Q2 2021 Rhythm Pharmaceuticals Inc Earnings Call

Good day and thank you for standing by the welcome to the region from a Kitty Con for Q2, 2021earnings conference call. At this time, all participants are gonna listen only mode. After the speaker's presentation. There will be a question and answer session to ask the question during the session. They will need to press the star 1 of your telephone.

Operator: Good day, and thank you for standing by. Welcome to the Rhythm Pharmaceuticals Q2 2021 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0.

The report of any figure of assistance. Please press the star and Carol I would now like to hand, the conference over to George Speaker today, maybe the kind of Lee head of Investor Relations and corporate communications for 3 of them. Thank you. Please go ahead.

David Connolly: I would now like to hand the conference over to our speaker today, David Connolly, Head of Investor Relations and Corporate Communications at Rhythm. Thank you. Please go ahead. Thank you. Good morning.

Oh, Thank you and good morning, I'm, David Connolly head of IR and corporate communications here at rhythm Pharmaceuticals with me today for our second quarter financial results and business update conference call are David Meeker share President and Chief Executive of Rhythm Pharmaceuticals, Murray Stewart, our Chief Medical Officer, Jennifer Chen Executive.

David Connolly: I'm David Connolly, Head of IR and Corporate Communications here at Rhythm Pharmaceuticals. With me today for our second quarter financial results and business update conference call are David Meeker, Chair, President, and Chief Executive Officer of Rhythm Pharmaceuticals, Maurice Stewart, our Chief Medical Officer, Jennifer Chien, Executive Vice President, Head of North America, Yann Mazabraud, Executive Vice President, Head of International, who is dialing in from Europe this morning, and Hunter Smith, our Chief Financial Officer, who is here in Boston with us. For those of you participating via conference call, the accompanying slides can be accessed and controlled by going to the events section of the investors page of our website, ir.rhythmtx.com.

The the Vice President head of North America, Yeah on massive Rowe Executive Vice President head of International who is dialing in from Europe. This morning, and Hunter Smith, our Chief Financial Officer, who was here in Boston with Us.

For those of you participating via conference call. The accompanying slides can be accessed and control by going to the events section of the investors page of our website IR dot rhythm TX Dot com.

David Connolly: This morning, we issued two press releases, one of which provides an update on our comprehensive expansion of our clinical development program with five new phase two and three trials planned to evaluate set melanotide in rare genetic diseases of obesity, and a second press release that provides our second quarter financial results and business update. Both press releases are available on our website. On today's call, on slide two, David will provide an overview and some introductory remarks, and Murray will provide an update on regulatory and clinical development plans. Jennifer will provide an update on U.S. commercial, and Yann will provide an update on international.

This morning, we issued 2 press releases, 1 of which provides an update on our comprehensive expansion of clinical development program with 5 new phase 2 and 3 trials planned to evaluate the CEP Atlanta tied in rare genetic diseases of obesity and the second press release that provides our second quarter financial results and business update both press releases are available on our website on.

On todays call on slide 2 David will provide an overview and some introductory remarks Moray will provide an update on regulatory and clinical development plans, Jennifer will provide an update on U S. Commercial [noise] Jan will provide an update on international and Hunter will provide an update on our finances and balance sheet lastly, the team will be available to answer.

David Connolly: And Hunter will provide an update on our finances and balance sheet. Lastly, the team will be available to answer questions. On slide three, I'll walk you through our forward-looking statement. I'll remind you that this call will contain 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.

Questions on slide 3 I'll walk you through our forward looking statement I'll remind you that this call will contain remarks concerning future expectations plans and prospects, which constitute forward looking statements actual results may materially differ may differ materially from those indicated by these forward looking statements as a result of various factors, including those discussed.

And 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 date, we specifically disclaim any obligation to update such statements with that I'll turn the call over to David.

David Connolly: With that, I'll turn the call over to David. Thank you, Dave. And I'd like to offer my welcome to everyone on Rhythm's first quarterly earnings call. Starting on slide five, as Dave highlighted, it's been a highly productive quarter, not a lot of flashy headlines, but we're really pleased with the significant progress that we've made, and I think you'll hopefully appreciate that, particularly on the clinical development front, which Murray will walk you through.

Thank you, Dave and I like the off of my welcome to everyone for rhythm is first quarterly earnings call.

Starting on slide 5 as Dave highlighted it's been a highly productive quarter not of lot of flashy headlines, but we're really pleased with the significant progress that we've made and I think you'll hopefully appreciate that particularly on the clinical development front, which Mary will walk you through.

David Connolly: Some of the highlights from the second quarter, on the clinical side, again, many discussions with the FDA and EMEA, leading to our current state with a newly named Phase 3 M&A trial, our newly named Phase 2 Daybreak trial, and then the Phase 3 study in pediatrics, children ages 2 to 6, and then two phase 3 trials for our weekly formulation. We're very encouraged by our first full quarter of NCIVRI availability. We're learning a tremendous amount, which Jennifer will walk you through, and we are making significant strides in building out our infrastructure. We got our European Commission authorization for incivory.

Some of the highlights from the second quarter on the clinical side again, the many discussions with the F. D. A N E M B, a leading to our current state with a newly named Phase III M&A trial, our newly named Phase 2 DAYBREAK trial, and then the phase III study in Pediatrics age children Ages 2.

The 6 and then 2 phase III trials for our weekly formulation.

We've been very encouraged by our first full quarter of in Sebree availability, we're learning a tremendous amount, which Jennifer will walk you through and we are making significant strides in building out our infrastructure.

We got our European Commission authorization from the Sebree on we knew this was coming but an incredibly important milestone nevertheless.

David P. Meeker: We knew this was coming, but it was an incredibly important milestone nevertheless. And I'm very happy with the indication, the labeled indication that we got. We're approved for the treatment of obesity and the control of hunger. We have hunger on the U.S. label, but on the European label, it is included in the indication and again signals the importance of that aspect of this disease given the underlying biology. Yann's going to take you through the progress in Europe and outside. We recently announced our agreement with Medicine Pharma to commercialize Sivri in Israel. Again, he'll go into a little more depth there.

I'm very happy with the the indication of the labeled indication that we've got some we're approved for the treatment of the city and the control of hunger on we have hunger in the U S label, but in the European label. It is included in the indication and again signals. The importance of this that aspect of this disease and given the underlying biology.

Johnson of take you through the progress in Europe and outside of them, We recently announced our agreement with medicine pharma and commercialize in Sebree in Israel and he'll go into a little more depth there, but this agreement signals again, our commitment to go global with this opportunity.

David P. Meeker: But this agreement signals again our commitment to go global with this opportunity. The CRIBS collaboration, again, recently announced, is an important step, certainly for the BBS community and Rhythm as we work to learn more about that opportunity and support that community. I firmly believe in the area of rare diseases; when you get a drug approved, you are truly just at the beginning of understanding that opportunity. By nature, you have very few patients that may have been treated in the clinical development program, so much of that learning does begin at that point, and this collaboration will give us a real opportunity to learn much more about the natural history of this disease, and, of course, we'll continue to track the benefits as patients move on to incivory.

The Cribbs collaboration again recently announced a is an important step, but certainly for the Bbs community and rhythm as we work to learn more about that opportunity and support that community and firmly believe in the area of rare diseases. When you get a drug approved you were truly just at the beginning of understanding that opportunity by nature you have very.

Few patients that it may have been treated in the clinical development program. So much of that learning does begin at that point and this collaboration will give us a real real opportunity to learn much more about the natural history of this disease and of course will continue the track the benefits as patients move on to ancillary.

David P. Meeker: And finally, URO, our gene panel that we support and offer to the community, which is the backbone of virtually everything we do. And we've provided an updated panel now that extends to 80 genes. Jennifer will walk you through a little more on that aspect. Turning to slide six.

Finally, our U R O R.

Our gene panel that we support and offered to the community, which is the backbone of virtually everything we do and we've provided a updated panel now that extends to 80 genes and Jennifer will walk you through a little more on that aspect.

Turning to slide 6 I know many of you on the phone are familiar of of course with what we do but I think it's worth reminding people on.

David P. Meeker: I know many of you on the phone are familiar, of course, with what we do, but I think it's worth reminding people. We're focused on rare genetic diseases of obesity, which is very distinct from general obesity. Many times they present in a similar fashion, but the underlying drivers and what they're experiencing are different, characterized by early-onset severe obesity and the very important aspect of hyperphasia, which is this pathologic hunger associated with persistent and potentially extreme food-seeking behavior and highly impactful in terms of a patient's overall quality of life.

We're focused on the rare genetic diseases of obesity, which is very distinct from general obesity. Many times. They are present in a similar fashion, but the underlying drivers on what they're experiencing is different characterized by early onset severe obesity and the very important aspect of hyperphagia, which is this pathologic hunger associated with the.

Persistent and potentially extreme food seeking behavior.

The highly impactful in terms of the patient's overall quality of life of genetically defined population by definition tends to be resistant of refractory to therapies and interventions, including bariatrics surgery and it is associated begin simple strictly as a function in many cases of the severity of obesity with all of the complications of Comorbidities.

David P. Meeker: It's a genetically defined population, by definition, tends to be resistant or refractory to therapies and interventions, including bariatric surgery, and it is associated again strictly as a function in many cases of the severity of obesity with all the complications and comorbidities we see in that population. So, in essence, this is a life-threatening disease with no approved therapies to date other than three indications that we were approved for in November of last year.

We see in that population so in essence the.

This is a life threatening disease with no approved therapies to date other than the.

3 indications that we were approved we had approved in November of last year.

David P. Meeker: So moving to slide 7, our focus as we seek to transform the care of patients with rare genetic diseases to obesity is fourfold. The U.S. is our first opportunity to learn and build on the commercial availability of emsyvery. That's on track. As we first start making a drug available, it's always interesting to see how patients, the initial patients, do who go on therapy outside of a clinical development program. And I'll just share one anecdote.

So moving to slide 7 of our focus as we seek to transform the care of patients with rare genetic diseases. The obesity is for fold.

The U S. As our first the opportunity to learn and build on the commercial availability of sebree that's on track.

As we first start are made.

The making of drug available, it's always interesting to see how patients the initial patients do on who.

We will go on therapy outside of the clinical development program and I'll just share 1 anecdote.

1 of the first patients to go on therapy was an 18 year old 8 year old girl, who experienced a decrease of BMI adds the 3 months. She cleared her reauthorization of where their payer, but more importantly, she experienced some of those more subtle things. We don't think about her glasses started fitting better for schuh started feeling better fitting better she had more energy in.

David P. Meeker: One of the first patients to go on therapy was an 8-year-old girl who experienced a decrease in her BMI at three months. She cleared her reauthorization with her payer. But more importantly, she experienced some of those more subtle things we don't think about. For example, her glasses started fitting better. And her shoes started fitting better.

Just an overall general improvement in her her quality of life. So again, it's just not forget.

David P. Meeker: She had more energy and just an overall general improvement in her quality of life. So again, it's just not to forget, you know; we get focused on the numbers, but some of these more nuanced aspects are what really transform people's lives. Secondly, the Clinical Development Program, and again, I'll leave it to Murray to take you through the details, but that's the backbone of everything we do. The community building, all the education, the development of experts, of course, patient awareness and testing, all of that will be anchored by our clinical development efforts, which are increasingly robust.

We get focused on the numbers, but some of these more nuanced aspects of what really transform people's lives.

Secondly, the clinical development program and again I'll leave it to marry the taken through the details, but that's the backbone of everything we do the community building of the all of the education of the development of experts of of course patient awareness of testing all of that will be anchored by our clinical development efforts, which are increasingly robust.

Third we're poised to deliver on our BARDA beetle opportunity with the filing on track as again, you will hear in the near term and we're excited about that opportunity I mean, that's a.

Highlighted that the.

The first 3 genes we've been pursuing that that opportunity will have tens of patients on near term many more long term, but the needle on the haystack and will take a little bit of time to get there, but BARDA Beatles are much better organised community in the 2500 plus patients in the U S equal or greater numbers as you'll hear from yen in the outside the.

David P. Meeker: Third, we're poised to deliver on our Bardet Beetle opportunity with the filing on track, as again, you will hear in the near term. And we're excited about that opportunity. I mean, that's a, you know, we've highlighted that the

The us again that we're focused on that and that's something that we want to get right.

David P. Meeker: The first three genes we've been pursuing, and at that opportunity, we'll have tens of patients in the near-term, many more in the long-term, but it's the needle in the haystack, and we'll take a little bit of time to get there. But Bartlett-Beetle's a much better organized community, and the 2,500-plus patients in the U.S., equal or greater numbers, as you'll hear from Yann, outside the U.S. Again, we're focused on that, and that's something that we wanna get right.

And finally on just as the highlighted we're excited about progress that the yen is making I think in the outside the U S. In many U S. Biotech small companies tend to shy away from Europe, It's a complex of hard to penetrate country by country differences that need to be understood and we're just incredibly unfortunate incredibly fortunate to have someone.

Unlike Yan with deep experience from leading that effort for us in and making the approval of the progress that he has been making and you know just for example, I mean, the the as we work with payers and 1 of the most important aspects of his efforts on our efforts as a company are to make sure that the whole community and certainly are the.

David P. Meeker: And finally, just as a highlight, we're excited about progress that Yann is making outside the U.S. And, you know, many U.S. biotech small companies tend to shy away from Europe because it's complex, hard to penetrate, country by country differences that need to be understood.

Payer part of that understands that these diseases are not obesity either of these rare genetic diseases, driven by clear deficits and a.

Pathway in the brain and that they happen to be associated with obesity and that I think cans made good progress with that.

David P. Meeker: And we're just incredibly fortunate to have someone like Yann with deep experience leading that effort for us and making the approval, the progress that he has been making. And, you know, just for example, I mean, as we work with payers, and one of the most important aspects of his efforts and our efforts as a company is to make sure that the whole community, and certainly the payer part of that, understands that these diseases are not obesity. These are rare genetic diseases driven by clear deficits in a pathway in the brain, and they happen to be associated with obesity. And I think Yann's made good progress with that.

So turning to the left side of my section Slide 8 this is a small pipeline cut if you will and are working.

Working on from the right side, we have the 3 genes approved and I think the message I want to leave here is the we are going very specifically gene by gene and so the expansion of this opportunity will be as we can get the additional genes approved and that's been our clinical development strategy. So we'll be filing for the Bbs and all strums in just 1.

Of note on all of Strums, as Mary will get to as well and we see clear responders there but.

We have I think a good understanding with both regulatory agencies that absolutely we should file make the case and I think we have reasonable optimism, but we.

David P. Meeker: So turning to the last slide of my section, slide eight, this is a small pipeline cut, if you will, and working from the right side, we have the three genes approved. And I think the message I want to leave here is that we are going very specifically gene by gene. And so the expansion of this opportunity will be as we can get additional genes approved, and that's been our clinical development strategy. So we'll be filing for the BBS and Alstroms, and just one note on Alstroms, as Mary will get to as well, and we see clear responders there, but

We will not 1 will not unduly impacted the other day will be looked at basically as independent genetic opportunities. The phase III trial again excited about the AR 5 genes were pushing through the phase 3 M&A trial, and then the day bake DAYBREAK trial is a highly efficient way I think of understanding additional.

Genes in that pathway no way that all 31 of course, they're going to respond and I think this will allow us to rapidly relatively rapidly begin to sort that group of 31 that we think based on existing knowledge tie them strongly to the pathway, but of course, the ultimate confirmation will come from their response to some Atlanta time and as we've said for.

David P. Meeker: We have, I think, a good understanding with both regulatory agencies that absolutely we should file, make the case, and I think we have reasonable optimism, but one will not unduly impact the other. They will be looked at, basically, as independent genetic opportunities.

Committed to the lifecycle management strategies for adopting so with that I'll turn it over to Murray for the clinical and regulatory update right great. Thank you. So let's go to slide 10.

David P. Meeker: The phase three trial, again, excited about the five genes we're pushing through the phase three M&A trial, and then the daybreak trial is a highly efficient way, I think, of understanding additional genes in that pathway the way that all 31, of course, are going to respond. I think this will allow us to rapidly, relatively rapidly, begin to sort that group of 31 that we think, based on existing knowledge, tie them strongly to the pathway, but, of course, the ultimate confirmation will come from their response to the fentanyl antibody. And as we said, we're committed to the life cycle management strategies we're adopting. So with that, I'll turn it over to Murray for the clinical and regulatory update. Great, thank you. Let's go to slide 10. As David said, we've been busy.

As David said, we've been busy we've been holding multiple meetings with both the FDA and EMA and the police report out to date the achieved agreement on regulatory submissions in separate clinical trial designs, which are important steps as we work to expand the label for central on a tight.

We submitted the briefing document for the F D and the Dupree S. N D. A meeting with them to discuss the content of our right to file for bar the beetle and also from syndromes.

The meeting was successful and the FDA of agreed to review the Bbs and also from data independently.

And for all we are cautiously optimistic given the totality of the data we do know that the more limited awesome data will not negatively affect of B B S submission.

So we are on track to complete and submit a rack leaf package for a supplemental NDA to the FDA in this quarter.

For Europe, we all saw the successful meeting and we are on track to complete our submission seeking of tight to the amendment to our European marketing authorization in the fourth quarter.

Murray: We've been holding multiple meetings with both the FDA and EMA, and we're pleased to report today that we've achieved agreement on regulatory submissions and several clinical trial designs, which are important steps as we work to expand the label for set melanotomy. We submitted a briefing document to the FDA and did a pre-SNDA meeting with them to discuss the content of our right to file for Barda, Beadle, and Ahlstrom syndrome. The meeting was successful, and the FDA has agreed to review the BBS and Ostrom data independently. And while we are cautiously optimistic given the totality of the data, we do know that the more limited OSM data will not negatively affect a BBS submission.

But we are excited about the transformation of expansion of our clinical development program with 5 new phase 2 and 3 trials all of which meaningfully broaden the rare genetic disease that Beastie patient population, we can help with and sebree.

The pivotal emanate trial studies, 5 specific genes and the M C for the our pathway.

Representing approximately 100 to 200000 patients in the U S who may respond to settle on tied with the similar number in Europe.

The phase 2 DAYBREAK trial is designed to value set monetize an additional 31 genes associated with the M C for a pathway.

Our phase II from pediatric patients aged 2 to 6 is designed to address the high unmet need of naval better airlift care for children with rare genetic disease at the BCD.

Murray: So we are on track to complete and submit a regulated package for a supplemental NDA to the FDA in this quarter. For Europe, we also had a successful meeting, and we're on track to complete our submission seeking a Type 2 amendment to our European Marketing Authorization in the fourth quarter. But we are excited about the transformational expansion of our clinical development program, with five new Phase II and III trials, all of which meaningfully broaden the rare genetic disease, obesity, patient population we can help in civil society.

And the 2 phase III trials for a weekly program of de Novo trial and the switch study.

The weekly program was the key aspect of of long term strategy, which will improve compliance and adherence and these lifelong chronic diseases.

Both agencies for Betty posted for the dressing the younger children.

The weekly program folded the joined the assessment by both agencies, culminating the 3 week conference with the rhythm F D and E.

The pathway studies involve briefing documents draft protocols and the taste of concrete feedback and get us to T. We were ready to plan the operational aspects of the studies.

Murray: The Pivotal Emanate trial studies five specific genes in the MC4R pathway, representing approximately 100 to 200,000 patients in the U.S. who may respond to septum lantide, with a similar number in Europe. The Phase 2 Daybreak Trial is designed to validate sepmolantide in an additional 31 genes associated with the MC4R pathway.

Slide 11.

We remain very excited about those guests we've made on par the beetle syndrome.

He had as the reminder of our bps and also from data from our pivotal trial, which has strong supportive of the successful registrational package.

Murray: A phase 2 trial in paediatric patients aged 2 to 6 is designed to address a high unmet need and enable better, earlier care for children with rare genetic diseases of obesity, and the two Phase 3 trials for our weekly program, a de novo trial and a switch study. The weekly program is a key aspect of our long-term strategy, which will improve compliance and adherence in these lifelong chronic diseases. Both agencies were very positive about addressing the younger children.

The pivotal trial met the primary and all key secondary endpoints, achieving statistical significance on delivering on clinically meaningful weight loss and hunger reduction.

The mean weight loss shown here, however, does not convey the real benefit of it includes not only idols, but children that were growing so when you look at the B B S D to alone and separated into 2 groups adults and children you see what we believe the real benefit and clinically meaningful response to set them on Todd.

Murray: The weekly program followed a joint assessment by both agencies, culminating in a three-week conference with Rhythm, FDA, and EMA. The pathway studies involve briefing documents, draft protocols, and meetings to incorporate feedback and get us to today, where we are ready to plan the operational aspects of these studies. Slide to the left.

The full range of the population.

Slide 12.

Recall with 20 patients with Bbs, who book 10 years old or older attend room at the patients and the primary analysis set.

Murray: We remain very excited about the progress we've made on BARDA-Beatles. Here is a reminder of our BBS and OSTRM data from our pivotal trial, which is strong and supportive of a successful registration package. The pivotal trial met the primary and all key secondary endpoints, achieving statistical significance and delivering clinically meaningful weight loss and hunger reduction. The mean weight loss shown here, however, does not convey the real benefit, as it includes not only adults but children that are growing.

53%, if I don't split bar to beat on syndrome achieved weight loss of 10 per cent of greater and 73 per cent, Nevada with B B S of cheap weight loss of 5% of greater.

It was the total of 16 patients with part of beat the system, who are younger than 18.

Including a few younger than 12 not included in the primary analysis.

2 of those 16, what's due prior to the 52.

The when we look at the remaining 14 children adolescence. The data really are quite remarkable.

13 out of the 14th achieved the reduction of zero point to a greater and the beer mindset scores.

Murray: So when you look at the BBS data alone, and split it into two groups, adults and children, you see what we believe is the real benefit in clinically meaningful response to septum lantide across the full range of the population. Slide 12.

The reminder, PMI said, it's a measure of standard deviation of body mass index from Cortez consist of normal based on some of its age and sex and a reduction of Cedar point too is considered clinically meaningful.

Murray: Recall that we had 28 patients with BBS who were 10 years old or older at enrolment, the patients in the primary analysis. 53% of adults with Barda-Biedl syndrome achieved weight loss of 10% or greater, and 73% of adults with BBS achieved weight loss of 5% or greater. There were a total of 16 patients with Barderby's syndrome who were younger than 18, including a few younger than 12, not included in the primary

Furthermore, 73 per cent of patients went on to enroll into the extension study.

We're looking for sharing more data from our B B S pivotal trials Judy on the medical conferences. This fall, including positive data from the 14th week placebo controlled period of the trial on full quality of life data.

While we've been excited about the state of for some time now.

We are even more excited about what this means for the bar the beetle community of zipped, no therapeutic options for the Sophia to Beastie and hyperphagia the greatly affected of lives.

I'm certain of this weekend to hear from the members of the community during the bar to be the Foundation and family Association Virtual conference and I was pleased to present, an update on central on the tied to this community Sunday night by video.

Murray: Two of those 16 withdrew prior to week 52, but when we look at the remaining 14 children and adolescents, the data really are quite remarkable. 13 out of 14 achieved a reduction of 0.2 or greater in their BMI-Z scores. As a reminder, BMI-Z is the measure of the standard deviation of body mass index from what is considered normal based on someone's age and sex, and a reduction of 0.2 is considered clinical

We're also excited about collaboration with Cribs Dot is the clinical registry investigating bar to beat the syndrome that we announced last week.

The more than 600 participants not to pin this registry.

Murray: Furthermore, 73% of patients went on to enroll in the extension. We're looking forward to sharing more data from our BBS Pivotal trial during the medical conference this fall, including positive data from the 14-week placebo-controlled period of the trial and full quality-of-life data. Well, we've been excited about this data for some time now. We are even more excited about what this means for the bard or beadle community, as they have no therapeutic options for the severe obesity and hyperphagia that greatly affect their lives. I was heartened this weekend to hear from members of this community during the Barda Beadle Foundation and Family Association Virtual Conference.

And we look forward to conducting the deepest examination to date on the natural history of weight gain hyperplasia on the quality of life in patients with BARDA Beadle syndrome.

Moving on to slide 13 on the first detailed slide of our clinical trials. So the pediatrics.

As of genetic disease DCP states per cent nearly age from just a few months old to 5 or 6 years old.

And we know from the sequencing results of it on uncovering rare obesity genetic test that approximately 20%. These tests are done in children 6 of younger.

On the hit rate for these diseases is consistent with the overall data we've reported.

The beef staying hyperplasia of severe in these children.

Murray: And I was pleased to present an update that set Malantide to this community Sunday night via video. We're also excited about our collaboration with CRIBS, that is the Clinical Registry Investigating Bader-Biedl Syndrome, that we announced last week. There are more than 600 participants now active in this registry, and we look forward to conducting the deepest examination to date on the natural history of weight gain, hyperphasia, and quality of life in patients with BARDA-Beetle syndrome. Moving on to slide 13, and the first detailed slide of our clinical trial. So the TDR.

The reference had point to the journal pediatric child health, which of Butte case, the pumps the deficiency in the April edition this year on it.

The 2 children from Sydney, Australia, which we will include in a clinical study.

This trial is a phase III study being conducted in North America, Europe, and Asia Pacific countries.

We plan to enroll at least 10 patients 5 was the be stay true to buy Lilly comp C. P. C. S. K oar leptin receptor deficiency and 5 with BARDA the pedal syndrome.

The study is 1 year long open label on the primary endpoint is the responder analysis with the responder is defined as patients achieving a decrease from baseline in the P. M. I said score of greater than Cedar point too.

Murray: As a genetic disease, these obesities present at an early age, from just a few months old to five or six years old. And we know from the sequencing results of our Uncovering Rare Obesity Genetic Test that approximately 20% of these tests are done in children 6 or younger. And the hit rate for these diseases is consistent with the overall data we've reported. The B-strain hyperphasia is severe in these children.

But actually set to dose the first patient in this trial on the second half of this year, we've already separate children, the identified and ready for screening.

Moving to slide 14.

Advancing on a weekly from leases set Montana is a key part of of corporate strategy and lifecycle of the drug.

I sort of mind do we presented interim data from a phase 2 study in general obesity competing the once weekly formulation of set month tied to daily dosing of 7 laptop.

Murray: For reference, I'd point to the Journal of Pediatric Child Health, which reviewed cases of POMC deficiency in the April edition this year and included two children from Sydney, Australia, which we will include in our clinical study. This trial is a Phase 3 study being conducted in North America, Europe, and Asia-Pacific countries. We plan to enroll at least 10 patients, 5 with obesity due to biallelic POMC, PCSK, or leptoinfector deficiency, and 5 with Barda-Bedelson disease.

The data showed that the weekly formulation of central on the tide achieved compatible weight loss on hunger reduction to the street to the daily formulation.

And both of the week clean the daily formulations of central on tide were observed to be generally well tolerated.

For a registration program with 2 trials.

A switch study of phase III randomized double blind trial of daily and weekly formulations, which will evaluate efficacy pharmacokinetics and safety.

Murray: The study is one year long, open-label, and the primary endpoint is a responder analysis, with responders defined as patients achieving a decrease from baseline in the BMI-Z score of greater than 0.2. We're actually set to dose the first patient in this trial in the second half of this year, and we have already several children identified and ready for screening. Moving to slide 14.

We will enroll a total of about 30 patients who are already in our ongoing long term open label trial and they've been on 2 milligrams 3 milligrams daily of certain land tied for at least 6 months.

We could beat the S patients by Lilly cortex pump C. P. C S K, let pompe patients.

20 patients will be creation 18 years of beach.

Murray: Advancing a weekly formulation of certain laminates is a key part of the corporate strategy and life cycle of the drug. As a reminder, we've presented interim data from a Phase 2 study in General Obesity, comparing the once-weekly formulation of cetylalantide to daily dosing of cetylalantide. The data showed that the weekly formulation of Cetalantide achieved comparable weight loss and hunger reduction to those treated with the daily formulation, and both the weekly and the daily formulations of Sentinel Antidote were observed to be generally well tolerated in a registration program with 2Tron.

The 5 will be between 12 and 17 and we include younger children between 6 and 11 years of age.

The trial starts for the 1 week running on daily dosing the patients will be randomized in the 120 basis.

The receipt by the blinded weekly second lot of tide and daily placebo on.

On the other on blinded daily set montage and weekly placebo.

That all patients will have an open label weekly dosing for 13 weeks.

The primary endpoint of responder analysis for the proportion of patients with no weight gain on increase of 5% above baseline to week 13.

Murray: A switch study, a phase 3 randomized double-blind trial of daily and weekly formulations which will evaluate efficacy, pharmacokinetics, and safety. We will enroll a total of about 30 patients who are already in our ongoing long-term open-label trial, and they've been on 2mg and 3mg daily of cetylalanthide for at least 6 months.

The point is we won't show the individuals maintain weight when switching from weekly to daily and the the drug is safe and well tolerated.

The Danone the studies of randomized double blind the notebook trial will enroll 40 bps patients.

Patients with Brown buys 1 to 1 to receive the 30 milligrams weekly of placebo weekly for 18 weeks.

All the patients then go on to see debt 2 milligrams weekly for a further 14 weeks.

Murray: We include BBS patients, bi-allelic or HETS, POMC, PCSK, and LEPR patients. 20 patients will be greater than 18 years of age, about 5 will be between 12 and 17, and we include younger children between 6 and 11 years of age. The trial starts with a one-week run-in on daily dosing, then patients will be randomised in a one-to-one basis to receive either blinded weekly set enlantide and daily placebo or, on the other arm, blinded weekly set enlantide and weekly placebo. All patients will have an open label, weekly dose for 13 weeks.

The primary endpoint will be the mean change in weight at 18 weeks competing central on tied to placebo.

Both of these weekly trials from the Pediatrics purchase on track records submissions and not the states in Europe in the last half of 2022 or early 2023.

Now moving to slide 15.

This is the phase 2 day break trial, which is designed to rapidly assess an additional 31 genes and move towards registration.

Is the 2 stage trial, it's out in central on type of patients for specific variance, but then 1 of the Sichuan genes in the pathway.

Murray: The primary endpoint is respondent analysis for the proportion of patients with no weight gain or increase of 5% above baseline to week 13. The point is that we want to show that individuals maintain weight when switching from weekly to daily and that the drug is safe and well tolerated.

For this trial, we expect to dose the first patient by the end of the year.

We'll enroll patients between the age of 6 and 60 by the book.

1 of the PMI, reaching 40 or wait to book the Ninety-seventh Centaur.

They both have a history of childhood obesity.

Bold to say steep hyperphagia and how of at least 1 genetic bidding and 1 of the 31 genes.

The 2 stage design allows for rapid advancement to proof of concept.

Murray: The de novo study is a randomized double-blind de novo trial; we will enroll 40 DBS patients. Patients will be advised one-to-one to receive either 30mg weekly or placebo weekly for 18 weeks. All patients will then go on to receive 30mg weekly for a further 14 weeks.

In stage 1 there is an open label running.

We will of crude approximately 500 patients 10 to 20 per gene for 16 weeks of therapy.

We estimate the would be a third of approximately 230 patients who go into stage 2.

Murray: The primary endpoint will be the mean change in weight at 18 weeks, comparing set melanotype to placebo. Both of these weekly trials in paediatrics put us on track for regular submissions in the United States and Europe in the last half of 2022 or early 2023. Now moving to slide 15.

The criteria to into stage 2 of patients greater than the 18, achieving 5% weight loss for baseline or those under 18 of BMI said decrease of at least theater of 0.1.

Now of stage 2 is the double blind placebo controlled randomized withdrawal. The last 24 weeks will be based on entry weight and stratified by gene for more prevalent genes.

Murray: This is the Phase 2 Daybreak Trial, which is designed to rapidly assess an additional 31 genes and move towards registration. It's a two-stage trial evaluating certain Lyme type patients with specific variants within one of the 31 genes that are in the pathway. In this trial, we expect to dose the first patient by the end of the year. We have enrolled patients between the ages of 6 and 65 that will have a BMI greater than 40 or weight above 97 centimeters. They will have a history of childhood obesity, report a history of hyperplasia, and have at least one genetic variant in one of the 31 genes. The two-stage design allows for rapid advancement to proof of concept.

Patients are then randomized 2 to 1 to receive certain land tied of placebo.

And the expectation is the dosing active therapy, we will continue to lose weight, whereas those on placebo will gain weight.

If the gain weight in the body weight increases by at least 5% from stage 2 entry wait patient may be rescued and converted to set montage and an open label setting.

Rescued patients would not be considered as responders.

Slide 16 goes through the endpoints.

The primary endpoint is the proportion of patients who enter stage, 2 who responders compared to the placebo group.

The sponsors above 18 years of age achieved 10% of greater body weight reduction from baseline.

Murray: In stage one, there's an open-label run-in. We will recruit approximately 500 patients, 10 to 20 per gene, for 16 weeks of therapy. We estimate there would be a third group, approximately 130 patients who go into stage 2. The criteria to enter Stage 2 are patients greater than 18 achieving 5% weight loss at baseline or those under 18 achieving a BMIZ decrease of at least 0.1. Now, Stage 2 is a double-blin

Respond to under 18 achieves the BMI reduction of grit and 0.3 from baseline.

Secondary endpoints include proportion of patients who meet pipes on weight loss compared to their historic rate.

Change in percentage of body weight in adults.

The BMI said reduction in children with <unk>.

So look waste of conference change in average hunger.

As well as the overall safety and Tolerability.

And further secondary measures will include quality of life, such as physical functioning scores.

On slide 17 is emanate face the trial.

This is a randomized double blind placebo controlled trial of violating set 1 tied in 5 genes within the mountain of carton for pathway, which we believe demonstrated proof of concept, which we announced in January.

Murray: The last 24 weeks will be based on entry, weight, and stratified by gene for more prevalent patients. Patients are then randomized two-to-one to receive stratalantide or placebo. An expectation is that those on active therapy will continue to lose weight, whereas those on placebo will gain weight. If they gain weight and the body weight increases by at least 5% from stage 2 entry weight, patients may be rescued and converted to Ceplantide in an open-label setting. However, rescued patients would not be considered as responders.

This trial is compromised of 5 independent sub studies, if all of this.

The second line tied in groups of patients. The first group of heterozygous variant of pumps see what types of escape 1.

The second of heterozygous variant and the leptin receptor gene.

The third cohort is those cutting biddings and Src 1 gene the.

Murray: Slide 16 goes through the end. The primary endpoint is the proportion of patients who enter stage 2 who are responders compared to the placebo group. Responders above 18 years of age achieve 10% of greater body weight reduction from baseline, whereas a responder under 18 achieves a BMI reduction of greater than 0.3 from baseline. Secondary endpoints include the proportion of patients who achieve 5% weight loss compared to their historic rate. Change in Percentage in Body Weight in Adults, A BMI said reduction in children. We'll also look at waist circumference, change in average hunger, as well as overall safety and tolerability. And further secondary measures will include quality of life, such as physical functioning scores.

Fourth in the S. Each to be 1 gene.

And finally, the fifth sub study is for patients who carry the P. C. S. K, 1 and 2 to 1 day deletion.

Each sub study is designed to enroll 110 patients randomized 1 to 1 so 55 will get treatment 55 will get placebo for a total of 550 patients.

It's important to note the patients in each study will be stratified for age and then Hertz Com C. P. C. S. K 1 on leptin receptor sub studies patients will be stratified based on their ACM Chi classification of their bidding.

All of these patients for whom basically of childhood obesity and hyperphagia, we will.

Look at individuals from 60 to 65 years and inclusion will could BMI of 30 of wait about the 19th of Centaur.

Murray: Now on slide 17, we have the M8 phase C trial. This is a randomized, double-blind, placebo-controlled trial evaluating set melantide in five genes within the melanocortin 4 pathway, which we believe demonstrated proof-of-concept, which we announced in January. This trial is composed of five independent sub-studies, evaluating a certain line of tide in groups of patients. The first group is heterozygous variant

Slide 18.

The treatment period is 52 weeks with potential for rescue treatment 20 C was 6 weeks at this of gaining weight of 5% or an increase in BMI of about 3%.

Given the duration of this trial, we will provide guidance for both diet and exercise.

That's something that we've done in our clinical development program to date.

Anecdotally, we know patients who failed dot next tax regimes previously, who then try and have been more successful because of the reduction of hyperphagia, which of cars when they're on central London time.

Murray: Second, a heterozygous variant in the leptin-6 gene. The third cohort is those carrying variants in the SRC1 gene, the fourth in the SH2B1 gene, and, And finally, the fifth sub-study is for patients who carry a PCSK1 N221D deletion. Each sub-study is designed to enroll 110 patients, randomized one-to-one, so 55 will get treatment, and 55 will get placebo, for a total of 550 patients. It's important to note that patients in each study will be stratified by age.

The primary endpoint will be identical across each of the 5 sub studies on the primary endpoint is the mean percentage change in P. M. On at 52 weeks comparing central on tied to placebo.

Slide 19 shows our other secondary endpoints.

We'll include the responder analysis with respond as defined as adults, having achieved 5% and 10% class of body weight on.

The adolescence and children young from 18, having achieved of BMI reduction of greater than or equal to 5% and 10% at the 52 time point.

We will also look of the additional secondaries mean percentage change in weekly average of most of hunger score the.

Murray: And in the HETS, POMPC, PCSK1, and leptin receptor sub-studies, patients will be stratified based on their ACMG classification of their variant. All these patients will have a history of childhood obesity and hyperplasia. We will look at individuals from 60-65 years old, and inclusion will include BMI above 30 or weight above the 95th cent. Slide 18.

The mean change in BMI of Bmi's debt.

We used the conference men.

I mean body weight loss and the early responders defined just dose, losing 5% number 1 of the first 14 weeks.

This is important as this will assess what the early responders predictor of greater weight loss at the end of the study.

We will also look at safety Tolerability and other secondary endpoints of quality of life measures such as official functioning score.

Murray: The treatment period is 52 weeks, with potential for rescue treatment at 26 weeks if there's a gain in weight of 5% or an increase in BMI of up to 3%. Given the duration of this trial, we will provide guidance for both diet and exercise. That's something that we've not done in a clinical development program to date. Anecdotally, we know patients who have failed diet and exercise regimes previously, who then try and have been more successful because of the reduction in hyperphagia, which occurs when they're on set melanin. The primary endpoint will be identical across each of the five substrates, and the primary endpoint is the mean percentage change in BMI at 52 weeks comparing Stentolantide to placebo. Slide 19 shows our other secondary.

On this study in particular, we have had several regulatory interactions with both the EMA and the FDA.

The primary concern of the ft, specifically with each of the cohort genes in the basket study with small uncontrolled and the responder analysis as opposed to the traditional mean weight loss analysis.

Initially we proposed to trial, but the responder analysis is the primary endpoint in the pooled placebo group across the 5 genes of the comparator.

The FDA encourage of different design with 5 separate subsidies each with its own placebo control using mean BMI change as the primary endpoint.

We've adopted these.

The strength of this defined as the allows for gene bunching the analysis.

It allows for children and adults street be combined in 1 of analysis using the change in BMI.

Additionally, this will include the strongest placebo dataset, we up to date on this program and will give us insight into natural history of these genetic diseases.

Murray: They will include a responder analysis with responders defined as adults having achieved 5% and 10% loss of body weight, or adolescents and children younger than 18 having achieved a BMI reduction of greater than or equal to 5% and 10% at the 52 week time period. We will also look at additional secondary outcomes, such as mean percentage change in weekly average of most hunger score. The mean change in BMI of BMI is that, waist circumference, mean body weight loss, and early responders, defined as those losing 5% or more in the first 14 weeks.

Now any of the gene specific subsidies can succeed on their own and a lot of per separate and independent supplemental nda's.

The results for each study will need to be clinically meaningful and statistically the bus to support registration and as always this will be a matter of PPE.

The FDA is interested in the pathogenic like the pathogenic patients and boost patient subgroups.

And we've stratified the pump C. P. C. S. K, 1 head study and the leptin receptor study, where this is relevant by a C. M. G classification.

In somebody with HUD constructive interactions with both agencies and have developed the clinical development program, which we believe address the concerns of both the agencies.

Murray: This is important as it will assess whether early responders predict greater weight loss at the end of the study. We'll also look at safety, tolerability, and other secondary endpoints of quality of life measures such as visual functioning. On this study in particular, we have had several regulatory interactions with both the EMA and the FDA. The primary concern of the FDA specifically was that each of the cohort genes in the basket study was small, uncontrolled, and their spawned analysis as opposed to the traditional mean weight loss analysis.

Slide 20, our operational approach.

With a wealth of operational plan to support these 2 studies in parallel.

Acute via a global clinical research partner was selected as the CLO.

Contracts have been executed on trough on boarding is well underway for both emanate and DAYBREAK.

We expect to have more than 75 sites active in 14 countries across the Globe North America, Europe, and the Middle East.

Murray: Initially, we proposed a trial with respond analysis as the primary end point in a pooled placebo group across the five genes as a comparator. However, the FDA encouraged a different design, with five separate sub-studies, each with its own placebo control, using mean BMI change as the primary endpoint, which we've adopted. The strength of this design is that it allows for gene branching analysis.

Well the net we're referring physicians and obesity treaters in the surrounding area as each trough of 5 to 10 refining centers.

We are on track to initiate and dosed the first patients in these trials by the end of the year.

It will take at least a year for 18 months to recruit and screen for each trial.

Emanate as of 52 week treatment period, but as we said earlier the independent sub studies may allow for 1 or 2 sub studies the readout in advance directly to the mission ahead of the others.

Murray: It allows for children and adults to be combined in one analysis using the change in BMI. Additionally, this will include the strongest placebo data set we have to date on this program and will give us insight into the natural history of these genetic diseases. Now, any of the gene-specific subsidies can succeed on their own and allow for separate and independent supplemental NDAs.

Day bakes treatment period of just a little less at 40 weeks and we may have the same flexibility with the opportunities for certain genes of certain cohorts readout faster than others.

Both the emanate and day Big trials and the enrollment will be driven by singular community building effort. This is designed to raise awareness of rare genetic seats obesity educate on the early onset obesity and hyperphagia and call for more genetic testing.

Murray: The result for each study will need to be clinically meaningful and statistically robust to support registration, and as always, this will be a matter of review. The FDA is interested in pathogenic, glycopathogenic patients, and boost patients as subgroups, and we've stratified the POMC PCSK1 HET study and the leptin receptor HET study where this is relevant by ACMG classification. In summary, we've had constructive interaction with both agencies and have developed a clinical development program which we believe addresses the concerns of both agencies.

On slide 21, before turning on to Jennifer I want to remind everyone of house seats, Atlanta dispose them to be over the years.

As of March 2021, we did minutes. The second line tied to 609 patients with 94 onset of pay for most of the year.

The 40 on therapy for more than 2 years.

17 for more than 3.3.

Murray: Slide 20, our operational approach. We have a well-thought-out operational plan to support these two studies in parallel. Acubia, a global clinical research partner, was selected as the CRO. Contracts have been executed, and trial siting and boarding is well underway for both M&A and Daybreak.

See for more than 4 and finally, 2 out of 5 on more than 5 years of therapy.

This is consistent safety and Tolerability approval on these numbers give us great confidence assumed back in the day break anemone trials.

With that I'll turn it over to Jennifer.

Thank you Larry.

If you go to slide 23, you'll see that on my main focus is building it can be on a day.

Murray: We expect to have more than 75 sites active in 14 countries across the globe, North America, Europe, and the Middle East, will have a network of referring physicians and obesity treaters in the surrounding area as each trial site will have 5 to 10 referring centers. We're on track to initiate and dose the first patients in these trials by the end of the year. It will take at least a year to 18 months to recruit and screen patients for each trial.

<unk> and providing educational resources and expertise as well as tools for identifying testing and supporting the diagnosis of patients died.

Diagnosis supports the adenosine.

And of patients, who maybe eligible for 1 of our clinical studies, but also supports identification of patients who may be eligible for surgery.

We are leveraging the clinical development program.

Network of trial investigators in addition to diagnosing and treating for questions.

Murray: MNAID has a 52-week treatment period, but as we said earlier, independent sub-studies may allow for one or two sub-studies to read out and advance directly to submission ahead of the other. Daybreak's treatment period is a little less than 40 weeks, and we may have the same flexibility with opportunities for certain genes or certain cohorts to read out faster than others. Both the MNAID and DABIC trials and their enrollment will be driven by a singular community-building effort.

The centers to Dell debt community.

Which in turn will help support our commercialization efforts.

Slide 24.

Genetic testing of course remains at the center of our corporate strategy.

For us that means uncovering rare obesity.

Or you're out of free genetic test designed to identify and help physicians diagnose patients with rare genetic diseases.

Murray: This is designed to raise awareness of the rare genetic disease obesity, educate people on early-onset obesity and hypophagia, and call for more genetic testing. On slide 21, and before turning over to Jennifer, I want to remind everyone of how safe Seton Land Tide has proven to be over the years. As of March 2021, we will administer Cetilantide to 639 patients, with 94 on therapy for more than a year and 40 on therapy for more than two years.

Okay.

As David mentioned, we extended the panel of tests for 80 genes with time, Inc.

To date, we have completed approximately 10000 you are around the tax.

It's important to note. The panel was just expanded credit all 80 of genes. So now all of its loans and M&A on DAYBREAK will be screened moving forward.

We have also evaluated and made additional improvements in the euro of program.

We developed a new website to make it easier for physicians to order of the past for.

Murray: 17 for more than three, 3 for more than 4, and finally 2 out of 5 on more than 5 years of therapy. This is consistent safety and tolerability approval. And these numbers give us great confidence as we embark on the Daybreak and MNA trials. With that, I'll turn it over to Jennifer. Thank you, Murray.

See for yourselves and access contact information for genetic counseling support.

Physicians, who oversee the test kits within 5 days and in partnership with prevention genetics, we can turnaround of adults within 'twenty 1 day.

Through the years, we have learned a tremendous amount about the orders the test and for him.

Jennifer: If you go to slide 23, you'll see that our main focus is building a community and providing educational resources and expertise, as well as tools for identifying, testing, and supporting the diagnosis of patients. Diagnosis supports the identification of patients who may be eligible for one of our clinical studies but also supports the identification of patients who may be eligible for MSIVRI. We are leveraging the Clinical Development Program, its growing network of trial investigators, in addition to diagnosing and treating physicians at referral centers to build this community, which in turn will help support our commercialization efforts. Slide 24

So far more than 16 hundreds of unique HCP have submitted cash with pediatric endocrinologists and pediatricians accounting for more than half of them.

Medical geneticist PCP and family practice.

Also accounts for a significant portion.

Age of patients also provides encouraging data about 20% of the cash come from children 6 years of age or younger with the remaining 80% of submitted samples coming from individuals equal or greater than 7 years of age.

Patients past day have had severe obesity with BMI of adults testing on <unk>.

Average greater than 40 kilograms per meter squared.

Jennifer: Genetic testing, of course, remains at the center of our corporate strategy. For us, that means Uncovering Rare Obesity, or URO, our free genetic test designed to identify and help physicians diagnose patients with rare genetic diseases of obesity. As David mentioned, we expanded the panel to test for 80 genes with ties to obesity. To date, we have completed approximately 10,000 tests. It's important to note the panel was just expanded to include all 80 genes, so now all the genes in MN8 and Daybreak will be screened moving forward. We have also evaluated and made additional improvements in the URO program.

Slide 25.

In addition to on personal loans and are you of royalty program. We are building out our sales teams to support communities they'll go on.

Starting with targeted disease education efforts surrounding our clinical site.

It is important to note that we have already identified more than 650 patients.

It could potentially enrolling the trial, which confirmed genetic variants.

Within a reasonable distance select trial site.

Slide 26.

Our field teams will include medical science liaisons or on the south and their focus is on medical communications.

Oh, well on physician engagement of cross Biallelic, Tom C. P. C S K, 1 and less of our deficiencies book.

Part of Ddos syndrome, and ready to rare genetic diseases of obesity.

Jennifer: We've developed a new website to make it easier for physicians to order the test, receive results, and access contact information for genetic counseling support. Physicians will receive the test kits within five days, and in partnership with Prevention Genetics, we can turn around results within 21 days. Through the years, we have learned a tremendous amount about who orders the test and for whom. So far, more than 1,600 unique ACPs have submitted tests, with pediatric endocrinologists and pediatricians accounting for more than half of them.

And M&A and DAYBREAK.

Many of them for and myself have been with us for several years educating physicians and kols on the MTA for our pathway and its effect on hyperphagia and obesity supporting collaborations and for educational forums. For example, our gold Academy has reached more than 1000 providers in the last few years.

Thanks to the work of our MSL.

Second the addition to our U S field force our area development.

Jennifer: Medical Geneticists, PCPs, and Family Practitioners also account for a significant portion. Age of Patients also provides encouraging data. About 20% of the tests come from children 6 years of age or younger, with the remaining 80% of submitted samples coming from individuals equal or greater than 7 years of age.

The managers or Atms.

We'll focus on community the.

Education of genetic testing to drive enrollment emanate DAYBREAK and other clinical trials.

Here, we are working to build out of referral network around the selected sites fantastic appropriate patients, while supporting trial enrollment by engaging with HCP is what the potential patients.

This supports the development of a local hub in the network for fares and facilitate the trial execution.

Jennifer: Patients tested had severe obesity, with the BMI of adults tested on average greater than 47 kg per meter squared. Slide 25. In addition to improvements in our URO program, we are building out our field teams to support community building, starting with targeted disease education efforts surrounding our clinical sites. It is important to note that we have already identified more than 650 patients who could potentially enroll in a trial with confirmed genetic variants who live within a reasonable distance of a trial site.

Third portion of our U S field force, it's specific to the Bbs.

We'll have a dedicated sales force on the ground, who will engage current Bbs traders and diagnosis.

Our focus here is on disease education.

Physicians understanding of the impact of obesity and hyperphagia on patients and families.

Also supporting additional Bbs patient diagnosis.

Slide 27.

Jennifer: Slide 26. Our field teams will include Medical Science Liaisons, or MSLs, and their focus is on medical communications, KOL, and physician engagement across biallelic POMC, PCSK1, and leper deficiencies, as well as rare genetic diseases of obesity being studied in M&A and Daybreak.

Yeah.

For the initial commercial availability of from separate for patients with Biallelic part C. P. C. S. K, 1 and library of efficiencies our initial months on the market have gone well.

U S based infrastructure focuses on our G D O disease education to support additional patient diagnosis.

Jennifer: Many of our MSLs have been with us for several years, educating physicians and KOLs on the MC4 pathway and its effect on hyperphagia and obesity, supporting collaborations, and facilitating educational forums. For example, our GOLD Academy has reached more than 1,000 providers in the last few years, thanks to the work of our MSLs. The second addition to our U.S. field force are our Area Development Managers, or ADMs.

<unk> patient and physician education on surfaces.

In securing market access and reimbursement.

On the per site, we have had positive payer decisions made on instead of free spanning from large and small plans commercial on Medicaid.

The prior authorization for an in place have been consistent with our pi, including genetic confirmation BMI greater than 30 and efficacy touch point between the weeks 12 for 16.

Jennifer: ADMs will focus on community building, education, and genetic testing to drive enrollment and emanate daybreak and other clinical trials. Again, here, we are working to build out a referral network around selected sites to test appropriate patients while supporting trial enrollment by engaging with HCPs with potential patients. This supports the development of a local hub-and-spoke network for referrers and facilitates trial execution. A third portion of our U.S. Field Force is specific

As David has outlined for these initial indications we expect tens of patients in the first year of Q of commercial availability and we are off to a solid start with 1 full quarter in the books.

But more importantly, we are learning and preparing for a commercial launch in DBS and the middle of next year pending regulatory approvals of course.

Slide 28.

We are working to accelerate the diagnosis of Bbs patients.

Jennifer: We will have a dedicated sales force on the ground who will engage current BBS treaters and diagnosers. Our focus here is on disease education, supporting physicians' understanding of the impact of obesity and hyperphagia on patients and families, while also supporting additional BBS patient diagnosis. Slide 27.

Importing the understanding of the impact of hyperphagia and obesity on patients and families while supporting market access from century.

We are supplementing our current support program to improve customer service and provide support for Hep's on patients.

We're in the process of hiring the Bbs territory managers and corporate accounts team to continue engagement with ACP and pairs.

Jennifer: For the initial commercial availability of MCIV-3 for patients with bioallelic POMC, PCSK1, and leper deficiencies, our initial months on the market have gone well. Our U.S.-based infrastructure focuses on RGDO disease education to support additional patient diagnosis. Supporting Patient and Physician Education and Services and Securing Market Access and Reimbursement. On the payer front, we have had positive payer decisions made on MCIFRI, spanning from large and small plans, commercial, and Medicaid.

Separate from the as Mary outlined earlier, we have announced the collaboration with cribs, well, we will learn more about the Bbs patients to support our understanding and help prepare us for alliance.

With that I will.

On the call over to Jan for an update on the international efforts.

Yes.

Thank you Jennifer and good morning, everyone.

It is the very exciting time for reason, but the international level.

2 weeks ago, we announced that the European Commission granted marketing authorization to ancillary for the.

Jennifer: Prior authorizations put in place have been consistent with our PI, including genetic confirmation, BMI greater than 30, and efficacy touchpoints between weeks 12 through 16. As David has outlined, for these initial indications, we expect tens of patients in the first year or two of commercial availability, and we are off to a solid start with one full quarter in the books. But more importantly, we are learning and preparing for a commercial launch in BBS in the middle of next year, pending regulatory approvals, of course. 528.

The treatment of obesity and the control of hungry on associated with genetically confirmed the loss of function from.

See pieces of Q1, all the power of deficiency in other.

And children 6 years of age in the book.

This mix in salaries of the first and only treatment option available for patients in Europe to address the underlying cause of obesity is driven by itself.

The email undercutting for receptor pathway.

In Europe in many key countries in the Middle East South America and elsewhere, we are executing on the similar strategy as Denise sales team in North America.

Jennifer: We are working to accelerate the diagnosis of BBS patients and support the understanding of the impact of hyperfascia and obesity on patients and families while supporting market access for MSIVRI. We are supplementing our current support program to improve customer service and provide support to ACPs and patients. We are in the process of hiring BBS Territory Managers and the Corporate Accounts team to continue engagement with ACPs and payers. Separately from this, as Murray outlined earlier, we have announced a collaboration with CRIBS where we will learn more about the BBS patients to support our understanding and help prepare us for launch. With that, I will turn the call over to Yann.

With the first focus on community building to support the robust clinical development program, the retail and the commercial defaults C go on securing market access for <unk> 3 on the country by country approach.

Planning for the launch.

Loans next year.

But there are some differences in Europe.

For the rare genetic disease of obesity Europe is somewhat better organized with a lot of historical expertise menu of national centers of excellence and 3 the well established European on the research that works with the total of 50 academic centers.

More genetic testing focused on this disease has been done as many of the center to their own genetic testing.

Yann Mazabraud: Thank you, Jennifer, and good morning, everyone. It is a very exciting time for Rhythm at the international level. Two weeks ago, we announced that the European Commission granted marketing authorization to MCV for the treatment of obesity and the control of hunger associated with genetically confirmed loss of function by allelic POMC, PCSK1, or lipar deficiency in adults and children six years of age and above. This makes Incivory the first and only treatment option available for patients in Europe to address the underlying cause of obesity driven by certain genetic defects in the melanocortin 4 receptor pathway.

On genetic testing there isn't the opportunity for us to complement <unk>.

This existing testing so that is what we are doing as we of all European genetic testing and diagnostic strategy.

Of course pricing and reimbursement of also different in Europe and vary by country. We are advancing of country by country of reimbursement process and work to make <unk> available to patients as rapidly as possible.

We can do more detail it seems the next slide.

Indications are recognized as the rare disease anywhere on making strides in establishing the value of rare disease from the pricing standpoint with already many successes.

You mentioned a bit later on.

Preparing for Bgs is somewhat different to with large pool of patients in the approximately 20 European centers of excellence, we can the first validate the hook.

Yann Mazabraud: In Europe and many key countries in the Middle East, South America, and elsewhere, we are executing on a similar strategy as Jennifer's team in North America, with the first focus on community building to support the robust clinical development program Murray detailed and the commercial effort. Michael Higgins, Securing Market Access for M3 on a Country-by-Country Approach, and Third, Planning for BPS Launch Next Year. But there are some differences in Europe.

Yeah on preventing somebody else with more center of sheets of turnkey.

Sure.

Okay.

There are approximately 2000 identified Bbs patients across 15 for strategic 2 day.

Shifting to 100 of them being in the fight.

Yann Mazabraud: First, for the rare genetic disease of obesity, Europe is somewhat better organized with a lot of historical expertise, many national centers of excellence, and three very well-established European reference networks with a total of 50 academic centers. More genetic testing focused on this disease has been done, as many of these centers do their own genetic testing. Therefore, there is an opportunity for us to complement this existing testing. That is what we are doing as we develop a European genetic testing and diagnostic strategy.

On the milk any additional standpoint, we anticipate Standalone F. G. H engine all managers in the major European countries and the U K by the end of the true.

A very sophisticated field medical team has been on the ground for the last 2 years focusing on commodity building enrollment for clinical trials patient identification and medical education.

The states that the 1.

For the pumps, the Pts Q1 in the commercial aspects on the country level, we will see a lot of progressing for the second half of this year and begin to see reimbursement in 2022.

Yann Mazabraud: Of course, pricing and reimbursement are also different in Europe and vary by country. We are advancing a country-by-country reimbursement process and working to make MCV available to patients as rapidly as possible. I will give you more details on the next slide.

In Germany, we've had very positive engagement with the authorities to date and the <unk> to launch in 2022.

In France, we secured last true fast direct stages, which speeds the launch by 6 to 9 months and.

And we did file as a reimbursement of C 12 days ago right that tells the EMEA approval.

Yann Mazabraud: These indications are recognized as rare diseases, and we are making strides in establishing the value of these diseases from a pricing standpoint, with already many successes that I will also mention a bit later. Preparing for BBS is somewhat different too; with large cohorts of patients in approximately 20 European centers of excellence, we can first validate European prevalence numbers with more certainty, and second, there are approximately 2,000 identified VBS patients across EU15 plus Turkey today. 1,500 of them being in EU5.

In the U K, we have been selected for highly specialized technology assessment of HST <unk>, which is the specifics that just reserve for companies, which are reaching rare and severe disease.

This is the lowest for economic justification of the higher price.

It's a nice committee meeting will happen in December.

Pricing and reimbursement dossier of in process for submission in several additional countries for.

On Paul we did submit literally 2 weeks ago.

And we are walking at the Spanish and Dutch ones.

Outside of outside of Europe, We very recently reached an agreement in Israel with Medicine, which is a very well known rare disease Israeli company with a robust blocks for them and they're not standing track record of successfully advancing programs from the registration and reimbursement processes in order to commercialize Inc. Shire in Israel.

Yann Mazabraud: From an organizational standpoint, we anticipate standalone affiliates and general managers in the major European countries and the UK by the end of this year. A very sophisticated field medical team has been on the ground for the last two years, focusing on community building, enrollment for clinical trials, patient identification, and medical education. Thanks, everyone.

We also have the new countries.

For the patient identification and establishing excess and we are in parallel evaluating partnerships in civil law countries.

Yann Mazabraud: For Bialybic, POMC, PCSK1, and LIPAR commercial aspects at the country level, we will see a lot of progress in the second half of this year and begin to see reimbursement in 2022. In Germany, we've had very positive engagement with the authorities to date and hope to launch in 2020. In France, we secured last year Fast Track status, which speeds up the launch by 6 to 9 months. And we did file the reimbursement dossier 12 days ago, right after EMEA approval.

As you heard we are making significant progress in several international markets for biology on seed pieces can went on the path with first sales to come next year and this bodes very well for the upcoming Bbs launch as well as the upcoming attributing a force to drive genetic testing and enrollment in the phase 2 and phase III baskets for items.

I will now turn over to Andrew.

Thank you John.

Now I'll do a brief review of the second quarter financials.

Considering the net revenue was approximately $274000 in the second quarter and there was no revenue in the comparable period of 2020.

R&D expenses totaled $25 million and SG&A totaled $15.5 million for a net loss of approximately $35.4 million.

Yann Mazabraud: In the UK, we have been selected for Highly Specialized Technology Assessment, or HST, which is a specific status reserved for companies that are treating rare and severe diseases that allows for economic justification of a higher price. The next committee meeting will happen in December. Pricing and reimbursement dossiers are in the process for submission in several additional countries. For example, we did submit them in Italy two weeks ago.

Shares outstanding were $50.2 million and our net loss per share was <unk> 70 cents.

Rhythm remains very well capitalized as of June 30 of 2021 cash cash equivalents of short term investments of approximately $368.2 million.

Including net proceeds of $98.4 million from the sale of our PRP and proceeds of $162 million from rhythm is underwritten public offering which closed in February.

Yann Mazabraud: And we are working on the Spanish and Dutch ones. Outside of Europe, we have recently reached an agreement in Israel with Medicine Pharma, which is a very well-known Israeli rare disease company with a robust platform and an outstanding track record of successfully advancing programs through the registration and reimbursement processes in order to commercialize MCV in Israel. We also have a new country leader in Argentina focused on patient identification and establishing access, and we are, in parallel, evaluating partnerships in several other countries.

This is sufficient to fund our operating expenses expenses and capital expenditure requirements into at least the second half of 2023.

As you heard from David Murray, Jennifer of John we're advancing a robust corporate from clinical development strategy toward a meaningful increase the identical patient population and building out our company to do so we are well capitalized for well positioned to achieve these goals. Thanks for the confidence and support we received from many of you on the call today.

With that I'll turn it over to David to conclude.

Great. Thanks Hunter.

Hopefully with the.

You've appreciated is that we're about halfway through a transformational year for rhythm on the first half of the year I was marked by our announcement of the proof of concept data in the head of patients Src 1 of S. H <unk> deficiency obesity, and we updated you on the genetic sequencing of epidemiology data at that time, Jennifer <unk>.

Yann Mazabraud: As you heard, we are making significant progress in several international markets for biolytic POMC, PCSK1 and Lipar, with first cells to come next year, and this bodes very well for the upcoming BVS launch, as well as our community-building efforts to drive genetic testing and enrollment in our Phase II and Phase III pathway trials. I will now turn over to Hunter. Thank you, Yann.

You're a little more insight into those efforts, which of course are continuing.

As you've heard made and simply the sebree commercially available and we started our phase II of hypothalamic obesity trial the.

Hunter C. Smith: And now I'll do a brief review of the second quarter financials. In February, net revenue was approximately $274,000 in the second quarter, and there was no revenue in the comparable period of 2020. R&D expenses totaled $25 million, and SG&A totaled $15.5 million for a net loss of approximately $35.4 million. Shares outstanding were $50.2 million, and our net loss per share was $0.70. Rhythm remains very well capitalized. As of June 30, 2021, cash, cash equivalents, and short-term investments were approximately $368.2 million, including net proceeds of $98.4 million from the sale of our PRV and proceeds of $162 million from Rhythm's underwritten public offering, which closed in February.

In the second half as even more milestones the.

The decision has already come in we will present full data analysis from the pivotal phase III trial on B B S. At SP. In 2021, we will have on U S and EU regulatory submissions for Bbs and all strums, we're initiating the phase III trial in peds, the phase III M&A for Phase 2 day Berry and the 2 phase III trials.

For the weekly formulation as you heard from Murray and we will be presenting initial data from the phase 2 ongoing basket study on the M. C for our rescue both patients and the initial data from the phase II trial in high performing piece of these in the first half of 2022.

So it will finish on the slide 36, and this is a look at our pipeline and I'll just leave you with that thought I think many are rare disease companies.

Pursuing a strategy, which where they'll have a therapy, which is specific for certain disease. They may have.

The multiple therapies for multiple different diseases.

Many of those companies are well viewed as they should be.

We're a company that has 1 therapy, but we're pursuing a gene by gene opportunity here and each 1 of these genes are where we can establish safety and efficacy does open up a very meaningful the potential opportunity and so the pipeline slide as you see here and this isn't the fence a truncated.

Hunter C. Smith: This is sufficient to fund our operating expenses and capital expenditure requirements into at least the second half of 2023. As you heard from David, Murray, Jennifer, and Yann, we're advancing a robust corporate and clinical development strategy toward a meaningful increase in our identifiable patient population and building out our company to do so. We are well capitalized and well positioned to achieve these goals thanks to the confidence and support we received from many of you on the call today. With that, I'll turn it over to Dan.

And of that certainly if we were to put it out of gene by gene it would be quite long.

What people often worry about with the single asset as you know what if there's a problem with that asset and I think again I'd encourage you to look at rhythm in the context of the safety data that Murray highlighted this is a product that's been in over 630 patients.

A couple of individuals out as much as 5 years and so we have a an asset that is very much de risked from that standpoint of course, not every gene is going to work here, but again hopefully you've heard that we have a program that will allow us to efficiently begin to sort those and really get at the patients who are most likely to benefit from this therapy.

David P. Meeker: to call today. With that, I'll turn it over to David to conclude. Great, thanks, Hunter. So hopefully, with a What you've appreciated is that we're about halfway through a transformational year for Rhythm. The first half of the year was marked by our announcement of the proof-of-concept data in the head patients, SRC1 and SH2B1 deficiency obesity. We updated you on the genetic sequencing and epidemiology data at that time. Jennifer gave you a little more insight into those efforts, which, of course, are continuing. We have, as you've heard, made InSivri commercially available, and we started our phase two hypothalamic obesity trial. The second half has even more milestones. The EU decision has already come in.

So again.

3 genes approved to Tim.

Pending filing here coming up and the number of ongoing trials.

We will be reporting out of over the upcoming years, It's a journey and we are well on our way so with that I'll open it up to questions and I'll turn it back to the operator.

Thank you Sir.

A reminder to ask the question you will need the press star 1 on your telephone.

Can we go on your question. Please press the pound of Husky.

Against the other 1.

And our first question comes from the line of for later from Cowen and Company. Your line is open.

Good morning, Congratulations on all of the progress and thanks for taking my questions. Just a few of clarifying questions on the new trial design sort of announced this morning.

First on the M&A trial.

Are you enrolling.

David P. Meeker: We will present full data analysis from the pivotal phase three trial in BBS at ESPY in 2021. Additionally, we will have our US and EU regulatory submissions for BBS and Ahlstroms. We're initiating the phase three trial in PEDS, the phase three MNA, the phase two Dabiric, and the two phase three trials for the weekly formulation, as you heard from Murray. And we will be presenting initial data from the phase two ongoing basket study and the MC4R rescued patients and initial data from the phase two trial in hypothalamic obesity in the first half of 2022. So we'll finish on slide 36, and this is a look at our pipeline. And I'll just leave you with one thought.

The variance pathogenic or likely pathogenic or rous for all 6 genotypes or are those specifically for pumps in the par with the other gene and types of enrolling just pathogenic correct.

Okay. It's Mike here, so starting in the first of all with the last 1 so the last 1.

By definition is just 1 variant so it's the deletion and then 2 to 1 so that.

The loan regarding Src, 1 message to be 1 we will include people with pathogenic convenience.

But we don't need to stratify for them for most of those will be pathogenic variants is particularly important for the hex distress. The pie by the pathogenic in foods. So it's just too that will particularly struck to paying for.

David P. Meeker: I think, you know, many rare disease companies are pursuing a strategy where they'll have a therapy that is specific for a certain disease. They may have multiple therapies for multiple different diseases, and I think many of those companies are well-regarded, as they should be. You know, we're a company that has one therapy, but we're pursuing a gene-by-gene opportunity here, and each one of these genes, where we can establish safety and efficacy, does open up a very meaningful potential opportunity.

Got it so the the.

The water well.

It will mostly be pathogenic variance.

Got it okay and the.

Then second on the DAYBREAK phase 2.

If I heard you correctly it looks like in under 18 years of using BMI as the endpoint why are you using b mind should it be him I said it seems like Hunter 18, you could of patients increasing there'd be my simply because of the current procure puberty are aging.

Yes, so the east from moving to BMI as PMI allows you to look at both.

David P. Meeker: And so a pipeline slide, as you see here, and this is, in a sense, a truncated version of that. Certainly, if we were to put it out gene-by-gene, it would be quite long. What people often worry about with a single asset is, you know, what if there's a problem with that asset? And I think, again, I'd encourage you to look at Rhythm in the context of the safety data that Murray highlighted; this is a product that's been in over 630 patients, with a couple individuals out for as much as five years. And so we have an asset that is very much de-risked from that standpoint.

Adults and children, so BMI correlate steady well with.

So BMI correct for your height and kids and obviously on idle should heighten changing so that's why actually BMI is very solid to us for adults and children. So in our studies going forward. We've learned from our previous analysis. The PMI is probably going to be the the major focus for us when you're dealing.

The kids you can look at <unk> said, you don't have charged but I don't see you kind of look of BMI said denials of BMI is probably going to be the more robust. The kids you can look at PMI P. M. I said all of the 19th the Centaur on 95% in the 95th center for a number of ways of doing it for our focus is shifting for PMI because of this ability to look at.

David P. Meeker: Of course, not every gene is going to work here, but again, hopefully you've heard that we have a program that will allow us to efficiently begin to sort those and really get at the patients who are most likely to benefit from this therapy. So again, three genes approved, two pending filings here coming up, and a number of ongoing trials here that we'll be reporting out over the next years. It's a journey, and we are well on our way.

Adults and children.

So for all of its David you're correct in the sense that the BMI said may add a little more in terms of sensitivity. If you will but we believe and I think with good reason that since the BMI does include the 1 major variable we're trying to adjust for of height that it will work.

Got it okay just.

Just a couple of more on the weekly de Novo phase 3 it looks like the primary endpoints of week 18, but there is a 14 week open label period after the primary endpoint.

David P. Meeker: So with that, I'll open it up to questions and turn it back to the operator. Thank you, sir. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, please press the kind of... [inaudible] And our first question comes from the line of Phil Nadeau from Cohen & Company. Your line is open. Good morning.

What's the purpose of the appeared is that something that the FDA requested or.

Just want to keep patients on therapy.

No we won't actually see for the the long term effect of the weekly is so I think at 18 weeks new on the Daily day, 2 we will show statistical significance and clinically meaningful and we may be able to file actually on the 18 weeks, but actually to see the long term data on the weekly will be beneficial to patients on to us.

Operator: Congratulations on all the progress and thanks for taking my questions. Just a few clarifying questions on the new trial designs that were announced this morning. First, on the M&A trial, are you enrolling variants pathogenic, likely pathogenic, or VOOC for all six genotypes, or are those specifically for POMC and LEP-R with the other genotypes enrolling just pathogenic? Okay, it's Murray here.

Okay, and then last question in terms of the pediatric phase III.

Do you need to have 1 patient at least of each of the pumps C. P. C. S. K 1 in my part of genotypes or would it be possible for the 5 patients that could have the extreme types like if they were all <unk>.

I'm sorry.

So its day.

They just see if the Greek trip on the 1 pump C. P. C. S cakes that for rare 1 let par and then 1 bps. So you really do see 3 and we've actually got them already lined up so I don't think the regulatory requirement for getting that data.

Murray: So, I'm starting in reverse order with the last one. So, the last one, by definition, is just one variant. So, it's a deletion, and then two to one. So, that's...

Murray: Regarding SRC1SH2B1, we will include people with pathogenic variants, but we don't need to stratify for them, for most of those will be pathogenic variants. It's particularly important for the HEX to stratify by the pathogenicity of foods, so it's just two that we will particularly be stratifying for. Got it.

We will reach that easily.

Got it so you need 1 of each and then the others, yes. It can be of any true okay. Perfect. Thanks for taking my questions and congrats on getting on the progress.

Thank you next question.

Our next question comes from the line of David Lebowitz from Morgan Stanley. Your line is open.

Hi, This is avatar Jones on for David. This morning, we have 2 questions first on the Cribbs registry collaboration do you anticipate this partnership will have an impact on 1 patient identification or of launch trajectory and Bard pedal syndrome, and our second question is on.

Murray: So the latter will mostly be pathogenic variants, so SRV1, yep, got it, okay. And then, second on daybreak phase two, if I heard you correctly, it looks like in under 18 years, you're using BMI as the endpoint. Why are you using BMI instead of BMI-Z? It seems like under 18, you could have patients increasing their BMI simply because they're going through puberty or age. Yeah, so the reason we're moving to BMI is BMI allows you to look at both adults and children. So BMI correlates very well with, and it corrects for your height in kids. And obviously, in adults, your height isn't changing.

On market access can you, possibly provide any quantitative metrics to date.

Yeah, Thanks, I've talked so Jennifer.

So the the Christmas registry.

Approximately.

625, ABS patients within the registry words of call of having approximately 675 patients by the end of the year and the vast majority of these patients are from the U S. So and of credible source of information.

Murray: So that's why BMI is very solid to use for adults and children. So in our studies going forward, we've learned from our previous analysis that BMI is probably going to be the major focus for us. When you're dealing with kids, you can look at BMI-Z. You don't have charts for adults, so you can't look at BMI-Z in adults. So BMI is probably going to be the more robust method. But with kids, you can look at BMI, BMI-Z, or the 95th centile, or 95% of the 95th centile. So there are a number of ways of doing it.

Just in terms of launch preparation.

Parallel with that.

Outlined we are working.

Working with our already existing in the South team and are currently recruiting Bbs territory manager team and because Bbs as syndromic.

We had the opportunity to be even more targeted in terms of fire disease education efforts and also patient identification efforts.

In parallel with the through or just broad Archie D. O at disease Education efforts. We are also on covering our biallelic patients that and path P. B S jeans there.

David P. Meeker: But our focus is shifting for BMI because of this ability to look at adults and children. So Phil, this is David. You're correct in the sense that the BMI-Z may add a little more in terms of sensitivity, if you will, but we believe, and I think with good reason, that since the BMI does include the one major variable we're trying to adjust for, height, that it will. Okay.

There's already existing patients in the hundreds in the U S that have been identified.

To.

The support robust lines, and we will be of course moving forward.

All of our interest in terms of supplementing that with additional patient finds through our field efforts.

Murray: Okay. Just a couple more. On the weekly de novo phase three, it looks like the primary end point is at week 18, but there is a 14-week open label period after the primary end point. What's the purpose of that period?

From a market access standpoint.

As I mentioned the feedback from the payers have been positive our real focus has been on really trying to differentiate.

Murray: Is that something that the FDA requested? You just want to keep patients on therapy. No, we want to actually see what the long-term effect of the weekly is. So I think in 18 weeks, knowing the daily data, we will show statistical significance and clinically meaningful. And we may be able to file on that 18 week trial, but actually, to see the long term data on the weekly will be beneficial to patients and to us.

Target patient populations from broad obesity based off of the genetic background and the.

The fact that fan early onset.

The hyperphagia and obesity caused by this mutation in the pathway on that.

Once again, we have been successful.

Is it for them.

Some of the payer decisions made to date with the vast majority of these being positive.

Murray: Got it. Okay, and then last question, in terms of pediatric phase three, do you need to have one patient at least of each of the POMC, PCSK1, and LEPR genotypes, or would it be possible for the five patients that could have those genotypes, like if they were all POMCs? So the agency has agreed to either one POMC PCSK, because that's so rare, one LEPR, and then one BBS. So you really just need three, and we've actually got them already lined up. So I don't think the regulatory requirement for getting that data; I think we'll reach that easily. Got it. So you need one of each, and then the others can be...

And we do encounter challenges.

We have a support team in place to really for she will overcome the challenges and get access for the patients.

Thank you for okay. Thank you overtime the next questions.

And our next question comes from the line of Disney Ahmad from Bank of America for your line is open.

Hi, good morning Congrats.

Congrats on the progress for me as well and thanks for taking my questions.

I have a few focus on commercial.

As of right now can you give us an idea of what the distribution is just based on.

What percentage of our commercial payors versus what percentage of your government payers.

Murray: Okay, perfect. Thanks for taking my questions and congrats again on... Thank you.

And then as you look forward to enrolling the M&A trial, you've given us an idea of basically of when you expect.

Operator: Next question. Our next question comes from the line of David Lebovitz from Morgan Stanley. Your line is open.

To file and so how has your.

The patient finding efforts resulted in you getting confidence at the rate of enrollment of the study.

Operator: Hi, this is Avatar Jones on behalf of David this morning. We have two questions. First, on the CRIBS registry collaboration, do you anticipate this partnership will have an impact on patient identification or the launch trajectory in barred fetal syndrome? And our second question is on market access. Can you possibly provide any quantitative metrics to date?

Yes, I think on the the commercial side of Denver, just 1 of them.

Alright, we can't provide for probably a lot more detail here at the same but the majority of the payers that we've talked to and have growth. So far have been commercial payors on by far I mean, we have been in the Medicaid population and the majority of the Medicaid on that we have been working with.

Jennifer: Yeah, thanks, Avatar. So Jennifer

We have rolled to date again have been positive not 100 per cent.

Jennifer: So, the CRRS Registry has approximately... 625 BBS patients within the registry with a goal of having approximately 675 patients by the end of the year, and the vast majority of these patients are from the U.S., so an incredible source of information just in terms of launch preparation. In parallel with that, as I outlined, we are working with our already existing MSL team and are currently recruiting BBS territory managers, and because BBS is syndromic, we have the opportunity to be even more targeted in terms of our disease education efforts and also patient identification efforts.

But I don't know if that helps.

Just say we have as a working assumption for this population that about a third of the patients will be Medicaid.

Okay and that the does that all of the long term on a long term basis is going to jump up and down as we get into more patients, but on the long term basis, we're working with a third as the as the baseline.

Okay and would that also called when you expand out to the.

Hunter potentially hundreds of the 200000 page.

Patients from your bigger indication.

I don't know that we have enough info yet on the demographic to say so all I would say is that for the most part of our patients are skewing younger and Medicaid.

Medicaid coverage among the young is higher than the among the total covered lives on the U S.

Got it okay.

And your second question on the M&A trial and enrollment.

Jennifer: In parallel with this, through our just broad RGBO disease education efforts, we are also uncovering biallelic patients that have BBS genes. So there are already existing patients in the hundreds in the U.S. that have been identified to, you know, support a robust launch, and we will be, of course, moving forward just in terms of supplementing that with additional patient finds through our field efforts. From a market access standpoint, as I mentioned, the feedback from payers has been positive.

Yeah, I think it's unfortunately or whatever early as well as gennifer highlighted there's in the screening efforts to date in the U S 650 patients with.

Would qualify for.

Either the emanate trial for the day break trial a ritual the original screen. He said that we have expanded our U R. O panel to include 80 genes at the current time and that does include all 31 genes in the day break in the 5 and the phase III M&A trial, our previous screen heading.

Jennifer: Our real focus has been on really trying to differentiate our target patient populations from broad obesity based on their genetic backgrounds, the fact that from early onset, you know, they have this hyperphagia and obesity caused by this mutation in the pathway. And so, once again, we have been successful with over 70 payer decisions made to date, with the vast majority of these being positive. When we do encounter challenges, you know, we have a support team in place to really work to overcome those challenges and get access for the patient.

Always included the the phase III emanate trial of genes. So a larger percentage of that 650, <unk> falls in that bucket and it only included 7 genes in our new 31 gene. So the expansion and that's been somewhat recent in terms of expanding the 80 Theres a good set of genes that were just.

<unk> to look for but.

Most importantly to your question on the M&A trial has been part of our hour of prior screening efforts were off for a good start and then of course as Yan said in Europe.

Those.

Centers tend to be again better organized with.

More definitive genetic testing done.

We see on the U S.

Jennifer: Thank you. Okay. Thank you, Avatar. Next question. And our next question comes from the line of Tazeen Ahmad from Bank of America. Your line is open.

Okay. Thank you.

Okay.

Next question.

And our next question comes from the line of Joseph Stringer from Needham and company. Your line is open.

Hi, good morning, Thanks for taking our questions 2 from US 1 is just following up on that last comment on <unk>.

Operator: Hi, good morning.

Operator: Congratulations on the progress for me as well, and thanks for taking my questions. I have a few focused on commercial. As of right now, can you give us an idea of what the distribution is just based on what percent are commercial payers versus what percent are government payers? And then, as you look forward to enrolling the MNA trial, you've given us an idea, basically, of when you expect to file. And so, how have your patient-finding efforts resulted in you getting confidence in the rate of enrollments in the study?

The slide I think slide 30 on some metrics for Bbs patients and.

You are making the comment that some of the European.

Markets, maybe 1 day.

More organized and say relative relative to the U S. Just curious David the number 2000, Bbs patients I need crossing.

Around 1500.

For plus U K.

How does how does that compare relative to say.

What what a U S. What's in the U S metrics may look like in.

In terms of.

Genetic identification and then secondly.

On the DBS algae oil.

Jennifer: Yeah, I think on the commercial side, Jennifer, just want to, we can't provide full, probably a lot more detail here, Tazeen, but the majority of the payers that we've talked to and have ruled in favor of so far have been commercial payers, by far. We have been in the Medicaid population, and the majority of the Medicaid that we have been working with, we have ruled to date, again, have been positive, not But I don't know if that helps. Tazeen, I would just say,

F&B is just curious thinking of your thoughts on discussions with regulators around the inclusion of the algae oil and the F&B egg.

I know there was some debate what potential debate about whether or not to include that based on some of the phase III data, but some more color on that would be helpful. Thank you.

Yep, great the lap of Jennifer comment just on the.

The U S numbers for Bbs relative to the European and then comment on the Bbs filings.

And so.

The Crimson registry has outlined that there are approximately 625 patients in the registry with the call of increase from that over the years.

Jennifer: I would just say we have as a working assumption for this population that about a third of the patients will be Medicaid patients.

Jennifer: Okay, and that's a, does that hold?

Jennifer: On a long-term basis, this is going to jump up and down.

The vast majority of these patients are from the U S. What's interesting is that you know in it and it makes sense in terms of of the patients that are followed a lot of these patients due to the younger because they have motivated parents, who are also interested in terms of.

Operator: Thank you for joining us today.

Jennifer: Okay, and would that also hold when you expand out to this, you know, 100, potentially 100 to 200,000? Patients and Your Bigger Indication.

Jennifer: I don't know that we have enough information yet on that demographic to say so.

The learning more about the disease and.

Jennifer: All I would say is that, for the most part, our patients are skewed.

Participating in tranches, the registry with the questions on sites.

Jennifer: Medicaid coverage among the young is higher than among the total covered lives in the United States. Got it. Okay.

Are there opportunities of course to them as we move forward with the specific therapy for treatment of these patients to get more of a disease education targeted disease education to identify additional patients that may have already been diagnosed and less of a sense on them, but all sorts of diagnosed patients who are have been seeking for.

Jennifer: And your second question on the M&A trial and enrollment. Yeah, I think it's, unfortunately, or whatever, early as well. As Jennifer highlighted, in the screening efforts to date in the U.S., 650 patients would qualify for either the MNA trial or the daybreak trial. Our original screen said that we've expanded our URL panel to include 80 genes at the current time, and that does include all 31 genes in the daybreak trial and the five in the phase three MNA trial.

For years for that accurate diagnosis.

Okay.

With regards to the the ahlstrom the agencies would actually welcoming to the roster of of Frank discussion. They were aware the Austin patient assemble we're small in the <unk> 3 the pivotal study that was just 6 alstom see a push for vulnerable on part of the dialogue. We went in and said we wanted to put in the totality of the data.

Jennifer: Our previous screen always included the phase three MNA trial genes, so a larger percentage of that 650 falls in that bucket. It had only included seven genes in our new 31 genes. So, the expansion, and that's been somewhat recent in terms of expanding to 80, there's a good set of genes that we're just starting to look for, but, you know, most importantly to your question, the MNA trial has been part of our prior screening efforts, so we're off to a good start. And then, of course, as Yann said, in Europe, those centers tend to be, again, better organized with more definitive genetic testing done than we see in the U.S.

Included phase II, and some supplemental and what do we do that we've got 12 volts from patients many of the Austin patients of young and showing some benefit this might be lost if you just look at weight. So we've put in place not of tips of the ostrom on both agencies, who are willing to a few of the awesome data as part of a separate indication.

Great. Thank you Inc.

That's good from thanks, the next question.

Sure.

Once again, if you wish to ask the question. Please press the star 1 on your phone.

And our next question comes from the line of.

Great Great of an image from Goldman Sachs. Your line is open.

Hey, good morning, everyone. Thanks for taking my questions.

Certainly got a busy second half.

Operator: Okay, thank you. And our next question comes from the line of Joseph Stringer from Lee Van Wink Company. Your line is open. Hi, good morning. Thanks for taking our call.

Before you.

If I could ask maybe 3 questions.

First.

Given all of the new trials that you've got that are about to start is there a way that perhaps you can use the easily just summarize when do you expect.

Operator: You're making a comment that some of the Europeans...

Operator: [inaudible] what what a US what some US metrics may look like in

Operator: in terms of genetic identification. And then secondly...

Submit timelines around.

Operator: on the BBS Algae Oil, SNDA; just curious to get your thoughts on discussions with regulators around inclusion of Algae Oil.

The Readouts for these multiple trials just to help for.

That for us and put it in context.

On the second question I have and maybe this question is better ask for for Hunter.

Murray: I know there was some debate, well, potential debate about whether or not to include that based on some of the phase 3 data, but some more color on that would be helpful.

In terms of the spend in Opex that we should anticipate in the second half you could provide some color on what that would like relative to the first half and then exiting the fourth quarter, how we should think about 'twenty 2.

Murray: Yep, great. I'll have Jennifer comment just on the US numbers for BBS relative to Europe, and then Murray can comment on the BBS filing.

Jennifer: The CRIBS registry has outlined that there are approximately 625 patients in the registry with a goal of increasing that number over the years. The vast majority of these patients are from the U.S. What's interesting is that, you know, and this makes sense, in terms of the patients that are followed, a lot of these patients appear to be younger because they have motivated parents who are also interested in terms of learning more about the disease and, you know, participating in terms of the registry with the questions and such.

And then I'll follow up of a third question after.

The answer the first 2 thanks.

Okay. Thanks, Thanks, Greg I'll start here and then the American amplify here so from a timeline standpoint, the standpoint, if you take the emanate the phase III trial for.

5 independent studies, they will enroll by definition at different rates. We indicated in this presentation that we expect overall, a 12 to 18 months enrollment period the.

And Q2 when the sub study is the most prevalent of the genes and we would fully expect that to enroll the fastest and be on the early side of that the pathogenic likely pathogenic portion of the Hertz is by far the least common and we would expect those to be the slowest.

Jennifer: There are opportunities, of course, to, as we move forward with a specific therapy for treatment of these patients, to do more disease education, targeted disease education, to identify additional patients that may have already been diagnosed and lost in the system but also to diagnose patients who have been seeking for years for that accurate diagnosis.

And so for the pumps he had on the left bar heads and they would be at the upper end of debt and again the teens question more to be learned about sort of how the rates of the these are going to play forward. The S. H T. B 1 Src 1 are somewhat in the middle of them.

Murray: With regard to the Ostroms, the agencies were actually welcoming for us to have a frank discussion. They were aware that Ostrom patients' numbers were small in the O2-3, the pivotal study. There were just 6 Ostroms, 3 of which were valuable.

I'll give you some numbers because that'll be the most helpful. Here in terms of prevalence is.

Murray: And part of the dialogue, we went in and said we wanted to put in the totality of the data, which included phase 2 and sub-supplemental. And when we do that, we've got 12 Ostrom patients. Many of the Ostrom patients are young and showing some benefit that may be lost if you just look at weight.

The the pathogenic or likely pathogenic part of the heads have a frequency in the severely Peru severe early onset obesity population of about 0.2, the S H to be won.

S. R C, 1 or 2% plus 2.2.5% and the and 2 to 1 D is around 5%. So you can see on a relative magnitude. If it was just a function of screening and frequency of binding based on the screening you can see how that that might on a.

Murray: So we put in the case narratives of the Ostroms, and both agencies were willing to review the Ostrom data as part of a separate indication. Great, thank you. Yep, that's good, Joe. Thanks. Next question. Once again, if you wish to ask a question, please press star 1 on your phone. And our next question comes from the line of... Grace Ovenevich from Goldman Sachs, Sharnan Zouk. Hey, good morning, everyone.

Roll forward.

The pediatric trial as Murray said that.

10 patients is the goal of 3 patients as the minimum those 3 in the sense already identified so that again, we expect to play forward over the next year.

Operator: Thanks for taking my questions. You certainly have a busy second half ahead of you. If I could ask maybe three questions. First, given all the new trials that you've got that are about to start, is there a way that perhaps you can easily just summarize when you expect approximate timelines around the readouts for these multiple trials just to help frame it for us and put it in context? The second question I have, and maybe this question is better asked for Hunter, in terms of the spend in OPEX that we should anticipate in the second half, you could provide some color on what that would look like relative to the first half and then, exiting the fourth quarter, how we should think about, you know, 22. And then I'll follow up with a third question after you hopefully answer the first two. Thanks. Thanks, Greg. I'll start here, and then Murray can amplify it.

And similarly with the weekly the first switch part of that study that includes patients by definition, who are already on therapy. So they're all identified and within the network that trial will initiate first in AR should be quite efficient. So again should playing forward in 2022.

What am I missing here Mary.

The phase 2 day break just so the empty it will take a while because if you've got 18 months recruitment and then 12 months for.

The actual study and that's all blinded youre not going to hear much from revenue for a while but the good news about the day break study is because we're looking at people coming in and we can look each gene in the first section of its open label, we'll get an idea of how that's going on so we'll hopefully be able to report out.

David P. Meeker: So, from a timeline standpoint, if you take the M&A, the Phase 3 trial, five independent studies, they will enroll, by definition, at different rates. We've indicated in this presentation that we expect an overall 12- to 18-month enrollment period. The N221D sub-study is the most prevalent of the genes, and we would fully expect that to enroll the fastest and be on the early side of that. The pathogenic, likely pathogenic, portion of the HETs is by far the least common, and we would expect those to enroll the slowest.

Next year on some of the the face to deeply genes and then accelerate then so I know you asked for a simple answer twin the timelines on unfortunately, it's complicated because we'll get quicker readouts in phase III longer readouts in the phase III and the pediatrics. If we do that quickly we can get data on that again and then.

<unk> of next year.

And Greg to your question about cash.

Cash usage as we as we go forward obviously the <unk>.

Much of the.

Enrolment in start up dependent on those types of things we of baseline assumptions for we had on operating use of cash of about $31 million in the quarter and we paid our 5.2.

David P. Meeker: And so, for the POMC HET and the LEPR HETs, they would be at the upper end of that. And, again, to Tazeen's question, more to be learned about sort of how the rates of these are going to play out. The SH2B1, and SRC1 are somewhat in the middle. And let me just give you some numbers, because that will be the most helpful here. In terms of prevalence, the pathogenic, likely pathogenic part of the HETS, has a frequency in this severe early-onset obesity population of about 0.2. The SH2B1, and SRC1 are 2% plus to 2.5%. And the N221D is around 5%.

Ipsen for the first commercial sale that we had accrued in the in the.

The first quarter and we do expect things to rise from there in Q3 and for but I'm not going to provide too much more guidance beyond the overall cash out timing of the second half of 2023.

Okay. Thank you and then my other question just has to do with the crimped. The Cribbs registry of the 600 patients to have their it could you maybe provide an idea as to what proportion of those patients do you think would be eligible for treatment and.

David P. Meeker: So you can see, relative to the relative magnitude, if it was just a function of screening and frequency of finding based on screening, you can see how that might roll forward. The pediatric trial, as Murray said, that, you know, 10 patients is the goal, three patients is the minimum. Those three, in a sense, are already identified.

Okay.

Some portion all of them.

However, you want to describe that and then beyond that.

How quickly assuming an approval.

In that indication do you think they could.

David P. Meeker: So that, again, we expect to play forward over the next year. And similarly, with the weekly, the first switch part of that study, that includes patients, by definition, who are already on therapy. So they're all identified and within the network. That trial will start first and should be quite efficient. And what am I missing here, Murray?

Get on therapy.

Yeah. Thanks, Craig So we want the we're not going to provide guidance for the launch yet, but the tenant to take the first part of your question.

Sure.

So in D B S.

For different publications and such are approximately 80% of the patients have obesity.

3 of the work of the Cribbs registry that captures an incredible amount of demographic data in the.

David P. Meeker: The phase two daybreak, just, so the MNA will take a while because if you get 18 months of recruitment and then 12 months of longer readouts in phase three. And the pediatrics, if we do that quickly, we can get data on that again at the end of next year.

The patients as well well gain a better understanding in terms of the split out of Asia.

By age and BMI and such that will also help guide. The question that you are asking on understanding in terms of uptake within each of these patient populations.

Hunter C. Smith: And Greg, to your question about cash usage as we go forward, obviously, much of this is enrollment and startup dependent and those types of things we have baseline assumptions for. We had an operating usage of cash of about $31 million in the quarter.

I also want to outlined.

<unk> outlined that.

And contrary to our P. P L band we like.

Study the.

Hunter C. Smith: and we paid our 5 million dollars to.

DBS study actually did have a large portion of the patients coming from the U S that is.

Hunter C. Smith: It's for the first commercial sale that we had accrued in the first quarter, and we do expect things to rise from there in Q3 and Q4, but I'm not going to provide too much more guidance beyond that.

You know a nice initial bullets in terms of patients that can be converted over to commercial patients as the starting point.

Operator: Thank you all for joining us. Okay, thank you. And then my other question just has to do with CRIBS, the CRIBS registry, and the 600 patients you have there. Could you maybe provide an idea as to what proportion of those patients would be eligible for treatment and, some portion, all of them, however you want to describe that, and then, beyond that, how quickly, assuming an approval in that indication, do you think they could get on therapy? Yeah, thanks, Greg. So we won't, we're not going to provide guidance for launch yet. But let Jennifer take the first part of your question.

And to that point of our goal is some of those patients will be used in the switch study and again, we're highly focused on getting that switch David switch study initiated and completed in time to coincide with the approval in the U S.

So I don't know for you answer all of your questions, Greg, but can we get there some of them.

You did thank you very much for taking the questions.

Thanks.

The question.

I don't know if I get the questions at this time I'd like to hand, the conference back to our speaker Mr. David Meeker. Please continue.

Jennifer: So in BBS, through different publications and such, approximately 80% of the patients have obesity. Through the work of the CRIBS registry, which captures an incredible amount of demographic data in the patients as well, we'll gain a better understanding in terms of the split out of patients by age and BMI and such, which will also help guide the question that you are asking and understanding in terms of uptake within each of these patient populations.

Okay, great well. Thanks again, all of you for joining into our first earnings call and we appreciate your questions and your interest as we go forward and we look forward to updating you again through a very meaningful second half of the year.

On.

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

Goodbye.

Okay.

Jennifer: I also want to outline that, contrary to our PPL by allelic study, the BBS study actually did have a large portion of the patients coming from the U.S. That is a nice initial bolus in terms of patients that can be converted over to commercial patients as a starting point.

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David P. Meeker: And to that point, our goal is that some of those patients will be used in a switch study. And again, we're highly focused on getting that switch study initiated and completed in time to coincide with approval in the U.S.

Okay.

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David P. Meeker: I don't know if we answered all your questions, Greg, but did we get there somewhat? You did. Thank you very much for taking my questions. Thanks. And there are no further questions at this time. I'd like to hand the conference back to your speaker, Mr. David Meeker. Please continue. Okay, great.

David P. Meeker: Well, thanks again, all of you for joining us on our first earnings call. And we appreciate your questions and your interest as we go forward. And we look forward to updating you again during a very meaningful second half of the year. Talk soon. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.

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