Q3 2023 Scholar Rock Holding Corp Earnings Call

November 7, 2023

Good morning, I'm actually not senior Vice President Corporate Affairs, and Investor Relations at scholar Rock welcome and thank you for joining us today for our Q3 2023 business update call.

Speaker 1: Good morning. I'm Rashmi Nafsir, Vice President of Corporate Affairs and Investor Relations at Scholar Rock. Welcome and thank you for joining us today for our Q3 2023 business update call. This call is audio only. You can access the slides that we'll be referring to on the events and presentations section of the investor relations page on the Scholar Rock website.

This call is audio only you can access the slides that we'll be referring to on the events and presentations section of the Investor Relations page on the scholar rock website.

Moving to slide two before we begin I want to note that we'll be making various statements about scholar rock's expectations plans and prospects that constitute forward looking statements for the purposes of the safe Harbor provisions under the private Securities Litigation Reform Act of 1995.

Speaker 1: Moving to slide two. Before we begin, I want to note that we'll be making various statements about Scholar Rock's expectations, plans, and prospects that constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

Any forward looking statements represent our views only as of today and should not be relied upon as representing our views as of any future date.

Speaker 1: Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any future date.

Speaker 1: Please refer to our SEC filings for the full disclosure of all the risks.

Please refer to our SEC filings for the full disclosure of all the risks.

Speaker 1: Turning to slide three, I'd like to introduce the members of the Solar Rock team who will be presenting during today's call and will be available for questions after the conclusion of the formal remarks.

Turning to slide three I'd like to introduce the members of the solid rock team, we'll be presenting during today's call and will be available for questions. After the conclusion of the formal remarks.

Speaker 2: I am joined by Jay Baxstrom, CEO of Scholar Rocks, Ted Miles, Chief Operating Officer and Chief Financial Officer, and Mo Cuttanani, Head of Research. I will now turn it over to Jay. Thank you, Rashmi. Good morning, and welcome to our Q3 Business Update.

I am joined by Jay Backstrom, CEO of scholar Rock, Ted Myles, Chief operating Officer, and Chief Financial Officer, and moat cuts and Ani head of research I will now turn it over to Jay Thank.

Thank you Raj and good morning, and welcome to our Q3 business update call. We have made excellent progress so far this year and in particular in the third quarter and I'm very excited about our future and believe we are well positioned for success moving to slide four.

Speaker 2: We've made excellent progress so far this year, and in particular in the third quarter, and I'm very excited about our future and believe we're well positioned for success. Moving to slide four.

Speaker 2: Before I review the details of our progress, I want to start with Scholar Rock's pioneering approach to targeting TGF-beta superfamily of growth factors.

Before I review the details of our progress I want to start with scholar Rock's pioneering approach to targeting TGF beta superfamily of growth factors the.

Speaker 2: The picture on the left of the slide depicts the latent complex that contains the inactive growth.

The picture on the left of the slide depicts the latent complex that contains the inactive growth factor.

Speaker 2: The scientific insight that led to the understanding of the structure of this latent complex is part of the foundation of our industry-leading platform that targets TGF-beta superfamily of growth factors by selectively and specifically blocking their activation by locking up the growth factor in the precursor-related form.

The scientific insight that led to the understanding of the structure of this late and complex is part of the foundation of our industry, leading platform that targets TGF beta superfamily of growth factors by selectively and specifically blocking their activation by locking up the growth factor in the precursor or latent form.

Speaker 2: This highly specific approach limits the off-target effects that have been observed with less selective approaches that target the active forms of the growth factors or interfere with their receptors such as the active end receptors. Apitocrine abrasion is ongoing due to the tremendous amount

This highly specific approach limits the off target effects that have been observed with less selective approaches that target. The active forms of the growth factors or interfere with their receptors such as the active and receptors or <unk>, our lead clinical program targeting late Myostatin.

Speaker 2: targeting latent myostatin, prevents the formation of the active form of myostatin, a negative regulator of muscle growth, and leads to an increase in muscle mass and function in nonclinical models, and is the first anti-myostatin therapy to demonstrate clinical proof of concept.

Prevents the formation of the active form of Myostatin, a negative regulator of muscle growth.

And leads to an increase in muscle mass and function in non clinical models and as the first anti myostatin therapy to demonstrate clinical proof of concept.

Moving to slide five.

I was very excited to announce that we are leveraging our R&D platform and deep knowledge of Myostatin biology to expand into a new therapeutic area of cardio metabolic disorders with our novel highly potent and selective anti myostatin antibody <unk> hundred 39 in combination with the <unk> receptor agonists.

Speaker 2: I was very excited to announce that we are leveraging our R&D platform and deep knowledge of myostatin biology to expand into a new therapeutic area of cardiometabolic...

Speaker 2: with our novel, highly potent, and selective anti-myostatin antibody, SRK439, in combination with a GLP-1 receptor action.

Speaker 2: Scholar Rock has a long standing interest in targeting myastand for cardiometabolic disqualification.

Scholar rock has a long standing interest in targeting myostatin for cardio metabolic disorders.

Speaker 2: giving the role that muscle plays in glucose metabolism and insulin sensitivity.

The role that muscle plays in glucose metabolism and insulin sensitivity.

Speaker 2: As you'll hear from later in this morning's presentation, our approach to blocking myostatin is ideally suited for use in both SMA and in cardiometabolic disorders, since by blocking myostatin and only myostatin, we avoid off-target talk.

As you'll hear from our later in this morning's presentation are approach to blocking myostatin is ideally suited for use in both SMA and in cardio metabolic disorders since by blocking Myostatin and only milestone we avoid off target toxicities safe.

Safety is critically important in treating SMA and in weight loss therapy, and we believe our selective approach as we've seen with the <unk> and in our SMA program to date should lead to a favorable overall benefit risk profile.

Speaker 2: Safety is critically important in treating SMA and in weight loss therapy. And we believe our selective approach, as we've seen with the Pythagorean Mabiner, our SMA program today, should lead to a favorable overall benefit risk profile. Moving to slide set.

Moving to slide six.

Speaker 2: Targeting the TGF-8 of Superfamily has broad therapeutic applications, given the central role this family of growth factors plays in wide range of cellular processes, including growth and differentiation.

Targeting the TGF beta superfamily has broad therapeutic applications given the central role of this family of growth factors plays and wide range of cellular processes, including growth and differentiation.

Our research teams have produced a robust pipeline of product candidates targeting latent myostatin and latent TGF beta one and very pleased with significant progress that we've made on our pipeline since the beginning of the year moves.

Speaker 2: Our research teams have produced a robust pipeline of product candidates, targeting late in myastad and late in TGF 1. I'm very pleased with the significant progress we've made on our pipeline since the beginning of the year.

Moving to slide seven.

For this mornings call I will start with an update on our clinical programs highlighting the status of <unk> hundred one our selective anti light and TGF beta one antibody in immuno oncology.

Speaker 2: For this morning's call, I will start with an update on our clinical programs. Highlighting the status of SRK-181 are selective, anti-latin TGF beta-1 antibody and immunolancology.

Speaker 2: followed by an update on the progress we've made with our number one priority, a pitagram app in SMA.

Followed by an update on the progress we've made with our number one priority <unk> and SMA.

Speaker 2: and then turn to mode and discuss our entry and a cardiometabolic disorders with our novel anti-miostatin SRK439. Moving to slide eight.

And then turned to mow to discuss our entry into cardio metabolic disorders with our novel anti Myostatin SRP 4009.

Moving to slide eight.

Slide eight provides an overview of the Dragon trial as a reminder, the main objectives of the Dragon study. In addition to dose ranging and safety included establishing proof of mechanism and proof of concept that by blocking TGF beta one.

Speaker 2: As a reminder, the main objectives of the Dragon study, in addition to dose ranging and safety, included establishing proof of mechanism and proof of concept that by blocking TGF beta 1, a key driver for resistance could check insects' Okay, here's the observation.

Key driver for resistance to checkpoint inhibitors with <unk> at 101 in combination with <unk> that we could overcome the immune suppressive environment and restore responsiveness to the checkpoint inhibitor.

Speaker 2: With SRK-1 at 1-8-1 in combination with Pembrolyzema, that we could overcome the immune-suppressive environment and restore responsiveness to the checkpoint inhibitor.

To achieve to achieve these objectives. The part B portion of the study included expansion cohorts in several tumor types.

Speaker 2: To achieve these objectives, the Part B portion of the study included expansion cohorts and several tumor types and required all patients to have progressed on the most immediate prior anti-PD-1 or PD-L1 treatment. The study is rich in biomarkers.

And required all patients who have progressed on the most immediate prior anti PD, one or PD lone treatment.

The study is rich in biomarkers, including paired biopsies to assess if ESR K 181 could overcome immune exclusion phenotype and drive CDA positive T cells into the tumor as was demonstrated in our non clinical models.

Speaker 2: to assess if SRK181 could overcome an immune exclusion phenotype and drive CD8 positive T cells into the tumor as was demonstrated in our nonclinical model.

<unk> made excellent progress with the Dragon study since the start of the year, culminating in two poster presentations at the annual meeting of the society for immunotherapy of cancer. This past weekend.

Speaker 2: The team made excellent progress with the Dragon Studies since the start of the year, culminating in two poster presentations at the annual meeting of the Society of Immunotherapy of Cancer this past week.

Speaker 2: The first poster focused on biomarker data in support of proof of mechanism.

The first poster focused on biomarker data in support of proof of mechanism.

Speaker 2: And the second provided a clinical and biomarker update from the Reno Cell Course in Oma cohort from the Part B expansion, the cohort with the most patient data and putting follow-up. I will start with the review of the biomarker poster. I will start with the first provided a clinical and biomarker update from the Part B expansion.

And the second provided a clinical and biomarker update from the renal cell carcinoma cohort from the part B expansion cohort with the most patient data, including follow up I will start with a review of the biomarker poster.

Moving to slide nine.

This poster focused on biomarker data in support of proof of mechanism.

Speaker 2: This poster focused on biomarker data and support a proof of mechanism.

And based on paired biopsy data demonstrated that <unk> hundred one in combination with an anti PD one therapy increase the infiltration of CDA positive T cells across several tumor types, including melanoma shown here.

Speaker 2: and based on paired biopsy data demonstrated that SRK181 in combination with an anti-PD1 therapy increased the infiltration of CDA positive T cells across several tumor types including melanoma shown here.

Speaker 2: This was seen in the compartmental analysis that measures the percentage of CD8 positive cells in the tumor margin and stroma from two melanoma.

This was seen in the compartmental analysis that measures the percentage of CDA positive cells in the tumor tumor margin in stroma from two melanoma patients.

Speaker 2: As shown on the grass on the left, there was an increase in CDA positive T cells observed after treats overcoming an exclusion or desert phenotype which was present at base.

As shown on the graph on the left there was an increase in CDA positive T cells observed after treatment overcoming an exclusion or desert phenotype, which was present at baseline.

Speaker 2: Similarly, as shown in the histopath image on the right, there's an increase in intensity of brown staining, representing CDA positive T cells in the post-treatment biopsy, also demonstrating the influx of CDA positive T cells into the tumor.

Similarly, as shown in the history of path image on the right. There is an increase in intensity of brown staining, representing CDA positive T cells in the post treatment biopsy also demonstrating the influx of CDA positive T cells into the tumor.

Speaker 2: We were excited to see these data, which essentially reproduced the non-clinical findings that formed the scientific rationale for SRK-181.

We were excited to see these data, which essentially reproduced the non clinical findings that formed the scientific rationale for <unk> 181.

Turning to slide 10.

Speaker 2: The second poster presented at CITZ provided an update on the Reno Cell car Sonoma cohort from Part B. Overall, 28 patients were available for receive.

The second poster presented at <unk> provided an update on the renal cell carcinoma cohort from part D. Overall 28 patients were Evaluable for response.

It's important to note that the patients enrolled represented a heavily pretreated population, who received a median of three prior lines of treatment, including a checkpoint inhibitor and tyrosine kinase inhibitor.

Speaker 2: It's important to note that the patients enrolled represented a heavily pre-treated population who received a meeting of three prior lives of treatment, including a checkpoint inhibitor and piracy in kinase.

Speaker 2: All had disease progression on their prior anti-PD1, PDO1 treat.

All had disease progression on their prior anti PD, one PD lone treatment.

Speaker 2: The slide includes three graphical displays from the poster and highlight the treatment duration shown in the swimmers plot, anti-tumor activity.

This slide includes three graphical displays from the poster and highlight the treatment duration is shown in the swimmers plot antitumor activity as shown in the waterfall plot and the Spider plot that illustrates both duration and tumor response as can be seen there is clear evidence of tumor reduction with a 21% overall response.

Speaker 2: and the spider plot that illustrates both duration and tumor.

Speaker 2: As can be seen, there is clear evidence of tumor reduction with a 21% overall response rate that is durable beyond six months and a disease control rate of 57%.

Right that is durable beyond six months and a disease control rate of 57%.

The overall response rate is significantly above what we'd expect from a checkpoint inhibitor alone in the setting of prior anti PD, one PD lone progression, which is expected to be less than 5%.

Speaker 2: The overall response rate is significantly above what one would expect from a checkpoint inhibitor alone in the setting of prior anti-PD-1, PD-L1 progression, which is expected to be less than five.

With respect to safety the combination was generally well tolerated with the most common treatment emergent adverse events predominantly skin toxicities of rash and pure items.

Speaker 2: With respect to safety, the combination was generally well-pullerated with the most common treatment emerging adverse events predominantly skinpoxicities of rash and curitans.

Moving to slide 11.

Speaker 2: In summary, the DRAGON trial delivered on its objectives of showing proof of mechanism and proof of concept with promising overall response rates in a heavily pretreated relapsed refractory patients with clear cell renal carcinoma, all who progressed on prior treatment with a PD-1 or PD-L1 therapy.

In summary, the Dragon trial delivered on its objectives of showing proof of mechanism and proof of concept with promising overall response rates in a heavily pretreated relapsed refractory patients with clear cell renal carcinoma, all who progressed on prior treatment with a PD, one or PD lone therapy.

Now the Dragon has met its objectives, we plan to close enrollment in December begin closeout activities, while we continue to treat those patients who continue to benefit from therapy and remain on study.

Speaker 2: Now that Dragon has met its objectives, we plan to enclose enrollment in December , begin close out activities, while we continue to treat those patients who continue to benefit from therapy and remain on study.

Speaker 2: We also plan to present ongoing data from Dragon at future medical meetings.

We also plan to present ongoing data from Dragon at future medical meetings.

Speaker 2: We would like to take this opportunity to thank the investigators, the study staff, and in particular, the patients and their families who participated in or are currently participating in DRAG.

We would like to take this opportunity to thank the investigators study staff and in particular, the patients and their families who participated in or currently participating in dragon.

Speaker 2: Regarding the SRK-1A1 program overall, we believe the data from Dragon support advancing the-

Regarding the <unk> program overall, we believe the data from Dragon support advancing the program and we plan to conduct an end of phase one meeting with FDA in the first half of 2024 to determine the next steps.

Speaker 2: And we plan to conduct an end of phase one meeting with FDA in the first half of 2024 to determine the next steps.

Turning to slide 12.

I will now focus on our lead clinical program with the pedigree mab in spinal muscular atrophy or SMA.

Speaker 2: I'll now focus on our lead clinical program with the Pythagramab and Spinal Mosquito Atrophy or SMA. As a reminder, SMA is an inherited neuro-muscular disorder caused by a deficiency in a protein, the SMA protein, but is essential for the survival of a motor neuron, which in turn is responsible for controlling muscle period.

As a reminder, SMA is an inherited neuromuscular disorder caused by a deficiency in a protein the SMN protein that is a central survival the motor neurons, which in turn is responsible for controlling muscle movement.

Speaker 2: When the SMN protein is deficient, the motor neuron degenerates, resulting in muscle weakness and atrophy, leading to significant impairments, including the inability to sit, stand, and walk depending on the extent of involve.

On the SMN protein is deficient the motor neurons degenerate, resulting in muscle weakness and atrophy, leading to significant impairments, including the inability to sit stand and walk depending on the extent of involved.

Currently there are three approved therapies for SMA, all work to increase the amount of SMN protein, but non target the muscle directly.

Speaker 2: Currently, there are three approved therapies for SMA. All work to increase the amount of SMN protein, but none target the muscle directly.

With critical mass by targeting late Myostatin prevents the formation of the active form of milestone a negative regulator of muscle growth and is the first anti myostatin to result in improvements in motor function as shown in our phase II proof of concept study co paths.

Speaker 2: of Pitigremab by targeting latent myostatin prevents the formation of the active form of myostatin, a negative regulator of muscle growth, and is the first anti-myostatin to result in improvements in motor function, as shown in our phase two proof of concept study, Topaz. Moving on.

Moving to slide 13.

Speaker 2: As we shared at the QSMA event in June , we were excited to present the 36-month data from the pooled non-ambulatory patients from Topaz, the same patient population included in our phase three registration study, SAFRA.

As we shared at the cure SMA event in June we were excited to present 36 month data from the pooled non ambulatory patients from Topaz. The same patient population included in our phase III registration study Sapphire.

Speaker 2: As shown, there was robust, consistent, and sustained improvement in the motor function scales, the extended Hammersmith and revised upper limb module, which are also the primary and secondary endpoints in SAFI.

As shown there was robust consistent and sustained improvement in the motor function scales, the extended Hammersmith and revised upper limb module.

Were also the primary and secondary endpoints and Sapphire.

As well as improvements in the patient reported outcome measures as reflected in an increase in activity activities of daily living and reduction in fatigue, all measures that are consistent with improvement in muscle strength.

Speaker 2: as well as improvements in the patient-reported outcome measures as reflected in an increase in activities of daily living and reduction in fatigue, all measures that are consistent with improvement in muscle strength.

Okay.

Turning to slide 14.

I am very pleased with the progress we've made this year towards executing on the promise of a pedigree mab in SMA, we have met or on track to meet all of the 2023 bowls for the program that we outlined at the beginning of the year.

Speaker 2: I'm very pleased with the progress we've made this year for executing on the promise of a Pittigrew Mabin SMA. We have met or are on track to meet all of the 2023 goals for the program that we outlined at the beginning of the year.

In addition to reporting a 36 month Topaz data in June at your SMA. We also opened the Onyx long term extension study, which will serve as a platform for patients from both topaz and Sapphire to continue to receive a pedigree Mab importantly, onyx provides an opportunity to further strengthen the body of evidence on long term say.

Speaker 2: In addition to reporting the 36-month Topaz data in June at QRSMA, we also opened the Onyx Long-Term Extension Study, which will serve as a platform for patients from both Topaz and SAFIRE to continue to receive a Pitigramab. Importantly, Onyx provides an opportunity to further strengthen the body of evidence on long-term safety, and that.

Ft and efficacy.

Speaker 2: As we announced in September , we completed enrollment of our phase three registration study, SAFIRE, a major milestone for the study, and look forward to reporting our top-line results in Q4 2025.

As we announced in September we completed enrollment of our phase III registration study Sapphire, a major milestone for this study and look forward to reporting our top line results in Q4 2024.

Assuming success and regulatory approval, we expect to be a commercial company in 2025.

Speaker 2: Assuming success and regulatory approval, we expect to be a commercial company in 2025. And from a commercial perspective, the launch of EpidigraMap will be leveraged by the established SMA market.

And from a commercial perspective, the launch of a critical mass will be leveraged by the established SMA market.

And finally, our team is in the planning stages for additional follow on SMA studies, including in children under the age of two in an ambulatory patients, allowing us to extend the potential benefit of a pit of the map to the broadest patient population possible.

Speaker 2: And finally, our team is in the planning stages for additional follow-on SMA studies, including in children under the age of two and in ambulatory patients, allowing us to extend the potential benefit of a Pitogramab to the broadest patient population possible.

Now moving to slide 15.

Speaker 2: Now moving to slide 15, I'd like to turn this portion of the program over to Mo who will provide an overview of the cardiometabolic program. Mo is the head of research and brings a wealth of experience in both neuromuscular and cardiometabolic disease.

Like to turn this portion of the program over to MAU, who will provide an overview of the cardio metabolic program.

<unk> is the head of research and brings a wealth of experience in both neuromuscular and cardio metabolic diseases as.

Speaker 2: As I mentioned in my opening remark, Mo's team has been working on targeting anti-myostatin for cardiometabolic diseases for quite some time. And Mo will walk you through this research. Mo?

As I mentioned in my opening remarks, most team has been working on targeting anti myostatin for cardio metabolic diseases for quite some time and Mo will walk you through this research Mo.

Speaker 3: Thank you, Jay, and good morning, everyone. Now on slide 16.

Thank you Jay and good morning, everyone now on slide 16.

Our approach of targeting the importance of <unk> allows us to have exquisite selectivity to inhibit <unk> signaling and nothing else.

Speaker 3: Our approach of targeting the pro and latent forms of MyStan allows us to have exquisite selectivity to inhibit MyStan signaling and nothing else.

Non selective approach that targets backwards outside of milestone or muscle has the potential to have built serious effects for.

Speaker 3: A non-selective approach that targets pathways outside of myosin or muscle has the potential to have deleterious effects.

Speaker 3: For example, inhibition of the closely related GDF11 growth factor signaling may have negative impacts on bone. And inhibition of active ends has demonstrated effects on reproductive biology, likely limiting the use of products which target this pathway in women of childbearing age.

For example, inhibition of the closely related to EDF 11 growth factor signaling they have no negative impact on bone and inhibition of <unk> has demonstrated effects on reproductive biology likely limiting the use of products, which target. This pathway in human in women of childbearing age.

By inhibiting Myostatin and <unk>, our antibody is provide a profile that drops efficacy without the potential liabilities that come with non selective approaches which is critical especially in this patient population.

Speaker 3: By inhibiting myosin and only myosin, our antibodies provide a profile that drives efficacy without the potential liabilities that come with non-selective approaches, which is critical, especially in this patient population.

We are now on slide 17.

Obesity is recognized as a top global public health challenge with an estimated 1 billion adults worldwide, including half of the population that <unk> projected to be abused by 2030.

Speaker 3: Obesity is recognized as a top global public health challenge with an estimated 1 billion adults worldwide, including half of the population in the US projected to be obese by 2030.

Speaker 3: This is associated with several serious comorbidities like heart disease and type 2 diabetes and staggering cost to the healthcare system.

This is associated with several serious comorbidities like heart disease, and type two diabetes and staggering cost to the health care system.

Weight loss by any means leads to loss of not only fat, but also lean mass and this is evident in the <unk> one receptor agonist mediated weight loss that are experiencing rapid uptake and we're lean mass losses may be 25% to 40% of the total body weight loss.

Speaker 3: Weight loss, by any means, leads to loss of not only fat, but also lean mass. And this is evident in the GLP-1 receptor agonist mediated weight loss that are experiencing rapid uptake and where lean mass losses may be 25 to 40% of the total body weight loss.

Lots of lean mass.

Key predictor of adverse outcomes and all the patients and maintaining lean mass through exercise room weight loss has demonstrated longer term benefits versus weight loss alone there.

Speaker 3: Therefore, it is important that, it is possible that maintaining lean mass in the context of weight loss may promote additional fat loss as well as greater long-term metabolic benefits.

Therefore, it is important that.

It is possible that maintaining lean mass in the context of weight loss may promote additional fat loss as well as greater long term metabolic benefits.

Moving to slide 18.

Speaker 3: Moving to slide 18, where we'll be discussing SRK 439.

We'll be discussing as okay 439.

I'll talk a 49 is a novel preclinical antibodies that antibody that is in development.

Speaker 3: SRK439 is a novel preclinical anti-myostin antibody that is in development. As mentioned earlier, we leveraged our extensive expertise in myostin structure and biology to develop this molecule to specifically address a patient population with cardiovascular disorder.

Mentioned earlier, we have leveraged our extensive experience expertise and my style structure on biology to develop this molecule specifically address the patient population and we've got a metabolic disorders.

Okay.

Speaker 3: Sake 439 has attractive properties and potential to address the muscle loss associated with weight loss.

Has attractive properties and potential to address a muscle loss associated with weight loss.

It has high end mutual affinity for <unk> to potentially leave two efficacy at lower doses.

Speaker 3: It has high in-vitro affinity for pro- and latent myosin to potentially lead to efficacy at lower doses.

Maintains milestone specificity with no Judy at 11 are active in a binding to limit any potential undesirable off target effects, especially in this patient population.

Speaker 3: It maintains my stance that specificity with no GDS-11 or active in A binding to limit any potential undesirable off-target effects, especially in this patient population.

It also maintains a good develop buildup profile and is amenable to subcutaneous subcutaneous formulation and dosing.

Speaker 3: It also maintains a good development profile and is amenable to subcutaneous formulation and dose.

Now on slide 19, where we show our efficacy data with US. Okay 439 in combination with <unk> one receptor agonist in diet induced obese mouse model the standard model used in the field.

Speaker 3: Now on slide 19, where we show our efficacy data with SRK439 in combination with GLP1 receptor agonist in diet-induced obesity mouse model, a standard model used in the field.

As expected the decrease in body weight induced by <unk>, one receptor agonist liraglutide in this case led to a decrease in not only fat mass, but also lean mass as you see with a sandbar.

Speaker 3: As expected, the decrease in body weight induced by CGLP1 receptor agonist, liraglutide in this case, led to a decrease in not only fat mass, but also lean mass, as you see with the TAM bar.

Speaker 3: Combining SRK439 with a GLP-1 receptor agonist confirmed our therapeutic hypothesis and led to dose-dependent reversal of lean mass loss in addition to enhancement of fat mass loss.

Combining <unk> hundred 39, with a <unk> one receptor agonist confirmed our therapeutic hypothesis and led to dose dependent reversal of lean mass loss. In addition to enhancements of fat mass loss.

Now on slide 20.

Slide 20 highlights the efficacy of <unk> in diet induced obese publicity mouse model in combination with some of the advice and more effective <unk> one receptor agonist.

Speaker 3: By 20 highlights, the efficacy of SRK 439 in diet induced obesity mouse model in combination with stomach lootide and more effective GLP 1 receptor agon.

Speaker 3: Semiglutide did lead to significant loss of lean mass in addition to fat mass loss as seen in the tan bond.

Some of it looked like it did lead to significant loss of lean mass. In addition to fat mass loss as seen in the sandbox.

Speaker 3: However, when combined with SRK439, the loss in lean mass induced by semaglutide alone was dose-dependently reversed, leading to maintenance of lean mass while enhancing fat mass loss.

However, when combined with <unk> 49 loss in lean mass induced by somebody who died alone was dose dependent Lee reversed leading to maintenance of lean mass, while enhancing fat mass loss.

It is worth noting that we see lean mass reservation with doses as low as <unk> three milligrams per kilogram up us okay for C&I, which highlights the favorable profile of <unk> for development in this indication.

Speaker 3: It is worth noting that we see lean mass preservation with doses as low as 0.3 milligram per kilogram of PASAKA429, which highlights the feral profile of PASAKA429 for development in this indication.

Turning to slide 21.

To summarize our approach is explicitly selective in targeting myostatin, myostatin, only and avoids potential liabilities of target inhibition.

Speaker 3: to summarize, our approach is explicitly selective in targeting my stand and my stand only, and avoid potential liabilities of our target inhibition.

The selective inhibition of milestone in combination with <unk> receptor agonists driven weight loss may lead to healthier more durable weight management and we look forward to testing this in the clinic.

Speaker 3: The selective inhibition of myostan in combination with GLP receptor agonist driven weight loss may lead to healthier, more durable weight management, and we look forward to testing this in the clinic.

Now on slide 22.

In summary, our preclinical data support advancing <unk> hundred 39, a novel investigational <unk> inhibitor for the treatment of cardio metabolic disorders with an initial focus on obesity.

Speaker 3: In summary, our preclinical data supports advancing SRK 439, a novel investigational milestone inhibitor for the achievement of Cardinal Bogdus orders for the initial focus on the beast.

Speaker 3: We are moving SRK 439 towards IND submission in 2025.

We are moving <unk> towards IND submission in 2025.

To inform the development of a surrogate for three nine we plan to initiate a phase II proof of concept trial, particularly in combination with <unk>, one receptor agonist and <unk> in 2024.

Speaker 3: To inform the development of AFRK-439, we plan to initiate a phase two proof of concept trial a particular map in combination with GLP-1 receptor agonist in obesity in 2024.

Speaker 3: The data readout of that trial is expected in mid 2025.

The data readout of that trial is expected in mid 2025.

Now I will turn it over to Ted for summary.

Speaker 2: Now I will turn it over to Ted for summary. Thanks Moe. Moving to slide 24, 2023 has been a year of significant execution across our portfolio. And we're well positioned going into 2024. We're seeing great productivity coming out of our scientific platform as our unique approach of targeting the latent form of growth factors to achieve exquisite selectivity appears to be proving patient outcomes in SMA and in oncology.

Thanks Mark.

Moving to slide 20 for 2023 has been a year of significant execution across our portfolio and we're well positioned going into 2024.

We're seeing great productivity coming out of our scientific platform as our unique approach of targeting the latent form of growth factors to achieve exquisite selectivity appears to be proving patient outcomes in SMA and in oncology.

We are excited to be applying this selectivity toward cardio metabolic disease areas, where we believe safety is so important and our approach is highly differentiated.

Speaker 2: We are excited to be applying this selectivity to a cardiometabolic disease areas where we believe safety is so important and our approach is highly differentiated.

Speaker 2: Our upsized public offering that we completed last month puts us in a strong financial position with our cash runway that extends into the second half of 2025.

Our upsized public offering that we completed last month puts us in a strong financial position with our cash runway that extends into the second half of 2025.

Speaker 2: We're focused on advancing the myostatin programs, SNA and cardiometabolic. Additionally, we believe we will position to bring in non-delivative funding as we continue to evaluate potential partnership opportunities for other programs within our portfolio.

We're focused on advancing the myostatin programs SMA in cardio metabolic. Additionally, we believe we are well positioned to bring in non dilutive funding as we continue to evaluate potential partnership opportunities for other programs within our portfolio.

We view strategic business development is an important way to advance promising programs by leveraging the infrastructure capital and expertise of other companies.

Speaker 2: We've used strategic business development as an important way to advance promising programs by leveraging the infrastructure, capital, and expertise of other companies.

We ended the third quarter with $219 million of cash and cash equivalents and our October capital raise netted approximately $93 million.

Speaker 2: We ended the third quarter with $219 million of cash and cash equivalent and our October capital raised netted approximately $93 million.

Our capital allocation strategy includes a substantial reduction in our spend on <unk> as we complete enrollment of Dragon and continue to support remaining patients on study.

Speaker 4: Our capital allocation strategy includes a substantial reduction in our spend on SRK-181 as we complete the enrollment of Dragon and continue to support remaining patients on study.

Speaker 4: Our primary focus as we conclude 2023 and look to 2024 includes investments to advance a PITGermab in SMA and our NULIA announced Cardiometabolic Program.

Our primary focus as we conclude 2023 and look to 2024 includes investments to advance our pedigree mab in SMA and our newly announced cardio metabolic program.

With the capital in hand, promising programs underway in our strategic imperatives aligned with our core competency unparalleled selectivity of Myostatin inhibition. We are excited about the future and our ability to serve patients with our important novel therapies.

Speaker 4: With the capital in hand, promising programs underway and our strategic comparatives aligned with our core competency on paralleled selectivity of myostatin inhibition, we are excited about the future and our ability to serve patients with our important novel therapy.

Speaker 4: This concludes our formal remarks. I'll now turn it over to the operator so we can start the Q&A operator. Okay.

This concludes our formal remarks, I'll now turn it over to the operator, so we can start the Q&A operator.

Thank you the floor is now open for your questions to ask a question at this time. Please press Star then the number one on your telephone keypad.

Speaker 5: to ask a question this time, please press start and the number one on your telephone keep at.

Just pause for just a moment to compile the Q&A roster.

Speaker 6: So just pause, produce a moment to compile the Q&A roster.

Okay.

Your first question comes from the line of Michael.

With Jefferies. Your line is now open.

Hey, guys. Thanks for the question and congrats on all the progress.

Speaker 7: Hey guys, thanks for the question and congrats on all the progress. We had two questions, one on SMA and one on cardio-metabolic.

We had two questions one on SMA and one on cardio metabolic.

Speaker 7: SMA in your phase three, I believe the primary analysis is based on two to twelve. And I was wondering if you have any thoughts around the proportion of the study that is probably more two to five versus say older.

SMA.

In your phase III I believe the primary analysis is based on two to 12.

And I was wondering if you have any thoughts around the proportion of the study that is probably more due to five versus say older.

Speaker 7: and whether there is any pre-specified analysis that has a analysis to look at the younger patients versus the older patients in that study after observing what happened with DMT gene therapy and how that played out, if there's a pre-specified analysis for younger patients.

And whether there is any pre specified analysis that has a analysis to look at the younger patients versus older patients in that study after observing what happened with.

DMD gene therapy, and how that played out if there was a pre specified analysis for younger patients and then on cardio metabolic.

Speaker 7: And then on cardiometabolic, an interesting hypothetical question, an OBSIDI drug that you're trying to develop to anticipate that the regulatory path is traditional obesity display loss, whether there's an endpoint also that would be accepted by the FDA for muscle gain. And I was wondering how you think about that. Thanks.

An interesting hypothetical question and I appreciate and in obesity drug that you are trying to develop.

Dissipate that the regulatory path is.

Traditional RBC just weight loss.

As an endpoint all show that would be accepted by the FDA for muscle gain and I was wondering how you think about that thank you.

Yes, it's good with Semiclad. Thank you. This is Jay thanks for the question.

Let me start with the SMA. So yes, our primary analysis is the two to 12.

We haven't disclosed the proportion of that group, who are between the ages of two and five and.

And at this juncture our primary analysis pre specified analysis certainly include the older cohort, but.

Speaker 2: And in this chapter, our primary analysis and pre-specified analysis certainly include the older cohort, but as you know upon top-line data, we have the opportunity to look across the age groups. So we will certainly look at that in the top-line results.

But as you know upon.

Top line data, we had the opportunity to look across the age groups. So we will certainly look at that in the top line results.

Speaker 2: So I think that took care of the question on the SMA patient population.

So I think that took care of the question on the SMA patient population with respect to cardio metabolic yet very interesting question I think with respect to the current approval for weight loss. It is the amount of weight loss that occurs that is the primary endpoint.

Speaker 2: With respect to cardiometabolic, yeah, very interesting question. I think with respect to the current approval for weight loss, it is the amount of weight loss that occurs. That is the primary endpoint. As you know, this isn't evolving field. And I think recognizing that, you know, the need to preserve lean muscle mass is really critical. And the efforts now that we're in and others are in, I think will help inform future regulatory endpoints.

As you know this is an evolving field and I think recognizing that the.

The need to preserve lean muscle mass is really critical and the efforts now that we're in and others are in I think will help inform future regulatory endpoints.

But we will need to demonstrate at some point across the program improvements in either function or patient reported outcomes.

Speaker 2: But, you know, we will need to demonstrate at some point across the program improvements in either function or patient-reported outcomes. So I think that will need to be a standard part. But I think it's a state tone that I think has been moved forward.

I think that will need to be a standard part, but I think it's a stay tuned as I think as we move forward.

Speaker 2: For our Pufa concept study, we're certainly going to be focused on demonstrating that we can't preserve and maintain the muscle mass. I think for a Pufa concept, that's mechanistically sound and that's our approach going for.

Our proof of concept study, we're certainly going to be focused on demonstrating that we can preserve and maintain lean muscle mass I think for a proof of concept that's mechanistically sound and that's our approach going forward.

Thank you guys.

Okay.

Our next question comes from the line of Allison <unk> from Piper Sandler.

Speaker 5: Our next question comes from the line of Allison Bratzel from Piper's.

Please go ahead.

Hi, good morning team. Thanks for the update today and thanks for taking my question.

Speaker 8: Hi, good morning team. Thanks for the update today and thanks for taking my question.

Speaker 8: So first, and SRK439 maybe a question for model.

So first and ask RK for three nine maybe a question from now.

Could you just provide some more color on the different properties of 439 compared to pick on map and just really distill for FY 14 is better suited to go forward and in obesity.

It seems the sub Q format.

Is it is a major differentiator there just curious if sub Q administration.

Speaker 8: is a major differentiator there. You know, just curious, it's up to you administration. Of a PIDICRMAP is something you've explored. Any color there would be helpful. And then just on our related note, could you help us understand what is gating to IND filing for a PIDICRMAP in obesity? And also the same question, you know, what's gating to...

<unk> is is something.

You've explored.

Any color there would be helpful. And then just on a related note could you help us understand what is gating to IND filing for <unk> in obesity and also same question, what's gating to one.

Speaker 8: I am defiling for for 439 and look as your confidence

IND filing for 439, and what gives you confidence.

That that IND filing will be ready to go and mid 25. Thanks.

Speaker 8: that I and you feeling will be ready to go in on mid 25. Thanks.

Hey, Ali this is Jay maybe I'll take one part of that three part question and then I'll turn it over to mow and as the question around the IND.

Speaker 2: Hey, Ellie, this is Jay. Maybe I'll take one part of that three-part question and I'll turn it over to Moe. And here's the question around the IND. What's required to get the IND filed for a Pytegrimment?

What's required to get the IND filed for a pedigree mab.

Speaker 2: Why I'm really delighted that we have the opportunity to prove a concert with a Pittergram ad is because it's already a clinical stage as.

Why.

We're really delighted that we have the opportunity to proof of concept with <unk>, because it's already a clinical stage asset. So it's a matter of really putting together the scientific rationale and submit the IND for a new division to agree and we get to cross referenced a lot of the existing documents and the current <unk> and SMA. So it's really a matter of kind of completing the regulatory.

Speaker 2: So it's a matter of really putting together the scientific rationale and submit the IND for a new division to agree and we get to cross-reference a lot of the existing documents in the current epitograms, IND and SMA. So it's really a matter of kind of completing the regulatory dossier to do that and then engage FDA. So that worked, frankly, we had started even prior to announcing our going into this.

Dossier to do that and then engage FDA. So that work frankly, we had started.

Even prior to announcing are going into this area and then maybe I'll, let <unk> talk about the IND, enabling work required for S. R. K 43, 9% and then more details yes.

Speaker 2: And then maybe I'll let Mo talk about the IND enabling works required for SRK 439.

Speaker 3: Yeah, thanks, Jay. I mean, I'll start with talking about circuit 49. But not exactly for 49 is a novel model that we developed based on our extensive understanding of my stand and the structure and the epitope space.

Yes, Thanks, Jay I'll start with talking about what's going on but also our square foot <unk> nine is a novel molecule developed based on our extensive understanding of <unk> and the structure and the epitope space. It is highly selective as we mentioned at all it binds myostatin utilizing our platform.

Speaker 3: It is highly selective, as we've mentioned, it only abides by utilizing our platform.

Speaker 3: It has attractive property and from the get-go, we developed it to target dispatient population. So it has very high in vitro affinity, leading to potential lower doses when you're looking at efficacy with these. And we've seen that in the mouse models that we've...

It has attractive property and from the get go we developed it to target. This patient population. So it has very high in vitro affinity.

Leading to.

Potentially lower doses when you're when you're looking at efficacy with these and we've seen that in the mouse models that we have.

Speaker 9: we've done and we continue to do in other models as well as we develop the molecule. It also amenable to high concentrations. Again, this is to support sub-Q profile, especially for this patient population.

We have done and we continue to do in other models as well as worried about the molecule.

It also.

Amenable to high concentrations again this is to support.

<unk> Q profile, especially for this patient population.

Overall profile of.

Speaker 9: The overall profile of SRK149 was designed by design for this patient population to have higher affinity efficacy with lower doses and concentration to enable subcutaneous dosing. From an IND-enabling studies, you know, we're going forward with the typical IND-enabling studies. We're initiating all of the IND-enabling studies as we move forward into next year, as you see the talks, the PK studies, and all of these things, as well as cell line developments, et cetera.

<unk> nine was designed by design for this patient population to have higher affinity.

Efficacy with lower doses and concentration to enable subcutaneous dosing from an R&D, enabling studies.

We're going forward with the typical R&D, enabling studies we're initiating.

All of the NII IND, enabling studies as we move forward into next year.

As you see that the talks that PK studies and all of these things as well.

Cell lung developments et cetera.

Got it thank you.

Speaker 10: Got it. Thank you.

Our next question comes from the line of <unk> with J P. Morgan.

Speaker 5: Our next question comes from the line of Tess Romero with JP Morgan.

Please go ahead.

Good morning, Thanks for taking my question two questions from US This morning, if we could.

Speaker 11: Good morning. Thanks for taking our questions. Two questions from us this morning if we could. First one is, how do you disclose the statistical test you are using and what the powering assumptions are for the sapphire trial around the primary endpoint of the mean hammers of change from baseline at 12 months? If not, what can you tell us at this time as to how we should be thinking about this?

First one is how do you disclose that.

Mr. <unk>, you are using and what the powering assumptions are for the Sapphire trial around the primary endpoint of the mean Hammersmith change from baseline at 12 months.

What can you tell us at this time as to how we should be thinking about that.

Speaker 11: And secondly, a related question, will you consider disclosing the baseline characteristics before the top line results next year? Thanks, guys.

And secondly, a related question will you consider disclosing the baseline characteristics before the top line results next year. Thanks, guys.

Yes. So this is Jamie I'll take the questions from the statistical powering assumptions you know, we've really not fully disclosed it but just to kind of put color to that for the Hammersmith.

Speaker 2: Yeah, so this is Jay. I mean, I'll take the questions. You know, from the statistical powering assumptions, you know, we've really not fully disclosed it, but just to kind of put color to that for the Hammersmith, you know, we expect to certainly be able to demonstrate a three-point change by the way we power the trial. And we have adequate power to demonstrate that. And again, we're doing hierarchical testing on that and then the following secondary.

We expect to certainly be able to demonstrate a three point change by the way we powered the trial and we have adequate power to demonstrate that.

And again, we're doing hierarchical testing on that and then the following secondary endpoints. So I think we're well positioned to to replicate in Sapphire, what we saw in the Topaz study.

Speaker 2: So I think we're well-positioned to replicate in Sapphire what we saw in the Topaz.

Speaker 2: And then with regard to baseline characteristics, you know, Ali, we're looking at that very critically as sort of our publication planning and data disclosure plans. Really, we try to do that time to important congresses as we think in conferences. We think about it over the year. So more to come as we disclose that, but not likely to occur anytime in the near term, given the cadence of the medical conferences. So thank you.

And then with regard to baseline characteristics.

Ali we're looking at that very critically as sort of our publication planning and data disclosure plans really we try to do that time two important congresses as we think in conference as we think about over the year. So more to come as we disclosed that but not likely to occur anytime in the near term given the cadence of.

The medical conferences.

Okay, great. Thanks for taking our questions.

Our next question comes from the line of Street Sweeper devote a corner I'm sure Securities. Your line is now open.

Speaker 5: Our next question comes from the line of Sri Kripa, Devara Konda, from Truer's securities. Their line is now open. Hey guys.

Hey, guys. Thank you so much for taking my question.

Speaker 12: As you developed a particular map and SRK for China and obesity, I actually had a couple of maybe basic questions on my stat in the obesity.

As you develop to come up with that.

Yes.

I actually had a couple.

Maybe a basic question on Myostatin in obesity.

Speaker 12: Some studies have shown that myofasciitis is upregulated in obesity, just wondering how well this dynamic has been characterized in patients? Is there a lot of variability?

Studies have shown that <unk> is up regulated in obesity, just wondering how whether this.

This dynamic has been characterized in patients is that a lot of variability and how do you think that could potentially impact how effective could DMD.

Speaker 12: And how do you think that could potentially impact how effective the drug could be in these patients, especially, you know, if you consider the background of obesity versus SMA where you have shown activity? And given that the studies show myostatin is also reduced as patients lose weight, do you think there's an optimal window where you treat patients with anti-myostatin?

DMD patients, especially if you consider the background of obesity versus SME shown activity.

And given that the studies show Myostatin is also reduced as patients lose weight do you think there's an optimal window, where do you treat patients with antibody subtle.

Thank you.

Yes, so maybe I'll start just talking about what we would expect to see in clinic with the <unk> and then followed with US our K 43 nine in obesity.

Speaker 2: Yes, maybe I'll start just talking about what we would expect to see in clinic with the pitigramab and then followed with SRK439 in obesity. I think what we can say, which is I think

What we can say, which is I think very clear now.

And we've shown that I believe in the Topaz study is that.

Speaker 2: We've shown that I believe in the Topaz study is that.

Speaker 2: Targeting myostatin does result in preservation, if not increase in lean muscle mass. I think we've shown that functionally in Topaz. I think there's consistent observation across. So myostatin is a very good target. And it certainly should be able to do that in the setting of obesity where you have normal muscle. So I think that's.

Targeting Myostatin does result in preservation not increase in lean muscle mass I think we've shown that functionally and topaz think theres consistent observation across semi stands a very good target and it certainly should be able to do that in the setting of obesity, where you have normal muscle. So I think thats the case.

The fact that there was up they're signaling is high in Myostatin I think is interesting, but I do believe the web and opportunity to demonstrate that.

Speaker 2: The fact that, you know, there was up, you know, that their signaling is high in myostatin, I think is interesting. But I do believe we'll have an opportunity to demonstrate that in this setting, just as we will demonstrate it in the SMA setting.

In this setting just as we demonstrated in the SMA side.

Okay.

Great. Thank you.

Our next question comes from the line of Ed Sur de risked from BMO capital markets. Your line is now open.

Speaker 5: Our next question comes from the line of Etzer Tera from BMO Capital Markets, your line is now open.

Speaker 13: Great. Thanks for taking the questions and congrats on the progress. How are you thinking about the development of SARK 439, I mean, given the size of the obesity?

Great. Thanks for taking the questions and congrats on the progress.

Thinking about the development of our case was 209 I mean, given the size of deal will be CD.

Speaker 13: and I guess is the proof-of-concept data with epidechromat, the catalyst for an update, if you will, on development plans. And then maybe on SRK 181, just, you know, maybe next steps for the program, maybe a little bit more color on what you described earlier.

The indication and I guess is the proof of concept data with Citigroup, Matt the catalyst for <unk>.

Date, if you will on development plans and then maybe on <unk> Q1 'twenty one.

Maybe next steps for the program, maybe a little bit more color on what you described earlier.

During opening remarks, and maybe the opportunity for future programs to be in sort of in earlier lines of RCC. For example, thank you.

Speaker 13: during opening remarks and maybe the opportunity for future programs to be in sort of an earlier lines of our RCC, for example. Thank you.

Yes, So let me start with with 43, 9% and proof of concept and sort of overall path forward.

Speaker 2: Yeah, so let me start with with 439 and proof of concept and sort of overall path forward. You know, again, I think we're designed, we've shown to date at Scholarock that we can run randomized phase 3 studies, we can run proof of concept trials. And so as I think about the cardiometabolic space, certainly to get

Again, I think we were designed we've shown to date at scholar rock that we can run randomized phase III studies, we can rent proof of concept trials and so as I think about the cardio metabolic space certainly to get.

<unk> proof of concept, which will really in my opinion validate our approach and as we report that out. We'll then at the time open up with $43 nine getting right into clinic really positions us to drive 43 nine rapidly forward also to that proof of concept and so that's our near term horizon.

Speaker 2: Cytogramab proof of concept, which will really, in my opinion, validate our approach. And as we report that out, we'll then at the time open up with 439 getting right into clinic, really positions us to drive 439 rapidly forward also to that proof of concept. And so that's our near-term horizon.

Speaker 2: You know, anything beyond that, I think really we're still open for discussions around how we get to bigger, broader trials. But I think for what we can do on our hand, I think we can certainly drive value, if you will, for the company by driving to the clinical data in that proof of concept setting. So that's really our thinking around and what Mo laid out very beautifully about how we're looking at both the Pitogramab and 439.

Anything beyond that I think really we're still open for discussions around how we get to bigger broader trials.

But I think for what we can do on our hand, I think we can certainly drive value. If you will for the company by driving to the clinical data and that proof of concept setting. So that's really our thinking around and what <unk> laid out very beautifully about how we're looking at both the <unk> and $43 nine.

For 181.

The data that I shared.

Speaker 2: You know, the data that I shared, you know, in a way I try to put the color on it.

In a way I try to put the color on it at.

Speaker 2: This is really a tough group to treat. And to see this level of response rate and this heavily pre-treated failed on checkpoint inhibitor, I think really shows that proof of concept, which is why we reached those conclusions.

This is really a tough group to treat and to see this level of response rate in this heavily pretreated <unk> on checkpoint inhibitor I think really.

<unk> that proof of concept, which is why we reach those conclusions, but I think like in any therapy, particularly in immunotherapy earlier lines of therapy, you really the place to take any such treatment. If you really want to have major impact because patients have been so beat up in progress. So much through these therapies are getting earlier makes sense and so frankly, that's that's.

Speaker 2: But I think like in any therapy, particularly in immunotherapy, earlier lines of therapy are really the place to take any such treatment if you really want to have major impact. Because patients have been so beat up and progressed so much through these therapies that getting earlier makes.

Speaker 2: And so, frankly, that's the whole concept behind the end of phase one meeting is really to engage FDA and review our data and then begin to work with them to kind of lay out what would be the next logical step.

The whole concept behind an end of phase one meeting is really to engage FDA and review of our data and then begin to work with them to kind of lay out what would be the next logical steps and any further development of 181 and as Ted said right now for US today really pleased with the way Dragon performed I think it has met its objective it's done it.

Speaker 2: in any further development of 181. And as Ted said, right now for us today, really pleased with the way Dragon performed. I think it's met its objective. It's done its job, if you will. We'll wind that down, reset, take a look at what's happening with the FDA interaction. But in the meantime, in 2024, it's really all on our focuses on our anti-myostatin programs.

Job, if you will we'll wind that down reset take a look at what's happening with the FDA interaction, but in the meantime at 2024, it's really all on our focuses on our anti myostatin programs.

Great. Thank you.

Our next question comes from the line of Suntrust small Donato.

Speaker 5: Our next question comes from the line of Andres Maldonado with HC Wainwright. Their line is now open.

H C. Wainwright your line is now open.

Hi, Thank you for taking my questions and I'll reiterate the congratulations on all the progress.

Speaker 14: Hi, thank you for taking my questions and I'll reiterate my congratulations on all the progress. So one quick question from us on 439. So I guess in the context that the goal of next generation obesity programs aims to really hone in and solve the issue of variability of patient response, you know, could you maybe talk about how much in this variant use?

One quick question from Us on 439, I guess in the context that the goal of next generation obesity programs aims to really hone in and Paul.

The issue of variability of patient response could.

Could you maybe talk about how much.

And this variance you ascribed muscle loss.

Speaker 14: you know, driving that variation of patient response. And then a follow-up question to that would be, you know, given the safety and tolerability of epidechromab and wishes and positives, are some of the treatment emergent events more worrisome in the context of the combination? Thank you very much.

Driving that variation patient response again.

Follow up question, because that would be given the safety and tolerability of growth, which has been positive or some of the treatment emergent events more worrisome in the context of the combination. Thank you very much.

So okay, maybe we'll do a tag team with Mo I think your question is sort of the variability in weight loss that occurs with the current <unk> one receptor agonist and UC.

Speaker 2: So, okay, maybe we'll do a tag team with Mo. I think your question is sort of the variability in weight loss that occurs with the current TLP1 receptor agonist. And you see kind of a range across. Some patients do well. There gets to be a plateau for some. I think it probably, in my, as I review the literature and look at the data, some of it may very well be starting points for the patient's ability to get to adequate doses. I think there's a lot of things that affect overall weight loss. From the

End of a range across some patients do well there gets to be a plateau for some I think it probably in my as I review the literature and look at the data some of them may very well be starting points for the patients ability to get to adequate doses I think theres a lot of things that affect the overall weight loss.

From the muscle mass.

We've seen there is a range, but it's a fairly split between 'twenty and say, 40% that is definitely related to that and so those are kind of related events, but our focus really is on that preservation of lean muscle mass, which we believe we should have a consistent effect across.

Speaker 2: There is a range, but it's a fairly, you know, it's what, between 20 and say 40% that is definitely related to that. And so those are kind of related events, but our focus really is on that preservation of lean muscle mass, which we believe we should have a consistent effect across.

Speaker 2: Hence, we'll look at our proof of concept studies to move forward. But I think that's the thinking.

Hence we will look at our proof of concept studies to move forward, but I think that's the thinking there.

And again I think it's really interesting to your point about safety and.

Speaker 2: And again, I think it's really interesting to your point about safety. And we've emphasized this because it really matters. It really matters. I think about weight loss therapies over time. They've been effective, but they've all been troubled by toxicities and safety issues that have prevented their continued use.

We've emphasized this because it really matters and it really matters I think about weight loss therapies over time, they've been affected but they've all been troubled by toxicities and safety issues that have prevented their continued use.

Speaker 2: I think what we're seeing with the GLP-1 receptor agonist is to date, and there's been wide patient exposure, you know, we're seeing some effects, but nothing like what we've seen in the past that would really warrant stopping these therapies. So that's a good.

What we're seeing with the <unk> one receptor agonist is to date and there has been wide patient exposure, we're seeing some effects, but nothing like what we've seen in the past it would really warrant stopping these therapies. So thats a good thing, but any additional therapy that comes into this space. That's an add on therapy, that's used to kind of offset some of the negative.

Speaker 2: But any additional therapy that comes into this space that's an add on therapy that's used to kind of offset some of the negative effects like loss in the muscle.

Effects like Los in the muscle.

Speaker 2: in my mind really needs to bring no additional risk of toxicities if possible.

My mind really needs to bring no additional risk of toxicities, if possible and that is where I believe if you look at all of the conversations going on in other areas other companies coming into lean muscle mass I do think our approach by hitting milestone and only myostatin will avoid off target effects.

Speaker 2: And that is where I believe if you look at all of the conversations going on in other areas, other companies coming into lean muscle mass, I do think our approach by hitting myostatin and only myostatin will avoid off-target effects. And I think Mo walked through that. If you look at what happens when you hit active in receptors A and B, you start to get into some things that you may not want to see, right, that over time could potentially be troublesome. And that's also true with GDL.

Bank My walk through that if you look at what happens when you hit active and receptors A&P you start to get into some things that you may not want to see that over time could potentially be troublesome and thats also true of the GDS 11, So I like our approach it shouldn't bring any additional risk to that risk benefit profile, we'll obviously.

Speaker 2: So I like our approach. It shouldn't bring any additional risk to that risk-benefit profile. We'll obviously see that when we report out our phase three data. But so far, and we're seeing that in Topaz, we have patients coming on four years with really a very, very clean signal.

<unk> that we reported out our phase III data, but so far and we're seeing that and topaz, we have patients coming on four years with really a very very clean safety profile I think in the cardio metabolic space, we definitely want to continue with that and I think we're positioned to show that.

Speaker 2: I think in the cardiometabolic space, we definitely want to continue with that. And I think we're positioned to share.

Our next question comes from the line of fairness tone with Vijay Kumar.

Speaker 5: Our next question comes from the line of Ernesto Rodriguez Dumont with Cohen.

Please go ahead.

Hi, Thank you for taking my questions and congratulations on the progress I'll just follow up on the on the miles on them obesity program functional endpoints for.

Speaker 15: Hi, thank you for taking my questions and congratulations on the progress. I'll just follow up on the obesity program functional endpoints for regulatory.

For regulatory.

Speaker 15: for regulatory purposes. So, other prioritizing programs that show multiple gains in other settings, are there any hints of functional changes from those programs that could lead the way to identifying a functional endpoint for the obesity program?

For regulatory purposes. So.

While the private marketing programs that show multiple games in other settings.

Is are there any hints of functional changes from those programs that could lead.

The way to identifying a functional endpoint for the there'll be CD program.

Speaker 15: And then also, do you expect the therapy to be a chronic therapy in conjunction with a GLP-1?

And then also do you expect.

The therapy to be a chronic therapy in conjunction with SDLP once.

Speaker 15: Or do you expect that there to be some kind of biomarker and limit to the therapy?

Or do you expect that.

To be some kind of a biomarker.

Limit to the to the to the <unk>.

So the therapy.

Thank you.

Speaker 2: Yeah, so I think there's a couple things. Again, back to the regulatory endpoints. And, you know, we're going to begin the engagement with FDA and other agencies as we advance through IND and get more interaction with our clinical program.

Yes, so I think Theres, a couple of things again back to the regulatory endpoints and we're going to begin the engagement with FDA and other agencies as we advance through IMD and get more interaction with our clinical programs.

But as an example.

Speaker 2: But as an example, you know, the functional measures, well, as you know, we've included functional measures in the SMA program. You know, those were tailored specifically for the underlying disease.

Functional measures.

We've included functional measures in the SMA program those were tailored specifically for the underlying disease theres other ways to measure the grip strength and certain other measures that we could could assess that would show that you are preserving and maintaining.

Speaker 2: There's other ways to measure the grip strength and certain other measures that we could assess that would show that you're preserving and maintaining motor function. So that's something to consider.

Motor function, so that's something to consider there.

Speaker 2: There's also measures that we can include that would look at quality of life measures. As you know, there are some significant associated GI effects with the current therapies.

Also measures that we can include that we'd look at quality of life measures. As you know there are some significant associated Gi effects with with the current therapies, it's possible for our approach and what MAU showed which I think is very intriguing is that we do have the potential to have some additive effect on weight loss and.

Speaker 2: It's possible for our approach and what Mo showed, which I think is very intriguing, is that we do have the potential to have some additive effect on weight loss. And by that.

And by that activity potentially getting the same effect on weight loss at lower doses. So so there is really I mean, we've got a lot of ideas around this we're really at the beginning of this effort are beginning of the effort of kind of mapping out the full clinical program to registration, but not at the <unk>.

Speaker 2: potentially getting the same effect on weight loss at lower doses. So there's really, I mean, we've got a lot of ideas around this. We're really at the beginning of this effort.

Speaker 2: beginning of the effort of kind of mapping out the full clinical program to registration, but not at the beginning efforts of our deep thinking around myostatin and targeting this space, right? So we've got a lot of good ideas, more to come, but I think we can do that. And then in terms of chronic therapy, that's a very, very interesting question.

<unk> efforts of our deep thinking around Myostatin and targeting this space right. So we've got a lot of good ideas more to come but I think we can we can do that and then in terms of chronic therapy, that's very very interesting question.

As you know I think there is a challenge with maintaining therapy on the current <unk> receptor agonists. There is the potential for rapid rebound if we take a look at muscle is a metabolic Oregon, which it is.

The chances of restoring and preserving that could have some very interesting effects on maintaining the weight loss, even at lower reduced click one therapy and what we're showing at least from our perspective is that we certainly can give a pedigree map chronically topaz data is really underscoring that as I mentioned earlier, we have patients.

On for years.

So again a lot of questions to address in the current in the clinical program, which is exciting for me, but I'm really excited by the fact that Mo and most team have for 309 that they've moved since I joined the company to now talking about moving towards IND really good progress from our research team.

Speaker 2: So again, a lot of questions to address in the current, in the clinical program, which is exciting for me. But I'm really excited by the fact that Mo and Mo's team have 439 that they've moved since I joined the company to now talking about moving toward IND. Really good progress from our research team.

Okay. Thank you very helpful.

Okay.

Speaker 5: There are no further questions at this time. Mr. Jay Baxter, my critical back.

There are no further questions at this time, Mr. Jay Backstrom I turn the call back over to you, yes. So listen. Thank you. Thank you for your interest again, just to reinforce I'm really delighted with the work. Our team has done very pleased with our progress and I really look forward to kind of driving through the rest of this year in <unk>.

Speaker 2: Yeah, so listen, thank you. Thank you for your interest. Again, just to reinforce, I'm really delighted with the work our team has done, very pleased with our progress. And I really look forward to kind of driving through the rest of this year and really running into 2024, where we have some really major milestones. So with that, we'll close the call.

Running into 2024, where we have some really major milestones so with that we'll close the call and once again. Thank you.

Please wait the conference will begin shortly.

Speaker 6: Please wait. The conference will begin shortly. Please wait. The conference will begin shortly.

Okay.

Yes.

Okay.

Yes.

Okay.

Sure.

Okay.

Yes.

Thanks.

Yes.

[music].

Okay.

[music].

Good morning, I'm actually not senior Vice President Corporate Affairs, and Investor Relations at scholar Rock welcome and thank you for joining us today for our Q3 2023 business update call.

Speaker 1: Good morning, I'm Rashmi Noxinger, Vice President of Corporate Affairs and Investor Relations at Scholar Rock. Welcome and thank you for joining us today for our Q3 2023 business update call. This call is audio only. You can access the slides that we'll be referring to on the events and presentation section of the Investor Relations page on the Scholar Rock website.

This call is audio only you can access the slides that we'll be referring to on the events and presentations section of the Investor Relations page on the scholar rock website.

Any forward looking statements represent our views only as of today and should not be relied upon as representing our views as of any future date.

Speaker 1: Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any future date.

Speaker 1: Please refer to our SEC filings for the full disclosure of all the risks.

Please refer to our SEC filings for the full disclosure of all the risk.

Speaker 1: Turning to slide three, I'd like to introduce the members of the Scholar Rock team who will be presenting during today's call and will be available for questions after the conclusion of the formal remarks.

Speaker 2: I am joined by Jay Backstrom, CEO of Scholar Rock, Ted Miles, Chief Operating Officer and Chief Financial Officer, and Mo Katsunani, Head of Research. I will now turn it over to Jay. Thank you, Rashmi, and good morning, and welcome to our Q3 Business Update.

I am joined by Jay Backstrom, CEO of scholar Rock, Ted Myles, Chief operating Officer, and Chief Financial Officer, and moat cuts and Ani head of research I will now turn it over to Jay Thank.

Speaker 2: We've made excellent progress so far this year and in particular in the third quarter, and I'm very excited about our future and believe we're well positioned for success. Moving to slide four.

Before I review the details of our progress I want to start with scholar Rock's pioneering approach to targeting TGF beta superfamily of growth factors.

Speaker 2: Before I review the details of our progress, I want to start with Scholar Rock's pioneering approach to targeting TGF-beta superfamily growth factors.

Speaker 2: picture on the left of the slide depicts the latent complex that contains the inactive growth

Picture on the left of this slide depicts the latent complex that contains the inactive growth factor.

Speaker 2: The scientific insight that led to the understanding of the structure of this latent complex is part of the foundation of our industry-leading platform that targets TGF beta superfamily of growth factors by selectively and specifically blocking their activation by locking up the growth factor in the precursor or latent form.

Scientific insight that led to the understanding of the structure of this latent complex is part of the foundation of our industry, leading platform that targets TGF beta superfamily of growth factors by selectively and specifically blocking their activation by locking up the growth factor in the precursor or latent form.

This highly specific approach limits the off target effects that have been observed with less selective approaches that target. The active forms of the growth factors or interfere with their receptors such as the active <unk> receptors are pitaka Mab, our lead clinical program targeting late Myostatin.

Speaker 2: Pitigramab, our lead clinical program, targeting latent myostatin, prevents the formation of the active form of myostatin, a negative regulator of muscle growth, and leads to an increase in muscle mass and function in nonclinical models, and is the first anti-myostatin therapy to demonstrate clinical proof of concept.

<unk> the formation of the active form of Myostatin, a negative regulator of muscle growth.

And leads to an increase in muscle mass and function in non clinical models and as the first anti myostatin therapy to demonstrate clinical proof of concept.

Moving to slide five.

Speaker 2: I was very excited to announce that we are leveraging our R&D platform and deep knowledge of myostatin biology to expand into a new therapeutic area of cardiometabolic disorders.

Speaker 2: with our novel, highly potent, and selective anti-myostatin antibody SRK439 in combination with the GLT1 receptor agonist.

Speaker 2: Scholarock has a longstanding interest in targeting myostatin for cardiometabolic disease.

Scholar rock has a long standing interest in targeting myostatin for cardio metabolic disorders, giving the role that muscle plays in glucose metabolism and insulin sensitivity.

Speaker 2: giving the role that muscle plays in glucose metabolism and insulin sensitivity.

Speaker 2: As you'll hear from a later in this morning's presentation, our approach to blocking myostatin is ideally suited for use in both SMA and in cardiometabolic disorders, since by blocking myostatin and only myostatin, we avoid off-target toxin.

Speaker 2: Safety is critically important in treating SMA and in weight loss therapy. And we believe our selective approach, as we've seen with the Pitigremab in our SMA program to date, should lead to a favorable overall benefit risk profile. Moving to slide seven.

Moving to slide six.

Speaker 2: Targeting the TGF beta superfamily has broad therapeutic applications given the central role this family of growth factors plays in wide range of cellular processes including growth and differentiation.

Our research teams have produced a robust pipeline of product candidates targeting latent myostatin and latent TGF beta one I am very pleased with significant progress that we've made on our pipeline since the beginning of the year moves.

Speaker 2: Our research teams have produced a robust pipeline of product candidates targeting latent myostatin and latent TGF beta 1. I'm very pleased with the significant progress we've made on our pipeline since the beginning of the year.

Moving to slide seven.

For this morning's call I'll start with an update on our clinical programs highlighting the status of <unk> hundred one our selective anti late and TGF beta one antibody in immuno oncology.

Speaker 2: For this morning's call, I will start with an update on our clinical programs, highlighting the status of SRK181, our selective anti-latent TGF-beta-1 antibody in immuno-oncology.

Speaker 2: Followed by an update on the progress we've made with our number one priority, a pedigree map in SMA.

Followed by an update on the progress we've made with our number one priority <unk> in SMA.

Speaker 2: And then turn to Mo to discuss our entry into cardiometabolic disorders with our novel antimyostatin SRK439. Moving to slide eight.

And then turned to mow to discuss our entry into cardio metabolic disorders with our novel anti Myostatin SRP 439.

Moving to slide eight.

Speaker 2: As a reminder, the main objectives of the DRAGON study, in addition to dose ranging and safety included establishing proof of mechanism and proof of concept that by blocking TGF-beta 1, a key driver for resistance to checkpoint.

By blocking TGF beta one a key driver for resistance to checkpoint inhibitors with <unk> at 101 in combination with <unk> that we could overcome the immune suppressive environment and restore responsiveness to the checkpoint inhibitor.

Speaker 2: with SRK181 in combination with pembrolizumab that we could overcome the immune suppressive environment and restore responsiveness to the checkpoint inhibitor.

To achieve to achieve these objectives. The part B portion of this study included expansion cohorts in several tumor types.

Speaker 2: To achieve these objectives, the Part B portion of the study included expansion cohorts in several tumor types and required all patients to have progressed on the most immediate prior anti-PD-1 or PD-L1 treatment. The study is rich in biomarkers.

And required all patients who have progressed on the most immediate prior anti PD, one or PD lone treatment.

The study is rich in biomarkers, including paired biopsies to assess <unk>, one could overcome and immune exclusion phenotype and drive CDA positive T cells into the tumor as was demonstrated in our non clinical models.

Speaker 2: to assess if SRK181 could overcome an immune exclusion phenotype and drive CDA positive T cells into the tumor as was demonstrated in our non-clinical model.

Speaker 2: The team made excellent progress with the DRAGON study since the start of the year, culminating in two poster presentations at the annual meeting of the Society for Immunotherapy of Cancer this past weekend.

Speaker 2: The first poster focused on biomarker data in support of proof of mechanism.

The first poster focused on biomarker data in support of proof of mechanism.

Speaker 2: And the second provided a clinical and biomarker update from the renal cell carcinoma cohort from the Part B expansion. The cohort with the most patient data, including follow-up. I will start with a review of the biomarker poster.

Moving to slide nine.

This poster focused on biomarker data in support of proof of mechanism.

Speaker 2: This poster focused on biomarker data and supported proof of mechanism.

And based on paired biopsy data demonstrated that <unk> 81 in combination with an anti PD one therapy increase the infiltration of CDA positive T cells across several tumor types, including melanoma shown here.

Speaker 2: And based on paired biopsy data, demonstrated that SRK181 in combination with an anti-PD1 therapy increased the infiltration of CD8 positive T cells across several tumor types, including melanoma shown here.

Speaker 2: This was seen in the compartmental analysis that measures the percentage of CD8 positive cells in the tumor, tumor margin and stroma from two melanoma.

This was seen in the compartmental analysis that measures the percentage of CDA positive cells in the tumor tumor margin in stroma from two melanoma patients.

Speaker 2: As shown on the graphs on the left, there was an increase in CD8 positive T cells observed after treatment, overcoming an exclusion or desert phenotype, which was present at baseline.

As shown on the graph on the left there was an increase in CDA positive T cells observed after treatment overcoming an exclusion or desert phenotype, which was present at baseline.

Speaker 2: Similarly, as shown in the histopath image on the right, there's an increase in intensity of brown staining representing CD8 positive T cells in the post-treatment biopsy, also demonstrating the influx of CD8 positive T cells into the tumor.

Speaker 2: We were excited to see these data which essentially reproduced the nonclinical findings that formed the scientific rationale for SRK181.

We were excited to see these data, which essentially reproduced the non clinical findings that formed the scientific rationale for <unk> one.

Turning to slide 10.

Speaker 2: The second poster presented at CITSI provided an update on the renal cell carcinoma cohort from Part B. Overall, 28 patients were available for research.

The second poster presented at <unk> provided an update on the renal cell carcinoma cohort from part D. Overall 28 patients were Evaluable for response.

Speaker 2: It's important to note that the patients enrolled represented a heavily pre-treated population who received a meeting of three prior lines of treatment including a checkpoint inhibitor and tyrosine kinase.

It's important to note that the patients enrolled represented a heavily pretreated population.

We received a median of three prior lines of treatment, including a checkpoint inhibitor and tyrosine kinase inhibitor.

Speaker 2: all had disease progression on their prior anti-PD-1, PD-L1 treatment.

All had disease progression on their prior anti PD, one PD lone treatment.

Speaker 2: The slide includes three graphical displays from the poster and highlight the treatment duration shown in the swimmers plot, anti-tumor activity.

Speaker 2: and the spider plot that illustrates both duration and tumor.

Speaker 2: As can be seen, there is clear evidence of tumor reduction with a 21% overall response rate that is durable beyond six months and a disease control rate of 57%.

That is durable beyond six months and a disease control rate of 57%.

The overall response rate is significantly above what we'd expect from a checkpoint inhibitor alone in the setting of prior anti PD, one PD lone progression, which is expected to be less than 5%.

With respect to safety the combination was generally well tolerated with the most common treatment emergent adverse events predominantly skin toxicities of rash and pure items.

Speaker 2: With respect to safety, the combination was generally well-polerated with the most common treatment emerging adverse events predominantly skinpoxicities of rash and curitis.

Moving to slide 11.

Speaker 2: Now that DRAGON has met its objectives, we plan to enclose enrollment in December , begin close out activities, while we continue to treat those patients who continue to benefit from therapy and remain on study.

Speaker 2: We also plan to present ongoing data from Dragon at future medical meetings.

We also plan to present ongoing data from Dragon at future medical meetings.

I'd like to take this opportunity to thank the investigators study staff and in particular, the patients and their families who participated in or are currently participating in dragon.

Speaker 2: Regarding the SRK181 program overall, we believe the data from Dragon support advancing the.

Speaker 2: And we plan to conduct an end-of-phase-one meeting with FDA in the first half of 2024 to determine the next steps.

Turning to slide 12.

I will now focus on our lead clinical program with <unk> in spinal muscular atrophy or SMA.

Speaker 2: I'll now focus on our lead clinical program with the pitogramab in spinal muscular atrophy or SMA. As a reminder, SMA is an inherited neuromuscular disorder caused by a deficiency in a protein, the SMN protein, that is essential for the survival of the motor neuron, which in turn is responsible for controlling muscle movement.

As a reminder, SMA is an inherited neuromuscular disorder caused by a deficiency in a protein the SMN protein that is essential for the survival of the motor neurons, which in turn is responsible for controlling muscle movement on.

When the SMN protein is deficient the motor neurons degenerate, resulting in muscle weakness and atrophy, leading to significant impairments, including the inability to sit stand and walk depending on the extent of involved.

Speaker 2: Currently, there are three approved therapies for SMA, all work to increase the amount of SMA and protein, but none target the muscle direct.

Currently there are three approved therapies for SMA, all work to increase the amount of SMN protein, but non target the muscle directly.

With critical mass by targeting late in Myostatin prevents the formation of the active form of milestone a negative regulator of muscle growth and is the first anti myostatin to result in improvements in motor function as shown in our phase II proof of concept study topaz.

Speaker 2: pitigramab by targeting latent myostatin prevents the formation of the active form of myostatin, a negative regulator of muscle growth, and is the first anti-myostatin to result in improvements in motor function, as shown in our phase two proof of concept study, Topaz. Moving on.

Moving to slide 13.

Speaker 2: As shown, there was robust, consistent, and sustained improvement in the motor function scales, the extended hammersmith and revised upper limb module, which are also the primary and secondary endpoints in SAFIRE. As well as improvements in the patient reported outcome measures as reflected in an increase in activities of daily living and reduction in fatigue. All measures that are consistent with improvement in muscle strength.

As shown there was robust consistent and sustained improvement in the motor function scales, the extended Hammersmith and revised upper limb module.

Were also the primary and secondary endpoints and Sapphire.

Okay.

Turning to slide 14.

I am very pleased with the progress we've made this year towards executing on the promise of a <unk> in SMA, we have met or on track to meet all of the 2023 bowls for the program that we outlined at the beginning of the year.

Speaker 2: I'm very pleased with the progress we've made this year for executing on the promise of a Pittigrew-Mabin SMA. We have met or are on track to meet all of the 2023 goals for the program that we outlined at the beginning of the year.

Speaker 2: to continue to receive a pedigree map. Importantly, ONIX provides an opportunity to further strengthen the body of evidence on long-term safety and that.

Ft and efficacy.

As we announced in September we completed enrollment of our phase III registration study Sapphire, a major milestone for this study and look forward to reporting our top line results in Q4 2024.

Assuming success and regulatory approval, we expect to be a commercial company in 2025.

Speaker 2: and assuming success and regulatory approval, we expect to be a commercial company in 2025. And from a commercial perspective, the launch of the Pythagram app will be leveraged by the established SMA Marks.

And from a commercial perspective, the launch of the critical math will be leveraged by the established SMA market.

Speaker 2: And finally, our team is in the planning stages for additional follow-on SMA studies, including in children under the age of two and in ambulatory patients, allowing us to extend the potential benefit of opitogramab to the broadest patient population possible.

And finally, our team is in the planning stages for additional follow on SMA studies, including in children under the age of two and in ambulatory patients, allowing us to extend the potential benefit of a pit of the map to the broadest patient population possible.

Speaker 2: Now moving to slide 15, I'd like to turn this portion of the program over to Mo, who will provide an overview of the cardiometabolic program. Mo is the head of research and brings a wealth of experience in both neuromuscular and cardiometabolic disease.

Now moving to slide 15.

Like to turn this portion of the program over to MAU, who will provide an overview of the cardio metabolic program.

<unk> is the head of research and brings a wealth of experience in both neuromuscular and cardio metabolic diseases as.

Speaker 2: As I mentioned in my opening remark, Mo's team has been working on targeting antimyostatin for cardiometabolic diseases for quite some time. And Mo will walk you through this research. Mo?

As I mentioned in my opening remarks, most team has been working on targeting anti myostatin for cardio metabolic diseases for quite some time and Mo will walk you through this research Mo.

Speaker 3: Thank you, Jay, and good morning, everyone. Now on slide 16.

You Jay and good morning, everyone now on slide 16.

Our approach of targeting the importance of <unk> allows us to have exquisite selectivity to inhibit <unk> signaling and nothing else.

Speaker 3: Our approach of targeting the pro and latent forms of MySTAN allows us to have exquisite selectivity to inhibit MySTAN signaling and nothing else.

Speaker 9: A non-selective approach that targets pathways outside of myosin or muscle has the potential to have deleterious effects.

Non selective approach that targets pathways outside of my stand or muscle has the potential to have bill serious effects for.

Speaker 9: For example, inhibition of the closely related GDF11 growth factor signaling may have negative impacts on bones. And inhibition of activants has demonstrated effects on reproductive biology, likely limiting the use of products which target this pathway in women of childbearing age.

For example, inhibition of the closely related to EDF 11 growth factor signaling they have no negative impact on bone and inhibition of <unk> has demonstrated effects on reproductive biology likely limiting the use of products, which target this backward and women and women of childbearing age.

By inhibiting Myostatin and <unk>, our antibodies provide a profile that drops efficacy without the potential liabilities that come with non selective approaches which is critical especially in this patient population.

Speaker 9: By inhibiting myosin and only myosin, our antibodies provide a profile that drives efficacy without the potential liabilities that come with non-selective approaches, which is critical, especially in this patient population.

We are now on slide 17.

Speaker 9: Obesity is recognized as a top global public health challenge with an estimated 1 billion adults worldwide, including half of the population in the US projected to be obese by 2030.

Obesity is recognized as a top global public health challenge with an estimated 1 billion adults worldwide, including half of the population that <unk> projected to be abused by 2030.

Speaker 9: This is associated with several serious comorbidities like heart disease and type 2 diabetes and staggering cost to the healthcare system.

This is associated with several serious comorbidities like heart disease, and type two diabetes and staggering cost to the health care system.

Weight loss by any means leads to loss of not only that but also being mass and this is evident in the <unk> one receptor agonist mediated weight loss that are experiencing rapid uptake and we're lean mass losses may be 25% to 40% of the total body weight loss.

Speaker 3: Weight loss, by any means, leads to loss of not only fat, but also lean mass. And this is evident in the GLP-1 receptor agonist-mediated weight loss that are experiencing rapid uptake and where lean mass losses may be 25 to 40% of the total body weight loss.

Lots of lean mass.

Speaker 9: Loss of lean mass is a key predictor of adverse outcomes in older patients, and maintaining lean mass through exercise during weight loss has demonstrated longer term benefits versus weight loss alone.

Key predictor of adverse outcomes and all the patients and maintaining lean mass through exercise room weight loss has demonstrated longer term benefits versus weight loss alone.

Speaker 9: Therefore, it is important that, it is possible that maintaining lean mass in the context of weight loss may promote additional fat loss as well as greater long-term metabolic benefit.

Therefore, it is important that.

It is possible that maintaining lean mass in the context of weight loss may promote additional fat loss as well as greater long term metabolic benefits.

Moving to slide 18.

Speaker 9: Moving to slide 18, where we'll be discussing SRK 439.

We'll be discussing as RK for three nine.

Speaker 9: FRK439 is a novel preclinical anti-myostin antibody that is in development. As mentioned earlier, we leveraged our extensive expertise in myostin structure and biology to develop this molecule to specifically address the patient population with cardiovascular disorders.

Our target for <unk> nine is a novel preclinical anti <unk> antibody that is in development.

Mentioned earlier, we have leveraged our extensive experience expertise and milestone structure on biology to develop this molecule to specifically address the patient population with cardio metabolic disorders.

Speaker 9: SACAE 439 has attractive properties and potential to address the muscle loss associated with weight loss.

Okay.

<unk> has attractive properties and potential to address the muscle loss associated with weight loss.

It has high end mutual affinity for <unk> to potentially lead to efficacy at lower doses.

Speaker 9: It has high in vitro affinity for pro and latent myosin to potentially lead to efficacy at lower doses.

Speaker 9: It maintains my stance specificity with no GDS-11 or active in A binding to limit any potential undesirable off-target effects, especially in this patient population.

Maintains milestone specificity with no Judy at 11 are active in a binding to limit any potential undesirable off target effects, especially in this patient population.

It also maintains a good develop ability profile and is amenable to subcutaneous subcutaneous formulation and dosing.

Speaker 9: It also maintains a good developability profile and is amenable to subcutaneous formulation and dosage.

Now on slide 19, where we show our efficacy data with US. Okay 439 in combination with <unk> one receptor agonist in diet induced obese mouse model the standard model used in the field.

Speaker 9: Now on slide 19, where we show our efficacy data with SRK439 in combination with GLP1 receptor agonist in diet-induced obesity mouse model, a standard model used in the field.

Speaker 9: As expected, the decrease in body weight induced by CGLP1 receptor agonist, liraglutide in this case, led to a decrease in not only fat mass, but also lean mass, as you see with the TAM bar.

As expected the decrease in body weight induced by <unk>, one receptor agonist liraglutide in this case led to a decrease in not only fat mass, but also the math as you see with a sandbar.

Speaker 9: Combining SRK439 with a GLP-1 receptor agonist confirmed our therapeutic hypothesis and led to dose-dependent reversal of lean mass loss in addition to enhancement of fat mass loss.

Combining <unk> hundred 39, with a <unk> one receptor agonist confirmed our therapeutic hypothesis and led to dose dependent reversal of lean mass loss. In addition to enhancements of fat mass loss.

Now on slide 20.

Speaker 9: Slide 20 highlights the efficacy of SRK439 in diet-induced obesity mouse model in combination with semaglutide and more effective GLP1 receptor agonists.

Slide 20 highlights the efficacy of a socket with renowned in diet induced obese obesity mouse model in combination with summit lubricants and more effective <unk> one receptor agonist.

Speaker 9: Semiglutide did lead to significant loss of lean mass in addition to fat mass loss as seen in the tan bond.

<unk> did lead to significant loss of lean mass in addition to fat mass loss as seen in the sandbox.

Speaker 9: However, when combined with SRK439, the loss in lean mass induced by semaglutide alone was dose-dependently reversed, leading to maintenance of lean mass while enhancing fat mass loss.

However, when combined with <unk> 49 loss in lean mass induced by somebody who died alone was dose dependent we reversed leading to maintenance of lean mass, while enhancing fat mass loss.

Speaker 9: It is worth noting that we see lean mass reservation with doses as low as 0.3 milligram per kilogram of SRK439, which highlights the favorable profile of SRK439 for development in this indication.

It is worth noting that we see lean mass reservation with doses as low as <unk> three milligrams per kilogram almost like a 14, nine which highlights the favorable profile of our survey for C&I for development in this indication.

Turning to slide 21.

To summarize our approach is explicitly selective in targeting myostatin and <unk>, only and avoids potential liabilities of target inhibition.

Speaker 9: To summarize, our approach is explicitly selective in targeting MiStan and MiStan only and avoids potential liabilities of off-target inhibition.

Speaker 9: The selective inhibition of myosin in combination with GLP receptor agonist-driven weight loss may lead to healthier, more durable weight management, and we look forward to testing this in the clinic.

The selective inhibition of milestone in combination with <unk>, one receptor agonist driven weight loss may lead to healthier more durable weight management and we look forward to testing this in the clinic.

Now on slide 22.

Speaker 9: In summary, our preclinical data supports advancing SRK439, a novel investigational match stand inhibitor for the treatment of cardiometabolic disorders with an initial focus on obesity.

In summary, our preclinical data support advancing <unk> hundred 39, a novel investigational <unk> inhibitor for the treatment of cardio metabolic disorders with an initial focus on obesity.

Speaker 9: We are moving SRK 439 towards IND submission in 2025.

We are moving as I gave was three nine towards IND submission in 2025.

To inform the development of our stock at 439, we plan to initiate a phase II proof of concept trial, particularly in combination with <unk> one receptor agonist in every city in 2024.

Speaker 9: To inform the development of SRK439, we plan to initiate a phase two proof of concept trial of a particular map in combination with GLP1 receptor agonist in obesity in 2024.

Speaker 9: The data readout of that trial is expected in mid-2025.

The data readout of that trial is expected in mid 2025.

Speaker 4: Now I'll turn it over to Ted for summary. Thanks, Mo. Moving to slide 24, 2023 has been a year of significant execution across our portfolio, and we're well positioned going into 2024. We're seeing great productivity coming out of our scientific platform as our unique approach of targeting the latent form of growth factors to achieve exquisite selectivity appears to be proving patient outcomes in SMA and in oncology.

Now I will turn it over to Ted for summary.

Thanks, Mo moving to slide 20 for 2023 has been a year of significant execution across our portfolio and we're well positioned going into 2024.

We're seeing great productivity coming out of our scientific platform is our unique approach of targeting the latent form of growth factors to achieve exquisite selectivity appears to be proving patient outcomes in SMA and in oncology.

Speaker 4: We are excited to be applying this selectivity to a cardiometabolic disease areas where we believe safety is so important and our approach is highly differentiated.

We are excited to be applying this selectivity toward cardio metabolic disease areas, where we believe safety is so important and our approach is highly differentiated.

Speaker 4: Our upsized public offering that we completed last month puts us in a strong financial position with our cash runway that extends into the second half of 2025.

Our upsized public offering that we completed last month puts us in a strong financial position with our cash runway that extends into the second half of 2025.

Speaker 4: We're focused on advancing the myostatin programs, SMA and cardiometabolic. Additionally, we believe we're well positioned to bring in non-deluded funding as we continue to evaluate potential partnership opportunities for other programs within our portfolio.

We're focused on advancing the myostatin programs SMA in cardio metabolic. Additionally, we believe we're well positioned to bring in non dilutive funding as we continue to evaluate potential partnership opportunities for other programs within our portfolio.

We view strategic business development is an important way to advance promising programs by leveraging the infrastructure capital and expertise of other companies.

Speaker 4: We view strategic business development as an important way to advance promising programs by leveraging the infrastructure, capital, and expertise of other companies.

Speaker 4: We ended the third quarter with $219 million of cash and cash equivalents, and our October capital raise netted approximately $93 million.

We ended the third quarter with $219 million of cash and cash equivalents and our October capital raise netted approximately $93 million.

Speaker 4: Our capital allocation strategy includes a substantial reduction in our spend on SRK 181 as we complete enrollment of DRAGON and continue to support remaining patients on study.

Our capital allocation strategy includes a substantial reduction in our spend on <unk> one as we complete the enrollment of Dragon and continue to support remaining patients on study.

Speaker 4: Our primary focus as we conclude 2023 and look to 2024 includes investments to advance epitogram and SMA and our newly announced cardio metabolic program.

Our primary focus as we conclude 2023 and look to 2024 includes investments to advance our pedigree mab in SMA and our newly announced cardio metabolic program.

Speaker 4: With the capital in hand, promising programs underway, and our strategic imperatives aligned with our core competency, unparalleled selectivity of myostatin inhibition, we are excited about the future and our ability to serve patients with our important novel therapy.

Speaker 4: This concludes our formal remarks. I'll now turn it over to the operator so we can start the Q&A. Operator?

This concludes our formal remarks, I'll now turn it over to the operator, so we can start the Q&A operator.

Thank you the floor is now open for your questions to ask a question at this time. Please press Star then the number one on your telephone keypad.

Speaker 5: To ask a question this time, please press start and the number 1 on your telephone keypad.

Speaker 6: We'll just pause for just a moment to compile the Q&A roster.

Just pause for just a moment to compile the Q&A roster.

Okay.

Your first question comes from the line of Michael <unk>.

With Jefferies. Your line is now open.

Speaker 7: Hey guys, thanks for the question and congrats on all the progress. We had two questions, one on SMA and one on cardiometabolic.

Hey, guys. Thanks for the question and congrats on all the progress.

We had two questions one on SMA and one on cardio metabolic.

Speaker 7: SMA, in your Phase 3, I believe the primary analysis is based on 2 to 12, and I was wondering if you have any thoughts around the proportion of the study that is probably more 2 to 5 versus, say, older.

Semey.

In your phase III I believe the primary analysis is based on $2 12.

And I was wondering if you have any thoughts around the proportion of the study that is probably more.

Five versus say holder.

Speaker 7: and whether there's any pre-specified analysis that has a analysis to look at the younger patients versus the older patients in that study after observing what happened with DMT gene therapy and how that played out, if there's a pre-specified analysis for younger patients.

And whether there is any pre specified analysis that has a analysis to look at the younger patients versus the older patients in that study after observing what happened with.

DMD gene therapy, and how that played out if there was a pre specified analysis for younger patients and then on cardio metabolic and.

Speaker 7: And then on cardiometabolic, an interesting hypothetical question, appreciating that this is an obesity drug that you're trying to develop, do you anticipate that the regulatory path is traditional obesity, just weight loss, whether there's an endpoint also that would be accepted by the FDA for muscle gain? And I was wondering how you think about that. Thank you.

An interesting hypothetical question and I appreciate that this is an obesity drug that you are trying to develop.

We anticipate that the regulatory path is.

Traditional RBC just weight loss.

There is an endpoint all showed that would be accepted by the FDA for muscle gain and I was wondering how you think about that thank you.

Yes, it's good with Semiclad. Thank you. This is Jay Thanks for the question, let me start with the SMA. So yes. Our primary analysis is the two to 12.

Speaker 2: Yes, good. So Michael, thank you. This is Jay. Thanks for the question. Let me start with the SMA. So yes, our primary analysis is the 2 to 12. We haven't disclosed the proportion of that group who are between the ages of 2 and 5.

We haven't disclosed the proportion of that group, who are between the ages of two and five and.

Speaker 2: And at this juncture, our primary analysis and pre-specified analysis certainly include the older cohort. But as you know, upon top line data, we have the opportunity to look across the age groups. So we will certainly look at that in the top line results.

And at this juncture our primary analysis pre specified analysis certainly include the older cohorts.

But as you know upon.

Top line data, we had the opportunity to look across the age groups. So we will certainly look at that in the topline results.

Speaker 2: So I think that took care of the question on the SMA patient population.

So I think that took care of the question on the SMA patient population with respect to cardio metabolic yeah very interesting question I think with respect to the current approval for weight loss. It is the amount of weight loss that occurs that is the primary endpoint. As you know this is an evolving field and I think recognizing that.

Speaker 2: With respect to cardiometabolic, yeah, very interesting question. I think with respect to the current approval for weight loss, it is the amount of weight loss that occurs that is the primary endpoint. As you know, this is an evolving field, and I think recognizing that, you know, the need to preserve lean muscle mass is really critical, and the efforts now that we're in and others are in, I think will help inform future regulatory endpoints.

The need to preserve lean muscle mass is really critical and the efforts now that we're in and others are in I think will help inform future regulatory endpoints, but we will need to demonstrate at some point across the program improvements in either function or patient reported outcomes. So I think that will need to be a standard part but.

Speaker 2: But, you know, we will need to demonstrate at some point across the program improvements in either function or patient reported outcomes. So I think that will need to be a standard part. But I think it's a stay tuned as I think as we move forward.

I think it's a stay tuned as I think as we move forward.

Speaker 2: For our proof of concept study, we're certainly going to be focused on demonstrating that we can preserve and maintain the muscle mass. I think for proof of concept, that's mechanistically sound, and that's our approach going forward.

There are a proof of concept study, we're certainly going to be focused on demonstrating that we can preserve and maintain lean muscle mass I think for a proof of concept that is mechanistically sound and that's our approach going forward.

Okay.

Thank you guys.

Okay.

Our next question comes from the line of Allison <unk> from Piper Sandler.

Speaker 5: Our next question comes from the line of Allison Bratzel from Piper's.

Please go ahead.

Hi, good morning team. Thanks for the update today and thanks for taking my question.

Speaker 8: Hi, good morning team. Thanks for the update today and thanks for taking my question.

Speaker 8: So, first, on SRK 439, maybe a question for Mo.

So first and SRP 439, maybe a question for Michael could you just provide some more color on the different properties at 439 compared to geopolitical map.

Speaker 8: Could you just provide some more color on the different properties of 439 compared to a pedigree map? And just really distill for us why 439 is better suited to go forward in obesity. It seems the sub-Q format.

And just really distill for FY for tinnitus is better suited to go forward and in obesity.

It seems the sub Q format.

Speaker 8: is a major differentiator there. You know, just curious if sub-Q administration of a pedigree map is something you've explored. Any color there would be helpful. And then just on a related note, could you help us understand what is gating to IND filing for a pedigree map and obesity? And also, same question, you know, what's gating to...

Is that is a major differentiator there just curious it is sub Q administration.

<unk> map is is something.

You've explored.

Color there would be helpful. And then just on a related note could you help us understand what is gating to IND filing for <unk> in obesity and also same question with <unk>.

<unk> two one.

Speaker 8: IND filing for 439 and what gives you confidence.

IND filing for 439, and what gives you confidence.

Speaker 8: that IND filing will be ready to go in mid-25. Thanks.

That that IND filing will be ready to go and not mid 25. Thanks.

Hey, Ali this is Jay maybe I'll take one part of that three part question and then I'll turn it over to mow and as the question around the IND.

Speaker 2: Hey, Ali, this is Jay. Maybe I'll take one part of that three-part question, and then I'll turn it over to Moe. And here's the question around the IND, what's required to get the IND filed for a PIDGRAM app?

What's required to get the IND filed for a pedigree map.

Speaker 2: Why I'm, you know, really delighted that we have the opportunity to proof of concept with the pitagoramab is because it's already a clinical stage assay.

Why.

Speaker 2: So it's a matter of really putting together the scientific rationale and submit the IND for a new division to agree. And we get to cross-reference a lot of the existing documents in the current epidemiogram IND and SMA. So it's really a matter of kind of completing the regulatory dossier to do that. And then engage FDA. So that work, frankly, we had started even prior to announcing our going into this.

Cory dossier to do that and then engage FDA. So that work frankly, we had started.

Even prior to announcing are going into this area and then maybe I'll, let <unk> talk about the IND, enabling work required for S. R. K three 9% and then more details yes.

Speaker 2: And then maybe I'll let Mo talk about the IND enabling work that's required for SRK439.

Speaker 3: Yeah, thanks, Jay. I mean, I'll start with talking about SARCAE-439. SARCAE-439 is a novel molecule that we developed based on our extensive understanding of myosin and the structure and the epitope space.

Yes, Thanks, Jay I'll start with talking about what's going on but not as a square foot.

<unk> is a novel molecule that we developed based on our extensive understanding of mice and in the structure and the epitope space. It is highly selective as we mentioned that <unk> binds myostatin utilizing our platform.

Speaker 3: It is highly selective, as we've mentioned, it only binds MySpan, utilizing our platform.

Speaker 9: It has attractive property and from the get-go we developed it to target this patient population. So it has very high in vitro affinity leading to potential lower doses when you're, when you're looking at efficacy with these. And we've seen that in the mouse models that we've, we've done and we continue to do in other models as well as we develop the molecule. It also amenable to high concentrations. Again, this is to support sub-Q profile especially for this patient population.

It has attractive property and from the get go we developed it to target. This patient population. So it has very high in vitro affinity.

Leading to.

Potentially lower doses when you're when you're looking at efficacy with these and we've seen that in the mouse models that we have.

We have done and we continue to do in other models as well as with about the molecule.

It also.

Amenable to high concentrations again this is to support.

<unk> Q profile, especially for this patient population. The overall profile of <unk> 49 was designed by design for this patient population drove higher affinity.

Speaker 3: The overall profile of RSV-149 was designed by design for this patient population to have higher affinity efficacy with lower doses and concentration to enable subcutaneous dosing.

Efficacy with lower doses and concentration to enable subcutaneous dosing from an R&D, enabling studies.

Speaker 3: From an IND-enabling studies, you know, we're going forward with the typical IND-enabling studies. We're initiating all of the IND-enabling studies as we move forward into next year, as you see the talks, the PK studies, and all of these things, as well as cell line developments, et cetera.

We're going forward with the typical R&D, enabling studies we're initiating.

All of the NII IND, enabling studies as we move forward them to next year.

As you see that the talks that PK studies and all of these things as well.

So a lot of developments et cetera.

Got it thank you.

Our next question comes from the line of Tessa Romero with Jpmorgan.

Speaker 5: Our next question comes from the line of Tess Romero with J.P. Morgan.

Please go ahead.

Good morning, Thanks for taking my question two questions from US This morning, if we could.

Speaker 11: Good morning. Thanks for taking our questions. Two questions from us this morning, if we could. First one is, have you disclosed the statistical test you are using and what the powering assumptions are for the SAFIRE trial around the primary endpoint of the mean hammers must change from baseline at 12 months? If not, what can you tell us at this time as to how we should be thinking about this?

First one is how do you disclose that.

Mr. <unk>, you are using and what the powering assumptions are for the Sapphire trial around the primary endpoint of the mean Hammersmith change from baseline at 12 months.

What can you tell us at this time as to how we should be thinking about that.

Speaker 11: And secondly, a related question, will you consider disclosing the baseline characteristics before the top line results next year? Thanks, guys.

And secondly, a related question will you consider disclosing the baseline characteristics before the topline results next year. Thanks, guys.

Yes. So this is Jamie I'll take the questions from the statistical powering assumptions you know, we've really not fully disclosed it but just to kind of put color to that for the Hammersmith, we expect to certainly be able to demonstrate a three point change by the way we powered the trial and we have adequate power to demonstrate that.

And again, we're doing hierarchical testing on that and then the following secondary endpoints. So I think we're well positioned to to replicate in Sapphire, what we saw in the Topaz study.

Speaker 2: So I think we're well positioned to replicate in Sapphire what we saw in the Topaz.

Speaker 2: And then with regard to baseline characteristics, you know, Allie, we're looking at that very critically as sort of our publication planning and data disclosure plans. Really, we try to do that timed to important conferences as we think in conferences we think about over the year. So more to come as we disclose that, but not likely to occur anytime in the near term given the cadence of, you know, the medical conferences.

And then with regard to baseline characteristics.

Ali we're looking at that very critically as sort of our publication planning and data disclosure plans really we tried to do that time two important congresses as we think and conferences, we think about over the year. So more to come as we disclosed that but not likely to occur anytime in the near term given the cadence of.

The medical conferences.

Okay, great. Thanks for taking our questions.

Our next question comes from the line of Santee Cooper, David a corner from choice Securities. Your line is now open.

Speaker 5: Our next question comes from the line of Sri Kripa Devarakonda from Truer Securities. Your line is now open. Hey guys.

Hey, guys. Thank you so much for taking my question.

Speaker 12: As you develop apitogramab and SRK439 in obesity, I actually had a couple of maybe basic questions on myostatin in obesity.

As you develop to come up with RCI.

We had a couple.

Basic question on Myostatin in obesity.

Speaker 12: Some studies have shown that myostatin is upregulated in obesity. Just wondering how well this dynamic has been characterized in patients. Is there a lot of variability?

Studies have shown that <unk> is up regulated in obesity, just wondering how whether this.

The dynamic hasn't kept pace in patients is that a lot of variability and how do you think that could potentially impact how effective could be patients, especially if you consider the background of obesity versus ethanol shown activity.

Speaker 12: And how do you think that could potentially impact how effective the drug could be in these patients, especially, you know, if you consider the background of obesity versus SMA where you've shown activity? And given that the studies show myostatin is also reduced as patients lose weight, do you think there's an optimal window where you treat patients with anti-myostatin?

And given that the studies show Myostatin is also reduced as patients lose weight do you think it isn't optimal window, where do you treat patients with annualized subtle.

Thank you.

Yes, so maybe I'll start just talking about what we would expect to see in clinic with the <unk> and then followed with <unk> hundred nine in obesity.

Speaker 2: Yes, maybe I'll start just talking about what we would expect to see in clinic with the pitigramab and then followed with SRK439 in obesity. I think what we can say, which is I think

I think what we can say, which is I think very clear now.

Speaker 2: We've shown that I believe in the Topaz study is that.

We've shown that I believe in the Topaz study is that.

Speaker 2: Targeting myostatin does result in preservation, if not increase in lean muscle mass. I think we've shown that functionally in TOPAZ. I think there's consistent observation across. So myostatin is a very good target. And it certainly should be able to do that in the setting of obesity where you have normal muscle. So I think that's it.

Targeting Myostatin does result in preservation not increase in lean muscle mass I think we've shown that functionally and topaz I think theres consistent observation across semi stands a very good target and it certainly should be able to do that in the setting of obesity, where you have normal muscle. So I think thats the key.

Case, the fact that there was up they're signaling is high in Myostatin I think is interesting, but I do believe the web and opportunity to demonstrate that.

In this setting just as we demonstrated in the SMA setting.

Okay.

Great. Thank you.

Speaker 5: Our next question comes from the line of Etzer Tera from BMO Capital Markets, your line is now open.

Our next question comes from the line of Ed Sir Sierra from BMO Capital markets. Your line is now open.

Speaker 13: Great. Thanks for taking the questions and congrats on the progress. How are you thinking about the development of SRK 439, I mean, given the size of the obesity?

Great. Thanks for taking the questions and congrats on the progress.

How are you thinking about the development of our case was 209 I mean, given the size of deal will be CD <unk>.

Speaker 13: indication, and I guess is the proof of concept data with a pedigree map, the catalyst for an update, if you will, on development plans. And then maybe on SRK 181, just, you know, maybe next steps for the program, maybe a little bit more color on what you described earlier.

Indication and I guess is the proof of concept data with Citigroup, Matt the catalyst for.

An update if you will on development plans and then maybe on <unk> Q1, 'twenty one just.

Maybe next steps for the program.

A little bit more color on what you described earlier.

Speaker 13: during opening remarks and maybe the opportunity for future programs to be in sort of an earlier lines of RCC, for example. Thank you.

During opening remarks, and maybe the opportunity for future programs to be in sort of in earlier lines of RCC. For example, thank you.

Speaker 2: Yeah, so let me start with, with 439 and proof of concept and sort of overall path forward. You know, again, I think we're, we're designed, we've shown to date at Scholar Rock that we can run randomized phase three studies, we can run proof of concept trials. And so as I think about the cardiometabolic space, certainly to get

Yes, So let me start with with 43, 9% and proof of concept and sort of overall path forward.

Speaker 2: which will really, in my opinion, validate our approach. And as we report that out, we'll then at the time open up with 439 getting right into clinic, really positions us to drive 439 rapidly forward also to that proof of concept. And so that's our near-term horizon.

<unk> proof of concept, which will really in my opinion validate our approach and as we report that out. We'll then at the time open up with 43 nine getting right into clinic really positions us to drive 43 nine rapidly forward also to that proof of concept and so that's our near term horizon.

Anything beyond that I think really we're still open for discussions around how we get to bigger broader trials.

For 181.

The data that I shared.

Speaker 2: You know, the data that I shared, you know, in a way I try to put the color on.

In a way I try to put the color on it at.

Speaker 2: This is really a tough group to treat, and to see this level of response rate in this heavily pretreated, failed on checkpoint inhibitor, I think really shows that proof of concept, which is why we reached those conclusions. But I think like in any therapy, and particularly in immunotherapy, earlier lines of therapy are really the place to take any such treatment if you really want to have major impact. Because patients have been so beat up and progressed so much through these therapies, that getting earlier may.

This is really a tough group to treat and to see this level of response rate in this heavily pretreated <unk> on checkpoint inhibitor I think really.

<unk> that proof of concept, which is why we've reached those conclusions, but I think like in any therapy, particularly in immunotherapy earlier lines of therapy or really the place to take any such treatment. If you really want to have major impact because patients have been so beat up in progress. So much through these therapies that getting earlier makes sense and so frankly, that's that's.

Speaker 2: And so frankly, that's the whole concept behind the end of phase one meeting is really to engage FDA and review our data and then begin to work with them to kind of lay out what would be the next logical steps.

The whole concept behind an end of phase one meeting is really to engage FDA and a review of our data and then begin to work with them to kind of lay out what would be the next logical steps and any further development of 181 and as Ted said right now for US today really pleased with the way Dragon performed I think it has met its objective it's done it.

Job, if you will we'll wind that down reset take a look at what's happening with the FDA interaction, but in the meantime at 2024, it's really all on our focuses on our anti myostatin programs.

Great. Thank you.

Our next question comes from the line of Suntrust small Donato.

Speaker 5: Our next question comes from the line of Andres Maldonado with HC Wainwright. Their line is now open.

H C. Wainwright your line is now open.

Hi, Thank you for taking my question I'll reiterate congratulations on all the progress.

One quick question from Us on 439, I guess in.

In the context that the goal of next generation obesity programs aims to really hone in and Paul.

The issue of variability of patient response.

Could you maybe talk about how much.

And this variance you ascribed muscle loss.

Speaker 14: you know, driving that variation of patient response. And then a follow-up question to that would be, you know, given the safety and tolerability of epidechromab and wishes in positives, are some of the treatment emergent events more worrisome in the context of the combination? Thank you very much.

Driving that variation of patient response again.

Follow up question to that would be given the safety and tolerability and the growth that we should have been positive or some of the treatment emergent events more worrisome in the context of the combination. Thank you very much.

So okay, maybe we'll do a tag team with Mo I think your question is sort of the variability in weight loss that occurs with the current <unk> one receptor agonist and UC.

From the muscle mass.

Speaker 2: Hence, we'll look at our proof of concept studies to move forward. But I think that's the thinking.

Hence we will look at our proof of concept studies to move forward, but I think that's the thinking there and again I think it's really interesting to your points about safety and we've emphasized this because it really matters and it really matters as I think about weight loss therapies over time, they've been affected but they've all been troubled.

Speaker 2: And again, I think it's really interesting to your point about safety, and we've emphasized this because it really matters. It really matters. I think about weight loss therapies over time, they've been affected, but they've all been troubled by toxicities and safety issues that have prevented their continued use.

By toxicities and safety issues that have prevented their continued use.

I think what we're seeing with the <unk> receptor agonists as to date and there has been wide patient exposure, we're seeing some effects, but nothing like what we've seen in the past it would really warrant stopping these therapies. So that's a good thing, but any additional therapy that comes into this space. That's an add on therapy, that's used to kind of offset some of the neck.

Speaker 2: But any additional therapy that comes into this space, that's an add-on therapy that's used to kind of offset some of the negative effects like loss of muscle.

<unk> effects like Los in the muscle.

Speaker 2: in my mind really needs to bring no additional risk of toxicities if possible.

In my mind really needs to bring no additional risk of toxicities, if possible and that is where I believe if you look at all of the conversations going on in other areas other companies coming in to lean muscle mass I do think our approach by hitting milestone and only myostatin will avoid off target effects.

Speaker 2: And that is where I believe if you look at all of the conversations going on in other areas, other companies coming in to lean muscle mass, I do think our approach by hitting myostatin and only myostatin will avoid off-target effects. And I think Mo walked through that. If you look at what happens when you hit active in receptors A and B, you start to get into some things that you may not want to see, right, that over time could potentially be troublesome. And that's also true with GDL.

I think my walk through that if you look at what happens when you hit active and receptors AMB you start to get into some things that you may not want to see that over time could potentially be troublesome and that's also true of the GDS 11, So I like our approach it shouldn't bring any additional risk to that risk benefit profile, we'll obviously.

Speaker 2: So I like our approach. It shouldn't bring any additional risk to that risk benefit profile. We'll obviously see that when we report out our phase three data. But so far, and we're seeing that in TOPAZ, we have patients coming on four years with really a very, very clean...

We see that we report out our phase III data, but so far and we're seeing that and topaz, we have patients coming on four years with really a very very clean safety profile I think in the cardio metabolic space, we definitely want to continue with that and I think we are positioned to show that.

Speaker 2: I think in the cardiometabolic space, we definitely want to continue with that. And I think we're positioned to share.

Speaker 5: Our next question comes from the line of Ernesto Rodriguez Dumont with Cohen.

Our next question comes from the line of fairness tone with Vijay Kumar.

Please go ahead.

Speaker 15: Hi. Thank you for taking my questions and congratulations on the progress. I'll just follow up on the obesity program functional endpoints for regulatory.

Hi, Thank you for taking my questions and congratulations on the progress I'll just follow up on the on the marathon on the obesity program functional endpoints for.

For regulatory.

For regulatory purposes. So.

While the private marketing programs that show multiple games in other settings.

Is are there any hints of functional changes from those programs that could lead the.

The way to identifying a functional endpoint for the there'll be CD program.

Speaker 15: And then also, do you expect the therapy to be a chronic therapy in conjunction with a GLP-1?

And then also do you expect.

The therapy to be a chronic therapy in conjunction with <unk>.

Speaker 15: Or do you expect that there to be some kind of biomarker and limit to the therapy?

Or do you expect there to be some kind of a biomarker.

And limit to the to the to the <unk>.

So the therapy.

Thank you.

So I think Theres, a couple of things again back to the regulatory endpoints and we're going to begin the engagement with FDA and other agencies as we advance through IMD and get more interaction with our clinical programs.

Speaker 2: Yeah, so I think there's a couple of things, again, back to the regulatory endpoints. And, you know, we're going to begin the engagement with FDA and other agencies as we advance through IND and get more interaction with our clinical program.

But as an example.

Functional measures.

Motor function, so that's something to consider there.

Speaker 2: There's also measures that we can include that would look at quality of life measures. As you know, there are some significant associated GI effects with the current therapies.

Speaker 2: It's possible for our approach and what Mo showed, which I think is very intriguing, is that we do have the potential to have some additive effect on weight loss. And by that.

Speaker 2: potentially getting the same effect on weight loss at lower doses. So there's really, I mean, we've got a lot of ideas around this. We're really at the beginning of this effort.

Speaker 2: As you know, I think there's a challenge with maintaining therapy on the current TLP1 receptor agonist.

Speaker 2: There is a potential for rapid rebound.

Speaker 2: If we take a look at muscle as a metabolic organ, which it is, the chances of restoring and preserving that could have some very interesting effects on maintaining the weight loss, even at lower reduced GLP1 therapy. And what we're showing, at least from our perspective, is that we certainly can give a Pitogramab chronically. Topaz data is really underscoring that. As I mentioned earlier, we have patients on four years.

On for years.

So again a lot of questions to address in the current in the clinical program, which is exciting for me, but I'm really excited by the fact that Mo and most team have $43 nine that they've moved since I joined the company to now talking about moving towards IND really good progress from our research team.

Speaker 2: So, again, a lot of questions to address in the clinical program, which is exciting for me. But I'm really excited by the fact that Mo and Mo's team have 439, that they've moved, since I joined the company, to now talking about moving toward IND. Really good progress from our research team.

Okay. Thank you very helpful.

Okay.

There are no further questions at this time, Mr. Jay Backstrom cleared the call back over to you, yes. So listen. Thank you. Thank you for your interest again, just to reinforce I'm really delighted with the work. Our team has done very pleased with our progress and I really look forward to kind of driving through the rest of this year in <unk>.

Speaker 5: There are no further questions at this time. Mr. Jay Baxter, my critical back.

Running into 2024, where we have some really major milestones so with that we'll close the call and once again. Thank you.

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