Q4 2021 Rhythm Pharmaceuticals Inc Earnings Call

Operator: Thank you for standing by, and welcome to the Rhythm Pharmaceuticals fourth quarter and fiscal year 2021 financial results conference call. At this time, all participants are in listen only mode.

Thank you for standing by and welcome to the rhythm Pharmaceuticals fourth quarter and 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 will need to press star one on your telephone as a reminder, today's program may be required.

Operator: 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 one 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.

I would now like to introduce your host for today's program. David currently with rhythm Pharmaceuticals. Please go ahead.

Thank you and good morning, I'm, James Connolly head of IR and corporate communications here at rhythm Pharmaceuticals span for those of you participating via conference call the accompanying slides.

David Connolly: 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.

Our available and can be controlled on the events section of the investors section of our website at IR Dot rhythm TX Dot 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.

David Connolly: As listed on slide two, 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.

As listed on slide two.

Two is our forward looking statement.

Hum.

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.

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.

David Connolly: 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 Officer is here. Linda Shapiro, our Chief Medical Officer. Yann Mazabraud, our Executive Vice President, Head of International. Hunter Smith, our Chief Financial Officer. And Jennifer Chien is also here for Q&A. She's the Executive Vice President, Head of North America.

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, Jan <unk>, Our executive Vice President and head of International Hunter Smith, Chief Financial Officer, and Jennifer Chen is also here for Q&A, She's executive Vice President head of North of <unk>.

America, and with that I'll turn the call over to David.

David Connolly: And with that, I'll turn the call over to David. 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 the 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 Bardet-Beetle syndrome. And I'll speak a little more about Mary's story in a moment.

David Meeker: And we also heard from two of the experts, Dr. Haas and Dr. Conroy, and that session gave us all, I think, a much stronger sense of both the challenges faced by individuals and families living with BBS, as well as how the experts view this community coming together and the ultimate opportunity for semelanotide. As you know, we recently heard 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.

Thank you, Dave and good morning, everybody. Thank you for tuning in this morning. So we're really pleased to report out a another strong quarter wrapping up what was an incredibly important year for rhythm and today will 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.

S launch and hopefully most of you have had a chance to review our sea or tune into our event about two weeks ago, where we heard from Mary Maurice a caregiver and mother of two children with.

Alright, it beetle syndrome, and I'll speak a little more about Mary story in a moment and we also heard from two of the experts Dr. <unk> and Dr. Conway 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 DBS as well as how the experts view this community coming together.

The ultimate opportunity for <unk>.

As you know we heard recently from the FDA requesting it.

Some additional analyses no new data was required but additional analyses all of which we felt were a good strong supportive over the overall filing and perhaps ultimately a better way of looking at the data. So no issue there, but it did come with an additional three months delay in our <unk> date, which is now set for June 16th.

David Meeker: We also indicated in our recent communication that we had made the strategic decision to remove Ahlstrom's syndromes from the file in Europe. This was based largely on a calculation that we didn't want to prolong the review in Europe, and there was a risk that engaging more around the Ahlstrom opportunity 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 a combination of BBS and Ahlstrom's made it a little more of a complicated file.

We also indicated in our recent communication that we had 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 prolonged review in Europe .

There was a risk that engaging more around the ahlstrom opportunity at that might do that also strategically I think as we look at market access opportunities Europe . It is advantageous to go into a layered way I think are going to the authorities with the combination of Bbs and <unk> made it a little more of a complicated file so again from a very strategic.

David Meeker: So again, from a very strategic standpoint, we decided to withdraw Ahlstrom's 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 Yann Mazabraud today about our international efforts, and I have come to understand, believe, and spend 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 is some of the more challenging healthcare systems in the world, and you'll hear from Yann about exciting progress in that sphere. We're also very pleased with our US commercial experience to date.

We decided to withdraw all strums at this time from our European application. There is no change to our plans for the U S.

Second we're going to you're going to hear from you on matters more today about our international and I have come.

Come to understand believes I spent time in Europe , and 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 health care systems in the world and Youll hear from John about exciting progress in that sphere.

David Meeker: 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, some 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.

We're also very pleased with our U S commercial experience to date I'll spend the one slide on that but its going as predicted and laying the foundation for our PBS launch and finally youll hear for Linda.

It takes us through a couple of different programs. Some that we're excited about.

We are progressing well, we have a number of milestones met with a number of these trials now underway and again, she will speak to that detail.

Next slide number six.

So this is a picture of.

Mary Maurice and her family are 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 Bharti <unk> syndrome, and their families face as they deal not only with obesity, but they deal with the underlying cause that.

David Meeker: 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 Bardet-Betel 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 on this as hyperphagia. This is not the hunger that you and I know. And again, when you listen to individuals who are suffering from it or living with somebody suffering from it, you begin to understand. I don't think we can fully understand if you don't experience it yourself, but you will begin to understand that this is not what you and I experience when we miss a meal.

Driven central defect, which causes the increased hunger and we focused this is hyperphagia. 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 want I experienced when we Miss a meal, we heard yesterday at our companywide meeting from a caregiver who told the story of her family and their sons challenges of living with BARDA butyl and BARDA.

David Meeker: 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 Bardet-Betel and Bardet-Betel syndrome. It wasn't, it was unique, of course, different in the sense that a 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 hyperphagia and the challenges of living with hyperphagia.

BARDA beetle syndrome. It wasn't it was unique of course different in a sense it 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 consequence, the obesity the weight gain the other <unk>.

David Meeker: The consequences, the obesity, the weight gain, the other factors, 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 in to fashion.

<unk> of course, we are 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.

David Meeker: Slide number seven just highlights again the progress or how we think about the framework for our BDS preparations. First is understanding the medical need, which I just spoke to, the importance of hyperphagia, but also the rapid weight gain, and severe obesity, which occurs early and is incurable. 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.

Slide number seven just highlights again, the progress or how we think about the frame for our Bbs preparations first is understanding the unmet medical need which I just spoke to the importance of the hyperphagia, but also the rapid weight gain as severe obesity, which crews early in incurring.

David Meeker: 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, but the amount of weight loss is important.

Back then 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 separately on Hittite I think is a targeted therapy addressing the <unk> four receptor and important four pathway, which governs hunger and energy.

<unk> expenditure.

The story is not completely in the numbers. The numbers are important 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 <unk> can change the overall picture and finally, we spoke about our preparations for launch and I feel really good about that number of US we have a.

David Meeker: The scales are important, but as you listen to the stories, you get a much better sense of how, in fact, a drug like setmelanotide can change the overall picture. And finally, we spoke about our preparations for launch, and I feel really good about that. We have a number of us.

David Meeker: We have a highly experienced team here led by Jennifer Qian 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, or 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 on the next slide, in terms of building this community and helping more and more patients come to diagnosis and, as I said, organizing the overall opportunity. So, next five, number eight.

Highly experienced team here led by Jennifer Chen and a number of people that are both she and I have worked with over the years as well.

Some new people to us who come from other deeply experienced background and thats. What it takes I think to be successful in a rare disease or 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.

So you 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 positions, where we had a strong understanding that they were carrying for individuals.

David Meeker: 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, and they were able to persist in an individual with Bartlett-Beetle syndrome. The goal of those visits was 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.

Individuals with BARDA pedal 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 is a large number of patients out there who are diagnosed today, but may not be actively engaged in that.

System, that's another opportunity.

As we've done genetic testing.

<unk> testing our current.

Panel 80 genes includes 23 genes for BARDA beetle and we know the hit rate when you do screen in individuals with a history of early onset obesity and hyperphagia four.

David Meeker: Now that doesn't mean that they will meet the diagnosis for Bartet beetle, but that does create a roadmap for somebody whose probability of having Bartet beetle may be slightly higher. And so again, falling into this suspected category. And as always, in rare diseases, 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.

BARDA beetle is on the order of one 5% of those individuals' will come back Biallelic for.

Barton beetle Jean now that doesn't mean that they will meet the diagnosis for BARDA middle but that does create a roadmap to somebody who is probability of having BARDA people may be slightly higher and so again falling in the 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 that sense.

If you can connect the docs 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.

David Meeker: 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 is they may see five to 10 different positions before somebody puts all the pieces together and says, you may have Bartet 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 so as a result, many of these patients are on this prolonged diagnostic Odyssey.

Their ability to get a diagnosis. Despite some classic parts of the presentation. They may see five to 10 different physicians before somebody puts all that together and says he may have BARDA fetal syndrome. So we feel good about the 350 plus patients we talked about the fact that the <unk> data has been pushed out by three months doesn't change anything.

David Meeker: And we'll continue those efforts and really look forward to June 16, 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 in revenues for 2021, with $1.8 million in the last quarter.

<unk> everything remains the same and we will continue those efforts and we look forward to 2016, 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 in revenues for 2021 with $1 8 million in the last quarter.

David Meeker: As, or more importantly, as we've learned, logistics are in place. Contact and interactions with payers are going well. And perhaps one of the most important things is that we bring in 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 a rare disease world that they can't always get from the healthcare system itself.

As or more importantly is what we've learned logistics are in place contact and interactions with payers is going well.

Perhaps one of the most important things as we bring up our patient services group and we have the opportunity to interact directly with patients who have consented and so 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 on what they can expect.

The onboarding as they start therapy and what they can expect from therapy and just again general support in a rare disease world that they can always get from the health care system itself.

David Meeker: And finally, on slide 10, I just want to remind you all that we announced in December our partnership with Railstone for the opportunity in China. Really excited about that. It's hard to do, maybe not so hard to do the deals.

And finally on slide 10, I just want to remind you all that we.

In December our partnership with rare stone for the opportunity in China.

Really excited about that it's hard to do.

Not so hard to do the deals I think it's hard to find the right partner and as that we've interacted over the past two months our confidence that we've got the right partner and rail stone it is growing.

David Meeker: 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. They are, and we're completely aligned from a cultural standpoint, from a philosophical standpoint. They're highly experienced, having taken a couple 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, as a result of that exercise, they will be in a position to be participants in our phase three effort, the MNA 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.

We're completely aligned from a cultural standpoint from a philosophical standpoint, they are highly experienced having taken.

Different products through the regulatory process and they are well underway with filings related to business opportunity itself and we're quite hopeful that in that exercise they will be in a position to be participants in our phase III effort emanate trials, specifically and contribute to that.

So with that I'd like to turn it over to Linda Shapiro, our CMO will take you through our regulatory and clinical update Linda great. Thank you very much David let's begin on slide 12.

Linda Shapiro: Thank you very much, David. Let's begin with slide 12. Let's begin on slide 12. So as David provided the update and the regulatory efforts relative to Bartlett-Biedelston-Johman-Alsham-Cinjum, I intend to focus on our robust clinical development efforts and demonstrate that melanatite and Rhythm's approach to rare genetic diseases of obesity is truly unique. We have known for decades that the MC-4R pathway regulates hunger, energy expenditure, and consequently body weight. And for just as long, it has been a target of biopharmaceutical companies looking to develop medications to impact it. To set Melanotite, Rhythm has shown we can do just that.

David provided update on the regulatory efforts.

Relative to part B, Nelson Chairman Al Shams and Joe.

Intend to focus on our robust clinical development efforts.

Atlanta type and rhythms approach to rare genetic diseases of obesity is truly unique.

Known for decades at the empty for our pathway regulate hunger energy expenditure and consequently body weight.

Just as long as it's been in targeted Biopharma companies.

Medications to impact it.

So Atlanta tight rhythm has shown we can do just that.

Linda Shapiro: Tetmolamatide 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, set in my appetite, we are undertaking a unique approach to obesity driven by our beliefs, which are 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.

<unk> is the first ever <unk> receptor agonist targeting the root cause of the debilitating hyperplasia and early onset severe obesity that are the hallmarks of rare genetic diseases of obesity.

In addition to our unique precision medicine, Atlanta tide, we are undertaking a unique approach to obesity driven by our belief, which is supported by decades of research.

All of the city is not the same.

Yesterday, we recognize rare disease day with an internal employee engagement.

Featuring a patient caregivers speaker, who is truly inspiring.

Along with some artwork generated took team building exercises to shine a light on rare diseases.

Importantly for the greater 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 in chronic nature of obesity as a disease as well as on weight.

Linda Shapiro: 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."

And stigma.

And Friday March for its world obesity date with this year's theme of everybody needs to act encouraging all of us to work together to ensure happier healthier longer lives for every body.

Linda Shapiro: I'm encouraging all of us to work together to ensure happier, healthier, and longer lives for everybody. With that in mind, I'd like to encourage you to check out leadforrareobicity.com, a website where the rhythm community offers educational resources, education on the importance of genetic testing, and shared stories. We welcome you to join us in leading the effort to provide education and access to treatment for the chronic disease of obesity. And with that, let's move to our clinical development program.

With that in mind I'd like to encourage you to check out lead for rare obesity dotcom website, where the rhythm community offers educational resources education on the importance of genetic testing and share stories. We welcome you to join us in leading the effort to provide education and access to treatment for rare diseases have obesity.

And with that let's move to our clinical development programs Slide 13.

Linda Shapiro: Flight 3rd. 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 announce that the first patient has been dosed in our Phase 3 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 EDS with genetic confirmation.

We are reporting updates on several clinical trials today in.

In addition to completion of enrollment in the hypothalamus 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 <unk> in Atlanta.

The stage two to less than six years with obesity due to Biallelic policy. Please just Q1 leptin receptor deficiency or with a clinical diagnosis of Bbs, but genetic confirmation.

In January .

Linda Shapiro: In January, we announced the dosing of the first patients in the Phase 2 Daybreak Clinical Trial, which is evaluating septum melanocytes for the treatment of severe obesity and hyperphasia 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 2 trial ever initiated for genetic diseases of obesity. Also in January, we announced the doses for the first patients in the Phase 3 switch trial, evaluating a once-weekly formulation of septinal amytitis in patients six years of age and older with rare genetic diseases of obesity who are currently taking the daily formulation of septinal amytitis. And we expect to initiate the Phase 3 M&A trial in the first half of 2022. We face some delays due to COVID and the overprone surge with our zero and other events. Slide 14.

We announced the dosing of the first patients in the phase II DAYBREAK clinical trial, which is evaluating <unk> for the treatment of severe obesity and hyperphagia potentially caused by genetic variant and one or more of 31 change was strong or very strong relevance to the FCC for our pathway.

They break as the most comprehensive phase II trial ever initiated rare genetic diseases have obesity.

Also in January we announced the dosing of the first patients in the phase III switch trial evaluating a once weekly formulation of central appetite six years of age and older with rare genetic diseases of obesity, who are currently taking the daily formulations separately.

And we expect to initiate the phase III emanate trial in the first half of 2022.

Faced some delays due to COVID-19 and <unk> with our CRM and other metrics.

Slide 14.

We also have quite a few data readouts coming in the next few months.

Linda Shapiro: 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 II 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 SRC-1 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.

Several patients with fr.

One deficiency or <unk> to be one deficiency advance from our exploratory phase II basket study to our open label long term extension study and we're looking forward to reporting 12 month data from those patients out of Congress. This spring.

As a reminder, last year, we presented three month data in patients with Src. One showed a mean weight reduction of seven 9% and adult responders and the BMI score reduction of 0.48 responder checker that 18 years.

Linda Shapiro: In SH2B1, adult responders achieved a mean reduction of 7.2%, and there was a mean reduction in BMIZ score of 0.25 in responders younger than 18 years. Also, we look forward to a full-sum presentation of 24-month data in patients with BARDA-Beetle syndrome.

And <unk> to be one adult responders achieved a mean reduction of seven 2% and there was a mean reduction in BMI score two five in responder chairman of 18 years.

Also we look forward to a fulsome presentation, a 24 month data in patients as part of <unk> syndrome.

Linda Shapiro: Dr. Bob Haas presented a preview of the BBS data last month with data from 19 patients at 24 months, showing a mean reduction of body mass index from a pivotal trial baseline of 14.3% [inaudible] immune reduction and body weight for pivotal trial baseline among six patients 18 years of age or older, 14.9%, and a mean reduction in BMIZ score from a typical trial baseline among 12 patients younger than 18 years of 0.7 We're also looking forward to presenting two-year data from patients with biallelic POMC, PCSK1, or leptin receptor deficiency obesity.

Dr. Bob has presented a preview of the Bbs data last month with data from 19 patients at 24 months, showing a mean reduction of body mass index pivotal trial baseline of 14, 3%.

I mean reduction in body weight for pivotal trial baseline among six patients 18 years of age or older a 14, 9%.

And a mean reduction in BMI squirt pivotal trial baseline amongst 12 patients younger than 18 years of zero seven Q.

We're also looking forward to presenting two year data for patients with <unk> or leptin receptor.

The city.

Linda Shapiro: And importantly, we expect these data to continue to build the case for the long-term therapeutic value of settinal antitide. As with the long-term data we've presented to date, we have consistently shown that settinal antitide achieves sustained meaningful effect. This is the first time we've ever seen a settinal antitide that achieved a sustained meaningful effect. Michael Michael Higgins, David Connolly, David Connolly, David Connolly. Now, let's turn to hypothermia.

Importantly, we expect these savings to continue to build the case for long term therapeutic value set in Atlanta.

As long term data, we presented to date have shelf consistently set melanocyte achieve sustained meaningful.

Slide 15.

Now, let's turn to the hypothalamus obesity.

Hypothalamic obesity is a rare acquired form of obesity that develops following injury to the Hypothermic region of the brain that control that contained the emcee for our pathway neurons and are responsible for controlling physiological functions, such as hunger and weight regulations.

Linda Shapiro: 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 is responsible for controlling physiological functions such as hunger and weight regulation.

I plan on obesity, most frequently follows it department of a cranial frenchie elma a rare brain tumor.

Linda Shapiro: I plan my obesity most frequently follows the development of a cranial fringyoma, a rare brain tumor, or its treatment by surgical removal or radiation. Approximately half of patients with craniopharyngioma experience rapid weight gain and insatiable hunger in the first six 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.

Treatment by surgical removal or radiation.

Approximately half of patients with cranial fringes experienced rapid weight gain and insatiable hunger in the first six to 12 months following tumor resection and ultimately develop severe obesity.

Our clinical and preclinical evidence, suggesting apparent efficacy for a deficiency in these patients the impact of the injuries the hypothalamus and its effect on the FC receptor itself remain difficult to ascertain.

Linda Shapiro: Currently, therapeutic options are very limited for patients with high blood macabre, Slide 16. Today we announce that we have completed enrollment in our Phase 2 Open Label Proof-of-Concept Study evaluating set melanocytes in individuals with hypoallergenic obesity. We enrolled 18 patients older than six years in this study. The trial consists of 16 weeks of treatment with step melanotide administered once daily by subcutaneous injection, including an initial dose titration

<unk> therapeutic options are very limited for patients with type of IMAX obesity.

Slide 16.

Today, we announced that we completed.

In our phase two open label proof of concept study evaluating certain Atlanta tied in individuals with high planets obesity.

Enrolled 18 patients older than six years of the study.

The trial consists of 16 weeks of treatment with certain Atlanta types administered once daily by subcutaneous injection, including an initial dose titration period.

Linda Shapiro: The primary endpoint is to report patients with a 5% or greater reduction in DMI from baseline after 16 weeks of settlement and Tai Chi, 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 hypoglycemic 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.

The primary endpoint is the proportion of patients with 5% or greater reduction in BMI from baseline. After 16 weeks of several amitai chicken compared to a historic control of less than 5% of this patient population.

We are fortunate to have one of the country's leading key opinion leaders pipeline like obesity is a principal investigator for this trial and Dr. Christian Ross Endocrine Division of Seattle Children's Hospital.

We're looking forward to sharing preliminary data from this trial in the middle of this year.

Linda Shapiro: And with that, I'll turn the call over to Yann for an update on InterFASHION. 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.

And with that I'll turn the call over to John .

International.

Thank you Linda and good morning, everyone.

Most of you know it is crucial to be in Europe and in key international markets to build a successful already this company.

Yann Mazabraud: Over the last 18 months, we've made a lot of progress building out our international organization. We are now 20 people, with most of the positions being across EU4 plus the United Kingdom, and also four positions in four other key regions of the 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 local payers and providing operational support for RHYSM, a robust clinical operation, as Linda just described for you.

Over the last 18 months, we've made a lot of progress building out our international recommendation.

20 people with most of the position being across you for Chris.

The United Kingdom, and also full positioning for key regions or country.

To ensure namely the Netherlands, the Nordics jerky in Argentina.

We are highly skilled and very engaged team working closely with the mainland Europe and centers of excellence and <unk> networks to increase disease awareness and drive diagnoses.

We can partner partnering with a local deals and providing operational support for rhythm 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.

Yann Mazabraud: Before I talk to you about our market access highlights, I want to say a few words about the European realities on Cape and how both the patients we serve and rhythm will benefit from them. In the last 20 years, I've had the privilege of launching and commercializing more than 10 types of these drugs in Europe, in Latin America, and in the US, and the European Rare Disease Ecosystem is by far better organized than any of the others.

Most of the patients we serve and rhythm 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 ease of use and.

In the European in the rare disease ecosystem as they felt better organized than any of your sales.

Yann Mazabraud: More than 20 years ago, European countries began a very well-structured approach to rare diseases, beginning with national plans with dedicated budgets and national centers of excellence, leading to better diagnosis and care for patients with rare diseases.

More than 20 years ago European countries began a very well structured approach to rare diseases, beginning with rare disease national brands with dedicated budget and national centers of excellence, leading to bit of diagnoses and care for patients with rare disease.

Yann Mazabraud: Then we saw the advent of European rare disease networks, ultimately leading to increased expertise and diagnosis acceleration. Specifically, for 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 Rhythm, there were already patients with rare genetic disorders of obesity diagnosed.

Then we saw the advent of the European rare these networks ultimately leading to increased expertise and diagnoses acceleration.

Specifically for the rare genetic disorder of the facility. We are extremely lucky as a company to leverage more than 30 years of research and clinical excellence in many large university hospitals in.

Most important European cities.

Yann Mazabraud: It has accelerated and increased. It restarted our mainly clinical trials back in 2014. And there are now more than 100 patients diagnosed with spiraledic compsy, PCS-K1, all the part-efficiency obesity being cared for, sorry, European centers' effects. And there are now more than 100 patients diagnosed with spiraledic compsy, PCS-K1. Another example in France, where the French H.S.

Before first before rhythm that we're already patients we array of genetic disorder with the TCE diagnosed it has accelerated and increased since we started our mainly clinical trials back in 2014, and John that will more than the 100 patients diagnosed with spy elite Chlumsky pieces Q1, only power deficiency obesity being careful.

So aynsley European centers of excellence.

Yann Mazabraud: and the National Reference Center for Rear Genetic Diseases of Obesity introduced last summer formal guidelines for the diagnosis and management of patients with reargenetic diseases of a baby. Next slide. As you can see on this timeline, we've made tremendous progress in the international market since Q3 2020, from submitting the Market Authorization Application for MCR in Palm CPCs K1 and Leapar in July 2020, followed by the European and United Kingdom Authorization in July and September 2021. We have been very busy. We 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.

Onboarding trends will differentiate <unk> and the national referral center for rare genetic disease of obesity introduced last summer formal guidelines for the diagnosis and management efficient to be the rail genetic diseases.

Next slide.

As you can see on this timeline, we've made tremendous progress in the international markets since Q3 2020 <unk>.

Submitting our market authorization application for <unk> in July 2020, followed by the European and United Kingdom authorization in July and September 2020, what we have been very busy we are.

Engage very early.

Most importantly, Europe NH T bodies.

Without getting it up as the number one key success factors in terms of market exits and today I'm happy to report many significant 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.

Yann Mazabraud: And today, I'm happy to report many significant successes across Europe, and more importantly, first commercial sales, which are expected in Germany and France in the second quarter of this year. Next slide. And just before I give you some details about these two countries, I am proud to say that there is genuine excitement about Syria in Europe.

Next slide.

Yann Mazabraud: And along this line, I'm very proud to report that in Syria has been highlighted two weeks ago in the EME's 2021 edition of its Human Medicines Highlight and listed as one of the eighth drugs with another from the in contribution to health within a total of 92 positive opinions, 20 last year. Next slide: Germany.

And just before to give you. Some details about these two countries I am proud to say that there is a genuine excitement about into Europe and along this line I'm very proud to report that <unk> has been highlighted two weeks ago.

As 2021 edition of its human medicines daylight and listed as one of the eight drug with another <unk> <unk> contribution to <unk> within a total of 92 positive opinions 20 last year.

Next slide.

Kevin.

Yann Mazabraud: So Germany is, as you know, the largest and most important country in Europe from a health care business point of view. In Germany, drugs classified as lifestyle drugs, which include those designed to affect weight loss, smoking cessation, and air loss, are not eligible for reimbursement. Today, we are excited to announce that the German Federal Joint Committee, or GBA, excluded MCV from its lifestyle drug for POMC, PCSK1, or lipart deficiency obesity. This first-ever exclusion marks an important recognition that IMS-CRE is designed to treat rare genetic diseases that manifest as obesity, and that this group of diseases is distinct from general obesity.

So Germany as you know is the largest and most important country in Europe on the healthcare business point of view in Germany drugs classified as lifestyle drugs, which includes those designed to affect weightloss smoking cessation airless I'm not eligible for reimbursement today, we're excited to announce that the German federal joint Committee or <unk>.

Excluding <unk> from the lifestyle group.

<unk> Q1 <unk>.

First extrusion marks an important recognition that <unk> is designed to treat rare genetic disease that manifests as obesity and at these group of disease.

Tom Generics.

With the exemption status instead, we will now be eligible for national coverage and reimbursement and we are looking forward to first commercial sales in Germany in the second quarter of 2020.

Yann Mazabraud: With this exemption status, IMSTIVRI will now be eligible for national coverage and reimbursement, and we are looking forward to the first commercial sales in Germany in the second quarter of 2020. Next slide. Friends now, last month, on the 19th of January, five weeks ago, the French Autotority Centre, or H.S.

Next slide.

Yann Mazabraud: Granted, paid the early access for inquiry for patients with POMC, P.S. K1, or LiPAR, deficient services, which means that any obesity specialist in France can now prescribe for genetically confirmed POMC-PCSK1 early partitions six years and above. This is a very strong recognition of the important medical leaders, on the value of Steadman and Tide, but also a testament to strong support coming from zero-visitry and rare genetic-visitry communities on KOL, which we enjoy in-friends This is a very very strong recognition of the important medical leaders, on the value of Steadman and Tide, but also a testament to strong support coming from zero-visitry and rare genetic-visitry communities on KOL, which we enjoy in-friends, Next slide.

French, though less troop last months on the.

The 19th of January until a few weeks ago. The French auto. It is something that is granted paid early access for <unk> for patients with <unk>, Alibaba efficient yogurt and cheese.

Which means that any obesity specialists influence got no prescribed for gender diversity.

We can confirm <unk> alibaba patients six years on the goals.

This is a very strong recognition of the important medical need it on the value of shipment on Titan, but also a testament to strong support coming from <unk> on the rail option if he could be your communities.

Which we enjoy and trips.

Next slide.

We will have more pending commercial stays to report in the coming months in 2021 were submitted to the <unk> Q1, only power investments do see Q4, President United Kingdom prison, Netherlands, plus Israel.

Yann Mazabraud: We will have more pending commercial sales to report in the coming months. In 2021, we submitted the POMC PCSK1 hourly power reimbursement dossier in EU4, plus the United Kingdom, plus the Netherlands, plus Israel. And we have already started to work on the next filing for Barley Vidal Syndrome. You've just heard about Germany and France, with feedback from Spain and Italy being 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 our own time for our market access plan.

And we have already started to walk into an exciting for bodybuilders syndrome.

You've just heard about Germany, and France initial feedbacks from Spain and Italy.

Positive and in the UK. Following the selection that is highly specialized technology, which is basically a very high bar to reach we've had so far very positive interactions with nice and the on time for our market access platform.

Next slide.

Yann Mazabraud: Next slide. Last but not least, a few words about the Barley-Biddle syndrome indication in Europe. We are expecting a CHP approval in the second semester of this year. The estimated European prevalence is 2,500 patients.

Last but not least of <unk> <unk>.

Syndrome indication in Europe , we are expecting to see it should be up hole in the signaling some it's still true.

He estimated European Provolone cheese, 2500 patients and Hello, again, a lot of patients already diagnosed with.

More than 1500 actually.

Yann Mazabraud: And here again, there are a lot of patients already diagnosed with the disease, more than 1,500 actually. I see. I would like to say that we are in a very good place in the most important European countries while opening your horizons in other 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 2021 financial results.

FCA, we'd like to see that we are in a very good place seems the most important European countries, while opening new horizons.

Key countries around the globe.

License of <unk> and <unk>.

Lucas.

I would like to turn the call over to until after a review of fourth quarter.

Full year 2021 financial results. Thank.

Yann Mazabraud: Thank you, Yann. Turning to slide 26. As David mentioned at the start of the call, we're 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 revenue, 3.2 million. All revenue came from sales of MCIVRI in the United States; there were no revenues during the comparable period of 2020.

Thank you Jan.

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 them separately in the United States. There were no revenues during the comparable period of 2020.

Loss from operations was $59 million in the quarter, an increase of $15 million over the comparable quarter of 2020.

Yann Mazabraud: Laws from Operations with $50.9 million in the quarter, an increase of $15 million over the comparable quarter of 2020. For the full year, 2021, the loss from operations was $170.1 million, an increase of $33.5 million over the prior year.

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 head count across our research and development commercial and G&A functions.

Hunter Smith: 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 delivery launch in BBS and ongoing efforts across Europe. Our share count was 50.3 million basic and diluted shares, and the common loss for a share was 85 cents and increased to 6 cents over the fourth quarter of 2020. And for the full year, our share count was 49.6 million basic and diluted shares, and the loss for the common share was $1.40, a decrease of 1.64 over the full year 2020.

We expect our operating expenses to continue to increase during 2022 due to costs associated with our expanding clinical development efforts as well as commercial commercialization activities related to potential <unk> launch in Bbs and ongoing efforts across Europe .

Our share count was $50 3 million basic and diluted shares in carbon loss per share was <unk> 85.

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 one six for over the full year 2020.

We concluded the year in a strong financial position with cash cash equivalents and short term investments of $295 million, which.

David Meeker: We concluded the year in a strong financial position with cash, 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 closing remarks. Thank you.

Which we believe will be sufficient to fund rhythms operations into the second half of 2023.

And now ill turn the call back over to David for concluding remarks. Thank you.

Great. Thank you Hunter. So I hope what you are taking away from this initial part of the presentation is that we feel great about 2021, but we're even more excited as we look ahead to 2022 number of milestones Linda took its through some that have already been achieved with the initiation of a number of these trials.

David Meeker: 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. On the number of milestones, Linda took us through some that have already been achieved with the initiation of a number of these trials. We're looking forward to some additional data readouts, which again, we're 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?

We're looking forward to some additional data readouts, which again, it's obviously.

Not in a position to predict but but these are exciting questions. How will we do on a hypothermic obesity world or in <unk> four receptor deficiency world. So again, when we look forward to reporting out those results from those studies.

David Meeker: So again, we look forward to reporting those results from those studies around the mid-year. And 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 launch. And finally, the BBS world, as we've highlighted and will continue to highlight, this remains an incredibly strong focus for Rhythm.

<unk>.

Year also we will have the long term data that we'll continue to roll forward as we collect more data on those patients with biallelic deficiencies.

<unk> variance and those patients who we have studied in our existing ongoing basket study.

We rolled into the long term extension.

And finally, the Bbs World as we've highlighted we 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.

David Meeker: It's extremely important that we get this right. There is a great 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. Certainly, ladies and gentlemen, if you do have a question at this time, please press star, then one. If your question is answered, and you'd like to remove yourself from the queue, please press the pound key.

Certainly ladies and gentlemen, if you do have a question at this time. Please press Star then one 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 Cowen and company. Your question. Please.

Operator: Our first question comes from the line of Philip Nadeau from Cowan & Company. Your question, please. Good morning.

Good morning, Thanks for taking my question and congratulations on the progress first question.

Philip Nadeau: 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 Hensovery? Great. Yeah, thanks, Joe. So, Jennifer Chien is joining us.

Can you discuss a bit more detail what you can do between now and the June <unk> to identify patients and.

And physicians, who could be amenable to considering.

Yes, thanks, Phil.

Jennifer Gennum is joining us.

Thanks for the question.

Jennifer Chien: Thanks for the question. You know, although we were disappointed just in terms of the news of the delay, it would say that a lot of the work that we are doing right now 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 are already within our sphere already through the work that was done by our field teams and MSLs on the ground. That work is ongoing.

Although we were disappointed just in tariffs.

So the delay I would say that a lot of the work that we are doing right now.

Our profile would be similar just in terms of the engagement that we are.

Duane correctly so.

As David mentioned, there are various different areas.

We have opportunities and trends.

One validated.

The number of <unk>.

Patients that were within our sphere already through the work that was done by our sales teams and Msos.

<unk>.

That work is ongoing in addition, there are several other opportunities in terms of.

One really fine.

Finding the Bbs patients that have already been diagnosed and are.

In the system and we have very targeted ways to go about that activity.

<unk> been finding and digesting and expediting the diagnosis of patients yet have not.

Not yet found the diagnosis so a lot of those activities and engagement with physicians are ongoing.

We will also support our next 12 months I think that's all right.

That's very helpful.

Great.

Oh no sorry.

No no I was just going to building that referring you back to.

David Meeker: Oh, no. No, no. I was just going to build on that, referring you back to Jennifer and the team who 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 the rare disease world, this never stops. You continue. You don't saturate a market in the sense you don't reach full penetration ever. I think it's an endless journey of continuing to increase awareness. These activities will, over time, continue to bear fruit. So, I'm sorry.

Jennifer and the team took everybody through it in a little more detail of the different tools that they're using which included our genetic screening.

And exercise working with like QVC on ICD, 10 coding and Algorithmically defining so theres a number of things that can that we can do them in a rare disease world.

This never stops.

You continue you don't you don't saturate a market in a sense you don't reach full penetration ever I think it's it's an endless journey.

Increase awareness.

These activities will over time continue to bear fruit, so I'm sorry, Phil.

Philip Nadeau: Thank you. Perfect, that's very helpful. Second question concerns the phase two 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?

Perfect that's very helpful.

Second question is on the phase two data in hypothalamic obesity can you discuss a bit what would be considered a proof of concept there how much weight loss versus changes in hyperphagia would you need to see to progress development.

Okay Linda.

Philip Nadeau: Thank you. Sure. Thank you for that question. So, similar to our other programs, demonstrating a clinically healing full improvement in and weighed body mass index or BMISD score would be adequate to demonstrate that proof of concept. And that's the way we've designed the trial and set up the practice. Perfect. That's helpful. And then my last question is about Germany.

Sure. Thank you for that question.

Similar to our other programs are demonstrating a clinically meaningful improvement in and weight, our body mass index or BMI discard.

Would be adequate to demonstrate that.

And that's why we've designed the trial and set up the prime rate.

Perfect. That's helpful. And then last question is on Germany.

Philip Nadeau: I think in the press release 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?

The press release, you mentioned that the exclusion from the Quipster list is.

Is it one year exclusion.

Did I interpret that correctly and if so does that decision has to be revisited every year or is there a point at which it becomes a final decision that is.

Yann Mazabraud: Or is there a point at which it becomes a final decision that is, It is perpetual. No, thank you. No, no, it's not a one-year exclusion. It's an exclusion for life. So we'll end this exclusion for the next 100 years. Perfect. Thanks for taking our questions. Thank you. Our next question comes from the line of Derek Archila from Wells Fargo. Your question, please. Hi, this is Adam on behalf of Derek.

That is perpetual.

Thank you and I know, it's not the one extrusion extrusion fall for life.

So we will introduce exclusions for the next two hundreds of vehicles.

Perfect. Thanks for taking our questions.

Thank you. Our next question comes from the line of Derek <unk> from Wells Fargo. Your question. Please.

Derek Archila: Thank you for taking our questions. I have just a few for you this morning. Do you believe the FDA requested additional analysis because they are questioning the efficacy of barbedo? Or is it a moral labeling consideration?

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 our middle or is it more of a labeling consideration and is there a possibility that FDA could complete their review before June .

Yes, Thanks Adam.

Derek Archila: And is there a possibility that the FDA could complete their review before June? Thanks, Adam. So, just to clarify that, what the FDA requested was analysis that was 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.

Just to clarify on that so but the FDA requested was.

Analysis, which were not part of our pre specified endpoint. So when we put the final and we put it in is of course you always do is based on your statistical analysis plan and your protocol and they came back and asked for some which specifically had to do.

David Meeker: 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, who were between 12 and 18. And so that group's still growing. And so, weight, in that case, was confounding.

Largely around analyzing the data by less than 18 in greater than 18, our primary endpoint to analyze the group of patients is 12 and above and of course. This introduced a confounding variable that those patients of which there were a number almost half of the primary analysis group or <unk>.

<unk> 12 in 2018, and so that group still growing in some ways in that case was compounding. So I think what they ask for we are fully supportive of is how we've talked about the data, but these were not pre specified so no I don't think it introduces.

David Meeker: So, I think what they asked for, we're 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 made sense, in terms of their ability to complete it at an earlier time point.

Risk if you will to the overall approval, but I do think the request that made sense in terms of their ability to complete it in an earlier time point.

David Meeker: 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. Sure, that makes sense, and then, related to my last question, how large is that amended data package? Thank you. That's a good question. In reality, it was over 300 pages.

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 final in front of them and so we have little expectation that we're going to get an.

An approval in advance of the pre specified the June 16th.

Sure that makes sense and then I suppose related to my last question, how large is that amended data package.

David Meeker: It was 100 plus data outputs of cutting the data, as David mentioned, across the age groups, also across genders, looking at weight, BMI, BMI, D-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 that no matter how we cut the data or looked at it, it was all supportive of the same thing.

Thank you that's a good question.

In reality it was over 300 pages.

Grid plus data output cutting the data as David mentioned across the age groups also cross gender with looking at weight BMI BMI at each store.

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.

Three months to review it.

Very encouraging news is no matter, how we cut the data I've looked at it. It was all supportive of the same thing. So there wasn't a subgroup by any of those cuts were set <unk> 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 those data.

The real question.

Okay, well I'll tell you. Thank you very much.

Thank you. Our next question comes from the line of Joseph Sprint from Needham <unk> Company. Your question. Please.

Derek Archila: Thank you. Our next question comes from the line of Joseph Stringer from Needham & Company. Your question, please. Hi, good morning. Thanks for taking our questions. Two from us. One, just given the reason, you know, request from F8 on BBS and all strums.

Hi, good morning, Thanks for taking my questions two from us.

John just given the recent.

Requests from FDA on Bds and Ahlstrom, just curious if thats changed your thinking or.

The design of the eminent phase III M&A trial.

Any way just in terms of.

Data analysis, there and secondly.

The diagnosed Bbs patients who may not be.

And the system more.

<unk> identified at an academic or.

Medical Center.

How what's the.

The reasons for it.

Why these diagnosed Bbs patients are not sort of part of the system is it just that there.

You'll have a less severe phenotype.

Or are these are sort of older patients that have kind of.

Going to sort of live with live with the disease.

Just make up a significant portion of the Bbs pop.

Population.

More specifically what are the specifics around it.

Catherine these potential.

Potential patients thanks for taking my questions.

Yeah. Thanks, Joe So Jennifer will 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 all storms, we analyze them together and as I explained we.

The.

The age greater than 12 issue. So they were very specific to the existing file so no change there.

Jennifer.

So.

David Meeker: So on the second question, I just wanted to make a maybe 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 also may be patients that are diagnosed that may not be visible to the company. So for us, that's where it really lies because we have had field teams on the ground really educating different physicians and interacting with them and also trying to understand if they do have a BBS patient on hand.

The second question I, just wanted to make maybe a clarifying point I think.

Similar to many different diseases.

Certainly a large pool of patients that have not yet.

Intuit diagnosis, but there also may be patients that are diagnosed right.

The principle to the company so for us that's where it really lies because we have had guilty background really educating different positions and interacting with them and also try to understand it.

Do you have ibs patients.

However.

David Meeker: However, through those efforts, they may not have gotten to all of the physicians who have BBS patients on hand, because our efforts were focused initially on BCV 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, and the ability to use different claims to try to identify HCPs 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.

And they may not have gotten to all of the physicians to have Bbs patient that had because our efforts were.

Our focus initially on.

BCB specialists or Pete on dose and dose and some of these patients may be on that.

Other specialties, including Pvp and GP that's Wow.

The mechanism, though one of the mechanisms that we are using different terms to try to identify those additional.

Ah patients, although theres not a specific Bbs ICD 10 code.

And there is a code where Bbs is one of several.

And.

The ability to use different claims to try to identify HCP is that more likely has a bbs patients because sometimes there's one targeted way of really going at that and trying to educate the right physician and interact with them and then once again trying to understand if they happen.

Diagnosed patients under their care.

David Meeker: And maybe Jennifer just came in when the 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? Yeah, so I think that it could, but it does not necessarily mean that they're less severe.

And maybe 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 theyre just equally severe an unrecognized.

So I think that it does not necessarily mean that they're less severe.

I think that they can.

As different diseases, where there are no therapeutic options.

They have been more persistent in terms of trying to identify the appropriate options in terms of managing their care, but over time as Theyre <unk>.

If that physician to physician and realized that there isn't anything in fact that they may have.

There have been less persistent because just no therapeutic options.

The potential availability of a therapy like in February and May.

I'll now provide our hope in terms of engagement and opportunity perspective.

Thanks Victor.

Joseph Stringer: Thanks for the question. Thank you. Our next question comes from the line of Michael Higgins from Lindenburg, Thurman. Your question, please. Thanks, operator. Good morning, guys.

Thanks, Joe next question.

Thank you. Our next question comes from the line of Michael Higgins from Ladenburg Thalmann. 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 mid year.

Michael Higgins: Thanks for taking some questions this morning. My question, I guess, questions, I guess, are really focused on the upcoming data here before midyear. And hypothalamic obesity, it's not genetically driven.

Michael Higgins: So the outcomes that you're expecting, would these be different from the previous data sets that you have had before, maybe in terms of hyperphagia or weight loss? Thanks.

And I put them called DCD.

Not genetically driven so the outcomes that you're expecting.

Would these be different from the previous datasets that you had before maybe terms of hyperphagia or weight loss.

Great Linda.

Linda Shapiro: 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 are actually similar, even though the etiology is different. So we are looking at the changes that weight and change the hunker scores similarly and would anticipate a similar act of some landed animals tied into the patient. So we are looking at the changes that weight and change the hunker scores similarly and would anticipate a similar act of some landed animals tied into the patient.

Thank you that's a great question. So you are correct, although the.

The etiology is not genetic it's acquired.

Presentation is similar so the outcomes actually are similar even though the etiology is different. So we are looking at the changes in wait until the second verse force Similarly, and would anticipate a similar set.

So atlanta tied into patient populations.

Okay and a couple of quick close from that if you would.

Linda Shapiro: Okay, and a couple quick follow-ups from that. If you could review for us again the control arm, I believe you mentioned historic controls, what you're expecting for that, and then related to the number of patients we may be seeing in that study. Sure. So, in the study, we have 18 patients who've been enrolled. It's an open-label treatment arm, so the control is a historical control, and it's based on data from patients who gain weight year over year after having the treatment for their craniopharyngioma or whatever tumor, and therefore, the resultant hypoglycemic obesity.

Could review for US again, the control arm.

Believe you had mentioned historic controls what youre expecting for that and then.

Relatedly to hear the number of patients that we may be seeing in that study.

Sure. So in this study we have 18 patients have been enrolled.

The open label treatment arm. So that control is a historic control and this is based on data of patients who gain weight.

Year over year after having the treatment for their the cranial French guiana or whatever tumor.

Linda Shapiro: Many of these patients have been tracked very closely since the diagnosis of their tumor and their treatment, and so we have their natural history on them, and then the interventions that Melana tied in, and we're looking at the change in that trajectory curve as well as the absolute change in the treatment period. So am I hearing their control is, is this kind of self-control based on their natural, their own natural history, not in the group of hypothalamic obesity patients? No, no; that's just an additional layer.

For the first of all tech pipeline with obesity.

Any of these patients have been tracked very closely since the diagnosis of their tumor in their treatment and so we have natural history on them and then the intervention set in Atlanta.

Looking at the change in that trajectory curve as well as the absolute change of the treatment period.

So am I hearing their controllers.

So because this is kind of a self control.

Based on their natural their own natural history, and the group of high profile, Mike obesity patients.

No no. That's just an additional layer so that the historic control.

Linda Shapiro: So the historical control is beyond these patients, but we are able to get an additional layer up to the individuals as well. I appreciate it. I think it's worth, maybe just want to comment, it's worth adding that.

That we are able to get an additional layer to the individuals as well.

I appreciate it Mike.

Maybe just wanted to kind of it's worth adding that.

David Meeker: This is, it's acquired, as Linda said, and it's a much better organized, defined community. And so there is more information out there in that sense. And there are many big unmet medical needs, again, as you can see to look into that as we obviously are doing. And a number of things have been tried, none with really significant medical effects.

This is it's acquired as Linda said and as a result, it's much better organized to find community and so there is more information out there in that sense and there's been a number of big unmet medical need again as you look into that as we obviously are doing.

A number of things have been tried none with.

Really significant medical effect here, so and large unmet medical need we will see how we do here, but this is clearly a group that's presenting with.

David Meeker: So in a large, unmet medical need, we'll see how we do here. But this is clearly Sending With Me an impairment in this pathway, consistent presentation, and so, therefore, the hope that a drug like setinelanotype will help. Next question. Our next question comes from the line of Jeff Hung from Morgan Stanley. Your question, please. Hey, thanks for taking the questions.

Clearly impairment in this pathway consistent presentation and so therefore, the hope thats a drug like setting Atlanta type can make it there.

Next question.

Our next question comes from the line of Jeff Hung from Morgan Stanley . Your question. Please.

Thanks for taking the questions.

Jeff Hung: Of the over 350 BDS patients that Rhythm has identified, how many of them are in CRIBS? And then I have a follow-up question for the Children's. So the 350 patients that have been identified have really been through the Rhythm-specific efforts. We, at this point in time, do not know or have access to the physicians or patients that are in the crib's registry, so I wouldn't be able to outline how much overlap there is between Chris versus the patients that we have identified.

Of the over 350 Bbs patients that rhythm has identified how many of them are in the Cribbs registry and then I have a follow up.

Jennifer.

So the 350 patients have been identified has really been through the rhythm specific efforts.

We at this point of time do you not know or have access to the physicians have patients that are in the credit spreads history, so I wouldn't be able to outline.

How much overlap there is between credits versus the patients that we have identified.

Okay understood.

Jennifer Chien: Okay, understood. And then in the past, you've talked about the potential launch of DBS 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 in DBS? You know, are there any constraints or gating factors why they can't all be treated in a relatively short time? Thanks. Yeah, Jeff, I think you're taking those comments from comments I've made in a number of different conversations. I wouldn't necessarily characterize it as a slow ramp,

And then in the past you've talked about the potential launch in DBS is a essentially 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 and DBS are there any constraints or gating factors on why they can't all be treated in relatively short order.

Yes, Jeff I think you are taking those comments from comments I've made a number of different conversations I wouldn't characterize it necessarily as a slow ramp I'd characterize the disease.

David Meeker: I'd characterize it as a characteristic rare disease ramp. And by that, I just mean that if you have a well-organized community, a 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 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.

Characteristic rare disease ramp and by that I, just mean that if you are a well organized community large indication you write a script and somebody goes to our local Cvs and picks it up but that's a very different setting in the world that we live in.

Need to get the whole system working as I pointed out we have positions who are perhaps writing for the first time, a prescription for a drug at a rare disease price point of $300000 plus drug we have a reimbursement process, which invariably requires a prior authorization and the number of cases.

David Meeker: We have a reimbursement process, which invariably requires prior authorization. In a number of cases, patients will need to go through appeals, not necessarily because they were judged as 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.

<unk> will need to go through appeal not necessarily because they were judged is not worthy. It's just that the system automatically says no and then you go back and you educate and get the approval through so these are the factors that caused the startup to be quite lumpy.

The additional three months.

David Meeker: The additional three months, if you will, continue 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 hands and wanting to go on therapy. And I'll again, refer you back to these stories, Mary's story, and you can hear the story we heard yesterday at our All Hands meeting. These are individuals who need therapy, and they, today.

You will of course continues to put us in a stronger and stronger position in the sense that the building of that community to more patients who are putting up their hand and wanting to go on therapy again reference you back to these stories of marriage story you can hear the story, we heard yesterday at our all hands meeting these are individuals who need therapy.

Today.

David Meeker: I assume once the drug is approved, we'll 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 6 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. Thank you. Our next question comes from Corinne Jenkins from Goldman Sachs. Your question, please. T.Y.

Two once the drug is approved we'll continue to put pressure on the system to respond so I'm not going to project its 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 yes. We will be further along in June than we were in March or will be a much.

Great. Thanks.

Thank you. Our next question comes from the line of Corinne Jenkins from Goldman Sachs. Your question. Please.

Yeah. Good morning, So I think that would be.

Corinne Jenkins: Good morning. So I think that the approval for BBS in Europe is going to come relatively shortly, around the same time as a lot of vision market access decisions you're talking about, but I'm curious if they apply across the multiple indications. Sorry, but does the exemption that we got from Germany apply?

Approval in <unk> in Europe is going to come relatively shortly.

Around the same time, there's a lot of good market access decisions youre talking about but I'm curious if they apply across multiple indications.

Alright, whether the exemption that we got from Germany.

Corinne Jenkins: No, so, like, well, 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 for BBS as well?

Well, we'll market our class of why the Bbs once you've made kind of had this conversations with payers in Europe does that apply to most of obligations or will you have to get back to that once you have the approval of DBS as well.

Yann Mazabraud: Yeah, so Yann, so the specific question is, we're going through presenting the initial approval for the POM-CLEP-R biallelic group, then we'll get BBS, do you have to go back again and represent each one of these health authorities, the BBS? Yes, so thank you, David. And thank you for the question. Yes, indeed, we have to do that. We have already started, by the way, both from a known medical need point of view and also from a growth point of view. We've started, and we are moving forward into filing, and it should be, Great. It's an important question.

Yeah. So.

The specific question is we're going through presenting the initial approval for the pumps. The left bar 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.

Thank you, maybe if I could.

Another question, yes, Indeed, we have to do that we have already started by the way.

The boost from the.

And then medicine equal need point of view and a slew of drug windows.

We have started and we are now.

Now moving forward into a filing an IND submission.

David Meeker: And as Yann 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 relationships. And Yann 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 country. So that's what allows us to go there with a new indication, but not as a new company or a new set of relationships. That's helpful.

Granted it's an important question and as John 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 in Jan and his team.

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.

Okay. That's helpful and then with respect to the Bbs launch in this kind of idea of 350 identified patients even more potentially out there.

Corinne Jenkins: And then with respect to the BBS launch and this kind of idea of 350 identified patients but even more potentially out there, just, 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? So, Jennifer, maybe you could speak a little bit.

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 and you've got identified and diagnosed population.

So Jennifer maybe you could speak a little bit so.

David Meeker: So, I mean, we've highlighted a few of the things Jennifer just spoke about, including things like testing. So, we're doing broad-based genetic screening in patients who have this history of early-onset obesity because BBS is one of the clear causes or drivers of that.

Highlighted a few of the things San Francis spoke to them, including things like the testing. So we're doing broad based genetic screening in patients who have this history of early onset obesity CBS is one of the clear causes or drivers of that secondly, we've talked about the algorithmic Lee.

David Meeker: 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 it 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 how we reach out and how to get connected with different people, and you grow from there. You know, it's not random.

Did you find if you will ICD 10 coding exercise, where we can 7% of that larger group, we can narrow down and that so those are two areas, which will continue to generate fresh leads with 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.

And it's not random.

Jennifer Chien: Yeah, so I would say that there's been one to the point that David just made through dating 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 would 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.

Yeah, So I would say.

Say that.

One to the point that David just made translating to specific opportunities for a diagnosis I think that.

Yes at least made strides just in terms of becoming much more efficient and targeted disease education efforts.

Well you were 10 plus years ago play.

Play that.

Is helping and I will say that in terms of the various different opportunity that we have outlined in terms of how we are going about our specific disease education efforts failed perspective, we have identified additional patients through those efforts.

Then encouraging which was also one of the reasons why we decided to.

Our field teams as well to support the effort.

It's really expedite that patient identification.

So I think the other aspect is.

Jennifer Chien: So it is a trickle of fact that in terms of our initial education, I've heard, as well as the sustained ability for those educated communities to be able to continue to identify patients. I'm moving forward as well.

Once you do get physicians, who are educated and since that day that can also have a chuckle attack and transact.

Those physicians also being able to.

Continue to identify additional patients along the way. So it is a check off that just in terms of our initial education effort that's fallen.

<unk> ability for those educated.

Nice to be able to continue to identify patients and making for desktop.

David Meeker: And Corinne, to that point, you know, as Jennifer said, there's a little bit of, you know, if you build it, they will come. As you mentioned earlier, 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 therapy, and they re-engage, so they come out.

And kind of that point Zephyr said, it's there's a little bit of if you build it they will come which you mentioned earlier many patients have disengaged from the system. Because there is nothing there and they are tired of being told not to go on a diet suddenly there's a therapy and they reengage. So they come out second is.

As we build the community and you identify physicians, who have an interest the theres a therapy. There is something to do they decided they want to make this a little bigger part of their overall practice, that's the build it and they will come in that new spin circulate through the community and they say Dr. So and so is a special interest maybe you should go see their efforts.

David Meeker: Second, 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 begins to circulate through the community, and people 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, you know, it starts maybe a little bit slow, but as you get it going, this becomes a very important driver of the overall process.

And so again these are the networking kind of effects that as you go in their bid exponential hopefully.

<unk>, maybe a little bit slow, but as you get it going this becomes a very important driver of the overall process.

I see that one and maybe going back to your question that was asked is in terms of severity and so I do think that it is indeed, the case that people too.

David Meeker: I think that one ad and maybe going back to a question that was asked, 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 crib Under 18 years of age, so there are 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.

Time, and they get disheartened.

Get a therapeutic options and going back to a comment that we.

We made earlier.

Earlier.

You know call a lot of the patient that we have within our sphere of a lot of the patients that are within the sphere of the cribs are younger and under 18 years of age.

So a lot of adults that likely have been diagnosed.

That are also in the App.

In need of therapy.

Adoption to be able to control its right there.

And the percentage of patients in the groups who are under 18, so the percentage of patients that were under 18 with.

80% of the credit strength of St.

Thank you Jennifer <unk> any other questions.

That's all thank you very much.

Thank you.

As a reminder, if you have a question at this time. Please press Star then one our next question comes from line of Tennessee Ahmed from Bank of America. Your question. Please.

Good morning.

Tazeen Ahmad: David, can you give a little bit more color about, you know, what you mean by, "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.

David can you give a little bit more color about.

What you mean by that.

The metrics would be like a rare disease launch now you are expert on rare disease launches no doubt.

But in this world there appear to be quite a wide array of qualities of lunches. So.

David Meeker: So, you know, we're following an HAE launch right now that's going much better than people had expected. But we're also looking at other launches for other rare diseases, DHT, etc., which people are expecting to be slower. So where would you kind of compare the genetic obesity launch that you're managing and will continue to expand upon if there is, you know, another rare disease, just so that we have a better sense of what ramp expectations could look like?

We're following that when they say EU launch right now that's going you know much better than people had expected.

Also looking at other launches for other rare diseases, THB et cetera.

Which people are expecting to be slower.

David Meeker: That's my first question. And then secondly, in a real world setting for BbF, what would you expect a 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?

So where would you kind of comp the genetic obesity launch that that youre, 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 secondly in a real world setting for Bbs.

What would you expect the discontinuation rate could be with users.

Based on your conversations with physicians, how long do you think the Doctor would keep a patient on drug before deciding if it's working or not thank you.

Tazeen Ahmad: Thank you. Hey, Tazeen, 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 things because there's a lot of unknowns, but I think as you framed it.

Thank you and thanks for helping organize my answer to your first part of the question. So it is hard to two.

Fully.

Specifically define at least because there's a lot of unknowns, but I think as you framed it so HLA registry angioedema, that's a population with existing therapies, it's been very well organized so if youre 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.

Rare disease.

Cystic fibrosis. Another example of a very well organized community. There is newborn screening patients are diagnosed early there as well establish centers of excellence around the world again, you bring a therapy compelling offering into that group rapid uptake in a relative sense.

David Meeker: 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 this engagement and 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.

The other groups.

Better worse I think Bbs is in that other group, where the first therapy yet.

And in a disease, which has all of the classic elements here.

No attention nothing to do about disengagement as gennifer highlighted over time and so we have to build it. So yes, we are going to be impact group I'll give you. One. Other example, again as you know coming out of Genzyme license almost storage disease world, those where diseases that when they first launched look more like Bbs or.

Worse in a sense that fewer patients identified maybe not all of the signs and symptoms that DBS has 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 youre 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.

David Meeker: So I would measure it based on sort of obviously your starting point in the degree of organ 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 350 plus, and I'll put the emphasis on plus, having 350 plus patients as a starting point in the U.S. Only, you're much better organized and have many more patients 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 have some starts.

I got to say, having 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 am expecting us to do better than the others, but it's still going to be lumpy.

Its fits and starts with people.

Tazeen Ahmad: The second part of your question concerns real-world discontinuation rates here. You know, we're still getting our arms around this. Clearly, 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. However, 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 caloric intake.

The second part of your question is some real world discontinuation rates here, we're still getting our arms around this clearly not every patient responds on every patient responds and exactly the same way, but I have to say what were 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.

At over weighed and we heard a story again yesterday that was told where the patient or the patient's family with just incredible discipline was managing the Cork intake and so that patients total Wade was they were overweight or obese, but clearly not as great as it might be if they lived in an unrestricted.

Tazeen Ahmad: And so the 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.

It environment that said the hyperphagia the child in the family we're 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 as much as equally great. So.

David Meeker: And so they may not demonstrate so much change in weight from baseline because they are already so tightly controlled. But the opportunity to transform their lives is equally great. I think 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 are a number of factors which will cause the patient to adhere.

I think the hyperphagia is the variable that is in many ways going to dictate the continuation rate will lose people for many different reasons.

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 are increasingly optimistic that theres, 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 randomize withdraw on our pumps. He left bar group. The hunger came back very quickly we've heard this anecdotally as well and so there is a reminder, that your drug was doing something you go off and feel it and they want to go back on in that setting.

Again things that give me hope that we may have reasonably good compliance.

Thank you.

Okay. Okay.

David Meeker: And so there's a reminder that your drug is doing something; you go off, you feel it; they want to go back on in that setting. So again, things that give me hope that we may have reasonably good compliance. Thank you all. Thank you. Thank you. Thank you all. Our next question is a follow-up to the line from Michael Higgins from Lattenberg-Dallman.

Our next question is a follow up from the line of Michael Higgins from Ladenburg Thalmann. Your question. Please.

Michael Higgins: Your question, please. Thanks guys for the follow up here. Just again, you had two data coming up in the first half where we see initial data from face to an NPC for our patients and the health fulfillment, as well as the long term data. There's a few patient numbers. Can you share that with us? I had a time.

Thanks, guys for the follow up here just looking ahead into data coming up in the first half where we see initial data from phase II and empathy for our patients.

Hey fulfillment.

As well as the long term debt was just looking for some patient numbers can you share that with us and at the time. Thanks.

Yes, so I'm sorry. So the question is about the patient numbers in each of those groups is that in general we have a number of improvement reporting out there. So just maybe the hypothalamus obesity number which we highlighted and then <unk>, which we haven't shared but we can give you a general sense.

Linda Shapiro: Right. So there are 18 patients in the hyperlimic obesity group. There's, as we mentioned, the long-term data, embedded fetal syndrome, and that was presented by Dr. Paz has, you know, 19 patients at 24 months.

Right.

So there is 18 patients in the pipeline like obesity group there.

As we mentioned the long term data BARDA <unk> syndrome, and that was presented by Dr. Oz has.

19 patients at 24 months, we're all in the range of this roughly a dozen patients plus finance and each of these cohorts is what we're anticipating reporting later this year.

Okay.

I appreciate the color 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.

Okay, 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.

Yes.

Thank you, ladies and gentlemen for your participation in today's conference. This does conclude the program you may now disconnect good day.

David Meeker: Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect.

Operator: Good day.. .. .. ....

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Joseph Stringer: Just curious if that's changed your thinking or design of the M&A, pastry 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 identified as an academic or medical center, how, what's the reason for, you know, why these diagnosed BBS patients are not sort of part of this system? Is it just that they're, you know, have a lot of severe phenotypes, or these are sort of older patients that have kind of gone to sort of live with the disease.

David Meeker: So, H-A, Regitarianjou Adema, 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, and treatments 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.

Michael Higgins: So the question is about the patient numbers in each of those groups, is that correct? Yeah, in general. We have a number of groups reporting out there, so maybe the hypothalamic obesity number that we highlighted, and then MC4, which we haven't shared, but we can give you a general sense.

Linda Shapiro: We're all in the range of this, you know, roughly a dozen patients plus or minus in each of these cohorts. This is what we're anticipating reporting later this year. 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. Okay, great. Well, thanks again to everyone for tuning in and for your questions. And we look forward to updating you on our progress as we go through the air. It's going to be an exciting year. Thank you, and we'll talk about it.

David Meeker: We also know that there are 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 Bartet beetle, and we know the hit rate when you screen an individual with a history of early onset obesity and hyperphagia for Bartet beetle is on the order of 1.5% of those individuals will come back biallelic for a Bartet beetle gene.

David Meeker: Remember, when they go off the drug, and we've seen this in our trials where we had a randomized withdrawal in our Palm Sea Lepard group, the hunger came back very quickly. You've heard this anecdotally as well.

Jennifer Chien: In addition, there are several other opportunities, such as 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 back to them. So we have to think about that activity and then finding and diagnosing and expediting the diagnosis of the patients who have not yet found the 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. That's very helpful. Go ahead, Philip.

David Meeker: So there wasn't a subgroup via any of those cuts where set my appetite 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. Okay, well, hey, thank you very much.

Jennifer Chien: 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 their care, but over time, as they're, you know, they've got from position to position and realize that there isn't anything effective, they may have, you know, been less persistent because they're just not therapeutic options. So the potential availability of a therapy like them, so free, may, you know, provide more hope in terms of engagement and opportunity for that perspective. Thanks, Jack. Thanks, Joe.

David Meeker: Again, as you know, coming out of Gen Zimbabwe, the license almost stored the 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 BBS 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.

Jennifer Chien: 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 patient identification. So I think the other aspect is, you know, once you do get positions who are educated and suspicious, that can also have a trickle effect in terms of those positions also being able to continue to identify additional patients along the way.

David Meeker: Justic 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 I, better or worse, I think BBS is in that other group.

David Meeker: And the percentage of patients in the crib are under 18. So the percentage of patients that were under 18 was 80% in the crib strip, and Jennifer Green, any other questions? (inaudible) That's all. Thank you very much. Thank you. As a reminder, if you have a question at this time, please press star then 1. Our next question comes from Tazeen Ahmad from Bank of America. Your question, please. Good morning.

Joseph Stringer: And they just make up a significant portion of the BBS population and maybe more specifically, where the specifics around sort of capturing these potential patients. Thanks for taking our questions. Yeah, thanks, so Jennifer, I 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 are no changes. This was a set of requests which were very specific to our somewhat unique trial design, which incorporated BBS and all streams. We analyzed them together, and as I explained, we have the [inaudible] that age greater than 12 issue. So they were very specific to the existing file. So there will be no change to that. Jennifer.