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spk10: Thank you for standing by and welcome to the Rhythm Pharmaceuticals fourth quarter fiscal year 2021 financial results conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1 on your telephone. As a reminder, today's program may be recorded. I would now like to introduce your host for today's program, David Connolly with Rhythm Pharmaceuticals. Please go ahead.
spk11: Thank you, and good morning. I'm Dave Connolly, head of IR and corporate communications here at Rhythm Pharmaceuticals. For those of you participating via conference call, the accompanying slides are available and can be controlled on the events section of the investors section of our website at ir.rhythmtx.com. This morning, we issued a press release that provides fourth quarter and year-end 2021 financial results and a business update, which is also available on our website. as listed on slide two, is our forward-looking statement. And I'll remind you that this call will contain certain 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. And on slide three is a list of today's speakers. We're all here today in Boston. David Meeker, chair, president, and chief executive officers here. Linda Shapiro, our chief medical officer. Yann Mazzebro, our executive vice president, head of international. Connor Schmidt, Chief Financial Officer, and Jennifer Chan is also here for Q&A. She's Executive Vice President, Head of North America. And with that, I'll turn the call over to David.
spk14: Thank you, Dave, and good morning, everybody. Thank you for tuning in this morning. So we're really pleased to report out another strong quarter, wrapping up what was an incredibly important year for Rhythm. And today we'll take you through some of the more recent highlights, which are captured on slide five. First and foremost, as we continue our preparations for BBS launch, and hopefully most of you have had a chance to review or see or tune in to our event about two weeks ago, where we heard from Mary Morris, a caregiver, a mother of two children with parted beetle syndrome. And I'll speak a little more about Mary's story in a moment. And we also heard from two of the experts, Dr. Haas and Dr. Conroy, and that That session gave us all, I think, a much stronger sense of both the challenges faced by individuals and families living with BVF, as well as how the experts view this community coming together and the ultimate opportunity for semilantotide. As you know, we heard recently from the FDA requesting some additional analyses. No new data was required, but additional analyses, all of which we felt were good, strong, supportive of the overall file, and perhaps ultimately a better way of looking at the data. So no issue there. But it did come with an additional three-month delay in our PDUFA date, which is now set for June 16th. We also indicated in our recent communication that we made the strategic decision to remove Ahlstrom syndromes from the file in Europe. This was based largely on a calculation that we didn't want to prolong the review in Europe. there was a risk that engaging more around the Alstrom opportunity that might do that. Also strategically, I think as we look at market access opportunities in Europe, it is advantageous to go in a layered way. I think going to the authorities with the combination of BBS and Alstroms made it a little more of a complicated file. So again, from a very strategic standpoint, we decided to withdraw Alstroms at this time from our European application. There's no change to our plans for the U.S. Second, we're going to hear from Jan Masbro today about our international, and I have come to understand, believe, spent time in Europe, that if you can get it right internationally in a rare disease opportunity, and most specifically in Europe, you can pretty much get it right anywhere. It's some of the more challenging healthcare systems in the world, and you'll hear from Jan about exciting progress in that sphere. We're also very pleased with our U.S. commercial experience to date. I'll spend one slide on that, but it's going as predicted and laying the foundation for our PBS launch. And finally, you'll hear from Linda as she takes us through a couple of different programs that we're excited about, meaning they are progressing well. We have a number of milestones met with a number of these trials now underway. And again, she'll speak to that in a little more detail. Next slide, number six. So this is a picture of Mary Morris and her family, her two children, Ashley and Carly. And again, if you have a chance to listen in, what we heard during that session is just the incredible challenges that individuals living with Barted Beetle Syndrome and their families face as they deal not only with obesity, but they deal with the underlying cause, that genetically driven central defect which causes the increased hunger. And, you know, we focus, this is hyperphasia. This is not the hunger that you and I know. And again, when you listen to individuals who are suffering or living with somebody suffering from it, you begin to understand. I don't think we can fully understand if you don't experience yourself, but you begin to understand that this is not what you and I experience when we miss a meal. We heard yesterday at our company-wide meeting from a caregiver, who told the story of her family and their son's challenges of living with Bartlett-Beetle syndrome. It was unique, of course, different in the sense that not completely different individual and family, but the nature of that. She spoke for an hour and literally 55 minutes of the hour was focused on the hyperphagia and the challenges of living with hyperphagia. The consequence, the obesity, the weight gain, the other actors, of course, were important, but what is so striking here is that this is a different disease. These are different diseases from what we see in patients who are living with general obesity. So, again, you can hear more about that if you tune into our session. Slide number seven just highlights, again, the progress or how we think about the frame for our BDS preparations. First is understanding the unmet medical need, which I just spoke to, the importance of the hyperphagia, but Also, the rapid weight gain is severe obesity, which occurs early. And the fact that it occurs early means that the complications of obesity come with it, and they start early. And so the cumulative effect over a lifetime is much greater. The solution, growing confidence in the solution, which is setmelanotide, I think is a targeted therapy addressing the MC4 receptor, lanocortin-4 pathway, which governs hunger and energy expenditure. The story is not completely in the numbers. The numbers are important. The amount of weight loss is important. The scales are important. But as you listen to the stories, you get a much better sense of how, in fact, a drug like set melanotide can change the overall picture. And finally, we spoke about our preparations for launch and feel really good about that. A number of us, we have a highly experienced team here led by Jennifer Chen and a number of people that both she and I have worked with over the years, as well as some new people to us who come from other deeply experienced backgrounds. And that's what it takes, I think, to be successful in a rare disease, are individuals with an entrepreneurial mindset and the ability to problem solve in a customized way. We've made great progress, and I'll speak a little more about that in the next slide, in terms of building this community and helping more and more patients come to diagnosis and, as I said, organize the overall opportunity. So next slide, number eight. Now, we spoke on the call about 350-plus individuals who have been identified. We spoke about the process of identifying those individuals, which consisted of going to physicians where we had a strong understanding that they were caring for an individual with Bartlett-Beetle syndrome. The goal of those visits were to connect in, to validate and confirm that, in fact, they were still following that patient. And so that represents one part of this group, the identified and diagnosed group. We also know that there's a large number of patients out there who are diagnosed today, but may not be actively engaged in the system. That's another opportunity. As we've done genetic testing, the genetic testing, our current panel of 80 genes includes 23 genes for Barded Beetle. And we know the hit rate when you do screen an individual with a history of early onset obesity and hyperthasia for Barded a barded beetle is on the order of 1.5% of those individuals will come back biallelic for a barded beetle gene. Now that doesn't mean that they will meet the diagnosis for barded beetle, but that does create a roadmap to somebody whose probability of having barded beetle may be slightly higher. And so again, falling in this suspected category. And as always in rare disease, by far the largest part of the population is undiagnosed. It is a syndrome. It has advantages in the sense that If you can connect the dots, you have a better chance of making a diagnosis. But you don't connect those dots if you haven't seen one in a reliable way. And you can look at something that's obvious to an expert as a non-expert, and you just miss it. And so as a result, many of these patients are on this prolonged diagnostic odyssey where their ability to get a diagnosis, despite some classic parts of the presentation, they may see five to 10 different positions before somebody puts all it together and says, you may have Bartlett-Beetle syndrome. So we feel good about the 350-plus patients we talked about. The fact that the PDUFA data has been pushed out by three months doesn't change anything. Foundationally, everything remains the same, and we'll continue those efforts and really look forward to June 16th, when we will hopefully be able to move into a commercialization phase. Next slide, number nine. So as I said, we're really pleased with where we are in terms of our initial commercial experience, and we reported 3.2 million patients. in revenues for 2021 with 1.8 million in the last quarter. As or more importantly is what we've learned, logistics are in place, contact and interactions with payers is going well. And the practice, one of the most important things is we bring up our patient services group and we have the opportunity to interact directly with patients who have consented and said they want to be in contact with Rhythm for all the services we can provide. It gives us greater insights into how we can best support this population, both in terms of disease education, what they can expect, the onboarding as they start therapy and what they can expect from therapy, and just, again, general support in the rare disease world that they can't always get from the healthcare system itself. And finally, on slide 10, I just want to remind you all that we announced in December our partnership with RareStone for the opportunity in China. Really excited about that. It's hard to do, maybe not so hard to do the deals. I think it's hard to find the right partner, And as we've interacted over the past two months, our confidence that we've got the right partner in Railstone is growing. We're completely aligned from a cultural standpoint, from a philosophical standpoint. They're highly experienced, having taken a couple of different products through the regulatory process, And they are well on the way with filings related to Rhythm's Opportunity itself. And we're quite hopeful that in that exercise, they will be in a position to be participants in our Phase 3 effort, the M&A trial specifically, and contribute to that. So with that, I'd like to turn it over to Linda Shapiro, our CMO, to take you through our regulatory and clinical update. Linda.
spk03: Great. Thank you very much, David. Let's begin on slide 12. So as David provided the update on the regulatory efforts relative to Bartlett-Beetle syndrome and Alsham syndrome, I intend to focus on our robust clinical development efforts. That melanotide and rhythm's approach to rare genetic diseases of obesity is truly unique. We've known for decades that the MC4R pathway regulates hunger, energy expenditure, and consequently body weight. And for just as long, it has been a target of biopharma companies looking to develop medications to impact it. With Cetmelanotide, Rhythm has shown we can do just that. Cetmelanotide is the first ever MC4 receptor agonist that targets the root cause of the debilitating hyperphagia and early onset severe obesity that are the hallmarks of rare genetic diseases of obesity. In addition to our unique precision medicine, Cetmelanotide, we are undertaking a unique approach to obesity driven by our belief, which is supported by decades of research, that all obesity is not the same. Yesterday, we recognized Rare Disease Day with an internal employee engagement event featuring a patient caregiver speaker who was truly inspiring, along with some artwork generated through team-building exercises to shine a light on rare diseases. Importantly for the greater Rhythm community, Rare Disease Day falls at the beginning of Obesity Care Week, which is a campaign to increase awareness, education, and action on the complexities and chronic nature of obesity as a disease, as well as on weight bias and stigma. And Friday, March 4th, is World Obesity Day, with this year's theme of Everybody Needs to Act, encouraging all of us to work together to ensure happier, healthier, and longer lives for every body. With that in mind, I'd like to encourage you to check out leadforrareobesity.com, a website where the Rhythm community offers educational resources, educates on the importance of genetic testing, and shares stories. We welcome you to join us in leading the effort to provide education and access to treatment for rare diseases of obesity. And with that, let's move to our clinical development programs. Slide 13. We are reporting updates on several clinical trials today. In addition to completion of enrollment in the hypothalamic obesity trial, which we'll talk about shortly, today we announced that the first patient has been dosed in our Phase III pediatric trial, evaluating set melanocytes in patients aged 2 to less than 6 years with obesity due to biallelic, POMC, PCSK1, or leptin receptor deficiency, or with a clinical diagnosis of BBS with genetic confirmation. In January, we announced the dosing of the first patients in the Phase II Daybreak clinical trial, which is evaluating sentinel antitides for the treatment of severe obesity and hyperphagia, potentially caused by a genetic variant in one or more of 31 genes, with strong or very strong relevance to the MC4R pathway. Daybreak is the most comprehensive Phase II trial ever initiated in rare genetic diseases of obesity. Also in January, we announced the dosing of the first patients in the phase three switch trial, evaluating a once-weekly formulation of set melanotide in patients six years of age and older with rare genetic diseases of obesity who are currently taking the daily formulation of set melanotide. And we expect to initiate the phase three MN8 trial in the first half of 2022. We faced some delays due to COVID and the Omicron surge with our CRO and other vendors. Slide 14. We also have quite a few data readouts coming in the next few months. Several patients with SRC1 deficiency or SH2B1 deficiency advanced from our exploratory phase 2 basket study to our open-label long-term extension study, and we're looking forward to reporting 12-month data from those patients at a congress this spring. As a reminder, last year we presented three-month data in patients with SRC1 that showed a mean weight reduction of 7.9% in adult responders and a BMI score reduction of 0.48 in responders younger than 18 years. In SH2B1, adult responders achieved a mean reduction of 7.2% and there was a mean reduction in BMI-Z score of 0.25 in responders younger than 18 years. Also, we look forward to a fulsome presentation of 24-month data in patients with part of Beatle syndrome. Dr. Bob Haas presented a preview of the BBS data last month with data from 19 patients at 24 months, showing a mean reduction in body mass index from pivotal trial baseline of 14.3%, a mean reduction in body weight from pivotal trial baseline among six patients 18 years of age or older of 14.9%, and a mean reduction in BMIC score from fibril trial baseline among 12 patients younger than 18 years of 0.72. We're also looking forward to presenting two-year data from patients with biallelic POMC, PCSK1, or leptin receptor deficiency obesity. Importantly, we expect these data to continue to build the case for long-term therapeutic value of set melanotide, as the long-term data we've presented to date have shown consistently that set melanotide achieves sustained meaningful effects. Slide 15. Now let's turn to hypothalamic obesity. Hypothalamic obesity is a rare, acquired form of obesity that develops following injury to the hypothalamic region of the brain that contains the MC4 pathway neurons and are responsible for controlling physiological functions such as hunger and weight regulation. Ipolymic obesity most frequently follows the development of a craniofringioma, a rare brain tumor, or its treatment by surgical removal or radiation. Approximately half of patients with craniofringioma experience rapid weight gain and insatiable hunger in the first 6 to 12 months following tumor resection and ultimately develop severe obesity. While clinical and preclinical evidence suggests an apparent MC4 deficiency in these patients, The impact of the injury to the hypothalamus and its effect on the MC4 receptor itself remain difficult to ascertain. Currently, therapeutic options are very limited for patients with hypothalamic obesity. Slide 16. Today, we announced that we completed enrollment in our Phase II open-label proof-of-concept study evaluating set melanotide in individuals with hypothalamic obesity. We enrolled 18 patients older than six years in this study. The trial consists of 16 weeks of treatment with set melanotide administered once daily by subcutaneous injection, including an initial dose titration period. The primary endpoint is a proportion of patients with 5% or greater reduction in BMI from baseline after 16 weeks of set melanotide treatment, compared to a historic control of less than 5% in this patient population. We are fortunate to have one of the country's leading key opinion leaders in hypoallergenic obesity as a principal investigator for this trial, Dr. Christian Roth of the Endocrine Division of Seattle Children's Hospital. We're looking forward to sharing preliminary data from this trial in the middle of this year. And with that, I'll turn the call over to Yann for an update on International.
spk07: Thank you, Linda, and good morning, everyone. As most of you know, it is crucial to be in Europe and in other key international markets to build a successful readiness company. Over the last 18 months, we've made a lot of progress building out our international recognition. We are now 20 people, with most of the position being across EU4 plus the United Kingdom, and also four positions in four other key regions of country with strong potential, namely the Netherlands, the Nordics, Turkey, and Argentina. We are a highly skilled and very engaged team, relentlessly working closely with the main European centers of excellence and their referral networks to increase disease awareness and drive diagnosis, Engaging and partnering with the local payers and providing operational support for RISM, robust clinical operation, as Linda just described for you. Before to talk to you about our market access highlights, I want to say a few words about the European rare disease landscape and how both the patients we serve and RISM will benefit from it. In the last 20 years, I've had the privilege to launch and commercialize more than 10 rare disease drugs in Europe, in Latin America, and in the U.S., and the European rare disease ecosystem is by far better organized than any of the others. More than 20 years ago, European countries began a very well-structured approach to rare disease, beginning with rare disease national plans with dedicated budgets and national centers of excellence, leading to better diagnosis and care for patients with rare disease. Then we saw the advent of the European rare disease networks, ultimately leading to increased expertise and diagnosis acceleration. Specifically for the rare genetic disorders of obesity, we are extremely lucky as a company to leverage more than 30 years of research and clinical excellence in many large university hospitals in the most important European cities. Before us, before RISM, there were already patients with rare genetic disorders of obesity diagnosed. It has accelerated and increased since we started our main clinical trials back in 2014. And there are now more than 100 patients diagnosed with biallelic POMC PCSK1 early power deficiency obesity being cared for in European Centers of Excellence. Another example in France where the French HHS and the National Reference Center for Rare Genetic Disease of Obesity introduced last summer formal guidelines for the diagnosis and management of patients with rare genetic disease of obesity. Next slide. As you can see on this timeline, we've made tremendous progress in the international market since Q3 2020. from submitting our market authorization application for MCVIRIN, POMC, PCSK1 and LIPAR in July 2020, followed by the European and United Kingdom authorization in July and September 2021. We have been very busy. We have engaged very early with the most important European HTA bodies, which is without any doubt the number one key success factor in terms of market access. And today, I'm happy to report many significant successes across Europe, And more importantly, our first commercial sales, which are expected in Germany and France in the second quarter of this year. Next slide. And just before, to give you some details about these two countries, I am proud to say that there is a genuine excitement about IMSIRI in Europe. And along this line, I'm very proud to report that IMSIRI has been highlighted two weeks ago in the EMEA's 2021 edition of its Human Medicines Highlight. and listed as one of the eight drugs with an outstanding contribution to public health, within a total of 92 positive opinions granted last year. Next slide. Germany. So Germany is, as you know, the largest and most important country in Europe from a healthcare business point of view. In Germany, drugs classified as lifestyle drugs, which include those designed to affect weight loss, smoking cessation, air loss, are not eligible for reimbursement. We are excited to announce that the German Federal Joint Committee, or GBA, excluded MCIVRI from its lifestyle drug for POMC, PCSK1, or lipar deficiency obesities. This first-ever exclusion marks an important recognition that MCIVRI is designed to treat rare genetic disease that manifests as obesity and that this group of disease is distinct from general obesity. With this exemption status, MCIVRI will now be eligible for national coverage and reimbursement and we are looking forward to first commercial cells in Germany in the second quarter of 2022. Next slide. France now. Last month, on the 19th of January, so five weeks ago, the French Haute Autorité de Santé, or HHS, granted paid early access for mCV for patients with POMC, PCSK1, or Lipar deficiency obesities, which means that any obesity specialist in France can now prescribe for genetically confirmed POMC, PCSK1, or Lipar patients six years and above. This is a very strong recognition of the important medical need on the value of St. Valentine, but also a testament to strong support coming from the obesity and rare genetic obesity communities and KOL, which we enjoy in France. Next slide. We will have more pending commercial sales to report in the coming months. In 2021, we have submitted the POMC-PCSK1 early power reimbursement dossier in EU4, plus the United Kingdom, plus the Netherlands, plus Israel, and we have already started to work at the next filing for barley-beadle syndrome. You've just heard about Germany and France. Initial feedback from Spain and Italy are very positive, and in the UK, Following the selection of highly specialized technology, which is, by the way, a very high bar to reach, we've had so far very positive interactions with NICE and are on time for our market access plan. Next slide. Last but not least, a few words about the Barde-Bidal syndrome indication in Europe. We are expecting a CHRP approval in the second semester of this year. The estimated European prevalence is 2,500 patients. And here again, there are a lot of patients already diagnosed, more than 1,500 actually. Actually, I would like to say that we are in a very good place in the most important European countries while opening new horizons in other key countries around the globe with a high sense of privatization and focus. Now, I would like to turn the call over to Hunter to review our fourth quarter and full year of 2021 financial results. Thank you, Yann.
spk00: Turning to slide 26, as David mentioned at the start of the call, we are pleased to report product revenue of $1.8 million in the fourth quarter of 2021. an increase of 80% over the third quarter. For the full year 2021, which is effectively three-quarters of sales, revenues were $3.2 million. All revenue came from sales of MCIVRI in the United States. There were no revenues during the comparable period of 2020. Loss from operations was $50.9 million in the quarter, an increase of $15 million over the comparable quarter of 2020. For the full year, 2021 loss from operations was $170.1 million, an increase of $33.5 million over the prior year. For both periods, these increases were due to increases in both clinical trial activity as well as higher headcount across our research and development, commercial, and G&A functions. We expect our operating expenses to continue to increase during 2022 due to costs associated with our expanding clinical development efforts as well as commercialization activities related to potential MCIV relaunch in BBS and ongoing efforts across Europe. Our share count was 50.3 million basic and diluted shares, and common loss per share was 85 cents, an increase of six cents over the fourth quarter of 2020. And for the full year, our share count was 49.6 million basic and diluted shares, and loss per common share was $1.40, a decrease of 1.64 over the full year 2020. We concluded the year in a strong financial position with cash equivalents and short-term investments of $295 million, which we believe will be sufficient to fund Rhythm's operations into the second half of 2023. And now I'll turn the call back over to David for concluding remarks. Thank you.
spk14: Great. Thank you, Hunter. So I hope what you're taking away from this initial part of the presentation is that You know, we feel great about 2021, but we're even more excited as we look ahead to 2022. Number of milestones, Linda took us through some that have already been achieved with initiation of a number of these trials. We're looking forward to some additional data readouts, which again, it's obviously not in a position to predict, but these are exciting questions. How will we do in a hypothalamic obesity world or an MC4 receptor deficiency world? So, again, we look forward to reporting out those results from those studies in and around the mid-year. Also, we'll have the long-term data that we'll continue to roll forward as we collect more data on those patients with biallelic deficiencies, genetic variants, and those patients who we have studied in our existing ongoing basket study rolled into the long-term extension. And finally, the VBS world, as we've highlighted and will continue to highlight, this remains an incredibly strong focus for Rhythm. It's extremely important that we get this right. There's a big unmet need. We think we have a meaningful solution and, again, feel good about our preparations to date for that. So with that, we'll turn it back to the operator and open it up for questions.
spk10: Certainly. Ladies and gentlemen, if you do have a question at this time, please press star then 1. If your question answered and you'd like to remove yourself from the queue, please press the pound key. Our first question comes from the line of Phil Nadeau from Cowan & Company. Your question, please.
spk08: Good morning. Thanks for taking our question, and congratulations on the progress. First question on the BBS launch, can you discuss in a bit more detail what you can do between now and the June PDUFA to identify patients and physicians who could be amenable to insincerity?
spk14: Thanks, Bill. So, Jennifer, Jen, who's joining us?
spk02: Thanks for the question. You know, although we were disappointed just in terms of the news of the delay, I would say that a lot of the work that we are doing right now up until approval would be similar just in terms of the engagement that we are doing currently. So, as David mentioned, there are various different areas that we have opportunities in terms of one, validating the number of patients that were within our sphere already through the work that was done by our field teams and MSLs on ground. That work is ongoing. In addition, there are several other opportunities in terms of one, really Finding the BBS patients that have already been diagnosed and are lost in the system, and we have very targeted ways to go about that activity. And two, then finding and diagnosing and expediting the diagnosis of patients who have not yet found a diagnosis. So, a lot of those activities and engagement with physicians are ongoing, and we will also support an excellent launch as we move forward.
spk14: That's very helpful. Go ahead, Bill. Oh, no.
spk08: Sorry, David. You go.
spk14: No, no. I was just going to do, Bill, referring you back to Jennifer and the team took everybody through it in a little more detail of the different tools that they're using, which include our genetic screening and an exercise working with IQVIA on ICD-10 coding and algorithmically defining. So there's a number of things that we can do. And in a rare disease world, this never stops. You continue. You don't saturate a market in a sense. You don't reach full penetration yet. I think it's an endless journey of continuing to increase awareness. These activities will, over time, continue to bear fruit. So, sorry, back to you, Phil.
spk08: Perfect. That's very helpful. Second question is on the Phase II data in hypothalamic obesity. Can you discuss a bit what would be considered proof of concept there? How much weight loss versus changes in hyperphagia would you need to see to progress development? Okay, Linda? Yeah.
spk03: Sure, thank you for that question. So similar to our other programs, demonstrating a clinically meaningful improvement in weight or body mass index or PMI-Z score would be adequate to demonstrate that proof of concept, and that's the way we've designed the trial and set up the primary endpoint.
spk08: Perfect, that's helpful. And then last question is on Germany. I think in the personal list you mentioned that the exclusion from the lifestyle list is a one-year exclusion. Did I interpret that correctly? And if so, does that decision have to be revisited every year, or is there a point at which it becomes a final decision that is perpetual?
spk07: No, thank you. No, no, it's not a one-year exclusion. It's an exclusion for life. So we will enter this exclusion for the next 100 or so years. Perfect. Thanks for taking our questions.
spk10: Thank you. Our next question comes from the line of Derek Archilla from Washington. Wells Fargo. Your question, please.
spk13: Hi. This is Adam on for Derek. Thank you for taking our questions. I have just a few for you this morning. Do you believe the FDA requested additional analyses because they are questioning the efficacy in barbed beetle, or is it more a labeling consideration, and is there a possibility the FDA could complete their review before June?
spk14: Thanks, Adam. Just to clarify on that, what the FDA requested and was analyses which were not part of our pre-specified endpoint. So when we put the file in, we put it in, as of course you always do, based on your statistical analysis plan and your protocol. They came back and asked for some which specifically had to do, driven largely around analyzing the data by less than 18 and greater than 18 Our primary endpoint analyzed the group of patients as 12 and above. And, of course, this introduced the confounding variable that those patients of which there were a number, almost half of the primary analysis group, were between 12 and 18. And so that group is still growing. Absolutely. weight in that case was confounding. So I think what they asked for were fully supportive. It's how we talked about the data, but these were not pre-specified. So no, I don't think it introduces a risk if you will, to the overall approval, but I do think the requests that made sense. In terms of their ability to complete it at an earlier time point, Again, if they were focused on this and we were the only file in front of them, I think for sure they could complete this review in shorter than three months. That said, we're not the only file in front of them, and so we have little expectation that we're going to get an approval in advance of the pre-specified June 16th date.
spk13: Sure, that makes sense. And then I suppose related to my last question, how large is that amended data package?
spk03: Thank you. That's a good question. In reality, it was over 300 pages. It was 100 plus data outputs of cutting the data, as David mentioned, across the age groups, also across gender with looking at weight, BMI, BMIC score, every which way you could imagine cutting the data that they asked us to cut the data. So it was quite a large package and therefore justifies their decision to take three months to review it. The very encouraging news is no matter how we cut the data and looked at it, it was all supportive of the same thing. So there wasn't a subgroup by any of those cuts where set melanotide did not demonstrate a clinically meaningful improvement. So that was very encouraging. And now it's just a matter of time for FDA to review all those data that they requested.
spk13: Okay, well, thank you very much.
spk10: Thank you. Our next question comes from the line of Joseph Springer from Needham & Company. Your question, please.
spk01: Hi. Good morning. Thanks for taking our questions. Two from us. One, just given the recent, you know, requests from FDA on BDS and Alstrom, just curious if that's changed your thinking or the design of the M&A, Phase III M&A trial in any way, just in terms of data analysis there. And secondly, on the diagnosed BBS patients who may not be in the system or, you know, identified at an academic or medical center, what's the reasons for, you know, why these diagnosed BBS patients are not sort of part of the system? Is it just that they're You'll have a less severe phenotype, or these are sort of older patients that have kind of learned to sort of live with the disease. And, you know, does this make up a significant portion of the BBS population? And maybe more specifically, what are the specifics around sort of capturing these potential patients? Thanks for taking our questions.
spk14: Yeah, thanks, Joe. So Jennifer, I'll take your second question on the BBS diagnosis. With regard to the FDA and whether this recent communication changes our plans for M&A, no, there's no change. This was a set of requests which were very specific to our somewhat unique trial design, which incorporated BBS and Allstrom's. We analyzed them together. And as I explained, we have the age greater than 12 issue. So they were very specific to the existing file. So no change to M&A. Jennifer?
spk02: So on the second question, I just wanted to make maybe a clarifying point. I think similar to many different rare diseases, there's certainly a large pool of patients that have not yet gotten to a diagnosis, but there are also maybe patients that are diagnosed but may not be visible to the company. So for us, that's where it really lies because we have had field teams on grounds really educating different physicians and interacting with them and also trying to understand if they do have a BBS patient on hand. However, through those efforts, they may not have gotten to all of the physicians who have BBS patients on hand because our efforts were, you know, focused initially on, you know, BCD specialists or pedendos or endos, and some of these patients may be in the hands of other specialties including PCPs and GPs as well. The mechanism though, one of the mechanisms that we are using just in terms of trying to identify those additional patients is although there's not a specific BBS ICD-10 code, there is a code where BBS is one of several indications. the ability to use different claims to try to identify HEPs that more likely has a BBS patient because of the symptoms is one targeted way of really going about and trying to educate the right physician and interact with them. And then once again, try to understand if they have an already diagnosed patient under their care.
spk14: And maybe Jennifer, just comment one other part of the question was, do you think these patients are sitting out there because they have a less severe form or they're just equally severe and unrecognized?
spk02: Yeah. So I think that it could, it does not necessarily mean that they're less severe. I think that in the case of different diseases where there are no therapeutic options, they may have been more persistent in terms of trying to identify the appropriate options in terms of managing the but over time, as they've gone from physician to physician and realized that there isn't anything effective, they may have been less persistent because there are just no therapeutic options. So the potential availability of a therapy like MCIVRI may provide more hope in terms of engagement and opportunity from that perspective.
spk14: Thanks, Jennifer. Thanks, Joe. Next question.
spk10: Thank you. Our next question comes from the line. Michael Higgins from Leidenberg Thalmann.
spk09: Your question, please. Thanks, Operator. Good morning, guys. Thanks for taking some questions this morning. My question, I guess, questions, I guess, are really focused on the upcoming data here before midyear. In hypothalamic obesity, it's not genetically driven, so the outcomes that you're expecting, would these be different from the previous data sets that you had before? maybe in terms of hyperphagia or weight loss. Thanks. Great. Linda?
spk03: Thank you. That's a great question. So you're correct. Although the etiology is not genetic, it's acquired, the presentation is similar. So the outcomes actually are similar, even though the etiology is different. So we are looking at the changes in weight and changes in hunger scores. similarly and would anticipate a similar effect of semilanotide in the patient population.
spk09: Okay. And a couple quick follow-ups from that. If you could review for us again the control arm. I believe you had mentioned historic controls, what you're expecting for that. And then relatedly to here, the number of patients we may be seeing in that study. Thanks.
spk03: Sure. So in this study, we have 18 patients who've been enrolled. It's an open-label treatment arm. So the control is a historic control, and it's based on data of patients who gain weight year over year after having the treatment for their craniofringioma or whatever tumor, and therefore the resultant hypolymic obesity. Many of these patients have been tracked very closely since the diagnosis of their tumor and their treatment. And so we have natural history on them, and then the intervention of set melanotide, and we're looking at the change in that trajectory curve, as well as the absolute change over the treatment period.
spk09: So am I hearing their control is kind of a self-control based on their own natural history, not in the group of hypothalamic obesity patients?
spk03: No, no, that's just an additional layer. So the The historic control is beyond these patients, but we are able to get an additional layer for the individuals as well.
spk14: I appreciate it. I think it's worth, maybe just one of the comments, it's worth adding that this is, it's acquired, as Linda said, and as a result, it's a much better organized, defined community, and so there is more information out there in that sense, and there have been a number of big unmet medical need, again, as you and to look into that as we obviously are doing. And a number of things have been tried, none with really significant medical effect here. So enlarge on that medical need, we'll see how we do here, but this is clearly a group that's presenting with clearly impairment in this pathway, consistent presentation, and so therefore the hope that a drug like Cetanolanotide can make a difference.
spk10: Next question. Our next question comes from the line of Jeff Hunt from Morgan Stanley. Your question, please. Thanks for taking the questions.
spk12: Of the over 350 BDS patients that Rhythm has identified, how many of them are in the CRIBS registry? And then I have a follow-up.
spk02: Jennifer? So the 350 patients that have been identified have really been through the Rhythm-specific efforts. we, at this point of time, do not know or have access to the physicians or patients that are in the CRIPS registry. So I wouldn't be able to outline how much overlap there is between CRIPS versus the patients that we have identified.
spk12: Okay, understood. And then in the past, you've talked about the potential launch in VBS as a potentially slow ramp. Now that you've identified the 350 patients, what are your expectations for how long it might take to treat those patients once you have approval on DBS. You know, are there any constraints or gating factors on why they can't all be treated and in relatively short order? Thanks.
spk14: Yeah, Jeff, I think you're taking those comments from comments I've made in a number of different conversations. I wouldn't characterize it necessarily as a slow ramp. I'd characterize it as a characteristic rare disease ramp. And by that, I just mean that If you have a well-organized community, large indication, you write a script and somebody goes to a local CVS and picks it up, but that's a very different setting than the world that we live in. We need to get the whole system working. As I've pointed out, we have physicians who are perhaps writing for the first time a prescription for a drug at a rare disease price point, a $300,000 plus drug. We have a reimbursement process, which invariably requires a prior authorization. In a number of cases, patients will need to go through appeal, not necessarily because they were Judge is not worthy. It's just that the system automatically says no, and then you go back and you educate and you can get the approval through. So these are the factors that cause the startup to be quite lumpy. The additional three months, if you will, of course, continues to put us in a stronger and stronger position in the sense that the building of that community, the more patients who are putting up their hand and wanting to go on therapy. And I'll, again, reference you back to these stories, a Mary's story you can hear, the story we heard yesterday at our all hands meeting. These are individuals who need therapy and they today, and I assume once a drug is approved, will continue to put pressure on the system to respond. So again, I'm not going to project, it's very difficult to project exactly what that means in terms of patient numbers over the first six to 12, but our confidence in where this is going and the opportunity here continues to grow. And, yeah, we'll be further along in June than we were in March or will be in March.
spk10: Great. Thanks. Thank you. Our next question comes from the line of Corinne Jenkins from Goldman Sachs. Your question, please.
spk05: Yeah, good morning. So I think that the approval in BBS in Europe is going to come relatively shortly or kind of around the same time as a lot of this market access. decisions you're talking about, but I'm curious if they apply across the multiple indications.
spk14: Sorry, whether the exemption that we got from Germany?
spk05: So, like, will market access apply to BBS once you've kind of had those conversations with payers in Europe? Does that apply to multiple indications, or will you have to go back to them once you have the approval of BBS as well?
spk14: Yeah, so Yann, the specific question is we're going through presenting the initial approval for the POMC-LEPR biallelic group, then we'll get BBS. Do you have to go back again and represent each one of these health authorities, the BBS case?
spk07: Yes, so thank you, David. Thank you for the question. Yes, indeed, we have to do that. We have already started, by the way, both from a non-medical need point of view and also a drug point of view. We started and we have...
spk14: moving forward into a filing and exhibition yeah great it's an important question is and as jan said i'll just reinforce what he just said there is i think the success we've had to date and looking forward the success we anticipate it is the early interactions and it's the relationships and jan and his team you know well over a year in advance have been working with these different health technology assessment groups and reimbursement teams within the countries so that's what allows, we'll be going there with a new indication, but not as a new company or a new set of relationships.
spk05: Okay, that's helpful. And then with respect to the BBS launch and this kind of idea of 350 identified patients, but even more potentially out there, can you help me think about how quickly you should be able to drive that patient identification and What are some of the efforts that are specifically required to help bring additional patients into that identified and diagnosed population?
spk14: So, Jennifer, maybe you could speak a little bit. So, I mean, we've highlighted a few of the things Jennifer just spoke to, including things like the testing. So, we're doing broad-based genetic screening in patients who have this history of early onset obesity. BBS is one of the clear causes or drivers of that. Secondly, we talked about the algorithmically defined, if you will, ICD-10 coding exercise where we can, as Jennifer said, that larger group, we can narrow down in that. So those are two areas which will continue to generate fresh leads. But, Jennifer, maybe you can just speak a little more about the network effects and as we reach out and how to get connected with different – and you grow from there. It's not random.
spk02: Yeah, so – I would say that there's been one to the point that David just made relating to specific opportunities for diagnosis. I think that, you know, over the years, we've made strides just in terms of becoming much more efficient in our targeted disease education efforts than we were 10 plus years ago. And so hopefully that is helping. And I will say that in terms of the various different opportunities that we have outlined in terms of how we are going about our specific disease education efforts from a field perspective. We have identified additional patients through those efforts, and they've been encouraging, which was also one of the reasons why we decided to increase our field teams as well to support these efforts and really expedite that patient identification. So I think the other aspect is, you know, once you do get physicians who are educated and suspecting, that can also have a trickle effect in terms of those physicians also being able to continue to identify additional patients along the way. So it is a trickle effect in terms of our initial education efforts as well as the sustained ability for those educated communities to be able to continue to identify patients moving forward as well.
spk14: And, Corinne, to that point, you know, as Amber said, there's a little bit of, you know, if you build it, they will come. As you mentioned earlier, you know, many patients have disengaged from the system because there's nothing there and they're tired of being told, you know, to go on a diet. Suddenly there's a therapy and they re-engage, so they come out. Second is the, as we build the community and you identify physicians who have an interest, there's a therapy, there's something to do, they decide they want to make this a little bigger part of their overall practice, that's the building they will come and that news spins to circulate through the community and they say, Dr. So-and-so has a special interest, maybe you should go see that person. And so, again, these are the networking kind of effects that as you go and they're a bit exponential, hopefully, It starts maybe a little bit slow, but as you get it going, this becomes a very important driver of the overall process.
spk02: I see that one add, and maybe going back to a question that was asked, is in terms of severity and such, I do think that it is indeed the case that people who, over time, may get disheartened because of the lack of therapeutic options. And going back to a comment that we made in an earlier call, A lot of the patients that we have within our sphere, a lot of the patients that are within the sphere of the CRIBS are younger and under 18 years of age. So there's still a lot of adults that likely have been diagnosed that are also in need of therapeutic options to be able to control and treat their disease.
spk14: And the percentage of patients in the CRIBS were under 18?
spk02: So the percentage of patients that were under 18 was 80% in the CRIPS registry.
spk14: Thank you, Jennifer. Corinne, any other questions?
spk05: I hope that's all. Thank you very much.
spk10: Thank you. As a reminder, if you have a question at this time, please press star then 1. Our next question comes in line. Tazin Ahmed from Bank of America. Your question, please.
spk04: Good morning. David, can you give a little bit more color about, you know, what you mean by, you know, the metrics will be, you know, like a rare disease launch? Now, you are an expert on rare disease launches, no doubt. But in this world, there appear to be quite a wide array of qualities of launches. So, you know, we're following an HAE launch right now that's going, you know, much better than people had expected. but we're also looking at other launches for other rare diseases, GHD, et cetera, which people are expecting to be slower. So where would you kind of comp the genetic obesity launch that you're managing and will continue to expand upon if there is to, you know, another rare disease just so that we have a better sense of what ramp expectations could look like? That's my first question. And then secondly, in a real-world setting for BBS, what would you expect the discontinuation rate to be with users? And based on your conversations with physicians, how long do you think a doctor would keep a patient on drugs before deciding if it's working or not? Thank you.
spk14: Hey, Justine, thank you, and thanks for helping organize my answer to your first part of the question. So, A, it is hard to fully or specifically define these because there's a lot of unknowns. But I think as you framed it, so HAE, hereditary angioedema disease, That's a population with existing therapies. It's been very well organized. So if you're entering into that world today, you have the benefit of coming in on the back of all the work that's been done previously. Patients are identified, what to expect from therapies there, treaters are in place. So that for sure, if you have a compelling offering, is a world where you could have a rapid uptake in a rare disease sense. Cystic fibrosis, another example of a very well-organized community. There's newborn screening. Patients are diagnosed early. There's well-established centers of excellence around the world. Again, you bring a therapy, compelling offering into that group, rapid uptake in a relative sense. The other groups you, and better or worse, I think BBS is in that other group, we're the first therapy in. And in a disease which has all of the classic elements here of you know, no attention, nothing to do about, disengagement, as Jennifer highlighted over time. And so we have to build it. So yes, we are going to be in that group. I'll give you one other example. Again, as you know, coming out of Genzyme, the lysosomal storage disease world, those were diseases that when they first launched looked more like BBS or worse. in the sense that fewer patients identified, maybe not all of the signs and symptoms that a patient with DBS has, which gives them, if you will, an advantage in getting diagnosed. And so they started slowly. Subsequent offerings that came in after that world had been built and was well-established had the potential for a much more rapid ramp. So I would... I would measure it based on sort of obviously your starting point and the degree of organization within the community. So, yes, we're in a bit more of a desert here, but in a relative sense of those that are starting fresh, I got to say, having, you know, 350 plus, and I'll put the emphasis on plus, having 350 plus patients as a starting point in U.S. only, Europe much better organized and many more to start with, that's pretty good. So I'm expecting us to do better than the others, but it's still going to be lumpy and, you know, have fits and starts of people. The second part of your question is real-world discontinuation rates here. You know, we're still getting our arms around this. Clearly not every patient responds, not every patient responds in exactly the same way. But I have to say what we're hearing over and over again is weight is not necessarily the best measure of response. And so Some patients may lose very significant amounts of weight. Other patients may not be that overweight. And we heard a story again yesterday that was told where the patient's family with just incredible discipline was managing the chloric intake. And so that patient's total weight was, they were overweight, they were obese, but clearly not as great as it might be if they lived in an unrestricted environment. That said, the hyperphasia that the child and the family were living with was devastating. And so they may not demonstrate so much change in weight from baseline because they were already so tightly controlled, but the opportunity to transform their life is equally great. So I think the hyperphasia is the variable that is in many ways going to dictate the continuation rate. We'll lose people for many different reasons, you know, again, some related to the drug, side effects, some unrelated to the drug. So I can't give you a number, but I can tell you that I am optimistic or increasingly optimistic that there's a number of factors which will cause the patient to adhere. Remember, when they go off the drug, and we've seen this in our trials where we had a randomized withdrawal in our POMC-LFR group, The hunger came back very quickly. And we've heard this anecdotally as well. And so there's a reminder that your drug was doing something. You go off, you feel it. You may want to go back on in that setting. So again, things that give me hope that we may have reasonably good compliance. Thank you.
spk10: Our next question is a follow-up from the line of Michael Higgins from Lattenburg-Dalman. Your question, please.
spk09: Thanks, guys, for the follow-up here. Just looking ahead again to data coming up in the first half where we see initial data from Phase II and MC for our patients and the hypothalamic, as well as the long-term data. Just looking for some patient numbers. Can you share that with us ahead of time? Thanks.
spk03: Yeah. So I'm sorry. So the question is about the patient numbers in each of those groups. Is that correct?
spk14: Yeah, in general. We have a number of groups reporting out there. So just... Maybe the hypothalamic obesity number, which we highlighted, and then MC4, which we haven't shared, but we can give you a general sense.
spk03: Right. So there's 18 patients in the hypothalamic obesity group. There's, as we mentioned, the long-term data from Bartlett-Beetle syndrome, and that was presented by Dr. Oz, has 19 patients at 24 months. We're all in the range of this, roughly approximately. A dozen patients plus-minus in each of these cohorts is what we're anticipating reporting later this year.
spk10: I appreciate the follow-up. Thanks, guys. Thank you. This does conclude the question-and-answer session of today's program. I'd like to hand the program back to David Meeker for any further remarks.
spk14: Great. Well, thanks to everyone, again, for tuning in and for your questions, and we look forward to updating you on our progress as we go through the year. It's going to be an exciting year. Thank you, and we'll sign off.
spk10: Thank you, ladies and gentlemen, for your participation at today's conference. This does conclude the program. You may now disconnect. Good day.
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