Q3 2024 Skye Bioscience Inc Earnings Call
Desiree: Ladies and gentlemen, thank you for standing by. My name is Desiree and I will be your conference operator today. At this time, I would like to welcome everyone to the SC&I Bioscience 3rd Quarter 2024 Earnings Call.
Desiree: 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.
Speaker Change: I would now like to turn the conference over to Bernie Hertel, Head of Investor Relations. Please go ahead.
Bernie Hertel: Hello, and thank you all for participating in today's call. Joining me today is Panit Dhillon, Sky's President and CEO, and Kaitlyn Arsenault, Sky's CFO.
Bernie Hertel: 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, including statements about Sky's expectations regarding its development activities, timelines, and milestones.
Bernie Hertel: 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 statement made today.
Bernie Hertel: I encourage you to review all the company's filings with the Securities and Exchange Commission concerning these and other matters.
I'll now turn the call over to Paneet Dhillon.
Paneet Dhillon: Good afternoon, everyone. Thank you for joining us on Sky's first earnings call, and we appreciate your continued interest in Sky and your support for our journey focused on developing metabolic medicine that we believe is relevant to the market and has the potential to be impactful for patients.
Paneet Dhillon: The third quarter and periods subsequent to the quarter have been momentous on the clinical front and with respect to new preclinical data. And I will provide an update on these accomplishments in an overall strategic context and ongoing efforts across our programs and operations.
Paneet Dhillon: We believe that the utility of the Ingrid and Mimetic drugs still begs improvement with respect to tolerability, lean mass preservation, and the sustainability of using such weight loss drugs.
Paneet Dhillon: The pharmaceutical obesity drug leaders themselves have been acknowledging that this need and the potential importance of non-increasing mechanisms via multiple announced acquisitions and partnerships.
Paneet Dhillon: We believe that CB1 inhibition has mechanistic attributes and potential clinical outcomes that position it as a promising complement or alternative to incredent mimetics such as GLP-1 receptor agonists.
Paneet Dhillon: The history of CB1 inhibition mechanism has provided promising clinical evidence of its utility. However, there's also been concerning neuropsychiatric adverse events associated with the first and second generation small molecules employing this mechanism.
Hence, we face an exercise to reset the evidence.
and discussion around CB1 class of drugs.
Paneet Dhillon: And we do this by conducting research and conveying data that delineates the role and requirement of peripheral versus central CB1 inhibition. And we also do this by highlighting the important differentiating outcomes that can potentially be realized from CB1 inhibition.
Paneet Dhillon: based on the distinguished approach of a monoclonal antibody such as Skye's nematomab versus the original approach of small molecules.
Paneet Dhillon: We recently have made an important stride to contribute to this knowledge base and discussion. So, let me first delve into our newly announced
Paneet Dhillon: pre-clinical data, and then I'll update you on our Phase 2 obesity clinical trial.
Paneet Dhillon: Just days ago, we issued a news release and conducted a satellite event at Obesity Week.
Paneet Dhillon: with our science team and KOLs that highlighted compelling preclinical data showing the prominent role played by peripheral CB1 inhibition and the lack of need for central CB1 inhibition to achieve significant dose-dependent weight loss.
Paneet Dhillon: We believe this was the first ever publishing of such evidence using a virtually, completely peripherally restricted CB1 inhibitor.
Paneet Dhillon: We believe this data is important because even though first and second generation small molecule CB1 inhibitors have both achieved clinically relevant weight loss, the data does not indicate the weight loss was driven by central CB1 inhibition.
Yet their accumulation in the brain induced neuropsychiatric adverse events.
Paneet Dhillon: Serious in the case of remonivant, mild to moderate in the recently reported case of mononivant.
Paneet Dhillon: These small molecule CB1 inhibitors collectively cause adverse events ranging from suicidality and depression to anxiety, irritability, and sleep disturbances.
Paneet Dhillon: In contrast, data from the prior Phase I and comprehensive non-human primate studies for Skye's NMASMAP, which is virtually undetectable in the central nervous system, and is to our knowledge the most perfectly restricted CB1 inhibitor, showed no neuropsychiatric adverse events.
Paneet Dhillon: I will also emphasize that referencing back to the high incidence of gastrointestinal concerns with GLP-1 receptor agonists in the Phase 1 study of namaxinab, the incidence of GI adverse events was below 5%.
Let's repeat simply.
Paneet Dhillon: We believe you need peripheral CB1 inhibition and that you do not need central CB1 inhibition.
Paneet Dhillon: If a CB1 inhibitor has exposure to the brain, it could create neuropsychiatric adverse events. And we don't think most observers view even mild to moderate neuropsychiatric adverse events as being acceptable in the context of a drug that must be used for extended periods.
Paneet Dhillon: and in maintenance mode, potentially forever. These limitations of small molecules underscore the need for a new approach of a novel molecule such as dimethamate.
Paneet Dhillon: By the way, I encourage you to watch the video at the Obesity Week event which is now posted on our website.
Paneet Dhillon: With the distinct positioning of the MassMap within the class of CB1 inhibitors, and with the compelling new insight from our preclinical work,
Paneet Dhillon: We could not have greater enthusiasm and energy to advance this program.
Paneet Dhillon: With our human CB1 knock-in model up and running, we have an ongoing research program to explore different parameters related to NMASMAP alone and in combination to arrive at further insight regarding CB1 inhibition and NMASMAP.
Paneet Dhillon: And we're applying maximum effort to what is obviously a vital outcome on translating this into the clinic.
Phase 2 data.
Paneet Dhillon: I can tell you that our Phase 2 obesity clinical trial named C-Beyond, which started enrolling patients in August throughout the U.S., is enrolling very well.
Paneet Dhillon: The study's tracking towards our anticipated goal of announcing interim data at 50% enrollment of the planned 120 patients after 26 weeks of treatment in Q2 next year and top-line data after full enrollment by the end of 2025.
Paneet Dhillon: CVON is a randomized, double-blinded study that is designed to demonstrate an 8% difference in mean weight loss using the Masumab versus placebo at 26 weeks.
Paneet Dhillon: Secondary and exploratory endpoints will evaluate safety, tolerability, neuropsychiatric and cognitive outcomes, and change in body composition by DEXA. The study is also assessing synergistic outcomes when numasinab is combined with sevaglutide, a GLP-1 receptor agonist.
Paneet Dhillon: Successful execution of the CBON trial will help refine our clinical development strategy, but also establish a counterpoint to the safety concerns that have been claimed against this class of drugs as a result of the small molecule CB1 inhibitors.
Paneet Dhillon: We believe that the Phase II CB-ON trial will recapitulate the Phase I safety data for nemathumab and establish that a truly peripherally restricted antibody can drive significant weight loss without neuropsychiatric liabilities.
Paneet Dhillon: Our objective is to demonstrate clinical proof of concept supporting our options to initiate a phase 2b trial and or advance closer to phase 3 readiness and Position the mass amount as a strong candidate in the anti-obesity medication landscape
Paneet Dhillon: These efforts are fully aligned with our broad goal of establishing SCI as a leader in non-incredent metabolic therapies.
Paneet Dhillon: Beyond these primary initiatives, we are naturally looking towards the horizon and laying a foundation for a comprehensive and differentiated clinical pipeline and therapeutic footprint in the metabolic health space. Our multiple initiatives include
Paneet Dhillon: First, pursuing key preclinical work to further understand pertinent metabolic-related mechanisms.
Paneet Dhillon: Second, we want to optimize the Mastin Labs clinical profile to ensure efficacy, safety, and ultimately market penetration.
Paneet Dhillon: And third, we're advancing the evaluation of additional GPCR targets that address the complexity of various metabolic pathways, with the focus on really complementing the mass mechanism of action and evaluating combinations of different drug targets.
Paneet Dhillon: Our goal is to create therapies that are not only effective, but also capable of providing a multimodal mechanism for treating comorbidities of obesity safely and sustainably.
Paneet Dhillon: Supporting this is long-term adherence to pharmacotherapy and safety, which are crucial, particularly for chronic disease management.
Paneet Dhillon: We look forward to sharing more on these initiatives in 2025.
Speaker Change: With that, I'll turn the call over to Kaitlin, our CFO. Thanks, Neat. After the market closed today, we issued a news release and filed Sky's Form 10-Q filing with the Securities and Exchange Commission, outlining our third quarter financials.
Kaitlin: We encourage you to reference the filing for details of our financials and the risk factors described in our other filings with the SEC.
Kaitlin: I will now provide a brief overview of key financial results for the third quarter ended September 30, 2024.
Kaitlin: Research and development expenses for the third quarter of 2024 were $4.9 million, as compared to $1.3 million for the same period in 2023.
Kaitlin: The increase of approximately 3.6 million was primarily due to contracted clinical and manufacturing costs associated with our phase two clinical trial for nemathumab and obesity.
Kaitlin: The remainder of the increase resulted from increases in employee benefits, travel, and consulting fees driven by increases in headcounts.
Kaitlin: General and administrative expenses for the third quarter were $4.6 million compared to $2.2 million for the same period in 2023.
Kaitlin: The increase was primarily due to increases in non-cash incentive stock-based compensation, professional services, and fees for tax, audit, and legal services related to our required regulatory filings, financial advisory services, and patent prosecution for the NMASMAB IP.
Kaitlin: These costs were offset by a period-over-period decrease in litigation-related fees.
Kaitlin: The net loss for the third quarter of 2024 totaled $3.9 million and included non-cash share-based compensation expense of $1.9 million.
Kaitlin: compared to a $24.9 million net loss for the third quarter of 2023, including non-cash share-based compensation expense of $0.2 million.
Kaitlin: The primary reason for the significant decrease related to the acquisition of the Namathumab in-process research and development asset for $21.2 million during the three-month-ended September 30, 2023, all of which was expensed upon acquisition.
Kaitlin: In addition, we recognized $1 million in interest income and $4.6 million in income from the partial derecognition of liabilities and the recovery of losses related to our legal proceedings.
Kaitlin: On September 30, 2024, Sky had cash and cash equivalents of $76.5 million, including its restricted cash.
Kaitlin: During the third quarter, our $5 million note was converted into shares of Sky Common Stocks. Subsequent to quarter end, the United States Court of Appeals for the 9th District vacated the judgment with respect to an outstanding litigation matter.
Kaitlin: As a result, the company will be able to recover the $9 million restriction on its cash related to the appeal bond, which is expected to be released before year end.
Kaitlin: We are currently burning approximately $6 million per quarter, which we expect to increase to approximately $9 million per quarter in 2025.
Kaitlin: We believe that our capital will fund our Phase II clinical trial for nemathemab and operations through the third quarter of 2027.
Kaitlin: extending our runway one quarter past our last estimate. Our priority is high-value metabolic programs, and we believe that this strong financial footing allows us to focus on reaching critical milestones without financial constraints.
I'll now turn the call back over to Puneet.
Thank you, Kate.
puneet: I want to highlight that we have purposefully worked to maintain an effective but relatively small team of well-qualified individuals who possess the right expertise and experience and who are focused and motivated.
puneet: We strive every day to make good strategic and tactical decisions while being unafraid to move forward on steps that will expedite our journey to get to data and answer the hard questions, and could potentially represent important inflection points.
puneet: It's important to emphasize that our primary focus is on the regulatory approval strategy and execution for nomasumab in the treatment of obesity.
puneet: The second is advancing opportunities with the MassMap in the clinic and evaluating other metabolic diseases. And we have a foundation on the preclinical model we highlighted in yesterday's announcement.
puneet: The third is to expand the pipeline to broaden the metabolic target.
puneet: So we're conscious about effective spending and always consider value rather than simply cost. And we're driven to have a cohesive but critical team advancing towards the milestones that we've laid out for our company and its stakeholders.
puneet: We are genuinely focused on creating value for patients and for our shareholders.
puneet: And with this overarching view, our team numbers 17 at this point. And in the third quarter, we added Dr. Puneet Arora, our chief medical officer. Dr. Arora is an endocrinologist with an extensive metabolic experience.
puneet: Since he started in early September, he has hit the ground running and has already made important contributions.
puneet: We've also aimed to have relevant and demanding but constructive board members. After evolving the board earlier this year, in the third quarter, we added Karen Smith as a new director. She has significant global biotech and pharmaceutical experience.
puneet: And Paul Grayson has also expanded his board role to become chairman, and we congratulate him on that important step.
puneet: We also rely on very competent service providers to execute key initiatives in the respective key functions of our company.
puneet: We have a sharp focus to strengthen the team and systems that allow Sky to move forward and our team's resilience, focus, and pursuit of innovation have enabled us to advance rapidly in this exciting and dynamic space.
And that is the essence as we move forward.
So, to quickly recap,
We believe NMASNAB's first-in-class profile as a perfectly targeting
puneet: CB1 inhibitor offers the right combination of efficacy and safety that position it to realize a significant opportunity for CB1 inhibition to drive meaningful dose-dependent weight loss.
puneet: fat mass reduction, and lean mass preservation, improve glycemic control and weight loss, and achieve other metabolic benefits, all without crossing the central nervous system and risking neuropsychiatric adverse events.
puneet: We view SCI as having the right combination of attributes to lead to the emergence of CB1 inhibition as an important additional mechanism in the obesity landscape and to play a broader role in enhancing metabolic health.
Speaker Change: Shareholders can expect that since launching our CPON clinical trial in Q3 2024, our goal is to achieve our Phase 2 clinical milestones while also advancing the necessary regulatory and manufacturing steps that prepare NMASMAP for late-stage clinical development.
Speaker Change: We have a comprehensive strategic roadmap that over the next three years positions us to deliver key clinical and preclinical data and lays the long-term foundation. And we are more optimistic than ever about our strategic path forward.
Speaker Change: I want to thank our investors, employees, development partners, and our clinicians and patients for helping us advance our mission. Together, we're building a future where impactful new treatments in metabolic health can become a reality.
Speaker Change: This concludes our prepared comments for today. Thank you very much for joining us, and we'll now open the call for questions from our covering sales side analysts. Operator, over to you.
Speaker Change: We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue.
Speaker Change: If you would like to withdraw your question, simply press star 1 again.
Speaker Change: Our first question comes from the line of Edward Tempoff with Piper Sander. Your line is open.
Bye.
Speaker Change: Great. Thank you so much for the update and I'm really excited with all of the progress and looking forward to the data next year. I wanted to ask, just in terms of
Speaker Change: CBON, can you give us a little more color on how enrollment is going?
Speaker Change: Is there excitement around this, I have to mention, especially with the potential of combining mechanisms?
Speaker Change: And, you know, when it comes to the data that we could get, the interim data look, I know you've given, you know, a sense of what we should expect in terms of monotherapy.
Speaker Change: Weight loss from Namazumab, what do you think we should be expecting in terms of combination data, since there'll be really kind of only a few patients, half of the patients, probably around 10 per arm at that point? Thanks so much.
Speaker Change: Thanks for joining the call, and I appreciate seeing you earlier in the week at the obesity week event. Yeah, so on the direct question on operations, we're executing very well on the C-BEYOND Phase 2 obesity study. The study has 18 sites across the U.S.
Speaker Change: Yeah, I think on the more finer point of what we expect in terms of data, the monotherapy is where the primary power is of the study, so that the end point there, the primary end point is 8% weight loss.
Speaker Change: placebo-adjusted, but the exploratory endpoint is looking at the combination with GLP-1, with a GLP-1 receptor agonist with semaglutide, and there we're looking for an additive and
Speaker Change: or synergistic kind of a weight response. So it should be higher and hopefully demonstrate improved.
tolerability.
Speaker Change: I think, overall, our purpose behind this study has really been about a robustness of a study plan, where we're asking all the critical questions of weight loss,
a body composition of durability.
Speaker Change: Across 3 active arms, right? So we have the monotherapy arm and then we go the arm.
And then the WCOPI plus the NMASAMAB arm.
Speaker Change: and then comparing that against placebo over 26 weeks. So I think that from, as well as the 13 week follow-up. So when you think about it kind of collectively with what's happening in the space.
Speaker Change: We believe it's going to be the key data point, the key next data point, not only in the CD1 class, but overall in the non-increasing class, as well as this important data point that you highlight in terms of the combination. So, I think that's...
Speaker Change: You know, should be quite exciting in terms of what we've been seeing so far coming off of obesity week and then and into the upcoming scientific meetings that are happening in 2025.
Speaker Change: Great. That's super helpful. I'm really excited to see the deal. Thanks so much.
Speaker Change: Our next question comes from the line of Jay Olsen with Oppenheimer. Your line is open.
Speaker Change: Oh hey, congrats on all the progress and thanks for providing this update. We have a few questions, maybe...
Speaker Change: Just to start, can you discuss any KOL feedback from the preclinical data you presented at?
Speaker Change: obesity week at your satellite event and especially with regards to the body composition findings in your preclinical model and potential to preserve lean muscle mass and any physician reactions to those findings and then we have a follow-up.
Thanks Jay, I appreciate your coverage of that event.
The key thing that we, the finer technical points that...
Speaker Change: We established that the meeting were really distinguishing between the peripheral versus.
central CB1 inhibition, that peripheral CB1 inhibition is
Speaker Change: is not only necessary, but sufficient for weight loss. And in terms of the KLL feedback, I think it's a much broader appreciation relative to the backdrop of the Monmouth data.
Speaker Change: So, if we go back, you know, about six weeks with the monolunar data, it basically revealed that central CB1 inhibition leads to adverse neuropsychiatric effects and without any additional benefit in terms of dose response.
So our
Speaker Change: event, I think, covered some very important background in terms of the sufficiency of peripheral response that the PK modeling that Chris shared in detail showed that there's an effective peripheral CP1 inhibition that's required.
in order to
To get the, the, the.
Speaker Change: Efficacy that we're looking at so when when we're looking at concentrations above I see 90 there there's with the massive map.
We're not seeing any of the exposure in the brain.
Speaker Change: And based on the modeling that he presented, the small molecules are exceeding IC90 in the brain at the mid and high doses.
Speaker Change: And I think that has really helped in terms of conveying the mechanism understanding with KOLs. Dr. Aroni was at the event and he's a fantastic speaker.
Speaker Change: I think he disclosed that he's an advisor to Novo. So I think he has been very, I think, impressed with how the peripheral restriction of numasumab
everyone encourage them to watch the overall.
Speaker Change: Event or look at the slides and you can kind of get into all the details that I'm explaining here But the key takeaway is that there's really strong preclinical efficacy of the mass map It's demonstrating a significant dose dependent weight loss and it's shown, you know, this improvement in terms of
Speaker Change: glucose metabolism, as well as lean mass preservation. So it's pointing towards a favorable impact on body composition as well.
Speaker Change: Great. That's super helpful. Thank you for that. And then just to follow up on your earlier comment that the focus of the C-BEYOND study will be on...
Speaker Change: the monotherapy treatment with Namasumab. I guess, just from a commercial perspective, how are you viewing the path forward for combinations of TLP1 drugs with Namasumab?
Speaker Change: in the treatment landscape and that opportunity as it compares to the monotherapy treatment opportunity in the commercial setting. Thank you.
Speaker Change: Yeah, it's a great question. I think it's clear that the field is really dominated by the incredent mimetics or most of the drugs, like how we've classified it as focused on appetite suppression.
I think the Massimab really stands out as an alternative.
Speaker Change: Certainly, you know, categorically a groundbreaking alternative, I would say, because it's a peripheral-driven mechanism.
and rather than just forcing caloric restriction.
Speaker Change: it's targeting peripheral CB1 receptors that really promote that metabolism. So.
What we're doing is restoring.
Speaker Change: by targeting fat metabolism, we're restoring insulin, we're restoring leptin sensitivity with this mechanism. And that's what we're trying to demonstrate in the clinical trial.
Speaker Change: This mechanism, I think, is very complementary to the GLP-1 class based on
Speaker Change: how, you know, we're evaluating this clinical trial based on input that we've been able to get in designing the trial from our advisory group. The goal here is to show a durable, high-quality weight loss and an overall improved metabolic health.
Speaker Change: I think it's evident that the GLP-1 and overall incredent combos are very effective. They're showing 20% plus weight loss.
Speaker Change: But at the same note, that's not entirely necessary across the entire cross section of the of the overweight or obese population. And there is a opportunity to focus in on the overweight on the class one.
Speaker Change: category, as well as kind of better appreciate the subtypes of obesity because of other comorbidities.
Speaker Change: So I think we have an opportunity to continue to demonstrate that with a sustainable, hopefully smarter weight management and overcome some of the issues with the
Speaker Change: With what's been only available to date and for us, you know, every, every meeting that we've been going to and every data point that we've been able to share has really helped in terms of.
Speaker Change: Broadening that confidence externally and in terms of our development execution in terms of
Speaker Change: KOLs and OPC doctors appreciating that there's a need for these non-incretin mechanisms.
Speaker Change: Excellent. We definitely appreciate the strategy there and thank you so much for taking our questions.
Thank you, Peter.
Speaker Change: Our next question comes from the line of George Farmer with Scotiabank. Your line is open.
Speaker Change: Hi, good afternoon. Thanks for taking my question. Yeah, in reference to the presentation that you had at Obesity Week,
Speaker Change: And, you know, being able to use such a powerful mouse model now at your disposal, I'm wondering if you have plans to, you know, do further preclinical work, say, comparing the mass map with other.
Speaker Change: small molecule CB1 modulators, or perhaps combining with incriminated mimetics and build a preclinical body of evidence before the ultimate clinical trial data reads out. That might be really helpful. I'm just wondering what you're thinking.
Speaker Change: Yeah, thanks, George. That's a great question. So, yeah, Chris is on the line, so I will –
Let him
you know, expand on this, but.
Speaker Change: But we're really happy that we have this proprietary DIO model up and running. So that's really foundation for.
Speaker Change: how we expect to continue to build on the data set. You know, as we've seen in the space, everyone's continuing to refine their DIO models and demonstrating different components of...
Speaker Change: Of that, we have additional data that hasn't been shared yet that came out of this experiment, which we'll continue to
make public.
Speaker Change: But the goal here is to continue to expand on our preclinical, to better understand the mass map mechanism, as well as evaluate combinations. So we are exploring other combinations.
Speaker Change: We haven't given any guidance on when all that data is available. There's certainly a goal here to be
continue to share that that.
Speaker Change: broader understanding of what the MassMaps mechanism is and what the relevance is in terms of other
non-incretin as well as the incretin mechanisms. And then
Speaker Change: I think the emphasis, I would say, has still been just execution on the clinical program. So everything kind of always goes back to what we are learning from the preclinical studies to support our better understanding of clinical.
Speaker Change: I hope I didn't take all the words out of Chris's.
But, Kurt, do you want to elaborate on anything?
Kurt: No, I think, well, I'll just briefly mention and thanks for the question, George, that
As pre-noted, we do have a
Kurt: Homozygous colony that's been expanded, so we're in a really nice position to. Set up a series of studies and you're correct to identify some of the.
Kurt: The comparators that we're going to be looking at not only the combination but importantly as you mentioned some other
potential anti-obesity medications.
Kurt: including some of the small molecule inhibitors that will be quite interesting. Do things that we're all considering in addition to the combos and really digging into not just weight loss, body composition, but other related mechanistic biomarkers and readouts. So we're really looking forward to sharing all that and yeah, we'll keep you posted as we do that.
Okay, great. Thanks very much.
Thanks, George.
Speaker Change: The next question comes from the line of Albert Lowe with Prague, HALO. Your line is open.
Speaker Change: Thanks for taking my questions. I just had one that I was curious about. Do you have any theories on perhaps if MathMap's unique mechanism of action could potentially underlie this well-tolerated profile that you've seen so far, especially with respect to GI adverse events?
Speaker Change: Yeah, Chris, I'll let you take that or. If you want, maybe Chris.
Chris: It's a great question. You know, we've certainly seen a very favorable, not only from a neuropsych perspective, but a GI perspective.
Speaker Change: The tox profile has been excellent with a fairly robust number of phase 1 patients. And you know, it's no secret relative to small molecules, people or inhibitors, that
That in general.
Speaker Change: Antibodies are incredibly specific and it may relate to really being a difference not so much
Speaker Change: in the target, but in the modality antibody versus small molecule.
Speaker Change: And that may relate to sort of the PK relationship and ultimately specificity, but we don't have a really clear answer. We just have the data, and to your point, so far it looks excellent, and we're hoping to build on that.
Speaker Change: I don't know, Dr. O'Rourke or two may have a different opinion.
Speaker Change: Yeah, there can be different mechanisms by which you get GI intolerance, especially with the GLP-1 agents, and they tend to be related. For example, I mean, take GLP-1 as a framework here, both to delay gastric emptying, which is helpful, but also their actions on the area of eczema can be helpful. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah.
Thank you.
Thank you.
Speaker Change: by those individual peptides. The same thing can be true of small molecules when they are able to penetrate. So yeah, being an antibody might make a difference. I think I agree with Chris here. We don't completely understand where all these actions come from, but we're happy to see the data.
Speaker Change: Got it. All right. Thanks for the explanation and thanks again for taking my question.
Thank you very much.
The next question comes from the line of
Bye.
Speaker Change: Hi, this is Catherine. For John, question about kind of putting the preclinical data that you guys have shown in your mouse model relative to some of the other data that we've seen kind of from some of the other compounds. I know that NOVA was extended data from their
Speaker Change: I believe it's 347. And I'm just wondering, how does this, how do you, what is the way to kind of look at this data? I know that it's animal data, taking it with a grain of salt, but is there anything that can be gleaned as far as the potency of the relative molecules or,
Speaker Change: Kind of, if you could provide a little bit of color on on how to how to contextualize the clinical data we're seeing.
Speaker Change: Yeah, I can just kick it off here with just a little bit of differentiation and then and then turn it over to Chris on.
Speaker Change: Chris, maybe you want to elaborate just in terms of the comments of these different models and how they're not... Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah.
Speaker Change: how they're how they're all you know unique in order to
Speaker Change: look at data side-by-side, I think some experiments have certainly been overzealous in terms of the way that they've been...
All right.
Speaker Change: positioning just to drive weight loss rather than overall metabolic gain. So I want Chris to touch on that. But regarding on differentiation, the Massimab
is clearly distinguished in terms of a pharmacokinetic advantage.
Speaker Change: We're starting with all of the data that we've shared over this last week and even with the PK data that we've shared earlier.
Speaker Change: It's showing a higher, more sustained peripheral exposure with minimal brain exposure and it's reducing any of the CNS side effects. So that's the clearest differentiation against small molecules.
Speaker Change: What's been evident is that monolid event and other small molecules.
Speaker Change: have limitations of peripheral efficacy, and partly due to the small molecule mechanism that's competing with natural ligands.
Speaker Change: And that's reducing the ability to achieve, I think, the important therapeutic concentration that is necessary once you bring on more drugs.
you're only opening up the issue of more brain exposure.
Speaker Change: The Masmab is unique in terms of its allosteric binding, it's an antibody, it's allowing for a safer, higher dosing, and without any of this PKPD limitation that we're seeing with small molecules effectiveness.
Speaker Change: So I think that that's the clearest in terms of the differentiation, but yeah, Chris, why don't you kind of.
to elaborate on the preclinical studies a bit more.
Chris: Yeah, I think back in just a half second and looking at the potency directly, that question I think is a fair one and certainly a bias towards beta-restin-based.
Chris: Recruitment in terms of a measure of potency, but if you look at the more classic.
Chris: a single KNP-based readout, very similar potency, whether you're with a small molecule on LunaVent or on the NASA map. So, from a potency perspective, you know, very similar. You can look at our modeling data, and that's pretty clear there, in terms of our –
Speaker Change: I see 50, I see 90 values. I think where, you know, in terms of translating DIO studies, and I think what Tameek was alluding to, really the way to do this is in the same study if you want to have that sort of direct.
Speaker Change: Comparator in terms of understanding relative efficacy. It can be difficult like clinical trials do cross trial comparisons. It can be challenging. And what we typically do to kind of get a soft comparison, if you will, is to use a benchmark where you dose at the same.
concentration, same dosing schema, and you can use them necessarily.
Speaker Change: In this case, we did use some Agri-Tide at 10 nanomolar.
For those who can see that that.
Speaker Change: We had a 5 to 10% weight loss over our dosing range, and that's in line with other published research. I would argue more of a suboptimal dose of Smagotide, but if we look at that as a benchmark, we can see that our highest dose of
Speaker Change: the mastodon actually would significantly improve, had a significant improvement relative to that semaglutide dose. So that's...
Speaker Change: One way of looking at it and sort of comparing to other therapeutics, benchmarking on somagrapide.
Speaker Change: but in the end, we really need to look at that head-to-head comparison, which is something we're interested in doing. We haven't really given guidance on what that will be and when that will come out, but that is something that I think is of interest. But overall, we feel very comfortable with our efficacy profile, especially considering it's the initial study, and I think we
Speaker Change: We have a lot of room to improve the efficacy results that we're really digging into.
Some of the key
Speaker Change: parameters to understand in this model what is the exposure, what are the kinetics of that exposure, and how do we achieve that inhibition, you know, very
Speaker Change: as quick as possible. This is an IP dose that we use, but we're exploring other routes to really get that inhibition happening quickly and really drive that efficacy down so more room to optimize the model and drive even better weight loss.
Thank you so much.
Thank you.
Speaker Change: And our next question comes from the line of Kristen Plaska with Cantor Fitzgerald. Your line is open.
Hi, this is a question. And everyone hearing.
Yes, I am.
Speaker Change: Great. Hi, thank you so much for taking our questions. First question on neuropsychiatric adverse events. Can you walk us through specifically what is happening through central CB1 targeting that leads to these events? And how quickly did others observe this impact in trials? And what gives you the confidence that peripheral targeting will not lead to this?
Speaker Change: Yeah, I'll turn it over to Dr. Arora to take that question.
Speaker Change: Yeah, I'm sorry, but could you just clarify that question for me again? I heard part of what you said, but I'd just like to be clear about what you're asking.
Speaker Change: I guess the first part of the question is really just...
Speaker Change: Trying to get a better understanding of what is happening to the central CUN targeting that's leading to the adverse, the neuropsychiatric adverse events and how quickly, yeah.
Speaker Change: And the second part is just how quickly others have observed this impact in child.
Speaker Change: Yes, so what's happening is that, you know, there are CB1 receptors that are all through the CNS. So CB1 is actually a really important pathway, and I think you can gauge that from even how much peripheral distribution it has in key organs, but certainly in the CNS.
Speaker Change: And if you look across literature, there are a lot of reports of how TB1 as a pathway and the endocannabinoids, which are the ligands for this, and are natural physiological ligands are involved in things like the responses to stress.
Speaker Change: for example, and maintaining people's general mood balance and so on. So what happens is, when you have...
Speaker Change: widespread distribution of a ligand to these receptors in the CNS and it blocks it and you block the action of the endocannabinoid receptors, then people lose their ability to respond as well to stress.
Speaker Change: and to get the right responses to it and to deal with anxiety, for example. So by blocking these pathways, we are...
Speaker Change: including people who are already prone to getting problems like anxiety and depression.
Speaker Change: to be at a higher risk of developing these problems. And that's what we saw when we were looking at the monoband. For example, the monoband.
Speaker Change: it leaks widely into the CNS. In fact, the monoband was designed quite happily with that purpose, because I think this was not completely understood.
at that point, and we saw these effects.
Speaker Change: And I believe we see these effects relatively early. So in the kinds of clinical data that we're seeing right now, you should already be seeing them. And in the month-long phase 1D study that we saw, we should have seen a glimmer of a signal already in that, and we did not see it.
Speaker Change: you can see from monolunar bands that they are getting some signals very early on. So this is not something that's very delayed. To some extent, you'll see differences between studies in terms of which patients they exclude. So a lot of studies right now are being done at least early on.
Speaker Change: with participants who've never had any issues or are not known to be prone to depression or anxiety. But nevertheless, this is a physiological pathway. And if you block it in a blanket manner in the CNS, that's the risk that you engender.
Speaker Change: Great, thank you so much for that. And if I might just ask a 2nd question with the additional therapy, how are you thinking about commercial use with patients? Like, we start on both and then stay on the CB1 inhibitor for a longer term maintenance. How are you thinking about that?
Speaker Change: Actually, all options are open. I'm going to ask Puneet to take that.
Puneet Arora: Yeah, I think I, I mean, I would just stress that, you know, it's.
Speaker Change: For us, we want to be really clear. I guess we get this question a lot. Obviously, there's a lot of options that are open there, but
You know what's what's important
Speaker Change: In terms of our takeaway, in terms of that general question, is that we really want to continue to emphasize that our primary focus is to get a regulatory approval for namazumab and get it across the finish line. And that is as a monotherapy to demonstrate weight loss. That's the way the FDA is looking at it. That's the way anti-OPC medications.
Thank you.
you know, if renouncing OPC medications have been approved.
Speaker Change: Certainly, as a non-INCRED, there's a great opportunity for CB1 because it has this multimodal mechanism. There are going to be a lot of interesting approaches from the post-GLP-1 market in terms of combination and all of that from a regulatory pathway, just so there's no ambiguity for
Speaker Change: a general investor audience is making sure that the regulatory pathway here is as a monotherapy. But yeah, as Dr. Arora indicated, all of our options are open. Of course, scientifically we're exploring those and we'll continue to do that.
Thank you, that was super helpful.
Speaker Change: That concludes the question and answer session. Mr. Punit Dilan, our CEO, I turn the call back over to you.
Speaker Change: Yeah, I thank you everybody for participating in our first call and it's certainly a great moment for CB1 as a class.
Speaker Change: And for Sky developing this molecule, I think what we've indicated multiple times, it's really an opportunity to re-underwrite what's our understanding of CB1 inhibition, especially with the backdrop of
Speaker Change: new data that continues to come out in this class, and the master map and how it's really positioned to separate from the pack. And we're looking forward to executing on our development strategy and stay tuned for additional updates.
Speaker Change: Ladies and gentlemen, this concludes today's conference call. You may now disconnect.