

Maybe we can leave it. As Linda said, those two were picked based on looking at the group and figuring that those two had the highest probability of responding, if neither one of those show any effect, then we're done with the pathway. If we see a significant effect, then of course we'll dive more deeply into the pathway. So the de-risking will occur through that. I think your question is how tightly those two are linked to all the others, and I think there's not a short answer to that question.

Got it. Okay. Thank you very much.

Thank you. The next question comes from Joseph Stringer from Needham & Company.

Hi, good morning. Thanks for taking our questions. Two from us. First one is on the CVS Alstrom. Did FDA request any additional data, excuse me, did FDA request any additional data analysis since you initially announced an update in February of this year? And then second question is on M&Aids. Do you anticipate the SRC1 and the SH2V1 sub-studies to enroll faster, just given the higher prevalence relative to the HESS sub-studies? Thanks for taking our questions.

Great question. I'll start with the M&Aids because that is the easier answer. So yes, we do anticipate just via the higher prevalence that there will be a faster enrollment of the SRC1 than the SH2V1 compared to the others. As far as the FDA, no additional requests for data other than that that we spoke about previously. Other than we did submit our periodic benefit risk evaluation report, that's part of our regular requirements, and they just had some follow-ups of that that we have responded to. But otherwise, we're on track and... No additional requests have been received to date.

Next question.

Thank you. Our next question comes from Michael Higgins from Lattenburg-Talman. Please go ahead.

Thanks, Amber. Good morning, guys. Thanks for taking the questions. First, just want to follow up on the comments you've made and also the press release for modification of the summary product characteristics in Europe following making adjustments to the moderate and severe renal impairment on a adjustment for dose escalation in a lower max dose. What led to that? Is that post-marketing? Is that something that's on the data? And how is that affecting the FDA review? Thanks.

Sure. Great question. So we conducted a trial in patients with renal impairment, mild, moderate, and severe renal impairment, and we assessed the pharmacokinetics, and based on the data from that trial, that is what came out of it. So we have submitted this data both to the FDA and to the EMA, slightly different pathways by which those regulatory approvals go through, but they are both kind of tied to our BBS submission. And in essence, the data show that there was no need for any dose adjustment in the mild and moderate renal impairment. But in patients with severe renal impairment, the data suggests starting at a lower dose and dose escalating slower. The max target dose can still be the same, but it will be dose escalated based on response, you know, clinical response efficacy and safety.

So just to follow up to that, would you look for the same type of language from the FDA?

Yes. Yes. We anticipate they would be quite similar.

Okay. Super helpful. And then just a follow-up on the BBS market. You've discussed the 350 patients that have been identified. There are 750 that the BBS group is has. What are your steps that you're taking to close that gap? Obviously, there's some patient confidentiality, but you're working so closely with that group. Also, wondering how that is coming together. And the last part of that would be, you mentioned identifying patients through ICD-10 codes. I don't think it's for BBS, so if you could expand on what that is you're finding in those codes. Thanks.

I think that just in terms of efforts overall and engagement, the relationship we have with the Marshall Clinic is extremely strong. Of course, they are the ones who own the registry, and as you outlined, there are some restrictions just in terms of our ability to access and such. I think based off of their interest also in terms of treatment of the patient population and also interest in the drug, that may be one opportunity also in terms of the playthrough of how things are communicated with patients that they are also in touch with. I think moving on to the question in terms of the ICD-10 code, You know, there is a benefit. Like I said, this is a very different launch from the initial indication because BBS is a syndromic indication. And based off of the various different symptoms, where it's eye involvement, you know, obesity, things around renal impairments, etc., There is an ability to sort of triangulate systems to try to understand which physicians have patients that may be a BABS patient. Particularly, if you start with one code, Q8786, where BBS actually resides, there may be an ability to tease out of the tens of thousands under that code. which physician may have diagnosed a BBS patient versus the 10 other plus indications that fall within that category. So we're just trying to be smart in terms of targeted efforts of how we go about disease educating.

And Jennifer, maybe one clarification. The 350 plus patients that your teams have identified, are not necessarily all in the registry.

Right. We, at this point in time, we don't really know the overlap in terms of the 350 plus patients versus the ones that are in the Marshfield, the CRIB registry right now. There may be, I would assume that there's not 100% overlap as, you know, our teams have been on ground educating and targeting various different physicians throughout the nation.

Did we answer it? Very helpful. Yes, it does. Thanks, David. Thanks, guys.

Thank you. As a reminder, if you have any questions, please press S01. Our next question comes from Morgan Stanley. Please go ahead.

Thanks for taking my questions. Ahead of the potential BBS launch, do you have a sense for what percentage of the 350 patients would be interested in being treated? Like what kind of prescreening have you done through the physicians? And then as we look towards the potential approval, how often should we expect updates for the number of identified and treated patients, or what kind of metrics might you provide regular updates on? Thanks.

Sure. In terms of the patients, Like I said, it's very difficult to really come up with an estimate just in terms of exact percentage that will be expected to go on therapy. Maybe if I could also caveat things in certain ways. When you think of the physician populations that we are targeting, A lot of our efforts have been in the past also around the pediatric endocrinologists, and from that perspective, they are having issues that they are going to these specific physician populations to address, and hence they may be a more motivated population in terms of wanting to really seek out a treatment for their obesity and hyperphasia component. So that's a positive factor just in terms of need to treat, desire to find a new option. I think in terms of the second question was relating to... Yeah, in terms of updates.

So maybe just one additional point, Jeff, on terms of the percentage. Jennifer said it's impossible to estimate. I think that the point that she made is the critical one, which is these patients that we are confirming in that 350 plus are engaged in the system. They're engaged in the system. They're seeking help. So they're going to get on therapy would be the prediction. It's the question, how long, when will they seek it? I mean, there's a lot of factors will dictate how much time it takes maybe to get them on therapy, but they've already signaled that they're out there looking for help. And so word will get around. In terms of metrics, again, I'll just say we're very early in terms of, you know, the obvious things. There's patient numbers. There's prescriptions written. There's a number of doctors who are writing prescriptions and the like. And what we'll do as we begin to get more experience here is try to look at things that we feel provide the most meaningful insight, and we'll share those. But at this point, we're not going to tell you exactly what metrics those will be.

Great. Thank you.

Thank you.

Last question.

Our next question comes from Karen Jenkins from Goldman Sachs. Please go ahead.

Yes. Good morning, everybody. So maybe totally different tack here, but as you expand these M&A and the Daybreak Basket studies, I'm curious if you're seeing any change in dynamics with respect to the receptivity or utilization of the URO test just given there's a higher kind of yield on being able to do something about the genetic screening test as they come back?

It's a very good question. We very much, in a sense, control that. You know, it's broadly available. People can just sign up for it and we ship the kit. That said, we are very much, we've shifted our strategy from in the beginning it was basically wide open. We are just trying to understand the epidemiology. We've now become much more focused, our field teams, around encouraging screenings at those sites, either the clinical trial sites themselves or clinics that are in some radius around a clinical trial site so that when a patient is quote-unquote diagnosed, they have a reasonable chance of being eligible, able to get into an emanator daybreak. So it's not a good number. The amount we're screening has gone up somewhat from our other numbers, but it's governed by a restrictive, if you will, by that effort.

Okay, thanks. That's helpful.

Thank you. Great. With that, I think we're at the end here, and I want to thank all of you for tuning in. And if there are any questions that we did not get to, can you please submit those to Dave Connolly, and we'll work to respond to those individually. And with that, thank you all for tuning in.

Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for participating. You may now disconnect.