Q3 2025 Skye Bioscience Inc Earnings Call

Only 25 financial results and business update call all lines have been placed on mute to prevent any background noise. After the speakers' remarks, there'll be a question and answer session I would now like to turn the conference over to Bernie Hertel head of Investor Relations. Please go ahead.

Hello, and thank you all for participating in today's call before we begin I'd like to caution that comments made during this conference call will contain forward looking statements under the safe Harbor provisions of the U S. Private Securities Litigation Reform Act of 1995.

Operator: Everyone, to the Skye Bioscience Q3 2025 financial results and business update call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. I would now like to turn the conference over to Bernie Hertel, Head of Investor Relations. Please go ahead.

Speaker #1: I apologize. I'm just waiting for Mitch to give us the live signal. 5, 4, 3. Ladies and gentlemen, thank you for standing by. My name is Jordan, and I'll be your conference operator today.

Including statements about sky's expectations regarding its development activities timelines and milestones.

Forward looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely and reported results should not be considered as an indication of future performance.

Bernie Hertel: Hello, and thank you all for participating in today's call. Before we begin, I'd like to caution that comments made during this conference call will contain forward-looking statements under the Safe Harbor Provisions of the US Private Securities Litigation Reform Act of 1995, including statements about Skye's expectations regarding its development activities, timelines, and milestones. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely, and reported results should not be considered as an indication of future performance. These forward-looking statements speak only as of today's date, and the company undertakes no obligation to revise or update any statements made today. I encourage you to review all of the company's filings with the Securities and Exchange Commission concerning these and other matters. I'll now turn the call over to Kaitlyn Arsenault, Skye's CFO.

Speaker #1: I would like to welcome everyone to the Skye Bioscience third quarter 2025 financial results and business update call. All lines have been placed on mute to prevent any background noise.

These forward looking statements speak only as of today's date and the company undertakes no obligation to revise or update any statements made today.

Speaker #1: After the speakers are marked, there will be a question and answer session. I would now like to turn the conference over to Bernie Hertel.

I encourage you to review all of the Companys filings with the Securities and Exchange Commission concerning these and other matters.

Speaker #1: Head of Investor Relations, please go ahead.

Speaker #2: Hello, and thank you all for participating in today's call. Before we begin, I'd like to caution that comments made during this conference call will contain forward-looking statements under the Safe Harbor Provisions of the U.S.

I'll now turn the call over to Caitlin Arsenal Sky's CFO.

Thanks, Bernie after the market closed today, we issued a press release and <unk>.

<unk> Form 10-Q, with the Securities and Exchange Commission.

Speaker #2: Private Securities Litigation Reform Act of 1995. Including statements about Skye's expectations regarding its development activities, timelines, and milestones. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely; reported results should not be considered an indication of future performance.

Outlining our quarterly financial results, we encourage you to reference our filings for the details of our financial and the risk factors described therein.

I will now provide a brief overview of our key financial results for the third quarter ended September 32025, we ended the third quarter with cash cash equivalents and short term investments totaling $35 3 million. We expect our current working capital to fund operations and key clinical milestones into 2027.

Kaitlyn Arsenault: Thanks, Bernie. After the market closed today, we issued a press release and filed Skye's quarterly 10-Q with the Securities and Exchange Commission, outlining our quarterly financial results. We encourage you to reference our filings for the details of our financials, and the risk factors described therein. I will now provide a brief overview of our key financial results for Q3 ended 30 September 2025. We ended Q3 with cash and cash equivalents and short-term investments totaling $35.3 million. We expect our current working capital to fund operations and key clinical milestones into 2027. This includes the completion of the extension of our phase IIA study for Nebasamab, and certain manufacturing and preparatory clinical activities needed to initiate the next study.

Speaker #2: These forward-looking statements speak only as of today's date in the company undertakes no obligation to revise or update any statements made today. I encourage you to review all the company's filings with the securities and exchange commission concerning these and other matters.

This includes the completion of the expansion of our phase III study for an amount of map and certain.

Speaker #2: I'll now turn the call over to Kaitlyn Arsenault, Skye's CFO.

During our preparatory clinical activities needed to initiate an expert. In addition, our runway continues to include a modest discovery R&D budget and the dose concentration and process intensification work required to support our expected TTP and Scanlan support later stage studies for new mathematics.

Speaker #3: Thanks, Bernie. After the market closed today, we issued a press release and filed Skye's quarantine queue with the securities and exchange commission. Outlining our quarterly financial results, we encourage you to reference our filings for the details of our financials and the risk factors described therein.

<unk> expenses for the three months ended September 32025 were $9 4 million as compared to $4 9 million for the same period in 2024.

Speaker #3: brief overview of our key financial results for the third quarter ended September 30th, 2025. We I will now provide a ended the third quarter with cash and cash equivalents and short-term investments totaling $35.3 million.

Kaitlyn Arsenault: In addition, our runway continues to include a modest discovery R&D budget, and the dose concentration and process intensification work required to support our expected TPP, and scale and support later stage studies for Nebasamab. R&D expenses for the three months ended 30 September 2025 were $9.4 million, as compared to $4.9 million for the same period in 2024. The increase was primarily due to contract manufacturing, clinical trial costs associated with our obesity study for Nebasamab, discovery R&D expenses, salary and stock-based compensation expense, and consulting, advisory, and professional fees. General and administrative expenses for the three months ended 30 September 2025 were $3.9 million, as compared to $4.6 million for the same period in 2024. The decrease was primarily related to decreases in consulting, advisory, and professional fees, recruitment fees, salaries, and stock-based compensation expense.

The increase was primarily due to contract manufacturing clinical trial costs associated with obesity study for new mathematics.

Speaker #3: We expect our current working capital to fund operations and key clinical milestones into 2027. This includes the completion of the extension of our Phase 2A study for Namastimab and certain manufacturing and preparatory clinical activities needed to initiate the next study.

R&D expenses salaries and stock based compensation expense and consulting advisory and professional fees.

General and administrative expenses for the three months ended September 32025, or $3 9 million as compared to $4 6 million for the same period in 2024.

Speaker #3: In addition, our runway continues to include a modest discovery R&D budget and the dose concentration and process intensification work required to support our expected TPP and scale and support later stage studies for Namastimab.

The decrease was primarily related to decreases in consulting advisory and professional fees recruitment fees salaries and stock based compensation expense.

Our net loss for the three months ended September 32025 totaled $12 8 million, including noncash share based compensation expense of $1 9 million compared to $3 9 million for the same period in 2024 with noncash share based compensation expense of $1 9 million.

Speaker #3: R&D expenses for the three months ended September 30, 2025, were $9.4 million, compared to $4.9 million for the same period in 2024. The increase was primarily due to contract manufacturing, clinical trial costs associated with our obesity study for Namastimab, discovery R&D expenses, salary and stock-based compensation expense, and consulting advisory and professional fees.

Now I'll turn the call over to our President and CEO.

Kaitlyn Arsenault: Our net loss for the three months ended 30 September 2025 totaled $12.8 million, including non-cash share-based compensation expense of $1.9 million, compared to $3.9 million for the same period in 2024, with non-cash share-based compensation expense of $1.9 million. Now, I'll turn the call over to our President and CEO, Punit Dhillon.

Thanks Kate.

So today and during this quarter and subsequent quarters, we're really focused on what matters. Most turning the answers from our C. Beyond study into the logical next steps.

Speaker #3: General and administrative expenses for the three months ended September 30, 2025, were $3.9 million, compared to $4.6 million for the same period in 2024.

To walk you through what we've learned from our phase II <unk> studies, so far and how that data is really sharpened our focus maintained.

Speaker #3: The decrease was primarily related to decreases in consulting, advisory, and professional fees, recruitment fees, salaries, and stock-based compensation expense. Our net loss for the three months ended September 30th, 2025 totaled $12.8 million, including non-cash share-based compensation expense of $1.9 million.

Our focus on our clinical path and strengthened our conviction in the mass amount of opportunity.

Punit Dhillon: Thanks, Kate. Today and during this quarter and the subsequent quarters, we're really focused on what matters most: turning the answers from our CBION study into the logical next steps. We're going to walk you through what we've learned from our phase IIA CBION study so far and how that data has really sharpened our focus, maintained our focus on our clinical path, and strengthened our conviction in the Nebasamab opportunity. From the start, we said that the next step for Nebasamab would be to determine an optimal dose for Nebasamab. To that end, the top-line data from the phase IIA study provided us with a wealth of information that we continued to mine for further insights.

From the start we said that the next step for <unk> would be determine an optimal dose for the mass amount and to that end the topline data from the phase Iia study provided us with a wealth of information that we continue to mine for further insights. Most importantly, it gave us evidenced in the biological activity of Nebraska.

Speaker #3: Compared to $3.9 million for the same period in 2024 with non-cash share-based compensation expense of $1.9 million. Now, I'll turn the call over to our president and CEO, Samit Dhillon.

Speaker #2: Thanks, Kate. So today and during this quarter and the subsequent quarters, we're really focused on what matters most: turning the answers from our CBON study into the logical next steps.

And the clarity on the PK to move forward confidently on a combination development pathway, while simultaneously planning to further understand the mass amount of benefit in a monitor in a monotherapy setting.

Speaker #2: We're going to walk you through what we've learned from our Phase 2A CBON study so far and how that data has really sharpened our focus, maintained our focus on our clinical path, and strengthened our conviction in the Namastimab opportunity.

On today's call.

We'll walk you through the progress that we've made over the next over the past 90 days.

Punit Dhillon: Most importantly, it gave us evidence in the biological activity of Nebasamab and the clarity on the PK to move forward confidently on our combination development pathway while simultaneously planning to further understand Nebasamab's benefit in a monotherapy setting. On today's call, we'll walk you through the progress that we've made over the past 90 days, the data that we've generated, and the path that we're really focused on in terms of charting forward. We're going to cover four key areas today. One is clinical development, specifically what we've learned from the CBION study, how those insights are shaping the potential for future next studies. Number two is CMC and product economics, how we're designing Nebasamab for scalability and long-term market penetration.

The data that we've generated and the path that we're really focused on in terms of charging forward.

Speaker #2: From the start, we said that the next step for Namastimab would be to determine an optimal dose for Namastimab. And to that end, the top line data from the Phase 2A study provided us with a wealth of information that we continue to mine for further insights.

To cover four key areas today.

One is clinical development, specifically, what we've learned from the <unk> study how those insights are shaping the potential for future next studies.

Two is CMC and product at <unk>.

The economics, how we're designing the mass amount for scalability and long term market penetration.

Speaker #2: Most importantly, it gave us evidence in the biological activity of Namastimab and the clarity on the PK to move forward confidently on our combination development pathway while simultaneously planning to further understand Namastimab's benefit in a monotherapy setting.

Number three is R&D and the work we're doing there the science that continues to validate the peripheral.

Peripheral CB one.

Antibody.

And.

Speaker #2: On today's call, we'll walk you through the progress that we've made over the past 90 days, the data that we've generated, and the path that we're really focused on in terms of charting forward.

Or sorry, the massive number of peripheral CB, one antibody is differentiated and it's a durable mechanism.

And for the continued emphasis on just really strong accountability and consistency how our actions this quarter measure against what we said that we would deliver.

Punit Dhillon: Number three is R&D and the work we're doing there, the science that continues to validate that peripheral CB1 antibody, and, sorry, the Nebasamab, our peripheral CB1 antibody, is differentiated, and it's a durable mechanism. Four, the continued emphasis on just really strong accountability and consistency, how our actions this quarter measure against what we said that we would deliver. I'm going to conclude with an outline of what's next, a look ahead at the key milestones and the catalysts over the coming 90 days. First, let's get into clinical development. We'll start with what we said last quarter and where we are now. In Q2, we committed to three different things. One was deliver top-line data in Q4 from CBION. Two was to use that data set to inform the dose ranging strategy for the next clinical phase.

Speaker #2: We're going to cover four key areas today. One is clinical development, specifically what we've learned from the CBON study, how those insights are shaping the potential for future next studies.

And I'm going to conclude with an outline of what's next a look ahead at the key milestones in the catalysts over the over the coming 90 days.

Speaker #2: Number two is CMC and product economics. How we're designing Namastimab for scalability and long-term market penetration. Number three is R&D and the work we're doing there, the science that continues to validate that peripheral CB1 antibody and our—sorry, the Namastimab, our peripheral CB1 antibody is differentiated and it's a durable mechanism.

So first let's get into clinical development.

Oh.

We'll start with what we said last quarter and where we are now in Q2, we committed to three different things one was deliver topline data in Q4 from CVR <unk> two was to use that data set to inform the dose ranging strategy for the next clinical phase and three maintain operational and regulatory.

Cory milestones and readiness to move efficiently into the next study and we've delivered on each one of those commitments Adobe.

Speaker #2: And four, the continued emphasis on just really strong accountability and consistency. How our actions this quarter measure against what we said that we would deliver.

At obesity week last week, Dr. Louis Dr. Lu Roni presented the late breaking results from <unk> and the findings are both clear and very encouraging.

Speaker #2: And I'm going to conclude with an outline of what's next. I'll look ahead at the key milestones and the catalysts over the coming 90 days.

Punit Dhillon: Three, maintain operational and regulatory milestones and readiness to move efficiently into the next study. We've delivered on each one of those commitments. At Obesity Week last week, Dr. Lou Aroni presented the late-breaking results from CBION, and the findings are both clear and very encouraging. We showed synergistic efficacy with Nebasamab plus semaglutide and achieved an additional approximately 3% weight loss at 26 weeks compared with semaglutide alone. This is with a p-value of 0.0372 on a modified intensity population. That's nearly a 30% improvement with this combination, with no observed plateau at 26 weeks. We also showed quality of weight loss, that the combination of Nebasamab and semaglutide improved lean-to-fat mass ratio of 0.26 versus 0.13, with a p-value of 0.0126, and reduced waist circumference by an additional 3.17cm, with a p-value of 0.0492.

We showed synergistic efficacy with the mass amount plus some glue tide and achieved an additional approximately 3% weight loss at 26 weeks compared with some a good tight alone. This is with a P value of 0.0 $3 72 on a modified intent to treat population.

Speaker #2: So first, let's get into clinical development. We'll start with what we said last quarter and where we are now. In Q2, we committed to three different things.

Speaker #2: One was deliver top line data in Q4 from CBON. Two was to use that data set to inform the dose ranging strategy for the next clinical phase.

Nearly a 30% improvement with this combination with no observed plateau at 26 weeks.

Speaker #2: And three, maintain operational and regulatory milestones and readiness to move efficiently into the next study. And we've delivered on each one of those commitments.

We also showed quality of weight loss with the combination of.

The combination of <unk> and some include tight improved lean to fat mass ratio of 0.26 versus 0.13 with a P value of 0.0126 and reduced waist circumference by an additional $3 107 centimeters with a P value of 0.04 92.

Speaker #2: At obesity week, last week, Dr. Louis Aroni presented the late-breaking results from CBON and the findings are both clear and very encouraging. We showed synergistic efficacy with Namastimab plus semaglutide and achieved an additional approximately 3% weight loss at 26 weeks compared with semaglutide alone.

We also showed durability in the 12 week post treatment follow up the mass amount plus some good Todd blunted wake regain with an only an 18% regain or 2.3 kilograms versus 50% regain or $4 seven kilograms on some good tight alone are the nuts with a P value of 0.006.

Speaker #2: This is with a P-value of 0.0372 on a modified intensity population. That's nearly a 30% improvement with this combination, with no observed plateau at 26 weeks.

Versus placebo.

Speaker #2: We also showed that the quality of weight loss at the combination of Namastimab and semaglutide improved the lean-to-fat mass ratio to 0.26 versus 0.13, with a P-value of 0.0126. Additionally, we reduced waist circumference by an extra 3.17 centimeters, with a P-value of 0.0492.

Punit Dhillon: We also showed durability that in the 12-week post-treatment follow-up, Nebasamab plus semaglutide blunted weight regain with only an 18% regain, or 2.3kg, versus 50% regain, or 4.7kg, on the semaglutide alone, with a p-value of 0.006 versus placebo. The safety signal has also been very positive. There's been no neuropsychiatric signal and no additive GI burden. This overall data really confirms that Nebasamab is biologically active, clinically meaningful in combination, and exceptionally well tolerated. They validate our long-held view that the mechanism is sound and that the value now lies in refining, really, the dose to unlock the Nebasamab true efficacy window and fully capture the therapeutic potential of a peripheral CB1 antibody. Additionally, in September, we completed enrollment of the 26-week extension study. A total of 43 patients were enrolled, with 19 and 24 patients in the combination and monotherapy cohorts, respectively.

The safety signal has also been very positive there has been no neuropsychiatric signal and no additive ti burden and so.

So this overall data really confirmed that no mass map is biologically active clinically meaningful in combination and exceptionally well tolerated.

They validate our long held view that the mechanism is sound and that the value now lies in the rift.

Speaker #2: We also showed durability that in the 12-week post-treatment follow-up, Namastimab plus semaglutide blunted weight regain with an only an 18% regain or 2.3 kilograms versus 50% regain or 4.7 kilograms on the semaglutide alone are.

Refining really the dose to unlock the massive true efficacy window and fully capture the food the therapeutic potential of our peripheral CB one antibody.

Additionally in September we completed enrollment of the 26 week extension study a total of 43 patients were enrolled with 19 and 24 patients in the combination and monotherapy cohorts respectively.

Speaker #2: And that's with a P-value of 0.006 versus placebo. The safety signal has also been very positive. There's been no neuropsychiatric signal and no additive GI burden.

Retention in the extension study has been very strong and the data from the 26 26 week extension study is expected in late Q1 early Q2 of 2026, and we will provide information on the potential.

Speaker #2: And so, this overall data really confirms that Namastimab is biologically active, clinically meaningful in combination, and exceptionally well-tolerated. They validate our long-held view that the mechanism is sound and that the value now lies in refining the dose to unlock Namastimab's true efficacy window and fully capture the therapeutic potential of a peripheral CB1 antibody.

For full treatment duration of 52 weeks, followed by a 12 week follow up period.

This long term follow up from the extension will be a new inflection point with a richer data set and a more complete understanding of <unk> clinical potential.

Punit Dhillon: Retention in the extension study has been very strong, and the data from the 26-week extension study is expected in late Q1, early Q2 of 2026, and will provide information on the potential for full treatment duration of 52 weeks, followed by a 12-week follow-up period. This long-term follow-up from the extension will be a new inflection point with a richer data set, and a more complete understanding of Nebasamab's clinical potential. In parallel, we're going to continue moving up the dose. The monotherapy extension study is evaluating a slightly higher dose, where we've stepped it up from 200mg to 300mg weekly, but our current plan is to even go higher. Analysis of our preliminary PK/PD model showed that patients achieving higher systemic levels of Nebasamab corresponded with a greater weight loss, and that aligns with the range where we expect to show clinically significant results.

Speaker #2: Additionally, in September, we completed enrollment of the 26-week extension study. A total of 43 patients were enrolled with 19 and 24 patients in the combination and monotherapy cohorts, respectively.

In parallel we're going to continue moving up the dose. So the monotherapy extension studies evaluating a slightly higher dose where we've stepped it up from 200 milligrams to 300 milligrams weekly, but our current plan is to even go higher.

Speaker #2: Retention in the extension study has been very strong. The data from the 26-week extension study is expected in late Q1, early Q2 of 2026 and will provide information on the potential for full treatment duration of 52 weeks, followed by a 12-week follow-up period.

Analysis of our preliminary PK PD model showed that patients achieving higher systemic levels and the massive mab corresponded with a greater weight loss.

And that aligns with the range, where we expect to show.

Clinically significant results our.

Our PK PD model based on the clinical data and the preclinical dose ranging really gives us confidence at the higher dose a higher dose of <unk> can potentially achieve better monotherapy efficacy and drive even further weight loss when combined with <unk>.

Speaker #2: This long-term follow-up from the extension will be a new inflection point with a richer data set and a more complete understanding of Namastimab's clinical potential.

Speaker #2: In parallel, we're going to continue moving up the dose. So the monotherapy extension study is evaluating a slightly higher dose where we've stepped it up from 200 milligrams to 300 milligrams weekly.

The parallel approach that we're taking with further clinical data from the extension study for for the durability, and then evaluating a higher dose ranging in a well powered phase two focused.

Punit Dhillon: Our PK/PD model, based on the clinical data and the preclinical dose ranging, really gives us confidence that a higher dose of Nebasamab can potentially achieve better monotherapy efficacy and drive even further weight loss when combined with semaglutide. The parallel approach that we're taking with further clinical data from the extension study for the durability, and then evaluating a higher dose ranging in a well-powered Phase II-focused combination study with understanding a better characterization of the monotherapy dose, will really keep the development of Nebasamab on track. We're really focused on that, and we think that that's the next logical step for understanding our next important decision points. Next, I'll move to CMC. Another area that we've continued to make progress in has been all of our manufacturing and CMC work, that includes our high-concentration formulation strategy.

Speaker #2: But our current plan is to even go higher. Analysis of our preliminary PK/PD model showed that patients achieving higher systemic levels of Namastimab corresponded with a greater weight loss.

Combination study.

With with <unk>.

Understanding a better characterization of the monotherapy dose.

Well really keep the develop into the Nevada Mab on track and we're really focused on that and we think that that's the next logical step for for understanding our next important decision points.

Speaker #2: And that aligns with the range where we expect to show clinically significant results. Our PK/PD model based on the clinical data and the preclinical dose ranging really gives us confidence that the higher dose of Namastimab can potentially achieve better monotherapy efficacy and drive even further weight loss when combined with semaglutide.

Next I'll move to CMC.

So another area that we've continued to make progress and it has been all of our manufacturing and and.

CMC work that includes our high concentration formulation strategy.

Speaker #2: The parallel approach that we're taking with further clinical data from the extension study for the durability and then evaluating a higher dose ranging in a well-powered phase two-focused combination study with understanding a better characterization of the monotherapy dose will really keep the development of Namastimab on track and we're really focused on that.

And that remains on track and we believe a path to achieving the formulations that really align with our clinical protocols and and expectations for our TPP.

As well as patient convenience remain on track. This this isn't simply a like a technical milestone for us it's really <unk>.

Rooted in our commercial.

Punit Dhillon: That remains on track, and we believe a path to achieving the formulations that really align with our clinical protocols and expectations for our TPP, as well as patient convenience, remain on track. This isn't simply a technical milestone for us. It's really rooted in a commercial TPP, and our focus is on reducing overall injection volume, lowering costs per gram, and ensuring we can compete as pricing pressures on incretins continue to intensify. This aligns, we believe, perfectly with our titration-free target product profile, and that's a key advantage over the incretin-based injectables that require a step-up dosing for tolerability. To clarify, Nebasamab has shown no additive GI burden at the 200mg once-weekly dose, and we expect to evaluate any higher dose without the need for titration, making it easier for both prescribers and patients.

Speaker #2: And we think that that's the next logical step for understanding our next important decision points. Next, I'll move to CMC. So another area that we've continued to make progress in has been all of our manufacturing and CMC work that includes our high concentration formulation strategy.

The commercial TPP and our focus is on reducing overall injection volume lowering cost program and ensuring we can compete.

Pricing pressures on <unk> continues to continue to intensify.

This aligns we believe perfectly with our titanium titration free target product profile and Thats a key advantage over the Incretin based injectables that require a step up dosing for tolerability.

Speaker #2: And that remains on track. And we believe a path to achieving the formulations that really align with our clinical protocols and expectations for our TPP as well as patient convenience remain on track.

To clarify no massive map has shown no additive Gi burden at the 200 milligram once weekly dose and we expect to evaluate.

Speaker #2: This isn't simply a technical milestone for us. It's really rooted in a commercial TPP and our focus is on reducing overall injection volume, lowering costs, program, and ensuring we can compete as pricing pressures on Incredence continues to intensify.

Any higher dose without the need for titration, making it easier for both prescribers and patients.

Equally important we're continuing to evaluate and manage and execute on measures that can significantly impact our cost of goods. This process includes optimization of the upstream and downstream manufacturing steps for NIM as map and scaling up.

Speaker #2: This aligns, we believe, perfectly with our titration-free target product profile, and that's a key advantage over the Incredence-based injectables that require a step-up dosing for tolerability.

Hi, Hi, fermentation volumes, and we're continuing to evaluate multiple delivery devices, including auto injectors that will improve the patient experience.

Punit Dhillon: Equally important, we're continuing to evaluate, manage, and execute on measures that can significantly impact our cost of goods. This process includes optimization of the upstream and downstream manufacturing steps for Nebasamab, scaling up into high-fermentation volumes, and we're continuing to evaluate multiple delivery devices, including auto injectors, that will improve the patient experience. Together, these activities will have a significant impact on reducing our cost of goods to support an eventual pricing model that aligns with Medicare and is rapidly influencing the obesity market. We're ultimately designing a product that is potentially not only clinically differentiated but commercially durable from a manufacturability and real-world affordability. Next, we'll move into R&D. Beneath all the clinical data sits an increasingly powerful scientific base.

Together these activities will have a significant impact on reducing our cost of goods to support an eventual pricing model that aligns with Medicare and it's rapidly influencing the obesity market.

Speaker #2: To clarify, Namastimab has shown no additive GI burden at the 200 milligram once-weekly dose and we expect to evaluate any higher dose without the need for titration, making it easier for both prescribers and patients.

We're ultimately designing a product that is potentially not only clinically differentiated but commercially durable from a manufacturer or manufacturer ability.

Speaker #2: Equally important, we're continuing to evaluate and manage and execute on measures that can significantly impact our cost of goods. This process includes optimization of the upstream and downstream manufacturing steps for Namastimab and scaling up into high fermentation volumes and we're continuing to evaluate multiple delivery devices including autoinjectors that will improve the patient experience.

And real World affordability.

Next we'll move into R&D, so beneath all of the clinical data sits in an increasingly powerful scientific base. The preclinical and translational work continued to show that no mass map reduces fat mass, while preserving lean mass improves insulin sensitivity and glucose control.

Speaker #2: Together, these activities will have a significant impact on reducing our cost of goods to support an eventual pricing model that aligns with Medicare and is rapidly influencing the obesity market.

Lord Lupton and increases <unk> one.

Reduces hepatic steatosis and inflammatory markers and maintains weight loss durability. After treatment stops and this is consistent with what we're seeing clinically.

Punit Dhillon: The preclinical and translational work continue to show that Nebasamab reduces fat mass while preserving lean mass, improves insulin sensitivity and glucose control, lowers leptin, and increases GLP-1, reduces hepatic steatosis and inflammatory markers, and maintains weight loss durability after treatment stops. This is consistent with what we're seeing clinically. Combination studies in DIO models with tirzepatide and semaglutide show greater than additive weight loss and minimal rebound, confirming that peripheral CB1 inhibition complements incretin biology mechanistically. Collectively, these results reinforce why Nebasamab is really the right molecule, the right mechanism, and the right program to move forward. Our message to investors, ever since we began development on the Nebasamab program, has been about discipline and delivery, and that remains true to today.

Speaker #2: We're ultimately designing a product that is potentially not only clinically differentiated but commercially durable from a manufacturability and real-world affordability. Next, we'll move into R&D.

Combination studies in DIR models with trees appetite and <unk> show greater than additive weight loss and minimal rebound confirming that peripheral CB, one inhibition complements incretin biology mechanistically.

And collectively these results reinforce why mnemosyne map is really the right molecule at the right mechanism and the right program to move forward.

Speaker #2: So beneath all of the clinical data sits an increasingly powerful scientific base. The preclinical and translational work continue to show that Namastimab reduces fat mass while preserving lean mass, improves insulin sensitivity and glucose control, lowers leptin and increases GLP-1, reduces hepatic steatosis, and inflammatory markers, and maintains weight loss durability after treatment stops.

Our message to investors ever since we began development on the math.

On the <unk> program has been about discipline and delivery and that remains true true today.

In Q2, we said we will we will complete the topline.

Readout by late Q3 early Q4, and we did that and we presented late breaking data at obesity week last week.

Speaker #2: And this is consistent with what we're seeing clinically. Combination studies and DIO models with tirzepatide and semaglutide show greater-than-additive weight loss and minimal rebound, confirming that peripheral CB1 inhibition complements Incredence biology mechanistically.

We also said we're going to continue with the current dataset to guide our dose ranging and that's what we're doing.

We're going to continue advancing our CMC readiness in parallel and we continue to improve manufacturing capability.

Punit Dhillon: In Q2, we said we'll complete the top-line readout by late Q3 or late Q4, and we did that, and we presented late-breaking data at Obesity Week last week. We also said we're going to continue with the current data set to guide our dose ranging, and that's what we're doing. We're going to continue advancing our CMC readiness in parallel, and we continue to improve manufacturing capability, as well as process improvements are going to continue to be ongoing. We're focused on the higher concentration formulation path, and that's on track and synchronized with our clinical development planning. We ultimately expect our monoclonal antibody to be the best way to target CB1 inhibition to enable confidence in the safety, and this pathway will ultimately show the clearest mechanism validation in terms of targeting this particular pathway.

Speaker #2: And collectively, these results reinforce why Namastimab is really the right molecule, the right mechanism, and the right program to move forward. Our message to investors ever since we began development on Namastimab program has been about discipline and delivery and that remains true to today.

As well as process improvements are going to continue to be ongoing that we're focused on the higher concentration formulation path and that's on track and synchronized with our clinical development planning.

We ultimately expect our monoclonal antibody to be the best way to target CB, one inhibition to enable confidence in the safety and this pathway.

Speaker #2: In Q2, we said we'll complete the top line readout by late Q3, early Q4, and we did that and we presented late-breaking data at obesity week last week.

We will ultimately show that the clearest.

Mechanism validation in terms of targeting this particular pathway with our phase Iia data. We have now provided an important initial demonstration of the mass maps utility. It does offer the validation of the mechanism and notably we did that by showing that there is no neuropsychiatric adverse events or other unexpected.

Speaker #2: We also said we're going to continue with the current data set to guide our dose ranging, and that's what we're doing. We're going to continue advancing our CMC readiness in parallel, and we continue to improve manufacturing capability, as well as process improvements, which are going to continue to be ongoing.

<unk> adverse signals across the different cohorts that received Nomas Smith and.

Speaker #2: We're focused on the higher concentration formulation path and that's on track and synchronized with our clinical development planning. We ultimately expect our monoclonal antibody to be the best way to target CB1 inhibition to enable confidence in the safety and this pathway will ultimately show the clearest mechanism validation in terms of targeting this particular pathway.

And we've just completed the fifth EMC meeting this past week with no concerns.

Punit Dhillon: With our phase IIA data, we have now provided an important initial demonstration of Nebasamab's utility that does offer the validation of the mechanism, and notably, we did that by showing that there are no neuropsychiatric adverse events or other unexpected adverse signals across the different cohorts that receive Nebasamab. We've just completed the fifth DMC meeting this past week with no concerns. Every commitment that we've made, we made it on time, we made it with precision, and we're going to continue doing that. Over the next 90 days and into 2026, our focus is on converting what we've learned from the clinical data into further execution. We're going to generate a more complete picture of Nebasamab's potential using insights from our PK/PD modeling and the ongoing extension study.

So every commitment that we've made we've made it on time, we've made it with precision and we're going to continue doing that.

Over the next 90 days and into 2026, our focus is on converting what we have learned from the clinical data into further execution.

We're going to generate a more complete picture of <unk> potentially using insights from our PK PD modeling and the ongoing extension study. We're finalizing the next phase II design. So we're concentrating on combination and also in the maintenance.

Speaker #2: With our Phase 2A data, we have now provided an important initial demonstration of Namastimab's utility that does offer the validation of the mechanism. Notably, we did that by showing that there are no neuropsychiatric adverse events or other unexpected adverse signals across the different cohorts that receive Namastimab.

Indications, where the data already point towards really strong direction.

And we're continuing to advance the formulation and manufacturing work so that the mass map can be delivered practically at scale and with the cost discipline that the market demands.

Speaker #2: And we've just completed the fifth DMC meeting this past week with no concerns. So every commitment that we've made, we've made it on time, we've made it with precision, and we're going to continue doing that.

Punit Dhillon: We're finalizing the next phase II design, and we're concentrating on combination and also in the maintenance indications where the data already point towards a really strong direction. We're continuing to advance the formulation and manufacturing work so that Nebasamab can be delivered practically at scale and with the cost discipline that the market demands. We'll also be presenting at several investor conferences beginning next week and into December, and gearing up for sharing new preclinical and clinical data at all the major scientific conferences and meetings in 2026. Across each of these fronts, the through line is really about consistency. We've said what we would do, and we've delivered on the data, on the timelines, and on the execution.

We will also be presenting at several investor conferences, beginning next week and into December and gearing up for sharing new preclinical and clinical data at all the major scientific conferences and meetings in 2026.

Speaker #2: Over the next 90 days and into 2026, our focus is on converting what we've learned from the clinical data into further execution. We're going to generate more complete picture of Namastimab's potential using insights from our PK and PD modeling and the ongoing extension study.

Across each of these fronts. The through line is really about consistency, we said, what we would do and we've delivered on the data and then on the timelines and on the execution. Our next steps are an extension of that same discipline and we're interested in continuing to focus on.

Speaker #2: We're finalizing the next phase two design. We're concentrating on combination and also in the maintenance indications where the data already point towards a really strong direction.

Translating all of this into momentum and the momentum into value.

Speaker #2: And we're continuing to advance the formulation and manufacturing work so that Namastimab can be delivered practically at scale and with the cost discipline that the market demands.

So this concludes the prepared remarks and comments today, we thank you everyone for joining the call and we will now open the call.

For questions from our covering sell side analysts operator over to you.

Punit Dhillon: Our next steps are an extension of that same discipline, and we're interested in continuing to focus on translating all of this into momentum, and the momentum into value. This concludes the prepared remarks and comments today. We thank you, everyone, for joining the call, and we'll now open the call for questions from our covering cell side analysts. Operator, over to you.

Speaker #2: We'll also be presenting at several investor conferences beginning next week and into December, and gearing up for sharing new preclinical and clinical data at all the major scientific conferences and meetings in 2026.

Thank you.

As a reminder, if you'd like to ask a question press star one on your telephone keypad will just take a brief moment to compile the Q&A roster.

Speaker #2: Across each of these fronts, the through line is really about consistency. We've said what we would do and we've delivered on the data and then on the timelines and on the execution.

Our first question comes from the line of Michael <unk> from Evercore ISI. Your line is live.

Speaker #2: Our next steps are an extension of that same discipline and we're interested in continuing to focus on translating all of this into momentum and the momentum into value.

Hi, guys. Thanks, so much for taking my question.

Bernie Hertel: Thank you. As a reminder, if you'd like to ask a question, press star one on your telephone keypad. We'll just take a brief moment to compile the Q&A robustly. Our first question comes from the line of Michael D'Fourier from Evercore ISI. Your line is live.

Just two for me.

Now that you've had some time to further digest the data from the trial have you gained any additional insight between weight loss exposure I recall at the time that the data were revealed you only had PK exposure versus weight loss up to 16 weeks. So thats My first question Mike.

Speaker #2: So this concludes the prepared remarks and comments today. We thank you everyone for joining the call and we'll now open the call for questions from our covering cell side analysts.

Speaker #2: Operator, over to you. Thank you. As a reminder, if you'd like to ask a question, press star one on your telephone keypad. We'll just take a brief moment to compile the Q&A roster.

Kaitlyn Arsenault: Hi, guys. Thanks so much for taking my question. Just two for me. Now that you've had some time to further digest the data from the trial, have you gained any additional insight between weight loss and exposure? Recalling at the time that the data were revealed, you only had PK exposure versus weight loss up to 16 weeks. That's my first question. My second question is regarding the 26-week extension. Simply, are there enough patients? Forty-three patients seems sort of low, and do you have enough patients to draw any statistically significant insights? Thank you.

My second question is regarding the 26 week extension.

Simply are there enough patients 43 patients seems sort of low end do you have enough patients to draw any statistical.

We have significant insights thank you.

Hey, Michael Thanks for dialing in and asking the questions. So I'll take the first question and hand, it over to Chris because you can further elaborate but as you as you kind of indicated there.

Speaker #2: Our first question comes from the line of Michael Diaforie from Evercore ISI. Your line is live.

Speaker #3: Hi, guys. Thanks so much for taking my question. Just two for me. Now that you've had some time to further digest the data from the trial, between weight loss and exposure?

Obviously, we showed a really strong validation of the mechanism in the combo efficacy the monotherapy.

Dosing I think has been evident in terms of.

Speaker #3: I recall at the time that the data were revealed, you only had PK exposure versus weight loss up to 16 weeks. So that's my first question.

Punit Dhillon: Hey, Michael. Thanks for dialing in and asking the questions. I'll take the first question and hand it over to Chris because he can further elaborate. As you indicated there, obviously, we showed a really strong validation of the mechanism in the combo efficacy. The monotherapy dosing, I think, has been evident in terms of an issue with dose, not the biology. The exposure response really has demonstrated that the observed concentrations at the 200mg dose did not achieve the efficacy that we would expect because patients were underdosed. Chris can further elaborate in terms of what we've seen now based on the 26-week data set, as well as anything he wants to point to from the preclinical data.

The issue was dose not the biology of the exposure response really has demonstrated that the observed concentrations.

Speaker #3: My second question is regarding the 26-week extension. Simply, are there enough patients, 43 patients seems sort of low, and do you have enough patients to draw any statistically significant insights?

At the 200 milligram dose didn't achieve the efficacy that we would expect because they were patients were under dosed.

But Chris Yeah can you further elaborate in terms of what we've seen now based on the 26 week dataset as well as anything he wants to point to from the preclinical data.

Speaker #3: Thank you.

Speaker #1: Hey, Michael. Thanks for dialing in and asking the questions. So, I'll take the first question and kind of hand it over to Chris because he can further elaborate.

Speaker #1: But as you kind of indicated there, obviously, we showed a really strong validation of the mechanism in the combo monotherapy dosing. I think it has been evident in terms of an issue with dose, not the biology.

Thanks, Tony.

To that point.

Harold in fact looked at a more complete dataset I would just note that the final PK PD analysis is still underway likely won't be available.

Speaker #1: The exposure response really has demonstrated that the observed concentrations at the 200 milligram dose didn't achieve the efficacy that we would expect because they were patients were under-dosed.

For another few more weeks to months.

But we do have a more robust build out and we looked at them mixed effects model.

Chris Twitty: Thanks, Punit. Yeah, to that point, we have, in fact, looked at a more complete PK data set. I would just note that the final PK/PD analysis, which is still underway, likely won't be available probably for another few more weeks to months. We do have a more robust buildout, and we looked at a mixed effects model, both controlling for the placebo effect, as well as doing a similar type of modeling where we controlled for the semaglutide effect and looked at that in a combo setting. In both instances, we see that there's really no bias in the residuals, so the models fit well. They align with the observed weight change that we saw in the trial. Importantly, they point to the point you're making, that is, we're seeing a nice slope, a very believable, credible slope that demonstrates this response related to exposure.

Both.

Controlling for the placebo effect as.

As well as doing a similar type of modeling.

Speaker #1: But Chris, yeah, can further elaborate in terms of what we've seen now based on the 26-week data set as well as anything he wants to point to from the preclinical data.

Where are we controlled for the summer who kind of fact and looked at that in the combo setting and in both instances, we see that Theres really no.

<unk> from the residual for the model fit well they align with what the observed weight change that we saw in the trial.

Speaker #2: Thanks, Puneet. Yeah, so to that point, we have in fact looked at a more complete PK data set. I would just note that the final PK/PD analysis, which is still underway, likely won't be available probably for another few more weeks to months.

And importantly, they point to.

Point, you were making that as well.

We're seeing a nice slope are very believable incredible slope that demonstrates this.

Speaker #2: But we do have some more robust build-out, and we looked at a mixed effects model both controlling for the placebo effect as well as doing a similar type of modeling where we controlled for the semaglutide effect and looked at that in a combo setting and in both instances, we see that there's really no bias in the residual.

Sparks.

Related to exposure and we feel very comfortable.

The PK data is holding will again have the final PK PD model, but we feel very confident that in fact, there is a go.

Dose response.

As we get to better better exposures, we will see better and better weight loss as both monotherapy and in combination and the other thing I'm just pointed briefly since we've last talked Michael.

Chris Twitty: We feel very comfortable. The PK data is holding. We'll again have the final PK/PD model, but we feel very confident that, in fact, there is a dose response. As we get to better and better exposures, we will see better and better weight loss as both monotherapy and in combination. The other thing I've just pointed briefly since we've last talked, Michael, the translation of the DIO data has been further validated. We've done some important biodistribution studies looking at where the compartments and how those fill relative to what's in the serum, and using that along with some other approaches to really get a good fit in terms of how the DIO data, which demonstrates very clean dose response as well, how that translates to the clinical doses.

Speaker #2: So the models fit well. They align with the observed weight change that we saw in the trial. And importantly, they point to the point you're making, that is we're seeing a nice slope very believable, credible slope that demonstrates this response related to exposure.

The translation of the Tio data has.

Then further valid.

<unk> done some important bio distribution studies looking at the.

At where are the compartments on how to sell relative to what's in the serum and using that along with some other.

Approaches to really get a good fit in terms of how the D. I O data.

Speaker #2: So we feel very comfortable the PK data is holding. We'll again have the final PK/PD model, but we feel very confident that in fact there is a dose response and as we get to better and better exposures, we will see better and better weight loss as both monotherapy and in combination and the other thing I've just pointed briefly since we've last talked, Michael, the translation of the DIO data has been further validated.

Demonstrate very clean dose response, as well and how that translates to the clinical doses. So both of those pieces are really supporting this concept of higher dosing in the clinic to see better weight loss.

Okay.

Michael would you mind just repeating your second question, where do we answer it.

So my second question is regarding the 26 week extension data.

It seems that only 43% 43 patients are enrolled it seems kind of on the low side and I was wondering if that's enough patients to draw any statistical.

Chris Twitty: Both those pieces are really supporting this concept of higher dosing in the clinic to see better weight loss.

Speaker #2: We've done some important biodistribution studies looking at the compartments and how those fill relative to what's in the serum and using that along with some other approaches to really get a good fit in terms of how the DIO data which demonstrates very clean dose response as well.

Statistical significant insights, but when the window when the trial wraps up.

Punit Dhillon: Michael, would you mind just repeating your second question, or did we answer it?

Kaitlyn Arsenault: No. My second question is regarding the 26-week extension data. It seems that only 43 patients are enrolled. It seems kind of on the low side. I was wondering if that's enough patients to draw any statistically significant insights when the trial wraps up.

Yes.

The good news on the extension is that enrollment.

Speaker #2: How that translates to the clinical doses. So both those pieces are really supporting this concept of higher dosing in the clinic to see better weight loss.

Has been obviously there was that was good.

We saw good interest in this study and then retention has continued to stay really strong.

It is.

Speaker #3: Michael, would you mind just repeating your second question or did we answer it?

A smaller number of patients relative to the core study that first first part, but we do believe that there'll be a clear separation that we would be able to see especially.

Punit Dhillon: Yeah. The good news on the extension is that enrollment has been, obviously, that was good that we saw good interest in the study, and then retention has continued to stay really strong. It is a smaller number of patients relative to the core study, the first part, but we do believe that there will be a clear separation that we would be able to see, especially as, if you recall, in the 26-week time point, the first 26-week time point in the combination, we did see a really strong difference, and then the slope was not plateauing. It continued. We hope that we are going to continue to see that separation between semaglutide alone. On the monotherapy, as we have indicated, we believe that there is still room to go higher in terms of dose. We will see what the data reveals.

Speaker #1: No, so my second question is regarding the 26-week extension data. It seems that only 43%, 43 patients are enrolled. It seems kind of on the low side.

If you recall on the 26 week time point, the first 26 week time point and the combination we did see a really strong.

Speaker #1: And I was wondering if that's enough patients to draw any statistical significant insights. When the trial wraps up.

Difference and then the slope.

Wasn't plateauing it continued.

So.

We hope that we're going to continue to see that separation between some good tight alone.

Speaker #3: Yeah, so the good news on the extension is that enrollment has been obviously good; we saw strong interest in the study, and retention has continued to stay really strong.

On the on the monotherapy as we've indicated.

We believe that there's still room to go higher in terms of dose. So we'll see what the what the data reveals but I'm at this point, it's a little tough to comment on that because.

Speaker #3: It is a smaller number of patients relative to the core study, the first part, but we do believe that there will be a clear separation that we would be able to see, especially if you recall in the 26-week time point, the first 26-week time point in the combination, we did see a really strong difference and then the slope wasn't plateauing.

We don't have that separation that we expected on the first 26 weeks.

That's great. Thanks, so much.

Your next question comes from the line of Andy.

<unk> from William Blair Your line is live.

Punit Dhillon: At this point, it's a little tough to comment on that because we don't have that separation that we expected on the first 26 weeks.

Great. Thanks for taking our questions. We have two one is more on the.

Speaker #3: It continued, so we hope that we're going to continue to see that separation between semaglutide alone. On the monotherapy, as we've indicated, we believe that there's still room to go higher in terms of dose.

Regulatory side. So so so we're curious very provocative data.

Kaitlyn Arsenault: That's great. Thanks so much.

Looking at the.

He found.

Bernie Hertel: Your next question comes from the line of Andy Isaya from William Blair. Your line is live.

Do you need.

Bobby therapy approval.

Before a potential approval just trying to get a senses.

Speaker #3: So we'll see what the data reveals, but at this point, it's a little tough to comment on that because we don't have that separation that we expected on the first 26 weeks.

Andy Isaya: Great. Thanks for taking our questions. We have two. One is more on the regulatory side. We're curious, very provocative data looking at the weight rebound. Do you need to have a monotherapy approval before a potential maintenance approval? Just trying to get a sense of the sequence and requirements based on your regulatory discussions with the agents. That's number one. Number two is we looked at comparative kind of randomized withdrawal studies, in particular step four with semaglutide. It seems like in that study, the weight regain was about 50% out to one year. In this study, the weight regain was much faster. I'm curious if there's any sort of patient baseline characteristics that you want to highlight that could explain the more rapid than expected weight regain from the semaglutide arm. Thank you.

The sequencing requirements based on your regulatory discussions with the agency. So that's number one.

Number two is we looked at comparative.

Speaker #1: That's great. Thanks so much.

Kind of random.

Speaker #4: Your next question comes from the line of Andy Isiah from William Blair. Your line is live.

Brian and Mike randomized withdrawal study in particular.

Or what's the neither side it seems like in that study.

Speaker #5: Great. Thanks for taking our questions. We have two. One is more on the regulatory side. So we're curious very provocative data looking at the weight rebound.

The gain was about 50% now.

One year in this study, though we regained much.

Faster so.

Curious, if there's any sort of.

Patient baseline characteristics that you'd want to highlight that could explain the more rapid than expected weight gain for this amazing.

Speaker #5: Do you need to have a monotherapy approval before a potential maintenance approval? Just trying to get a sense of the sequence and requirements based on your regulatory discussions with the agency.

Thank you.

Yes, I think these are both great questions and interrelated.

Speaker #5: That's number one. Number two is we looked at comparative kind of randomized withdrawal studies in particular step four with semaglutide and it seems like in that study the weight regain was about 50% out to one year.

And pass it over to Dr. Aurora to take those and then come back with some additional commentary on the maintenance setting.

Yeah.

Andy.

Question, Yes.

If we were to do a maintenance therapy with my snap as a mono therapy that would require Paul Tennessee approval, although if that if that is the strongest so far the problem than the approval could be as maintenance as.

Punit Dhillon: Yeah. I think these are both great questions and interrelated. I can pass it over to Dr. Arora to take those, and then I might come back with some additional commentary on the maintenance setting.

Speaker #5: In this study, the weight regain was much faster. So I'm curious if there are any sort of patient baseline characteristics that you want to highlight that could explain the more rapid-than-expected weight regain from the semaglutide arm.

Puneet Arora: Yeah. Andy, to address your first question, yes. If we were to do maintenance therapy with Nebasamab as a monotherapy, that would require monotherapy approval. Although if that is the strongest suit for the drug, then the approval could be as maintenance as well. As part of our plan as we go forward is to continue looking at the monotherapy to find that optimal dose and frequency on how to dose monotherapy for varying indications, including maintenance. That's a question that we will be discussing with the agency, and I think that will be part of our continuing interaction with them as to how to push both monotherapy and combination forward and what differential path each one may need. I'm sorry, what was your second question?

Well and we are as part of our plan as we go forward is to continue looking at the mono therapy to find that optimal dose and three.

Speaker #5: Thank you.

Frequency on how to dose monotherapy for varying indications including maintenance.

Speaker #3: Yeah, I think these are both great questions and interrelated. I can pass it over to Dr. Arora to take those and then Mike come back with some additional commentary.

So that that you know that's a question that we will be discussing with the agency and I think that will be part of our continuing our interaction with them as to how to push both monotherapy and combination forward then what differentiate bought each one may need.

Speaker #3: On the maintenance setting.

Speaker #1: Yeah, Andy, to address your first question, yes, if we were to do maintenance therapy with Nimafenab as a monotherapy, that would require monotherapy approval, although if that is the strongest suit for the drug, then the approval could be as maintenance as well.

So I'm sorry, what was your second question.

It's just on the regain pizza, Dr. I think well yeah. So if you look if you look across.

They look at.

Good rebound data across a bunch of studies.

Speaker #1: And we are, as part of our plan, as we go forward, is to continue looking at the monotherapy to find that optimal dose and frequency on how to dose monotherapy for varying indications, including maintenance.

Step one with golf I mean, I think it's one of the ones you are cool.

Had some and then there's appetite.

Randomized withdrawal in one year.

Punit Dhillon: It's just on the regain piece, Dr. Arora. I think.

Oh wait regain its about hub and it does tend to be somewhat accelerated in the first half because they.

Puneet Arora: Oh, yeah. If you look at weight rebound data across a bunch of studies, there was a step one withdrawal study. I think it's one of the ones your cohort had some. Tirzepatide did some randomized withdrawals. In one year, the weight regain is about percent. It does tend to be somewhat accelerated in the first half because the weight regain is faster initially, and then tends to plateau a little. We do see a somewhat faster regain in this study. We don't know why. We don't know of particular characteristics that we're seeing in the demographics, which in the study are frankly the same as you see in most other studies. We don't know why these patients regained their weight this quickly, but they did. Being a randomized trial, we figure that both the cohorts are effectively similar.

Speaker #1: That's a question that we will be discussing with the agency, and I think that will be part of our continuing interaction with them as to how to push both monotherapy and combination therapies forward, and what differential path each one may need.

The matrix can foster initially and then tends to plateau a little weak.

We don't see a somewhat faster regain in the study we don't know why.

It's.

We don't know what they can look at this thing. So we are seeing in the demographics and the study of frankly, the same as you'll see in most other studies. So we don't know why these patients regained their weight this quickly, but they did and being randomized trial, we forgot about the call.

Speaker #1: So I'm sorry, what was your second question?

Speaker #3: It's just on the regain piece, I think.

Speaker #1: Oh, yeah. So if you look across, if you look at weight rebound data across a bunch of studies, there was a Step One withdrawal study; I think it's one of the ones you're quoting.

Effectively Salem.

Yes, if I can just to elaborate on one one thing and say look the durability data that we've showed last week with the only 18% regained versus 15, 50%.

Speaker #1: Had some, and then tirzepatide did some randomized withdrawals. In one year, the weight regain is about and it does tend to be somewhat accelerated in the first half because the weight regain is faster initially and then tends to plateau a little.

For some a good title loan.

I believe a real cornerstone of our strategy and it really validates what were you saw from an R&D preclinical perspective, it shows that peripheral CB one inhibition can provide a durable effect.

Speaker #1: We do see a somewhat faster regain in this study; we don't know why. We don't know a particular characteristic we're seeing in the demographics, in the study, frankly the same as you see in most other studies.

Punit Dhillon: Yeah. If I can just elaborate on one thing, Andy. The durability data that we showed last week with the only 18% regain versus 50% for semaglutide alone is, I believe, a real cornerstone of our strategy, and it really validates what you saw from an R&D preclinical perspective. It shows that peripheral CB1 inhibition can provide a durable effect after treatment stops, which is a significant issue for the Incretin-only therapies. I noticed coming from Obesity Week, there has been a growing emphasis of the Incretins or companies that have Incretin pipelines focusing on the maintenance market as well.

After treatment stops, which is a significant issue for the Ingrid and only therapies and I noticed you know but.

Speaker #1: So, we don't know why these patients regain their weight this quickly, but they did. Being a randomized trial, we figure that both the causes are effectively similar.

From coming from obesity week.

There has been growing emphasis of the increments.

Or companies that have incurred in pipelines focusing on the maintenance market as well.

Speaker #3: Yeah, if I can just elaborate on one thing, Andy. So, look, the durability data that we showed last week—with only 18% regain versus 15% for semaglutide alone—is, I believe, a real cornerstone of our strategy, and it really validates what we saw from an R&D preclinical perspective.

We believe that.

This the comment we made at the last earnings call and we stand by it as we do believe that we really have.

An interesting opportunity for the massive mab to aggressively pursue them.

Maintenance indication, which we can formally kind of look at once we finalize our dosing strategy, but we see a massive commercial opportunity that's differentiated because it's it's more likely and doctors will confirm this.

Speaker #3: It shows that peripheral CB1 inhibition can provide a durable effect after treatment stops, which is a significant issue for the increment-only therapies. I also noticed from attending Obesity Week that there's been a growing emphasis on the increments, with companies focusing on the maintenance market as well.

Punit Dhillon: We believe that this comment we made at the last earnings call, and we stand by it, is we do believe that we really have an interesting opportunity for Nebasamab to aggressively pursue a maintenance indication, which we can formally kind of look at once we finalize our dosing strategy. We see a massive commercial opportunity that's differentiated because it's more likely, and doctors will confirm this, that they would treat with a differentiated mechanism rather than maintenance with another Incretin after induction of Incretin is completed. I know Tu's investigated that from a commercial standpoint from the survey that we've done, and that's been confirmed. Tu, do you want to just expand on that? Yeah. I think you kind of covered it pretty well.

They would treat them with a differentiated mechanism rather than a maintenance with another increment after induction of <unk> is completed.

And no tus investigated that from a commercial standpoint from the survey that we've done.

Speaker #3: We believe that this comment we made at the last earnings call, and we stand by it, is we do believe that we really have an interesting opportunity for Nimafenab to aggressively pursue a maintenance indication, which we conformally kind of look at once we finalize our dosing strategy.

And Thats been confirmed to you do you want to just expand on that.

Yeah.

Yeah, No I think you've kind of covered it pretty well I think it is important to understand that the maintenance approach.

Therapy is something that's being looked at a lot not just by sky, but from investigators.

Speaker #3: But we see a massive commercial opportunity that's differentiated because it's more likely, and doctors will confirm this, that they would treat with a differentiated mechanism rather than maintenance with another increment after induction of increment is completed.

And clinicians as well as obviously.

Other companies since then.

<unk> said.

Right now theres not a lot of options other than another GOP line for patient to go on.

Punit Dhillon: I think it is important to understand that the maintenance approach therapy is something that's being looked at a lot, not just by Skye, but from investigators, clinicians, and obviously other companies. As Punit said, right now, there's not a lot of options other than another GLP-1 for patients to go on. Physicians are generally either reluctant or, in fact, at least the ones I've spoken to, generally actually put them on something else other than a GLP-1, like a phentermine or something like that. To them, it makes more sense because it's a different mechanism of action, even though phentermine may have some other comorbidity issues as well as maybe not be as effective. I think, again, in that space, I think there's a real market for a drug like Nebasamab that we think we can, where we think we can win.

And so physicians are generally either reluctant or in fact, and I say at least the ones I've spoken to you.

Speaker #3: And I know two investigated that from a commercial standpoint from the survey that we've done, and that's been confirmed too. Do you want to just expand on that?

Generally actually put them on something else other than NGL, feeling like <unk> or something like that that makes more sense, because it's a different mechanism of action, even though entry may have some other comorbidity issues as well as maybe not be as effective.

Speaker #1: Yeah, I think you kind of covered it pretty well. I think it is important to understand that the maintenance approach in therapy is something that’s being looked at a lot, not just by Skye, but by investigators and clinicians as well as, obviously, other companies.

So I think again in that space.

There is a real market.

For a drug like <unk>.

We think we can.

Where we think we can win.

Okay. Thanks, so much.

Yes.

Speaker #1: And as Puneet said, right now there's not a lot of options other than another GLP-1 for patients to go on. So, physicians are generally either reluctant or, in fact, I would say at least the ones I've spoken to generally actually put them on something else other than the GLP-1, like phentermine or something like that, which to them makes more sense because it's a different mechanism of action.

Your next question comes from the line of a non goes from H C. Wainwright. Your line is live.

Hi, guys. Thanks for taking my question I'm Gonna installations on the Accommodator looks really a perfect. One last question I have is.

Like you know.

Andy Isaya: Okay, thank you so much.

What what what kind of the magnitude of that though I do believe it can be it clinically and commercially viable. When you are thinking about Ghana Congo Congo potential and was also curious for more what was the quality of weight loss in terms of the lean months.

Punit Dhillon: Yep.

Speaker #1: Even though phentermine may have some other comorbidity issues as well as maybe not be as effective. So I think, again, in that space, I think there's a real market for a drug like Nimafenab that we think we can where we think we can win.

Bernie Hertel: Your next question comes from the line of Ananda Ghosh from HC Wainwright. Your line is live.

Ananda Ghosh: Hi guys. Thanks for taking my question, and congratulations on the accommodator. Looks really impressive. One of the questions I have is what kind of the magnitude of data do you believe can be clinically and commercially viable when you are thinking about the combo potential? I was also curious to know what was the quality of weight loss in terms of the lean mass. That would be helpful. Thanks.

That's definitely helpful.

Yeah I think this is Greg thanks, Ananda I'll turn it over to Penny to Aurora you can take both those questions.

Speaker #2: Okay. Thank you so much.

Speaker #1: Yeah.

Speaker #4: Your next question comes from the line of Ananda Ghosh from HC Wainwright. Your line is live.

Yes Ananda.

Thanks for that question, you've seen that a lot of the effective weight loss medications.

Speaker #5: Hi, guys. Thanks for taking my question, and congratulations on the Accommodator. It looks really impressive. One of the questions I have is, what kind of magnitude of delta do you believe can be clinically and commercially viable when you are thinking about combo potential?

Out there cluster it isn't around the 2022% range.

If you could speak to most recently finished centennial that a lot of patients don't even need the beta frankly, once you start exceeding about 10th Claudio can reverse and lots of comorbidities, but.

Punit Dhillon: Yeah. I think that's great. Thanks, Ananda. I'll turn it over to Punit Dhillon. He can take both those questions.

Puneet Arora: Yes, Ananda. Thanks for that question. You've seen that a lot of the effective weight loss medications that we have out there cluster in around the 20%, 22% range. In fact, if you speak to most obesity physicians, they'll tell you that a lot of patients don't even need 20% weight loss. Frankly, once you start exceeding about 10% weight loss, you can reverse a lot of comorbidities. Insofar as the benchmark today is about 20%, semaglutide or a generic GLP-1 usually gives you about 15%. You start seeing the other combinations adding up to another 5%, 6% like you see with tirzepatide. That's the differential that we would hope for. We're already seeing in our protocol set here a 14-point something percent weight loss at 26 weeks, which is 3.5% more than semaglutide alone. It's about a 35% increase.

Insofar as the benchmark today, it's about 20% of semi glow died or a genetic GMP one usually it would be about 15%.

Speaker #5: And was also curious to know what was the quality of weight loss in terms of the lean mass. That would be helpful. Thanks.

Let me start seeing the other combinations are adding up to another five 6% legacy with two separate died.

Speaker #3: Yeah, I think it's great. Thanks, Ananda. I'll turn it over to Puneet Arora. He can take both those questions.

We would hope for we're already in ARPA protocol set here of 14 and up 14 point something percent weight loss at 26 weeks, which is a 3.5% Barton Tim Argo diet alone that's about a 35% increase and we think that when we do a full 52 actually a 68 week treatment.

Speaker #1: Yes, Ananda, thanks. Thanks for that question. You've seen that a lot of the effective weight loss medications that we see out there, clustering around the 20, 22% range, in fact, if you speak to most obesity physicians, they'll tell you that a lot of patients don't even need 20% weight loss.

With this matter all of these are measured.

<unk>.

Speaker #1: Frankly, once you start exceeding about 10% weight loss, you can reverse a lot of comorbidities. But insofar as the benchmark today is about 20%, semaglutide or a generic GLP-1 usually gives you about 15%.

We then have a combination treatment effect that will be in the range or better than what we've seen with all these other combinations.

We are actually seeing improvement in body composition, along with the study.

Puneet Arora: We think that when we do a full 52, actually a 68-week treatment, which is where all these are measured, we will have a combination treatment effect that will be in the range or better than what we are seeing with all these other current combinations. We are actually seeing improvement in body composition along with this 30% extra weight loss. We had planned this at Obesity Week as well. What we're showing is that if you just look at the crude numbers, semaglutide alone has about a 72% fat loss and 28% lean mass. When you add Nebasamab to it, this actually becomes a 76% fat loss and only 24% lean loss. There is a transition towards fat mass loss. When we break this down, we see that, as you know, there is 30% extra weight loss, right?

So we have this.

Speaker #1: And then we start seeing the other combinations. Adding up to another 5, 6%, like you see with tirzepatide. That's the differential that we would hope for.

Obesity week as well.

We're showing you is that if you just look at the crude numbers.

Speaker #1: We're already seeing in our protocol set here a 14 point something percent weight loss at 26 weeks, which is three and a half percent more than semaglutide alone.

Alone has about a 72% fat loss from 28% lean mass and when you I know my snap to it actually becomes a 76% fat loss and only.

Speaker #1: So it's about a 35% increase. We think that when we do a full 52, actually a 68-week treatment—which is where all these are measured—we will have a combination treatment effect that will be in the range or better than what we are seeing with all these other current combinations.

And only 24% plus so that.

That is a transition towards fat mass loss and when we break this down we see that as you know there is 30% extra weight loss right, but the fat loss goes from 15% for semi to more than 20%, but if you look at the combination, whereas the lean mass loss almost doesn't change it goes from about $5.

Speaker #1: We are actually seeing improvement in body composition along with this 30% extra weight loss. So we had planned this at obesity week as well.

5% to 6% and that is what is.

Speaker #1: What we're showing is that if you just look at the crude numbers, semaglutide alone has about a 72% fat loss and 28% lean mass.

That is the effect that we have seen in the lean to fast pass ratio and why the body composition is improving so all of the additional.

Puneet Arora: The fat loss goes from 15% for semaglutide to more than 20% when we look at the combination, whereas the lean mass loss almost doesn't change. It goes from about 5.5% to 6%. That is the effect that we are seeing in the lean to fat mass ratios and why the body composition is improving. All of the additional weight loss that we're seeing is almost all fat mass loss. Our secondary endpoint, to be specific, was lean to fat mass ratio. That ratio should increase with weight loss, and the more the increase, the better your body composition is. In our trial, semaglutide increased that lean to fat mass ratio by 0.13, and the combination improved it by 0.26, which is twice the improvement. This number was actually significant. The p-value was 0.01.

Weight loss of Athene is almost all fat mass loss, our secondary endpoint to be specific both linked to fat loss ratio and that ratio should increase with weight loss and the more the increase the better your body composition is and in our trial semi could that increase that leaned too fat.

Speaker #1: And when you add Nimafenab to it, this actually becomes a 76% fat loss and only 24% lean loss. So there is a transition towards fat mass loss.

Speaker #1: And when we break this down, we see that, as you know, there is 30% extra weight loss, right? But the fat loss goes from 15% for semaglutide to more than 20% when we look at the combination, whereas the lean mass loss almost doesn't change.

My 0.13, and the combination of improved it by <unk>.

Because it is twice the improvement in this number was actually significantly it was zero.

Zero one.

Speaker #1: It goes from about 5.5 to 6%. And that is what is that is the effect that we are seeing in the lean to fat mass ratios and why the body composition is improving.

Okay. Thanks, that's very helpful.

Okay.

Your next question comes from the line of Jay Olson from Oppenheimer. Your line is live.

Speaker #1: So all of the additional weight loss that we're seeing is almost all fat mass loss. Our secondary endpoint to be specific was lean to fat mass ratio.

Exactly.

Oh, Hey, thank you for providing the update we have two questions. Our first question is about your current thinking around the potential for studying a combination of no massive plus some magnified for induction of weight loss versus maintenance of weight loss, while acknowledging the regulatory.

Speaker #1: And that ratio should increase with weight loss. The more it increases, the better your body composition is. In our trial, semaglutide increased that lean-to-fat mass ratio by 0.13.

Ananda Ghosh: Got it. Thanks, that was very helpful.

Bernie Hertel: Your next question comes from the line of Jay Olson from Oppenheimer. Your line is live.

Speaker #1: And the combination improved it by 0.26, which is twice the improvement. And this number was actually significant. The p-value was 0.01.

Considerations it seems like they both may offer a potentially significant commercial opportunities. So.

Andy Isaya: Oh, hey. Thank you for providing this update. We have two questions. Our first question is about your current thinking around the potential for studying a combination of Nebasamab plus semaglutide for induction of weight loss versus maintenance of weight loss. While acknowledging the regulatory considerations, it seems like they both may offer potentially significant commercial opportunities. How are you weighing the pros and cons of induction versus maintenance? I had a second question, if I could.

How are you weighing the pros and cons of induction versus maintenance and then I had a second question if I could.

Speaker #5: Got it. Thanks. That was very helpful.

Yeah. Thanks, Jason Thanks for joining the call today, that's a key question.

Speaker #4: Your next question comes from the line of Jay Olson from Oppenheimer. Your line is live.

We are certainly focused on the induction side.

Speaker #6: It's not great.

When we are seeing this improvement that we've showed over the course of this early dataset with no observed two of 26 weeks.

Speaker #5: Oh, hey, thank you for providing this update. We have two questions. Our first question is about your current thinking around the potential for studying a combination of Nimafenab plus semaglutide for induction of weight loss.

It really demonstrates.

Punit Dhillon: Yeah. Thanks, Jay. Thanks for joining the call today. That's a key question. We are certainly focused on the induction side. When we're seeing this improvement that we've showed over the course of this early dataset with no observed plateau at 26 weeks, it really demonstrates a synergistic activity, and it's been very encouraging. We're looking forward to seeing what the 52-week data reveals. The current focus for the phase IIb is on evaluating the right and optimal dose in combination with SEMA. I think there's a little bit of other supportive data that we've seen from a preclinical perspective that Chris might be able to point to in terms of why we feel confident that dosing higher can lead to a better, deeper weight loss in SEMA because of the data that we've seen so far with Tirzepatide and SEMA in combination.

It's a synergistic activity.

Speaker #5: Versus maintenance of weight loss. While acknowledging the regulatory considerations, it seems like they both may offer potentially significant commercial opportunities. So how are you weighing the pros and cons of induction versus maintenance?

It's been very encouraging.

We're looking forward to seeing what the 52 week data revealed but the current.

Focus for the phase two b is on evaluating.

On the right and the optimal dose in combination with summer.

Speaker #5: And then I had a second question if I could.

<unk>.

I think there is.

Speaker #3: Yeah, thanks, Jay. Thanks for joining the call today. That's a key question. We are certainly focused on the induction side. When we're seeing this improvement that we've showed over the course of this early data set, with no observed plateau at 26 weeks, it really demonstrates a synergistic activity.

Little bit of other supportive data that we've seen from a preclinical perspective that Chris might be able to point to.

In terms of why we feel confident of dosing higher can lead to a better <unk>.

Deeper wafers, a deeper weight loss in <unk>.

Because of the data that we've seen so far which was appetite in semi in combination Chris do you want to.

Discuss that.

Speaker #3: And it's been very encouraging. We were looking forward to seeing what the 52-week data reveals, but the current focus for the phase 2B is on evaluating the right and optimal dose in combination with Sema.

Sure.

To that point, we directly asked that question in light of our recent clinical data is important to understand as we get better exposure moving from what we've modelled to be something very similar.

Speaker #3: And I think there's a little bit of other supportive data that we've seen from a preclinical perspective that Chris might be able to point to in terms of why we feel confident of dosing higher can lead to a better deeper weight loss in Sema because of the data that we've seen so far with tirzepatide and Sema in combination.

Two our CVR massingham dose, which we're calling sort of a suboptimal dose and this vio preclinical model and then a more active dose.

Punit Dhillon: Chris, do you want to discuss that?

Kaitlyn Arsenault: Sure. Yeah. To that point, we directly asked that question in light of our recent clinical data. It was important to understand, as we get better exposure, moving from what we've modeled to be something very similar to our CBION Nebasamab dose, which we're calling sort of a suboptimal dose in this DIO preclinical model, and then a more active dose. An active dose represents something that we're looking towards potentially using in future trials. Comparing the difference between the active and the suboptimal, you can, of course, see that as a monotherapy in terms of weight loss. Importantly, when we look at this in the setting of combination, we see while the additive effect is there, we really see a large improvement beyond the magnitude you might expect with the monotherapy.

A dose represents something that where we're looking towards potentially.

Using in future trials, so comparing the difference between.

The active and the sort of optimal or you can of course see that.

Monotherapy in terms of weight loss and importantly, when we look at this in the setting of combination we see while the D. A.

Speaker #3: Chris, do you want to discuss that?

Adding to the fact is there are we really see a large improvement beyond the magnitude you might expect.

Speaker #5: Sure. Yeah, to that point, we directly asked that question in light of our recent clinical data is important to understand as we get better exposure moving from what we've modeled to be something very similar to our CBON Nimafenab dose, which we're calling sort of a suboptimal dose in this DIO preclinical model.

With the monetary so it seems to really unlock a combo potential as well.

Maybe even beyond what we said the monotherapy. So it's important we think to really get the dose right as we look towards.

Sort of that industrial that combination approach.

Speaker #5: And then a more active dose, an active dose represents something that we're looking towards potentially using in future trials. So comparing the difference between the active and the suboptimal, you can, of course, see that as a monotherapy in terms of weight loss.

The clinic.

And I think it's just important to for us to emphasize that it's a really relevant in terms of being a.

Kaitlyn Arsenault: It seems to really unlock the combo potential as well, maybe even beyond what we see with the monotherapy. It's important, we think, to really get the dose right as we look towards sort of that induction or that combination approach in the clinic.

Truly.

Differentiated alternative or orthogonal approach to what's out there in terms of current combination so although the data's early in the 26 week data.

Speaker #5: And importantly, when we look at this in the setting of combination, we see while the additive effect is there, we really see a large improvement beyond the magnitude you might expect with the monotherapy.

Is is very very encouraging when you do stock it up across these other combinations, it's really interesting to see how deep that responses initially so like.

Punit Dhillon: I think it's just important for us to emphasize that it's really relevant in terms of being a truly differentiated alternative or orthogonal approach to what's out there in terms of current combinations. Although the data's early and the 26-week data is very encouraging, when you do stack it up across these other combinations, it's really interesting to see how deep that response is initially. We're all excited to see how that reveals in a longer 52-week data point. At the moment, it makes a very compelling case for us to evaluate this in a phase IIB combo.

Speaker #5: So, it seems to really unlock the combo potential as well, and maybe even beyond what we said for the monotherapy. So, it's important we think to really get the dose right as we look towards sort of that induction or that combination approach in the clinic.

We're all excited to see what how that reveals and in a in a longer a 52 week data point, but it makes.

At the moment it makes a very compelling case for us to evaluate this in our phase II combo.

Speaker #3: And I think it's just important for us to emphasize that it's really relevant in terms of being a truly differentiated alternative or orthogonal approach to what's out there in terms of current combinations.

J J. This is too I just wanted to sort of also.

Add in the relevance of this sort of.

This rebound.

Data and what I think that also means potentially for a market opportunity not just in the maintenance setting, but also more in the combination setting where you can get that injection of weight loss.

Speaker #3: So although the data's early in the 26-week data, it's very encouraging. When you do stack it up across these other combinations, it's really interesting to see how deep that response is initially.

And if in the real world locations.

Kaitlyn Arsenault: Jay, this is Tue. I just wanted to sort of also add in the relevance of this rebound data and what I think that also means potentially for a market opportunity, not just in the maintenance setting, but also more in the combination setting where you can get that induction of weight loss. If in the real world where patients need to go on a dosing holiday for whatever reason, maybe they're actually going on holiday, they just don't want to bring their drug with them, or maybe they have other things, maybe there's access issues, things like that.

Speaker #3: So we're all excited to see what how that reveals in a longer 52-week data point. But it makes a at the moment, it makes a very compelling case for us to evaluate this in a phase 2B combo.

Need to go out a dosing holiday for whatever reason, namely they are actually going on holiday. They just don't want to bring their drug with them.

Or maybe there are other things, maybe there's access issues things like that.

You know what our data suggests is that that's not going to be a big big of a problem as it has been when patients do either lose access to the AGL to one or the or have to go on vacation or other reasons that theyre not going to have a significant rebound like we're seeing in that like the step one data has shown in that you can have this sort of holiday.

Speaker #1: Jay, Jay, this is too. I just want to sort of also add in the relevance of this rebound data and what I think that also means potentially for a market opportunity, not just in the maintenance setting, but also more in the combination setting, where you can get that induction of weight loss. And if in the real world, where patients need to go on a dosing holiday for whatever reason, maybe they're actually going on holiday.

Without sort of losing the gains that you've that you've achieved through through.

Kaitlyn Arsenault: What our data suggests is that's not going to be as big of a problem as it has been when patients do either lose access to their GLP-1 or have to go on vacation or have other reasons, that they're not going to have a significant rebound like we're seeing, and that the step one data has shown, and that you can have this sort of holiday without sort of losing the gains that you've achieved through the treatment. I think that's really meaningful. I think a lot of physicians are looking at that. What that means is how you can manage patients' weight over a much longer period of time than just these sort of compressed times you're seeing in clinical trials, and what that really means in the real world for patients.

Through the treatment. So I think that's really meaningful adding a lot of physicians are looking at that and what that what that means is how you can manage patients weight.

Over a much longer period of time than just sort of these sort of compressed time youre seeing in clinical trials and what that what that really means in the real world for patients.

Speaker #1: They just don't want to bring their drug with them. Or maybe they have other things. Maybe there's access issues, things like that. What our data suggests is that that's not going to be a big of a problem as it has been when patients do either lose access to their GLP-1 or lose or have to go on vacation or have other reasons, that they're not going to have a significant rebound like we're seeing and that the step one data has shown and that you can have this sort of holiday without sort of losing the gains that you've achieved through the treatment.

Okay, great. Thank you that's it.

Very helpful and if I could ask a second question.

Can you. Please talk about any kols feedback you've received on your topline see beyond phase Iia data and also any feedback you may have received.

Kidney week.

Yes, I think Chris or sorry to play versus two and Doctor or you guys can take those questions.

Ananda Ghosh: Great. Thank you. That's super helpful. If I could ask a second question, can you please talk about any KOL feedback you've received following the top-line CBION phase IIA data, and also any feedback you may have received at Obesity Week?

Yeah. Thanks for the question Jay I will say that I think the reaction was positive I think they see the combination data as.

Speaker #1: So I think that's really meaningful. And I think a lot of physicians are looking at that and what that means as well, how you can manage patients' weight over a much longer period of time than just sort of these sort of compressed times you're seeing in clinical trials.

It's very intriguing I think that the responses that theyre seeing are are different.

Punit Dhillon: Yeah. I think Chris is—oh, sorry, Tue, probably first. Tue and Dr. Arora, you guys can take those questions.

Speaker #1: And what that really means in the real world for patients.

And they definitely look forward to us looking at much.

Speaker #5: Okay, great. Thank you. That's super helpful. And if I could ask a second question, can you please talk about any KOL feedback you've received following the top line CBON phase 2A data and also any feedback you may have received obesity week?

It's sort of a dose ranging study they obviously see that that's a key.

Kaitlyn Arsenault: Yeah, thanks for the question, Jay. I'll say that I think the reaction was positive. I think they see the combination data as very intriguing. They think that the responses that they're seeing are different, and they definitely look forward to us looking at much—it's sort of this dose-changing study. They obviously see that that's a key, and that's going to be really important for us to establish that sort of baseline, what that optimal dose is going to be. In terms of the blunting of the rebound data, that also has kind of resonated with a number of physicians and KOLs that we've spoken to, to the point that I actually just brought up earlier. One specific physician actually brought that up and said, this is really cool data.

And thats going to be that's going to be really important for us to establish that sort of baseline what that what that optimal dose.

Dose is going to be in terms of the.

Is that.

The blending of the rebound data that also as kind of resonated with a number of physicians and kols that we've spoken to.

Speaker #3: Yeah, I think Chris is—sorry, to probably verse two—and Dr. Aurora, you guys can take those questions.

To the point that I actually just just brought up earlier, one specific physician actually brought that up and said. This is this is really cool data and if if this means that a patient can.

Speaker #1: Yeah, thanks for the question, Jay. I'll say that I think the reaction was positive. I think they see the combination data as very intriguing.

Go on a dosing holiday and not have to worry about gaining their way back and this can be really meaningful for their practice. So.

Speaker #1: They think that the responses that they're seeing are different. And they definitely look forward to us looking at much at sort of this dose ranging study.

Yes, I think ultimately positive.

The.

And again from a monotherapy side I think they recognize our need to dose higher.

Speaker #1: They obviously see that that's a key and that's going to be really important for us to establish that sort of baseline what that optimal dose is going to be in terms of the that the blunting of the rebound data that also has kind of resonated with a number of physicians and KOLs that we've spoken to to the point that I actually just brought up earlier.

And but they don't see that as necessarily a deterrent for the future of the program.

Kaitlyn Arsenault: If this means that a patient can go on a dosing holiday and not have to worry about gaining their weight back, then this can be really meaningful for their practice. Yeah, I think ultimately positive. Again, from a monotherapy side, I think they recognize our need to dose higher, but they do not see that as necessarily a deterrent for the future of the program.

And I think that.

Some of the leading physicians of their had experience with PD one before so that's the way they've had interest in for a long time and the fact that you have.

In the course of <unk>.

Speaker #1: One specific physician actually brought that up and said, "This is really cool data." And if this means that a patient can go on a dosing holiday and not have to worry about gaining their weight back, then this can be really meaningful for their practice.

I think they're really enthusiastic about the idea that you can get these effects and get them in a safe and tolerable manav. So.

Punit Dhillon: I think that.

Puneet Arora: Some of the leading physicians out there had experience with CBION before. It's a pathway they've had interest in for a long time. The psychiatric events have been a source of trouble. I think they're really enthusiastic about the idea that you can get these effects and get them in a safe and tolerable manner. There's a rekindled interest now that we are showing that there's biological activity, and you can do that with an antibody without crossing the blood-brain barrier and getting these neuropsychiatric effects.

He can do interact with all of them just showing that the biological activity and you can do that with an antibody without crossing the blood brain barrier and getting the halo effect that took effect.

Speaker #1: So yeah, I think ultimately positive and again, from a monotherapy side, I think they recognize our need to dose higher and but they don't see that as necessarily a deterrent for the future of the program.

Yes.

That's great that you emphasize a doctor or I mean, I think that was the biggest.

Immediate takeaway once the data hit the hit the tape that we saw.

When we spoke to our clinical advisory board and other other investigators that.

Speaker #5: And I think that.

Speaker #1: Well, having the some of the leading physicians out there had experience with CBON before. So it's a pathway they've had interest in for a long time.

A lot of folks had just.

Yeah.

Recognize that this was a big leap forward for the class. So the first time that any dataset.

Punit Dhillon: Yeah. That's great that you emphasize that, Dr. Arora. I mean, I think that was the biggest immediate takeaway once the data hit the tape that we saw when we spoke to our clinical advisory board and other investigators, that a lot of folks had just recognized that this was a big leap forward for the class. This is the first time that any dataset has been shared with no neuropsychiatric adverse events. That's a really important kind of step for us in being able to give us the comfort to be able to dose higher, and we feel confident that there's going to be biological activity.

Speaker #1: And the psychiatric events have been a source of trouble, really. I think they're really enthusiastic about the idea that you can get these effects and get them in a safe and tolerable manner.

Been shared with no neuropsychiatric adverse events.

So that's that's a really important step for us in being able to give us the comfort to be able to dose higher and we feel confident that there's a biological activity.

Speaker #1: So there's a rekindled interest now that we are showing that there's biological activity and you can do that with an antibody without crossing the blood-brain barrier and getting these neuropsychiatric effects.

Speaker #3: Yeah, that's great that you emphasize that, Dr. Aurora. I mean, I think that was the biggest immediate takeaway once the data hit the tape that we saw when we spoke to our clinical advisory board and other investigators that a lot of folks had just recognized that this was a big leap forward for the class.

Excellent that's super helpful. Thanks for taking the question.

Thanks Jay.

Your next question comes from the line of John Walsh from citizens. Your line is live.

Hi, This is Katherine on for John kind of a quick question about why.

That's from the monotherapy arm and the 26 week update what do you want to see in order to give you confidence.

Ananda Ghosh: Excellent. That's super helpful. Thanks for taking the question.

Hi, Excusing the path forward I know that we've talked a lot about the combo arm.

Punit Dhillon: Thanks, Jay.

Speaker #3: This is the first time that any data set has been shared with no neuropsychiatric adverse events. So that's a really important kind of step for us in being able to give us the comfort to be able to dose higher and we feel confident that there's going to be biological activity.

Bernie Hertel: Your next question comes from the line of John Wullipin from Citizens. Your line is live.

But just wondering about that.

Hey, Katherine thanks, Thanks for joining the call and stepping in for John.

Andy Isaya: Hi. This is Katherine on for John. I think I have kind of a quick question about what you expect from the monotherapy arm in the 26-week update. What do you want to see in order to give you confidence in kind of choosing the path forward? I know that we talked a lot about the combo arm for obvious reasons. I'm just wondering about that.

Yes, so from from the the next 26 week data. The differences here is that we've got added.

To increase the dose from 200 milligrams to 300 milligram, what we have emphasized.

Speaker #5: Excellent. That's super helpful. Thanks for taking the question.

Speaker #3: Thanks, Jay.

Obviously too to our clinical sites. This is a really.

Speaker #4: Your next question comes from the line of John Wolobin from Citizens. Your line is live.

Punit Dhillon: Hey, Katherine. Thanks for joining the call and stepping in for John. Yeah. From the next 26-week data, the differences here are that we've increased the dose from 200mg to 300mg. What we have emphasized, obviously, to our clinical sites is really making sure that there's strong follow-through in terms of not only from a patient retention standpoint, but ensuring that if there's any noise here regarding compliance, we rectify that. At the end of the day, what we're really looking for is a better understanding for our PK model at this dose. In terms of efficacy, it's really hard to predict at this point in terms of what that's going to be relative to what we've seen so far in the first based on the 26-week data.

Making sure that there is strong.

Speaker #6: Hi, this is Catherine on for John. I think I have kind of a quick question about what you expect from the monotherapy arm in the 26th week update.

Follow through in terms of the.

Not only from a.

Patient retention standpoint, but ensuring that if there was any noise here regarding compliance we rectify that.

Speaker #6: What do you want to see in order to give you confidence in kind of choosing the passport? I know that we talked a lot about the combo arm because for obvious reasons.

So at the end of the day, what we're really looking for is a better understanding for our PK model.

Speaker #6: I'm just wondering about that.

Speaker #3: Hey, Catherine. Thanks for joining the call and stepping in for John. So, from the next 26-week data, the difference here is that we've increased the dose from 200 milligrams to 300 milligrams.

At this at this dose in terms of efficacy.

Really hard to predict at this point in terms of what that's going to be relative to what we've seen so far in the first.

Based on the 26 week data.

Speaker #3: What we have emphasized obviously to our clinical sites is a really making sure that there's strong follow-through in terms of the not only from a patient retention standpoint, but ensuring that if there's any noise here regarding compliance, we rectify that.

We are obviously.

Encouraged by the PK PD modeling that we've done at higher doses that we should be able to reach the 5% or higher bar.

But we need to see.

That data and we wanted to make sure that we have.

Improvement in terms of our sensitivity around the PK PD understanding.

Punit Dhillon: We are obviously encouraged by the PK/PD modeling that we've done at higher doses that we should be able to reach the 5% or higher bar. We need to see that data, and we want to make sure that we have improvement in terms of our sensitivity around the PK/PD understanding.

Okay.

Just to clarify we did we did use a slightly higher dose in the extension, but as.

Speaker #3: So at the end of the day, what we're really looking for is a better understanding for our PK model at this dose. In terms of efficacy, it's really hard to predict at this point in terms of what that's going to be relative to what we've seen so far in the first based on the 26-week data.

At this time I don't need to help us help us refine our PK models, we will be when we do a phase II study, we will look at meaningfully higher doses in <unk>.

Current exposure.

<unk>.

A more positive trend.

Puneet Arora: Yeah. Just to clarify, we did use a slightly higher dose in the extension, but as Puneet said, primarily to help us refine our PK models. When we do a phase II study, we will look at meaningfully higher doses, different exposures, and we think that will give us a more positive result.

Speaker #3: We are obviously encouraged by the PK/PD modeling that we've done at higher doses that we should be able to reach the 5% or higher bar.

And I know that in the past you've said about the south.

<unk> thousand milligrams have you changed your thinking at all on that on the <unk>.

Or is it for the higher dose.

Speaker #3: But we need to see that data, and we want to make sure that we have improvement in terms of our sensitivity around the PK/PD understanding.

Yes, we're still we're still working through that Kathryn.

For monotherapy, we expect basically to unlock efficacy at higher doses.

Like we said.

Andy Isaya: I know that in the past you said about 1,000, you're going to go up to 1,000mg. Have you changed your thinking at all on the target for the higher dose?

Speaker #1: Catherine, just to clarify, we did use a slightly higher dose in the extension, but as Punit said, it's primarily to help us refine our PK models.

It's in line with our exposure response modeling it hasn't necessarily ruled out that the 203 hundred.

Our effective doses as well I think we had.

Punit Dhillon: Yeah. We're still working through that, Katherine. For monotherapy, we expect basically to unlock efficacy at higher doses. Like we said, it's in line with our exposure and response modeling. It hasn't necessarily ruled out that the 200 and 300 are effective doses as well. I think we had some lack of consistency in terms of what we saw in the first 26 weeks. In our slides that we shared during the top-line data review, I think we showed some indication of what the optimal dosing would have revealed. Those patients that had increased exposure response tended to do really well versus the patients that were suboptimally dosed or had lower exposure response. I think what we need to see is if that is kind of course-correcting in what we're evaluating.

Speaker #1: We will be, when we do a phase 2 study, we will look at meaningfully higher doses and different exposures and we think that will give us a more positive result.

Some lack of <unk>.

Consistency in terms of what we saw in the face and the first 26 weeks in our slides that we shared during the topline data review I think we showed some some indication of what the optimal dosing would have revealed in those patients that had increased of.

Speaker #6: And I know that in the past you've said about 1,000 you're going to go up to 1,000 milligrams. Have you changed your thinking at all on that on the target for the higher dose?

Exposure response.

Speaker #3: Yeah, we're still working through that, Catherine. For monotherapy, we expect basically to unlock efficacy at higher doses. As we've said, it's in line with our exposure and response modeling, and it hasn't necessarily ruled out that the 200 mg and 300 mg are effective doses as well.

<unk> tended to do really well versus the patients that were sub optimally dose or to had lower exposure response.

So I think what we need to see is if.

If that is kind of course correcting in the in the and what we're evaluating and then we have confidence that dosing higher is is definitely going to show.

Speaker #3: I think we had some lack of consistency in terms of what we saw in the phase in the first 26 weeks. In our slides that we've shared during the top-line data review, I think we showed some indication of what the optimal dosing would reveal. Those patients that had increased exposure response tended to do really well, versus the patients that were suboptimally dosed or had lower exposure response.

A higher likelihood of efficacy signal that we expect to see and we expect that to be over 5% at 26 weeks at these higher doses that we want to evaluate.

Thank you.

Punit Dhillon: We have confidence that dosing higher is definitely going to show a higher likelihood of an efficacy signal that we expect to see. We expect that to be over 5% at 26 weeks at these higher doses that we want to evaluate.

Your next question comes from the line of Ted comes off from Piper Sandler Your line is live.

Great. Thank you so much for taking that.

Question I wanted to.

Maybe dig into the other side of going higher dose from the combination of earlier studies preclinical data in the initial <unk> results, obviously, we're going to keep a close eye on.

Speaker #3: So I think what we need to see is if that is kind of course-correcting in the what we're evaluating and then we have confidence that dosing higher is definitely going to show a higher likelihood of efficacy signal that we expect to see.

Andy Isaya: Thank you.

Bernie Hertel: Your next question comes from the line of Ted Hensall from Piper Sandler. Your line is live.

Ananda Ghosh: Great. Thank you so much for taking that question. I wanted to maybe dig into the other side of going higher on dose. From the combination of earlier studies, preclinical data, and then the initial CBION results, obviously, we're going to keep a close eye on potential CNS side effects. Is there anything else that we should be really focused on or that could sneak up on us from a safety standpoint of taking the doses to these substantially higher levels? Thanks so much for answering the question.

Potential CNS side effects is there anything else that we should be really focused on or as I could sneak up on us from a safety standpoint.

Speaker #3: And we expect that to be over 5% at 26 weeks at these higher doses that we want to evaluate.

Speaker #6: Thank you.

<unk> Zip doses.

To the substantially higher levels. Thanks, so much for it for the.

Speaker #4: Your next question comes from the line of Ted Tensaw from Piper Sandler. Your line is live.

Good question.

Hey, Thanks, Ted Yeah, I think we feel really confident about the safety signal and allowing us the room to go higher.

Speaker #7: Great. Thank you so much for taking the question. And I wanted to maybe dig into the other side of going higher on dose. And from the combination of earlier studies, preclinical data, and then the initial CBN results, obviously we're going to keep a close eye on potential CNS side effects.

In terms of dose, especially from the standpoint of any concern of neuropsychiatric adverse events. So we even in this study based on our phase one data based on our talks laid out there's a substantial amount of room.

Punit Dhillon: Hey, thanks, Ted. Yeah, I think we feel really confident about the safety signal and allowing us the room to go higher in terms of dose, especially from the standpoint of any concern of neuropsychiatric adverse events. In this study, based on our phase one data, based on our tox data, there's a substantial amount of room relative to where we're at in terms of dosing. In terms of other safety concerns, I think we have to see. We don't have the data yet at higher doses over this longer period of time, whether that's a change in terms of GI tolerability. We feel at this point, based on the data that we've seen in the phase two, that there wasn't any concerns to be able to go higher. Across the class, it seems to be a little bit different.

Relative to where we're at in terms of dosing in.

Speaker #7: Is there anything else that we should be really focused on or that could sneak up on us from a safety standpoint of taking the doses to the substantially higher levels?

In terms of other safety concerns I think where we have to we have to see so we don't have the <unk>.

Data too.

Too.

Yet at higher doses over this longer period of time, whether that's a change in terms of Gi tolerability, but.

Speaker #7: Thanks so much for answering the question.

Speaker #3: Hey, thanks, Ted. Yeah, I think we feel really confident about the safety signal and allowing us the room to go higher in terms of dose especially from the standpoint of any concern of neuropsychiatric adverse events.

But we feel at this point based on the data that we've seen in the phase.

Two that there wasn't any.

Any concerns to be able to go to go higher.

But.

Across the class it seems to be.

Speaker #3: So even in this study, based on our and on phase 1 data, based on our talks data, there's a substantial amount of room relative to where we're at in terms of dosing.

It'll be different some small small molecules have had only about 30%.

GI issues and then the more lunar bad data recently showed about 60% Gi issues.

Speaker #3: In terms of other safety concerns, I think we have to see. So we don't have the data to yet at a higher doses over this longer period of time, whether that's a change in terms

We don't know if that's linked to CB, one yet or if it's.

Yeah.

Or it's like its molecule specific.

At the moment, though there seems still seems to be substantial room for us to be able to evaluate that and mechanistically. It's not.

Punit Dhillon: Some small molecules have had only about 30% GI issues. The monouniband data recently showed about 60% GI issues. We do not know if that is linked to CBION yet or if it is molecule-specific. At the moment, there still seems to be substantial room for us to be able to evaluate that. Mechanistically, it is not the same. The mechanism is different than what the GLP-1 drugs are doing. We feel that we should not have any exacerbated GI burden. Dr. Arora, sorry, you might want to take that further.

It's not to say it doesn't the mechanism is different than what the <unk> one drugs are doing.

So we feel that we shouldnt have any exacerbated.

<unk> burden.

But Dr. Ross, sorry, you might want to.

Pick that further.

Yeah, you know, it's been my sense that even even with the data I should go back to the amount of bands that even though they showed 30% Gi effects there was a sudden.

A placebo effect as well, that's what's comparing to which seem to suggest that the gi effects and you'll see with the C. V. One part we are not that significant and of course with no lost time, youre showing even better results at the stores, where essentially there's no difference between placebo and what we have seen with the drug some wood.

Puneet Arora: Yeah. It's been my sense that even with the data, if you go back to rimonabant, even though they showed 30% GI effects, there was a certain placebo effect as well that's worth comparing to, which seemed to suggest that the GI effects that you see with the CB1 pathway are not that significant. Of course, with nimacimab, we are showing even better results at this dose where essentially there's no difference between placebo and what we are seeing with the drug. With the GLP-1s, which is where all the attention comes from, I believe that a lot of the GI effects tend to come because of the central action on places near the hypothalamus, like the area postrema, whose job is to see what's going on in your blood and cause you to have nausea or vomiting if they think that there is something that's deleterious.

The DLP ones, which is where all the attention comes from the <unk>.

I believe that a lot of the Gi effects tend to come because of the central action on the on any other on places near the hypothalamus like the any upstream average whose job is to see what's going on in New York, London cause you to have nausea or vomiting, if they think that that is something that's deleterious stimulating receptors.

Other than that and it's very possible that the C. V. One mechanism it doesn't actually do that and that's why you see Gi effects being so much more muted with this mechanism and especially with the antibody NIM asthma. We will test this spring with higher doses, but we are pleased to see that at least with the dose that we've tested.

Puneet Arora: Stimulating receptors are causing that. It is very possible that the CBION mechanism does not actually do that. That is why you see GI effects being so much more muted with this mechanism, and especially with the antibody nimacimab. We will test this, as Puneet said, with higher doses. We are pleased to see that at least with the dose that we have tested, we are seeing really neutral effects.

We have seen really neutral effects.

The placebo effect is also worth comparing, as it suggests that the gastrointestinal effects associated with the CV1 pathway are not that significant. Of course, with NASA, we are showing even better results at this stage, where essentially there is no difference between the placebo and what we are observing with the drug, some with the GL.

Yes, that's correct and ism externally how long do you think you'd be able to dose. Thanks, so much for taking my questions.

Ones, which is where, you know, all the attention.

Thanks Ted.

Yes.

Oh go ahead go ahead Douglas.

The phase two study I mean, we would do.

We want those people all the way out to a year of 52 weeks, but we haven't been looking at what the primary structure of the study should be what we'd like is to design a study that will move us meaningfully towards doing pivotal studies. So we may still read out data at 26 weeks, where you know you can get a substantial.

Ananda Ghosh: Yeah, that's great. In the next study, how long do you think you'd be able to dose? Thanks so much for taking my questions.

Punit Dhillon: Thanks, Ted.

Puneet Arora: Yeah.

Punit Dhillon: Oh, go ahead.

Puneet Arora: Go ahead, Punit.

Punit Dhillon: No, go ahead.

Puneet Arora: In a phase two study, I mean, we want to dose people all the way out to a year, 52 weeks. We are still looking at what the primary structure of the study should be. What we'd like is to design a study that will move us meaningfully towards doing pivotal studies. We may still read out data at, say, 26 weeks, where you can get a substantial indication of how individual doses are working and get a lot of safety information. We do want to design studies in the end where the patients that we recruit get longer-term treatment and can be treated for a year or even longer.

Asian of how individual doses are working and get a lot of safety information, but you know we don't we don't wanted to design studies, and the and where the patients that we recruit to get longer term treatment and can be treated for a year or even longer.

That's delicious and stimulating receptors that are causing that, and it's very possible that the CV1 mechanism doesn't actually do that. And that's why you see GI effects being so much more muted with this mechanism. Especially with the antibody Nasmat, we will test this, as Punit said, with higher doses. But, uh, we're pleased to see that at least with the dose that we've tested, we are seeing really neutral effects.

Yeah, that's great I really appreciate all the all the answers guys. Thanks, so much.

Yeah, that's great. And is the next study? How long do you think you'd be able to dose? Thanks so much for taking my questions.

Thanks, Ed.

There are no further questions for the Q&A session.

Go ahead, go ahead. Go ahead. So, you know, in a Phase 2 study. I mean, we would...

Thank you for attending Sky Biosciences third quarter 2025 earnings call you may disconnect.

Ananda Ghosh: Yeah, that's great. I really appreciate all the answers, guys. Thanks so much.

Punit Dhillon: Thanks, Ted.

Bernie Hertel: There are no further questions for the Q&A session. Thank you for attending Skye Bioscience's third quarter 2025 earnings call. You may disconnect.

We we want to those people all the way out to a year of 52 weeks, but you know, we haven't, we're still looking at what the primary structure of the study should be, what we'd like is to design a study that will move us meaningfully towards doing pivotal studies. So we may still read out data at say 26 weeks where, you know, you can get uh a substantial indication of how individual doses are working and get a lot of safety information. But you know we do we do want to design studies in the end where the patients that we recruit get longer term treatment and can be treated for a year or even longer

Yeah that's great. I really appreciate all the uh all the answers guys. Thanks so much.

There are no further questions for the Q&A session. Thank you for attending. Scott biosciences, third quarter 2025 earnings, call. You may disconnect

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