SKYE

Good afternoon, and thank you for standing by. My name is Abby, and I will be your conference operator today. At this time, I would like to welcome everyone to the Skye Bioscience 2025 fourth quarter financial results and business update call.

Good afternoon.

All lines have been placed on mute.

My name is Abby.

All lines have been placed on mute to prevent any background noise.

I would like to welcome everyone.

There will be a question and answer session. If you would like to ask a question during that time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one again. Before we begin, please note that today's discussion includes forward-looking statements subject to risks and uncertainties described in Sky's SEC filings. Actual results may differ materially. Thank you. I would now like to turn the conference over to Punit Dhillon, Chief Executive Officer. You may begin.

Good afternoon, everyone. Thank you for joining us. I'll start with what we've accomplished since our Q3 update. CBeyond established a potential path for nimacimab alongside existing incretin therapies with additive weight loss, encouraging durability, and favorable tolerability. At the same time, we strengthened the plan around the signal with 52-week combination data and a clearer high dose rationale and as well as a feasible cutaneous or subcutaneous path for delivery. We've continued to work on the regulatory alignment and target product profile. In short, we've moved from a promising signal to a more coherent development case. That is the backdrop for the next question. What has objectively changed over the last two years? Since launching nimacimab into an obesity first indication, we've delivered a series of firsts for the CB1 field.

A first-in-class allosteric GPCR antibody designed for peripheral inhibition, the first human obesity program to evaluate a CB1 monoclonal antibody and create a direct readout for the mechanism without any neuropsychiatric events, and three, the best or the first to test that mechanism in combination with the GLP-1. We also built the translational infrastructure and the R&D infrastructure to support our clinical program with a human CB1 knock-in DIO workflow, coupled with the quantitative biodistribution that really frames the CNS risk in a way that small molecules historically could not. CBeyond has now given us three key learnings. One, the combination signal is clinically meaningful and consistent with the mechanism. At 26 weeks, nimacimab plus semaglutide delivered a clinically meaningful 3% improvement in weight loss over semaglutide alone, with no plateau observed, with statistically significant improvements in waist circumference and lean to fat mass ratio.

In the 52-week extension, the combination arm achieved 22.3% mean weight loss with no plateau observed. This is the first reported clinical CB1 + GLP-1 combination data set and one of a few dual target approaches that combine a peripherally targeted mechanism with a predominantly centrally driven incretin mimetic. Number two, nimacimab 200 mg demonstrated a favorable safety profile with placebo-like tolerability. Through 52 weeks, we also saw no nimacimab-associated neuropsychiatric signal, and in combination with semaglutide, we did not see an additive GI burden. The third point is that the monotherapy arm taught us a very solvable development variable, that the 200 mg weekly underexposed peripheral tissues.

That is why we're initiating a Part C expansion study of CBeyond to evaluate higher doses, and in parallel, enabling a practical higher exposure subcutaneous delivery with Halozyme's ENHANZE technology for our planned phase IIb. As a reminder, CB1 biology is clinically validated, but the first generation approach failed for a specific reason. Small molecules promoted central CB1 inhibition and carried unacceptable neuropsychiatric risk. Nimacimab is designed to improve energy metabolism by inhibiting CB1 in the periphery while minimizing brain exposure. With that overall framing, I'll turn it over to Chris Twitty, our Chief Scientific Officer, to walk through the dosing and exposure to efficacy rationale and how it informs our near-term clinical plan.

Thanks, Punit. I'll focus on one question. Why 200 mg weekly was a reasonable starting point for CBeyond, and what the translational data now tell us about the exposure required for robust efficacy. Before phase II, we had robust phase I SAD/MAD safety and PK data and sufficient drug product. The highest phase I dose, approximately equivalent to 200 mg weekly, was well tolerated and showed encouraging trends in MAFLD-related biomarkers. While phase I was not designed to show weight loss, it did provide a high-quality PK data set. Using that data set, we modeled phase II steady-state Ctrough levels and compared this exposure to the known IC90 concentration for nimacimab. We also modeled published phase I PK data for Novo Nordisk small molecule CB1 inhibitor, monlunabant, and compared its exposure to its IC90 concentration.

On this basis, we projected that 200 mg weekly nimacimab dose to achieve approximately seven times the IC90 concentration in the serum. It's comparable to the 20 mg once daily mid dose evaluated in Novo Nordisk phase II monlunabant study. That made the 200 mg nimacimab dose a reasonable starting dose for our CBeyond trial. Despite similar projected levels of serum CB1 inhibition, clinical outcomes diverged. Monlunabant at 20 mg daily achieved 6.3% weight loss at 16 weeks, whereas nimacimab at 200 mg weekly resulted in a more modest 1.5% reduction at 26 weeks. The key reason is distribution. Small molecules and antibodies can show similar serum target engagement, yet deliver very different tissue exposure. Since CBeyond started, we have generated biodistribution data in our human CB1 knock-in obese mice.

These data show nimacimab distributes to key peripheral tissues relevant to metabolic efficacy, including adipose tissue, liver, GI tract, and muscle, while central nervous system exposure remains minimal, consistent with the clinical safety profile. When we integrate DIO dose-response and biodistribution into a compartmental exposure model, we believe the conclusion is clear. At 200 mg weekly, peripheral tissue concentrations are below IC90, the level we require for full inhibition of CB1 signaling. This translational work indicates that a half log increase to approximately 600mgs allows for full tissue engagement to occur and allows for robust inhibition and productive metabolic activity, including meaningful changes in weight loss and associated mechanisms. Equally important, even with conservative assumptions for brain penetration, modeled central target engagement remains a fraction of IC90, both at 200mgs and 600mgs.

Maintaining that peripheral versus central separation is fundamental to nimacimab's therapeutic index. The takeaway is that CB1 monotherapy result at 200mgs is an exposure question, not a pathway question. The higher dose expansion is designed to rapidly confirm PK and safety at higher exposures before we finalize dose selection for phase IIb. Back to you, Punit.

Thanks, Chris. With that exposure framework, our near-term work is confirm safety and PK at higher doses, ensure a scalable subcutaneous path, and refine a phase IIb clinical trial that is both regulatory informed and clinically relevant. Our objective is to focus nimacimab where we believe an orthogonal mechanism can be most differentiated, particularly in patients already treated with GLP-1 who still need more weight loss. Tu, our chief operating officer will cover additional details and share updated durability data from our CBeyond program.

Thank you, Punit. As we heard today, we believe that nimacimab has the potential to fill an important void in the current and future anti-obesity medicine landscape. While our conviction is strong, we recognize that we must have the clinical data to back it up. With that context, our focus is straightforward. First, we announced today an expansion of the CBeyond study to include new intravenous cohorts to rapidly generate safety and PK data at higher exposures, while specifically monitoring for neuropsychiatric events and continued safety monitoring through our independent DMC. Participants will enroll into one of two cohorts, 400mgs of nimacimab or placebo IV once weekly, or 600 mg nimacimab or placebo IV once weekly. These groups will be randomized 3-to-1, with six participants receiving active drug and two receiving placebo for a total duration of 16 weeks.

For context, it is important to note that compared to subcutaneous doses, the 400 mg and 600 mg IV doses represent approximately 700 mg and 1,000 mg subcutaneous doses respectively. Based on our biodistribution work in mice and non-human primates, we have concluded that nimacimab's brain to serum ratio is approximately 0.01%. Based on these data, we expect central target engagement to remain well below levels associated with neuropsychiatric risks observed historically with small molecule CB1 antagonists. Even so, this expansion is designed to provide a clean safety data set with doses intended, we intend to take forward in future clinical trials. Second, in January, we announced a research and collaboration agreement with Halozyme to develop a co-formulation of nimacimab using their proprietary ENHANZE technology, a recombinant human PH20 enzyme.

This collaboration will allow us to evaluate high volume subcutaneous injections of nimacimab in our planned phase IIb study. In parallel, we are advancing development of a high concentration nimacimab formulation up to 200mgs per mL, and we see a longer-term opportunity for next generation nimacimab with extended half-life through Fc domain modifications. Taken together, these improvements could support the objective of reducing injection volume and further improve dose convenience for nimacimab.

Lastly, we received written feedback from the FDA in response to our Type C meeting request, including comments on our proposed phase IIb clinical trial design and our questions regarding potential registration path and on the data package relevant to potential combination therapy development for nimacimab with GLP-1s. While we are still completing our review of the written minutes, the feedback has helped sharpen how we are evaluating dose, duration, endpoints, and inclusion criteria for phase IIb. The agency's responses have provided insight into expectations for combination therapies. It also provides a clearer framework for how we think about potentially studying the nimacimab as a complementary add-on therapy alongside incretins, particularly in settings where durability and per-persistence may matter. We are incorporating that input as we refine the phase IIb protocol.

Before I pass it back to the team, I want to take the opportunity to share updated data from the CBeyond study. If you recall, we previously reported weight regain data from participants who did not participate in the extension study and instead went off therapy. In this analysis, we showed that participants on semaglutide alone saw 38.7% of weight regained over 13 weeks, which is in line with what we have previously seen in the STEP 1 extension study. However, participants on the combination of nimacimab plus semaglutide only regained 17.8% over that same period. These data are consistent with those we previously shared in our in vivo DIO studies, which we have shown durable weight loss for 20+ days after stopping nimacimab.

We believe the potential for nimacimab to drive more durable and tolerable weight loss for patients who may need to come off therapy because they go on holiday or lose access to therapy due to insurance limitations is a meaningful outcome and is a primary opportunity in the current anti-obesity medicine landscape. In the same follow-up population, we evaluated body composition during the 13-week off-therapy period, showing that while the main driver of weight regain in the combination cohort was lean mass gain, patients maintained their fat mass loss. These data suggest meaningful differences in body composition among patients who received nimacimab plus semaglutide, demonstrating that nimacimab's orthogonal mechanism of action has the potential to drive synergistic weight loss when combined with GLP-1s. I will leave you with one last comment relating to the target product profile of nimacimab.

As Skye has stated multiple times, nimacimab is being developed as complementary, not competitive, to GLP-1s. We think that positioning is important because first-line obesity therapy will likely remain both crowded and increasingly price-compressed. Against that backdrop, the more differentiated opportunity may be in the second-line add-on setting, particularly for GLP-1-experienced patients. In that setting, nimacimab is not simply another incretin nimacimab maintenance story. It is an add-on strategy intended to expand what the incretin base can achieve through an orthogonal mechanism. We believe an important point in this category is that the opportunity extends beyond first-line induction. As the GLP-1 treatment population grows, so does the number of patients who are unable to achieve their weight loss goal, plateau, become titration limited, or need another therapy to maintain their weight loss for a more durable period of time.

That is the setting where an orthogonal mechanism like nimacimab may have the clearest opportunity to matter if the data continues to support incremental efficacy without sacrificing tolerability. This distinction is in positioning matters in a market where first-line incretin pricing is compressing, competition is increasing, and where persistence and quality of weight loss continue to drive real-world outcomes. The blunt version of this is first-line incretin companies are trying to defend their installed base. Nimacimab is not wasting capital trying to dislodge that base. We are using that base as the entry point to address an unmet need. Back to you, Punit.

Sorry, I realized I was on mute. Thank you, Tu. Actually, before I close, we want to highlight a separate R&D update that speaks to longer-term platform value, and it's our first antibody peptide conjugate program. Chris is going to offer more insight into the latest data on that program.

Thanks, Punit. Using both in vitro and in vivo systems, our R&D team has identified four distinct mechanistic pillars through which nimacimab modulates metabolic pathways that drive weight loss. These pillars that include blunting obesity-related inflammation, improving glycemic control, modulating appetite-regulating hormones, and enhancing lipid metabolism, have been characterized in published research as well as our own preclinical models, giving us a high degree of confidence in this differentiated profile of this asset. While there is some overlap, nimacimab's mechanism of action are primarily orthogonal to those of incretins, providing a strong rationale for a combination approach. Preclinical studies pairing nimacimab with either tirzepatide or semaglutide demonstrated additive, and in some cases, synergistic weight loss. Our phase two clinical data reinforced this finding. Even at suboptimal dose of nimacimab, the combination with semaglutide produced greater weight loss than either agent alone.

The mechanistic, preclinical, and even clinical evidence all converge on the same conclusion. Combining CB1 inhibition with an incretin-based therapeutic has the potential to meaningfully raise the ceiling on safe, durable, and efficacious weight loss outcomes. Sky has taken that insight a step further. I'm pleased to share early data on our first-generation antibody peptide conjugate, or APC, a molecule designed to unite nimacimab's unique mechanism of action and extended half-life with the power of a GLP-1 receptor agonist in a single unimolecular therapeutic. We have run two studies to date and are sharing data from the most recent experiment today. Each study was designed to evaluate the individual components alongside the APC, with inclusion of controls to enable a clean interpretation of the results.

Both the nimacimab and the APC were dosed at 75 mg per kg every three days, with the APC additionally delivering 1 micromole per kg of a GLP-one receptor agonist peptide on the same three-day schedule. Control arms included vehicle, an active dose of semaglutide at 10 nanomolar per kg daily, and SBI-403, that's our GLP-1 receptor agonist peptide, engineered specifically for conjugation to the APC, delivered at 333 nanomolar per kg daily. While these studies capture a rich data set, including caloric intake, body composition, rebound kinetics, or distribution plus pharmacokinetics, today we are focused on sharing weight loss during the active treatment phase. Looking at vehicle-adjusted change in body weight from baseline, the nimacimab produced approximately 14% weight loss. Meaningful as a monotherapy, though somewhat less than semaglutide or the SBI-403, is that 21% and 23% respectively.

Consistent with our prior work and the orthogonal mechanisms we have outlined, both the mixed combination arm and the APC arm produced highly encouraging additive weight loss. Most importantly, the APC dosed every three days achieved efficacy equivalent to the daily combination regimen, a compelling proof of concept for this approach and a meaningful step forward for the platform. We are excited by what these early results represent. Our R&D team, working alongside leading experts in peptide chemistry and bioconjugation, continues to advance a growing pipeline of novel antibody-peptide conjugates. These molecules are grounded in well-validated incretin biology, including GLP-1, and extend into peptidomimetic therapeutics beyond the incretin class, incorporating both stable and releasable conjugate chemistries tailored to the biology of each target. I will now turn it back to Punit.

Thanks, Chris. This is a very exciting new product category for our pipeline and the cardiometabolic landscape. The takeaway is straightforward. We're seeing combination-like efficacy in a unimolecular construct with a potential to simplify dosing while preserving the mechanistic complementarity we've emphasized. That's appetite plus energy balance. And importantly, this isn't a one-off molecule. It is the first proof point for a bioconjugation-enabled antibody platform designed to attach one or more active agents to an antibody scaffold, and is supporting multi-mechanism metabolic combinations beyond CV one alone. We overall view this as the first proof point for the platform, and we intend to use nimacimab as the initial scaffold for this work, leveraging a clinically characterized GPCR antibody backbone while preserving the program's central sparing intent.

The platform is mechanism-flexible, and we're applying a discipline selection framework prioritizing candidates with clear pharmacology, developability, and translational readouts before advancing any conjugate into formal preclinical development. All right, on to the business execution side and capital discipline side. We took steps to align our cost structure with the work that matters the most over this last period. As we discussed in our 10-K, we ended 2025 with $25.7 million in cash equivalents, and short-term investments, and we've been managing our operating plan to extend our runway through Q4 2026, including now with the new clinical data set that we expect with the CBeyond expansion study and the higher dose cohorts that we went over today. Let me close on two slides, the key takeaways from today and the anticipated catalysts through 2026. First, we initiated the CBeyond expansion study.

This study is designed to rapidly generate safety and PK data at higher exposures that we intend to take forward in future clinical studies. Second is the off-treatment follow-up suggests a differentiated mechanism of weight regain. Body composition data show that fat mass loss was maintained after a 13-week off treatment and is supporting our hypothesis that nimacimab is differentiated and orthogonal to GLP-1s and is well-suited for combination treatment. Third, we delivered proof of principle for our APC program, a proprietary unimolecular dual-mechanism biologic designed to simplify dosing. Fourth, we are designing a very deliberate Phase IIb study, carefully selecting our TPP and development path in combination with an incretin. Our product is not trying to out-incretin the incretin field, especially in a first-line indication.

The winning lane for nimacimab is an add-on for the GLP-1 experienced patient who has already proven willingness to be treated and has reached or is approaching maximum incretin exposure and still has a residual problem of plateau, tolerability, durability, body composition quality, or even economics. Then looking ahead, here are the anticipated catalysts throughout 2026. In Q1, we reported interim CBeyond extension data. We received the FDA Type C meeting minutes and initiated the CBeyond expansion study, the Part C that we're referring to. We also expect to complete the ENHANZE compatibility and in-use study. In Q2, we expect cohort two to initiate enrollment and for enrollment to complete for both cohort one and cohort two. We also plan to share additional preclinical bioconjugation data and complete the feasibility work on our high concentration formulation program.

In Q4, we expect top-line clinical data from the expansion study alongside our planned phase IIb final study design and overall execution readiness. That includes the final protocol and the operational plan we aim to complete once dose selection, the regulatory input, and the drug product work are sufficiently mature. That cadence is really designed to set up a clear dose selection decision and a practical subcutaneous path before we commit to the phase IIb. That's the plan. It does not require reproving the pathway, and we're not trying to displace what first-line incretins have already established. Our objective is to determine whether peripheral CB1 inhibition can create meaningful value after incretin initiation.

In 2026, our goal is to answer this very important value-driving question, what exposure and duration of peripheral CB1 engagement is required to produce clinically meaningful efficacy, and can we achieve that reliably with an acceptable safety margin? The expansion study and the related endpoints are designed to set up a clear dose selection decision and a practical subcutaneous path before we move into the phase IIb trial. All right, that's it for today, and thank you so much, and we'll now open up the call for analyst questions.

Thank you. We'll now begin the question and answer session. If you have dialed in and would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one a second time. If you are called upon to ask your question and are listening via speakerphone on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. Again, it is star one to ask a question. Our first question comes from the line of Jay Olson with Oppenheimer. Your line is open.

Oh, hey. Congrats on the progress, and thanks for taking our questions. Can you talk about your plans to share data from the higher dose cohorts above 200mgs? Also, can you just talk about the status of your formulation work using the Halozyme technology and if you plan to use a subcutaneous self-administered pen in future studies? Also, do you need to have that formulation available at higher doses before proceeding to phase IIb? Thank you.

All right, Jay. Thanks so much for joining and the questions. I'll take the first part. As you heard today, we are expanding into the Part C expansion study, so that is the next important clinical data that we expect from the CBeyond study. Our objective here is that the higher exposure produces, you know, a clear PK step-up. It preserves the CNS sparing safety profile that we've seen and shows directionally that the monotherapy activity is consistent with that exposure response that would materially change how that overall program, you know, shows activity relative to what we saw in the earlier 200 mg dose.

As we've gone over today, there's a very clear rationale of increasing that dose from what was in the 200 mg, which didn't get to the right peripheral exposure that we expected. So that's what we would expect to have before the end of the year. We're trying to generate that data as fast as possible, and we should, you know, everyone should expect that update from us as soon as that data is available. Right now we're guiding Q4 of 2026. With regards to the formulation work, I'm gonna turn that over to Tu, and he can give you some updates regarding that.

Thanks, Punit. Hey, Jay. Thanks for the question. I think you were asking just about the status of our co-formulation work with ENHANZE. Yeah, that work is ongoing. We do expect it to be ready in time for the phase IIb study. We have disclosed in the past that the use of that co-formulation will be done through what was referred to as a mix-and-deliver approach, meaning that the two components will actually be mixed at the site and subcutaneously delivered at the site by either the patient or the participant or a nurse or a coordinator that's administering the drug. We have As a part of the Type C meeting, we did submit some questions around the co-formulation work and what the expectations are with the FDA, and they have given us guidance around that. We are working very closely with Halozyme as well as a part of the collaboration. They have obviously a lot of experience with this process, so we're quite confident, you know, we'll be able to meet those requirements laid out by the FDA to be able to not just use the product in this mix and deliver approach for the phase IIb study, but also be prepared to use it in a truly co-formulated formulation that will be likely delivered as a prefilled syringe first or something in that format.

I think the second part of your question is whether or not the drug will be delivered in a, auto-injector type format as well.

Yes, that is obviously the intention, from a commercial standpoint. All of that work will need to be completed and done and prepared in advance of any phase III study.

Jay, to answer your question on the timeline side of what Tu just answered, we're moving that work in parallel with the execution of the phase IIb, but we would have the auto-injector component for the phase III trial.

Great. Thanks for taking all the questions, and congrats again on the progress.

Thank you.

Our next question comes from the line of Ted Tenthoff with Piper Sandler. Your line is open.

Great. Thank you very much for all of the updates, and great to see the progress. I'm wondering, when it comes to the expansion, do you think you're going high enough? Is there a reason to explore maybe even higher doses of nimacimab based on the low brain penetration that we saw, and likely safe CNS, or are you worried about going beyond the doses that you laid out? Thank you.

Thanks, Ted. Great to have you on the call. I'll let Chris answer that from a dosing rationale. I can just set it up here. In terms of what we've seen so far, what we expect to see is a clean exposure separation with these doses that we've selected. The exposure levels that we have outlined today in the call are consistent with what we've modeled in terms of peripheral target engagement, and that's what we would like to see in terms of that specific zone needed for the phase IIb selection. We believe that that's the bar. Of course, you know, we are continuing to evaluate higher dosing, but at the moment that we feel that these two doses that have been selected are sufficient.

Chris, do you wanna elaborate?

I think you covered it well. I might just add a little bit of color. There's a couple pieces that we've really delved into, and one is the actual CBeyond data itself. We have pretty robust preliminary models that are clearly demonstrating a dose response, and those are getting finalized, and we feel very confident that that data set alone speaks to increased dosing, allowing for a more efficacious response. As I covered in the report, in the earnings call itself, we've looked carefully at a series of both non-human primate, the published human data, as well as our own DIO data, and we're able to carefully translate that exposure.

Critically, as Punit was saying, the exposure in the peripheral tissues really seems to be the fundamental driver of achieving that inhibition. We know much better now, the learnings from our study, coupled with the biodistribution data, tells us that we can get to that meaningful inhibition, really drive response. That's very clear from our DIO studies, and we see evidence of that in the non-human primate studies as well. Ultimately, addressing the last piece of your question, very comfortable with that, limited exposure in the CNS. That therapeutic index is really there. We feel we can get, you know, really beyond what, as you noted, beyond what we're potentially looking at, and still have that very comfortable, safety kind of built in, to this approach.

I think it's a great starting point. We're gonna see a nice dose response, and we should be able to maintain that safety even if we wanted to go up higher. Hopefully that adds a bit more context.

That's great. That's really, really helpful color. I appreciate it. A quick question on the new program. What do you sort of see as the profile for that? Is that the goal to improve in safety, efficacy, both? I mean, it seems to me like, the safety is pretty clear at this point. What really is the goal, and how do you anticipate developing that space?

Hey, Ted. Yeah, I'm sure Chris is gonna love to go into a lot of detail on that, so we're gonna save a little bit for later on in the year because we will have opportunities to talk a lot more about that. I'll just say that we're really treating it as long-term optionality. It's not a lead kind of near-term value driver. Obviously, we're really betting on how we're moving forward with our TPP on nimacimab as the near term. As we've talked to you before, nimacimab remains that core value driver. The APC data today that we showed is really interesting scaffold that supports a much broader combination platform over time.

We've alluded to this in the past, and now to finally start seeing data, repeated, coming out of the R&D group, it's been really exciting and that adds to a significant upside. Again, not to distract away from our near-term, clinical data points. Chris, do you wanna give any additional color to that?

No, you know, I would just note that, you know, from a scientific perspective, it's just it's incredibly exciting. You know, a bit like, just there's so many directions we can go, and there's clearly benefits just from a, you know. Tu could probably comment better on this in terms of, you know, the strategic angle in terms of its clinical development, having this unimolecular asset, not only from an IP perspective, but just, you know, thinking about leveraging our favorable half-life and all the safety that comes with that.

You know, getting engagement with this GLP-1 receptor agonist in the periphery and seeing pretty comparable weight loss to something that is, you know, a true combination that can, you know. At face value, engage in the centers of the brain and, you know, beyond that blood-brain barrier, yet we're able to achieve that with a three-day dosing as opposed to the daily dosing with semaglutide or our own SBI 403. It's really interesting. It really opens your eyes to what's possible with this platform. We're looking at, as I said, not just GLP-1 receptor agonists or not even incretins, looking even beyond that. Just, you know, a huge sort of ability to look at all kinds of metabolic modulators. The science is just super exciting for us.

Yeah, we'll have more. We'll have updates later on in the year, but it's, yeah, it's incredibly exciting for our R&D group.

Very cool. Thanks, guys.

Our next question comes from the line of Michael DiFiore with Evercore ISI. Your line is open.

Hi, guys. Thanks so much for taking my question. Two questions from me. The first one is, as we think about the monotherapy versus combination therapy options, I guess one way to interpret it is that different peripheral compartments may contribute differently to efficacy. That said, how do you think about which peripheral tissues are the most important for nimacimab's clinical effect? And does that differ, or might that differ between monotherapy and combination therapy? I have a follow-up.

Hey, thanks for joining, Michael. I'll let Chris maybe take those questions.

Yeah. That's a great question. Yes. The short answer is yes. I think there's likely to be sort of a different profile in terms of the metabolic tissue that are most relevant to either a mono or a combo play. If we're just focused on nimacimab, either monotherapy or even in combination, we really do think the adipose tissue is really critical in that, one, we think the lipid metabolism, although we certainly see this in the liver, so those two tissues kind of are both very important. Clearly, adipose tissue is a big player there in the productive changes in lipid metabolism. Also, we think that controlling appetite is really important, and that is really maintaining and reestablishing leptin signaling. We know that our that nimacimab does a great job of bringing that back into play, controlling hyperleptinemia. In a lot of our models, we see that clearly. Adipose tissue is one of the key ones. We see huge improvements in glycemic improvement, control of glucose, and that sort of. You know, whether you're pre-diabetic or even diabetic, that pathway is critical. When we think about the monotherapy, those are key peripheral tissues that are, you know, important, critical. Now, if we think about in the context of a combination, while still, you know, important, you know, we think maybe that there's a sort of a leverage point around the complementary.

Maybe control of the hormone-regulating peptides, so these hormones that can modulate appetite, you know, maybe aren't as critical in the combination context because we know the incretins do a great job of that. You know? Those may not be as relevant. Engagement in the GI tract, which we know nimacimab can do, maybe not quite as well as the incretins. That might not be the key engagement, but maybe more around ENHANZE energy expenditure and productive changes in body compositions, which we know are quite important, particularly in the context of sarcopenic obesity, et cetera. Again, maybe thinking about more the engagement in the adipose and in the liver compartment, those tissues might be a bit more relevant in terms of the combination with nimacimab, if that's helpful.

Those would be some of the thoughts I would have to that question, that first part of your question.

Great. Very helpful, Chris. Thank you. My final question is just more of a, I guess, a housekeeping query on why you're choosing to use IV in this Part C phase of the study instead of just using ENHANZE that's reconstituted at the site. Is it just simply too early to use ENHANZE at this point? I would have thought that Part C would have just employed the on-site reconstitution with ENHANZE.

Yeah. Thanks, Michael. Yeah, it's a good, very good observation. You're right. IV provides us the cleanest and fastest way to generate that high exposure PK and safety information. We're not presenting IV as the end-state product, obviously. We're just using IV right now to get that program data as fast as possible and building a practical and subcutaneous path with ENHANZE for the Phase IIb. We wouldn't have been able to start the expansion study as fast as we did if we had to rely only on ENHANZE instead. That'll be ready for Phase IIb.

I see. Thanks again.

Our next question comes from the line of Andy Hsieh with William Blair. Your line is open.

Thanks for taking our question. Just two quick ones for the expansion study, Part C. One is, I see that you kind of mentioned that 400 mg IV is equivalent to 600 or 700 mg subcutaneous.

I'm just curious about what is that based on? Was there any sort of, you know, PK modeling that supports that? And just to clarify, Tu, you said 700, but then the presentations are 600. So I just wanna make sure that, you know, which number was correct. And then the second part is, you know, since now it's transitioned to an IV formulation, do you have a good sense of how long the infusion time will be? And then just the logistical things regarding, you know, how long the patients will be on the trial site visits, all that kind of things for the Part C part of the expansion study. Thank you.

Tu, I'll put the slide up for you, but you wanna take that?

Yeah. That's a good catch, Andy. It is closer to 700mgs, you're right, not 600mgs. We did conduct a bioavailability study in the past. This was an older study that was conducted to evaluate IV dosing versus sub-Q dosing. In that study, it was determined that the sub-Q dose has relative bioavailability compared to the IV of about 56%. That's what we base the sort of conversion factor on. In terms of the actual operations of the IV dose, how long it's gonna take and the sort of management of the patients at the clinical trial, we expect the IV dose to be about an hour in terms of the infusion time.

The first few doses, we'll be asking patients to stay on site a little bit longer to continue to evaluate safety. After the first few doses, patients, you know, will generally be pretty much done within a couple hours after receiving the dose and doing some of the post-dose assessments.

I see.

Yeah.

Cool. Thank you so much.

Our final question comes from the line of Albert Lowe with Craig-Hallum. Your line is open.

Hi. What do you see as the bar for success from the expanded study as far as the dose to be taken forward for monotherapy?

Yeah. Thanks, Albert. Right now, kinda our current posture is to be disciplined that the Part C is really primarily a PK and safety study. The expectation here isn't an efficacy readout, but the expectation is whether the monotherapy directionality appears at the higher exposure in a way that validates the model that we just went over today. Every modest emerging kind of signal really matters for us on the monotherapy activity. It's obviously accompanied by this work that we put into understanding what we've learned from the 200 mg dose, as well as the DIO work and biodistribution work that Chris went over today.

It's expected that the PK and safety is gonna be in line with that behavior. At the end of the day, like we're expecting that it really helps finalize and reshape our Phase IIb dosing with that confidence.

Do you still plan to share the full extension data with the 300 mg monotherapy patients?

Yeah. At the moment, based on the dosing rationale that we presented today, we wouldn't anchor any expectations on efficacy signal from the 300 mg dose. It's the likely value for us and what we are planning to review with that data once it's available is that it's gonna improve our sensitivity of the PK model, sharpens our exposure response curve, and it's definitely not, you know, to define the commercial intent of our efficacy zone that we're expecting with these doses that we plan on moving into with Phase IIb. We will, once that data is available, it'll inform our PK and that'll be shared as a part of our PK modeling.

Okay. Thanks for taking the question.

Ladies and gentlemen, thank you for standing by. My name is Jordan, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Skye Bioscience, Inc. Third Quarter 2025 financial results and business update call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, 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, including statements of Skye Bioscience, Inc.'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 concerning these and other matters. I'll now turn the call over to Kaitlyn Arsenault, Skye's CFO.

Thanks, Bernie. After the market closed today, we issued a release and filed Skye Bioscience, Inc.'s Form 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 the third quarter ended September 30, 2025. We ended the third quarter 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 2a study for Nimazumab, certain manufacturing, and preparatory clinical activities needed to initiate the next study. In addition, our runway continues to include a modest discovery R&D budget, the dose concentration, and process intensification work required to support our expected TPP and scale and support later-stage studies for Nimazumab. R&D expenses for the three months ended September 30, 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 Nolasimab, 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 September 30, 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. Our net loss for the three months ended September 30, 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, Kaitlyn. Today and during this quarter and the subsequent quarters, we're really focused on what matters most: turning the answers from our CBEYOND study into the logical next steps. We're going to walk you through what we've learned from our Phase 2a CBEYOND 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 Nimazumab opportunity. From the start, we said that the next step for Nimazumab would be to determine an optimal dose for Nimazumab. 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. Most importantly, it gave us evidence in the biological activity of Nimazumab and the clarity on the PK to move forward confidently on our combination development pathway while simultaneously planning to further understand Nimazumab's benefit in a monotherapy setting. On today's call, we'll walk you through the progress that we've made over the past ninety 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 CBEYOND study, how those insights are shaping the potential for future next studies. Number two is CMC and product economics, how we're designing Nimazumab 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, or sorry, the Nimazumab or peripheral CB1 antibody is differentiated, and it's a durable mechanism. 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. 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 ninety days. 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. One was to deliver top-line data in Q4 from CBEYOND. Two was to use that dataset to inform the dose-ranging strategy for the next clinical phase, 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. At Obesity Week last week, Dr. Louis Aroni presented the late-breaking results from CBEYOND, and the findings are both clear and very encouraging. They showed synergistic efficacy with Nimazumab plus semaglutide and achieved an additional approximately 3% weight loss at twenty-six weeks compared with semaglutide alone. This is with a p-value of 0.0372 on a modified intent-to-treat population. That's nearly a 30% improvement with this combination with no observed plateau at twenty-six weeks. We also showed quality of weight loss that the combination of Nimazumab 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 3.17 centimeters with a p-value of 0.0492. We also showed durability that in the twelve-week post-treatment follow-up, Nimazumab plus semaglutide blunted weight regain with only an 18% regain or 2.3 kilograms versus 50% regain or 4.7 kilograms on the semaglutide alone arm. 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. And so this overall data really confirms that Nimazumab 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 Nimazumab true efficacy window and fully capture the therapeutic potential of a peripheral CB1 antibody. Additionally, in September, we completed enrollment of the twenty-six-week extension study. A total of forty-three patients were enrolled with nineteen and twenty-four patients in the combination and monotherapy cohorts, respectively. Retention in the extension study has been very strong. And the data from the twenty-six-week extension study is expected in late Q1 2026, and we'll provide information on the potential for full treatment duration of fifty-two weeks followed by a twelve-week follow-up period. This long-term follow-up from the extension will be a new inflection point with a richer dataset and a more complete understanding of Nimazumab's clinical potential. 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 two hundred milligrams to three hundred milligrams weekly, but our current plan is to even go higher. Analysis of our preliminary PKPD model showed that patients achieving higher systemic levels of Nimazumab corresponded with greater weight loss. And that aligns with the range where we expect to show clinically significant results. Our PKPD model based on the clinical data and the preclinical dose-ranging really gives us confidence that a higher dose of Nimazumab 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 2 focused combination study. With understanding a better characterization of the monotherapy dose, will really keep the development of Nimazumab on track and 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. 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. 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. This isn't simply, like, 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, Nimazumab has shown no additive GI burden at the two hundred 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. Equally important, we're continuing to evaluate and manage execute on measures that can significantly impact our cost of goods. This process includes optimization of the upstream and downstream manufacturing steps for Nimazumab and scaling up into high fermentation volumes, and we're continuing to evaluate multiple delivery devices, including autoinjectors, 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. Ultimately designing a product that is potentially not only clinically differentiated but commercially durable and real-world affordability. From a manufacturability standpoint, next, we'll move into R&D. So beneath all of the clinical data sits an increasingly powerful scientific base. The preclinical and translational work continue to show that Nimazumab reduces fat mass while preserving lean mass, improves insulin sensitivity and glucose control, lowers leptin, increases GLP-1, reduces hepatic steatosis and inflammatory markers, and maintains weight loss durability after treatment stops. And 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. And collectively, these results reinforce why Nimazumab 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 Nimazumab program has been about discipline and delivery, and that remains true today. 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 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. 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. With our Phase 2a data, we have now provided an important initial demonstration of Nimazumab'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 Nimazumab. 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. Over the next ninety 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 Nimazumab's potential using insights from our PKPD modeling and the ongoing extension study. We're finalizing the next Phase 2 design. We're concentrating on combination and also in the maintenance indications where the data already point towards a really strong direction. And we're continuing to advance the formulation and manufacturing work so that Nimazumab 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 said what we would do, and we've delivered on the data, 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 translating all of this into momentum and the momentum into value. 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 sell-side analysts. Operator, over to you.

Thank you. As a reminder, if you'd like to ask a question, press 1 on your telephone keypad. Our first question comes from the line of Michael D'Afurrier from Evercore ISI. Your line is live.

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 late weight loss and exposure? Recalling at the time that the data were revealed, only had PK exposure versus weight loss up to sixteen weeks. That's my first question. My second question is regarding the twenty-six-week extension. Simply, are there enough patients? Forty-three patients seem sort of low, and do you have enough patients to draw any statistically significant insights? Thank you.

Hey, Michael. Thanks for dialing in and the questions. So I'll take the first question and kind of hand it over to Chris because he can further elaborate. But as you indicated there, obviously, we showed a really strong validation of the mechanism in the combo efficacy. Monotherapy dosing, I think, has been evident in terms of issue with dose, not the biology. The exposure response really has demonstrated that the observed concentrations at the two hundred milligram dose didn't achieve the efficacy that we would expect because they were patients were underdosed. But Chris, yeah, can further elaborate in terms of what we've seen now based on the twenty-six-week dataset as well as any he wants to point to from the preclinical data.

Thanks, Punit. Yeah. So to that point, we have, in fact, looked at a more complete PK dataset. I would just note that the final PKPD analysis is still underway, likely won't be available probably for another few more weeks to a month. But we do have a 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 residuals, 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, a very believable, credible slope that demonstrates this response related to exposure. We feel very comfortable that the PK data is holding. We'll again have the final PKPD 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. We've done some important biodistribution studies looking at where are 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. So both those pieces are really supporting this concept of higher dosing in the clinic to see better weight loss.

Michael, would you mind just repeating your second question? Or did we answer it?

No. So my second question is regarding the twenty-six-week extension data. It just seems that only forty-three patients are enrolled, it seems kind of on the low side. And I was wondering if that's enough patients to draw any statistically significant insights for when the trial wraps up.

Yeah. So the good news on the extension is that enrollment has been well, obviously, that was good. That we saw a good interest in the study, and then retention has continued to stay really strong. You know, 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 twenty-six-week time point, the first twenty-week time point in the combination, we did see a really strong difference. And then the slope wasn't plateauing. It continued at So we hope that we're going to continue to see that separation between semaglutide alone. On the monotherapy, you know, as we've indicated, we believe that there's still room to go higher in terms of dose. 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 in the first twenty-six weeks.

Great. Thanks so much.

Your next question comes from the line of Andy Isaiah from William Blair. Your line is live.

Great. Thanks for taking our questions. We have two. One is more on the regulatory side. So we're curious, you know, 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, you know, based on your regulatory discussions with the agency. So 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. So 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.

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.

Yeah. Andy, to address your first question, yes. If we were to do maintenance therapy with Nimazumab as a monotherapy, that would require monotherapy approval. Although, you know, if that is the strongest suit for the drug, then the approval could be as maintenance as well. And, you know, 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. 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. So I'm sorry. What was your second question?

It's just on the regain piece. Yeah. Dr. Arora, I think Oh, yeah.

So, you know, 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 had some. And then tirzepatide did some randomized withdrawals. In one year, the total weight regain is about it does tend to be somewhat accelerated in the first half because the weight begins faster initially and then tends to plateau a little. We do see a somewhat faster regain in this study. We don't know why. It's, you know, we don't know particular characteristics that we're seeing in the demographics. The study of, frankly, the same as you see in most other studies. So we don't know why these patients regain their weight this quickly, but they did. And, you know, being a randomized trial, we figure that both the cohorts are effectively similar.

If I could just elaborate on one thing, Andy. So you look. The durability data that we've showed last week with the only eighteen percent regain versus fifty percent 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. And I noticed, you know, from coming from Obesity Week, there's been a growing emphasis of the incretins or companies that have incretin pipelines focusing on the maintenance market as well. We believe that it's 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 Nimazumab to aggressively pursue a maintenance indication, which we, you know, conformally kind of look at once we finalize our dosing strategy. 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 incretin after induction of incretin is completed. And, no twos investigated that from a commercial standpoint, from the survey that we've done. And that's been confirmed. Two, do you want to just expand on that?

Yeah. No. I don't I think you 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 Skye Bioscience, Inc., but from investigators and clinicians as well as obviously, you know, other companies. And then as Punit said, you know, right now, there's not a lot of options other than another GLP-1 to go on. And so physicians are generally either reluctant or, in fact, I said at least the ones I've spoken to, generally, I should put them on something else other than a GLP-1. Like a phentermine or something like that. That makes more sense because it's a different mechanism of action. Even though it 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 Nimazumab. That we think we can where we think we can win.

Oh, great. Thank you so much. Yep.

Your next question comes from the line of Ananda Ghosh from H.C. Wainwright. Your line is live.

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

Yeah. I think it's a great thanks, Ananda. I'll turn it over to Puneet Arora. He can take both those questions.

Yes. Ananda, thanks for that question. Now you've seen that a lot of the effective weight loss medications that we've cluster is around the 22% range. In fact, if you, you know, if you speak to most basic physicians, they'll tell you that a lot of patients don't even need, 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% and then you start seeing the other combinations adding up to another 6% like you see with tirzepatide, the differential that we would hope for. We're already seeing in our protocol set here of 14 and 14 something percent weight loss. At twenty-six weeks, which is three and a half percent more than semaglutide alone. So about a 35% increase. And we think that when we do a full 52, actually, a sixty-eight-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 thirty extra. So we had planned this at Obesity Week as well. What they're showing is that if you just look at the crude numbers, semaglutide alone has about 72% fat loss and 28% lean mass. And when you add Nimazumab to it, this actually becomes 76% fat loss and only 24% lean fat loss. So there 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 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%. And that is what is showing that is the effect that we are seeing in the Lean2FatMask ratios and why the body composition is improving. So all of the additional weight loss that we've seen is almost all fat mass loss. Our secondary endpoint, to be specific, was linked to fat mass ratio. And that ratio should increase with weight loss. And the more the increase, the better your body composition is. And in our trial, semaglutide increased that lean to fat mass by 0.13. 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.

Got it. Thanks. That was very helpful.

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

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 Nimazumab 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. So how are you weighing the pros and cons of induction versus maintenance? And then I had a second question, if I could.

Yeah. Thanks, Jay. Thanks for joining the call today. That's a key question. We are certainly focused on the induction side, you know, when we're seeing this improvement that we've showed over the course of this early dataset with no observed plateau at twenty-six weeks. It really demonstrates a synergistic activity. And it's been very encouraging. We're looking forward to seeing what the fifty-two-week data reveals, but the current focus for the Phase 2b is on evaluating the right and optimal dose in combination with sema. 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 that dosing higher can lead to a better deeper weight loss in sema because of the data that we've seen so far, which tirzepatide and SEMA in combination. Chris, do you want to discuss that?

Sure. Yeah. To that point, we directly ask that question in light of our recent clinical data. It's important to understand as we get better exposure moving from what we've modeled to be something very similar to our CVRN lumasiran 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. So, 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. So it seems to really unlock the combo potential as well and maybe even beyond what we said with 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.

And I think it's just important to 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. So although the data is early in the twenty-six-week data, it is very, very encouraging. When you do stack it up across these other combinations, it's really interesting to see how deep that response is initially. So like, you know, we're all excited to see what how that reveals in a longer fifty-two-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. Hey, Jay. Jay, this is two. I just wanted 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 induction of weight loss. And if, you know, in the real world for patients, you know, 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. You know, what our data suggests is that that's not going to be a big as 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 by like, we're seeing in that, like, 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. So I think that's really meaningful. I think a lot of because 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. And what that really, really means in the real world for patients.

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 your top-line, CBEYOND Phase 2a data and also any feedback you may have received at Obesity Week?

Yeah. I think Chris is, or sorry. Two, probably versed and two and Dr. Arora, you guys can take those questions.

Yeah. Thanks for the question, Jay. I'll say that 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 at sort of the dose-ranging 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 with that optimal dose. 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 in one specific physician actually brought that up and said, this is really cool data. And if this means that a patient can, you know, go on a dosing holiday and not have to worry about gaining their weight back, then this can be really meaningful for their practice. So, yeah, I think ultimately, positive. They 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.

And I think that, you know, some of the leading physicians out there had experience with CB1 before. So that's where they've had interest in for a long time. And the, you know, psychiatric events have been a source of trouble. They're really I think they're really enthusiastic about the idea that you can get these if and get them in a safe and tolerable manner. So there's a rekindled interest now that we are showing with this biological activity, and you can do that with an antibody without crossing the blood-brain barrier and getting these neuropsychiatric effects.

Yeah. That's great that you emphasized 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 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. 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.

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

Thanks, Jay.

Your next question comes from the line of John Wolleben from Citizens. Your line is live.

Hi. This is Catherine on for John. I got kind of a quick question about what you expect from the monotherapy arm. In the twenty-sixth-week update. What do you want to see in order to give you confidence in kind of choosing the password? I know that we talk a lot about the comm arm because for obvious reasons. I was wondering about that.

Hey, Catherine. Thanks for joining the call and stepping in for John. We, yeah. So from the next twenty-six-week data, the differences here is that we've added increased the dose from two hundred milligrams to three hundred milligrams. What we have emphasized, obviously, to our clinical sites is 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. 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, so 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, you know, based on the twenty-six-week data. We're obviously encouraged by the PKPD modeling that we've done at higher doses that we should be able to reach the five percent or higher bar but we need to see that data, and we want to make sure that we have improvement in terms of our sensitivity around the PKPD understanding.

Okay. So much. Definitely. That's just to clarify, we did use a slightly higher dose in the extent but as Punit said, primarily to help us help us refine our PK models. 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.

And I know that in the past, said about a thousand you're going to go up to a thousand milligrams. Have you changed your thinking at all on that on the target for the higher dose?

Yeah. We're still working through that, Catherine. For monotherapy, we expect basically to unlock efficacy at higher doses. So we've, you know, like we said, it's in line with our exposure in response modeling, and it hasn't necessarily ruled out that the two hundred and three hundred are effective doses as well. I think we had some lack of consistency in terms of what we saw in the face in the first twenty-six weeks and in our slides that we shared during the top-line data review. I think we showed some indication of what the optimal dosing would reveal and those patients that had increased exposure response, they tended to do really well. Versus the patients that were suboptimally dosed or had lower exposure response. So I think what we need to see is if that is kind of course-correcting in 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 and we expect that to be over five percent at twenty-six weeks. At these higher doses that we want to evaluate. Thank you.

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

Great. Thank you so much for taking that 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 CBEYOND 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 the substantially higher level? Thanks so much for answering the question.

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. So we, you know, 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. So we don't have, you know, the data yet with at higher doses over this longer period of time, whether that's a change in terms of GI tolerability. But we feel at this point, based on the data that we've seen in the Phase 2 that there wasn't any concerns to be able to go higher. But, you know, across the class, it seems to be a little bit different. Some small molecules have had only about 30% GI issues, and then the 60% GI issues. And we don't know if that's linked to CB1 yet or if it's, you know, or it's, like, if it's molecule specific. At the moment, though, there still seems to be substantial room for us to be able to evaluate that. And mechanistically, it's not, you know, it's not the same. It doesn't the mechanism is different than what the GLP-1 drugs are doing. So we feel that we shouldn't have any exacerbated GI burden. But, Dr. Arora, you might want to take that further.

Yeah. You know, it's been my sense that even with the data, if you go back to rimonabant, that even though they showed 30% GI effects, there was a certain placebo effect as well that's worth comparing to, which seems to suggest that the GI effects that you see with the CB1 pathway are not that significant. And, of course, with Nimazumab, 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. Some with the GLP-1s, which is where, you know, all the attention comes from, I believe that a lot of the GI effects tend to come because of the central action on the area 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 and stimulating receptors that is causing that. And it's very possible that the CB1 mechanism 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, Nimazumab. We will test this as Punit said, with higher doses, but 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. And in the next study, how long do you think you'd be able to dose? Thanks so much for taking my questions.

Thanks, Ted. So in a yeah.

Oh, go ahead. Go ahead, Punit.

Yeah. Go ahead. So in a Phase 2 study, I mean, we would we wanted those people all the way out to a year of fifty-two weeks, but 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, twenty-six weeks where, you know, you can get a substantial indication of how individual doses are working and get a lot of safety information. But, you know, 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 answers, guys. Thanks so much.

Thanks, Ted.

There are no further questions for the Q&A session. Thank you for attending Skye Bioscience, Inc.'s Third Quarter 2025 earnings call. You may disconnect. We are now back in private mode. Great job, everybody. Have a great day.