Skye Bioscience - Earnings Call - Q1 2025
May 8, 2025
Executive Summary
- Q1 2025 was operationally solid: enrollment in the CBeyond Phase 2a obesity trial was completed ahead of schedule; IRB approved a 52-week open-label extension; and three DSMB safety reviews raised no concerns.
- Financially, R&D rose materially on trial execution; net loss widened to $11.1M; diluted EPS of $(0.28) modestly beat consensus of $(0.29); revenue remains non-existent for this development-stage program.
- Guidance/timing: topline 26-week weight-loss data is expected late Q3/early Q4 2025; 52-week extension aims to bolster safety and durability; cash runway reiterated through at least Q1 2027.
- Strategic narrative: management emphasized nimacimab’s peripherally restricted CB1 mechanism, additive combo potential with GLP-1/GIP agonists, and tariff/manufacturing agility; formulation collaboration with Arecor seeks higher concentration to improve dosing convenience.
What Went Well and What Went Wrong
What Went Well
- “We completed enrollment in our Phase 2a CBeyond Trial ahead of schedule,” positioning for a full topline read in late Q3/early Q4 and enabling a 52-week extension to strengthen safety/efficacy evidence.
- Compelling preclinical data: nimacimab monotherapy showed ~23.5% weight loss; the nimacimab+tirezepatide combo reached >30% in DIO models; in vitro potency remained stable under elevated endocannabinoids vs. small-molecule CB1 inhibitors.
- Safety oversight: DSMB has completed three reviews with no concerns; quarterly reviews continue, supporting risk management around neuropsychiatric AEs.
What Went Wrong
- Higher OpEx: R&D expenses increased to fund Phase 2a trial and manufacturing; G&A ticked up on IR/marketing/consulting, widening net loss vs. prior-year period.
- Macro/policy uncertainty: management flagged evolving U.S. drug pricing/regulatory leadership; CFO discussed potential tariff impacts and mitigation, introducing planning complexity despite limited near-term exposure.
- External read-through risk: prior Novo monlunabant updates created negative stock read-through; management continues emphasis on mechanistic differentiation to reduce future misinterpretation risk.
Transcript
Operator (participant)
Ladies and gentlemen, thank you for standing by. My name is Jale, and I will be your conference operator today. At this time, I would like to welcome everyone to the Skye Bioscience first quarter fiscal 2025 earnings call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. I would now like to turn the conference over to Bernie Hertel, Head of Investor Relations. Please go ahead.
Bernie Hertel (Head of Investor Relations)
Hello, and thank you all for participating in today's call. Joining me today is Punit Dhillon, Skye's President and CEO, Chris Twitty, CSO, and Kaitlyn Arsenault, Skye's CFO. 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 Skye's expectations regarding its development activities, timelines, and milestones. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely, and reported results should not be considered as an indication of future performance. These forward-looking statements speak only as of today's date, and the company undertakes no obligation to revise or update any statements made today. I encourage you to review all the company's filings with the Securities and Exchange Commission concerning these and other matters.
I'll now turn the call over to Punit Dhillon.
Punit Dhillon (CEO)
Good afternoon, and thank you for joining us. I'm here with members of our management team to review Skye's first quarter 2025 performance. I'll briefly recap our key upcoming clinical milestones and highlight our operational roadmap for the rest of 2025 before turning it over to our CSO and CFO to share more details around our preclinical data and financials. We delivered meaningful scientific, clinical, and operational progress this quarter. Most notably, we completed enrollment in our phase IIA CBION trial ahead of schedule. We've now moved forward with an amendment to extend the study to 52 weeks. This positions us to collect longer-term data on safety, tolerability, and efficacy, both as monotherapy and in combination with GLP-1. Lastly, we generated compelling new preclinical data that further validates the potential of nimacimab as a weight loss therapy.
Nimacimab continues to stand out with a differentiated mechanism that is distinct from both peripherally restricted small molecule CB1R inhibitors and GLP-1 agonists. Importantly, our recent preclinical studies demonstrated a truly peripherally restricted antibody like nimacimab can potentially result in significant weight loss similar to a less restricted small molecule, and nimacimab has the potential to provide additive weight loss to an incremental memetic like tirzepatide. Later, our CSO, Dr. Chris Twitty, will discuss this new data in more detail. These findings reinforce our belief that nimacimab has the potential to deliver durable weight loss with fewer safety concerns. We'll present additional data, including mechanistic and combination findings, at key scientific and investor events this year, starting with ECHO next week and ADA in June. Clinically, we are on track. Patients continue to receive treatment. The Data Safety Monitoring Committee has completed three reviews with no safety concerns.
Site engagement remains high. Based on this progress, we expect to report top-line weight loss data from the 26-week primary analysis of CBION in late Q3 or early Q4. Before I pass it on, I want to address one topic proactively: the evolving policy environment. While our focus remains on disciplined execution, we're operating in a period of regulatory uncertainty marked by potential shifts in drug pricing policy and a lack of clear direction from federal healthcare leadership. Ongoing transitions at the FDA and NIH raise important questions about how innovation will be balanced with regulatory oversight in the years ahead. At Skye, we've assessed our exposure and believe it's limited in the near term as we prioritize our clinical development milestones. We're on track, and we're tracking developments carefully, and we have preserved flexibility in our supply chain and capital deployment planning.
Kait will speak more to how we've accounted for these variables in our financial outlook. Overall, we feel that we're in a solid position to move forward with the next stages of nimacimab's development life cycle and that we're uniquely positioned to help address the chronic nature of obesity and the need for sustainable long-term solutions. Chris, over to you.
Chris Twitty (Chief Scientific Officer)
Thank you, Punit. I'm pleased to share our thoughts on a few recent preclinical studies with nimacimab, our novel antibody-based peripherally restricted CB1R inhibitor. These studies were designed to not only address the hypothesis that a truly peripherally restricted CB1R inhibitor, such as nimacimab, can effectively drive weight loss, but to also generate mechanistic data to support Skye's differentiated approach to CB1R inhibition. Recent biomarker analyses from our initial mouse DIO study have further extended the impact of the dose-dependent weight loss observed with nimacimab treatment. Specifically, now we can report nimacimab-dependent reduction in fasting insulin levels that complement significant glycemic control as well as productive modulation of key appetite-regulating hormones, including GLP-1 and leptin. Additional datasets also highlighted significant reduction of inflammation in adipose tissue as well as liver steatosis.
We are also happy to report that this initial study has now been repeated by an independent lab with very reproducible results, not only in terms of the magnitude of weight loss and body composition—that is, preservation of lean mass with significant reduction of fat mass—but also with positive changes in glycemic control. This repeat study also looked carefully at food consumption and noted a significant reduction in cumulative caloric intake, slightly less but in line with semaglutide. Collectively, these studies highlight that nimacimab-dependent efficacy is driven by multiple peripheral pathways coordinated through different organ systems. Building on our monotherapy studies, we compared nimacimab, monlunaban, a small molecule CB1R inhibitor, and the dual GLP-1 GIP agonist tirzepatide, both alone and in combination with nimacimab, using our DIO model.
We chose to use higher yet clinically translatable doses of CB1R inhibitors, with nimacimab having a similar level of exposure as the current phase II dose and monlunaban being slightly higher than its 20-day daily phase II dose. Both CB1R inhibitors demonstrated significant weight loss over 23%, driven by reduced fat mass with lean mass preservation. We are encouraged that Skye's highly restricted nimacimab drove similar efficacy compared to the less peripherally restricted CB1R inhibitor monlunaban in a DIO model at clinically relevant doses. This study further highlighted that while an active yet suboptimal dose of tirzepatide could yield a similar level of weight loss as nimacimab, the combination with nimacimab produced 31.5% weight loss. These results, combined with our mechanistic data, strongly support the potential for nimacimab to be effective as both a monotherapy and as part of a combination approach to address the growing obesity epidemic.
These in vivo studies continue to support our belief that our differentiated antibody approach can provide meaningful efficacy without the challenge that current small molecule inhibitors face, which is brain exposure that can cause unwanted neuropsychiatric side effects. To address this potential advantage, we ran a series of in vitro potency experiments designed to leverage a critical mechanistic difference between nimacimab and small molecule inhibitors. Unlike small molecule CB1R inhibitors such as monlunaban that bind to the CB1R receptor at the orthosteric site—that is, the same site as the endogenous agonist, primarily the endocannabinoids AEA and 2-AG—nimacimab binds at the allosteric site and inhibits CB1R in a non-competitive manner. We modeled a low concentration of CB1R agonist at 50 nmol representing potential physiological conditions, where both drugs showed similar potency.
However, when challenged with an elevated concentration at 2,000 nmol, mimicking a pathological state such as obesity in which endocannabinoids become upregulated, nimacimab potency remained remarkably stable while monlunaban's activity was significantly compromised. This differentiated mechanism has significant clinical implications. In obesity, where endocannabinoids can be greatly upregulated, small molecule CB1R inhibitors such as monlunaban may face increasing competition to bind to the receptor. This circumstance may potentially require higher doses of the small molecule inhibitor, which will increase brain exposure and the potential for neuropsychiatric risks. Conversely, nimacimab's allosteric binding avoids this competition, maintaining relatively similar potency regardless of endocannabinoid concentration. These data suggest that nimacimab may offer the widest possible therapeutic window among CB1R inhibitors, potentially delivering significant metabolic benefits without having to navigate around the hurdle of neuropsychiatric side effects associated with achieving an appropriate peripheral exposure.
We look forward to continuing our preclinical research efforts focused on further characterizing nimacimab's differentiated and clinically relevant mechanism of action and having more data to share over the next month. Now, I will turn the call over to our Chief Financial Officer, Kaitlyn Arsenault.
Kaitlyn Arsenault (CFO)
Thanks, Chris. After the market closed today, we issued a press release and filed Skye's Form 10-Q with the Securities and Exchange Commission, outlining our quarterly financial results. We encourage you to reference the filing for details of our financials and the risk factors described in our other filings with the SEC. I will now provide a brief overview of key financial results for the first quarter ended March 31, 2025. Cash and cash equivalents and short-term investments totaled $59.2 million as of March 31, 2025. Our cash flow guidance remains intact, with the expectation that our current capital will fund operations and key clinical milestones through at least Q1 2027, allowing us to achieve completion of the phase IIA study for nimacimab and phase IIB manufacturing activities in anticipation of our future dose-ranging study.
Research and development expenses for the three months ended March 31, 2025, were $7.2 million as compared to $1.9 million for the same period in 2024. The increase was primarily due to contract manufacturing and clinical trial costs associated with our phase IIA clinical study for nimacimab, salaries and stock-based compensation, consulting, and depreciation expense. Our general and administrative expenses for the three months ended March 31, 2025, were $4.6 million as compared to $4.2 million for the same period in 2024. The increase was primarily related to investor relations, marketing, and communication costs and consulting and advisory fees. Our net loss for the three months ended March 31, 2025, totaled $11.1 million, with non-cash share-based compensation expense of $2.2 million, compared to $5 million for the same period in 2024, with non-cash share-based compensation expense of $2.5 million.
In closing, I'd like to briefly address how we view the uncertainty and implications of the proposed tariffs by the current U.S. administration and any potential impact we anticipate as it relates to our manufacturing activities. Our drug substance is currently being manufactured in Germany, with no expected impact from tariffs on raw materials or excipients, as they are shipped directly to our European partner from sources outside the U.S. Our final drug substance is shipped to the U.S. and is currently unaffected due to its classification under the applicable customs code. Our final drug product is finished in the U.S., and we currently foresee no significant impact on this stage of the supply chain, though we are closely monitoring developments. We anticipate that tariff pressures will affect pharmaceutical products that are manufactured and finished outside of the U.S. and sold into the U.S.
market, but that U.S.-based manufacturing could also face increased costs due to imported raw materials from other regions. We are actively tracking these changes and engaging with multiple global manufacturing partners domestically and abroad to maintain an agile, long-term strategy. Our goal is to de-risk future supply planning as the CB1R program advances. 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 sell-side analyst. Operator, over to you.
Operator (participant)
Thank you. The floor is now open for questions. 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. If you would like to withdraw your question, simply press Star 1 again. If you're called upon to ask a question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your questions. One moment for your first question. Your first question comes from the line of George Farmer of Scotiabank. Your line is open.
Hi, this is Chloe on for George. Thank you for taking our questions, a couple from us. Number one, in terms of preclinical data, what can we expect to see at ADA? I believe you mentioned ECHO next week, so a little more detail around that would be helpful. Number two, on monlunaban, we know that Novo has said that they are planning on presenting their full phase IIA data this year. Last September, when they had the data, that had pretty bad negative read-through to your stock. Do you think by now, now that you have all this preclinical data out in the public domain, investors have kind of begun to grasp the difference between nimacimab and monlunaban? Do you think this time around the reaction will be more muted, if not positive, on your stock?
I have a follow-up after that.
Punit Dhillon (CEO)
Hey, Chloe, this is Punit here. I'm going to defer the ADA versus the ECHO presentation and what to expect there to Chris, because him and his team have been working really hard on that data package. I appreciate the little bit of a layup on the other question regarding monlunaban and the full dataset. We were carefully paying attention to what guidance Novo has been giving regarding that. On the same note, I think what's been very important to us as a management team and overall in terms of differentiation is being very clear in terms of our mechanism. We've, as you've seen multiple times, really tried to differentiate ourselves from the small molecule space. We've now demonstrated nimacimab's weight loss efficacy in these preclinical models, and it's not only comparable to monlunaban, but it's also shown additive effect to tirzepatide in combination.
That's the last dataset that was just publicly made available, where we achieved over 30% weight loss in DIO models. I think it's just hard to predict. At this point, we do think that the street is better equipped with that background. We've been received well from the information that we've laid out, even received well from our counterparts because we've had a chance to have dialogue there as well. That combination potential is also, I think, really evident in terms of now with preclinical data, and everyone wants to see that read-through with our clinical data with the semaglutide combo. I hope that your prediction's right and there's going to be a better kind of separation from that.
That is why the rest of the work that we're doing on the preclinical side continues to be very data-intensive, and we're making an effort to be at these scientific conferences. I'll turn it over to Chris, and he can tell you expectations on that side.
Chris Twitty (Chief Scientific Officer)
Thanks, Punit. Yeah, regarding ECHO, we've developed and sort of put together a pretty cohesive model based on published clinical data that looks at the peripheral versus the central activity of different CB1R inhibitors. It overlays our own phase II dose, really looking at this from the lens of PK and PD activity. We went into some depth and really focused on really presenting that model. You can look forward to that at ECHO, and not to give away the punchline, there's actually a lot of interesting pieces that come out of this work. Ultimately, I think it makes a really convincing case for the necessity for peripheral CB1R inhibition and speaks to the central, the brain activity that unfortunately is a hurdle that the small molecules are contending with. It really presents that as driving the neuropsychiatric AE.
A bunch of strong data that helps really bring that to focus. That will be the driver there at ECHO. In terms of ADA, we'll be showing more in-depth and additional preclinical data. We have a bunch of very interesting biomarker data, some of which came out in a press release and is up on our current deck you can find online. There is more of that. Really looking at mechanistic data that helps really support this concept of coordinated organ systems driving peripheral mechanisms that allow weight loss to occur, not just from anorexogenic drivers, but really a few different pathways. We think it's quite compelling. In addition to that, in our initial DIO setting, we have combination data, which will also be highlighted there, along with some very interesting biomarker data in support of that. That will be the thrust of ADA.
I think we mentioned this last time. We have now multiple colonies with multiple collaborators and labs running in parallel. Our cadence of research is just increasing. There's a lot of interesting questions and datasets on the horizon. We look forward to sharing that beyond ADA.
Great. Thank you. Super helpful. If I may squeeze in one last question, this is regarding regulatory interactions. You have talked about what you see in the nimacimab fitting into this obesity treatment paradigm, right, across different populations, exposed refractory or non-responders to incretins, for instance. Have you had these conversations with FDA yet or plan to? Just walk us through your plan there.
Punit Dhillon (CEO)
Yeah, that's a great question. I can kick it off. I know Dr. Arora is on the line. I see him on the portal. I'm going to let him talk about the regulatory interactions. There's been two kind of key activities, Chloe, that's important for us. One is being very clear, crystal clear in terms of what's that roadmap for approval. The approval regulatory development strategy in obesity or anti-obesity medications hasn't shifted. Even with the new guidance, we're sticking to that overall strategy in terms of obtaining approval as a monotherapy. The big but there is that there's obviously an advancing kind of landscape with the incretin class continuing to demonstrate success. At the same time, there's this opportunity of patients coming off drug, discontinuation rates, tolerability issues, maintenance opportunities, and there lies a significant opportunity.
One activity that we've been really active in is the discussion with KOLs and how that defines the target product profile and how that refined target product profile goes after a very clear market. We probably have some of that information become available later in Q2. The second strategy is the regulatory strategy, which a lot of it gets defined after the data readout on the 2A. If Dr. Arora wants to elaborate, I'm going to turn it over to him.
Puneet Arora (Chief Medical Officer)
Yeah, sure. Thank you. Chloe, in the not-so-distant future, I'd say in the near future, we are going to have an opportunity to have these regulatory interactions. As Punit pointed out, we're going to have data from the phase IIA, which will be available in Q4 this year. We're going to take that data and take that opportunity to have discussions with the FDA and possibly with other regulatory authorities, both in terms of seeking their advice and also proposing definitive dose-ranging phase IIB study to them. That will be an opportunity for us also to discuss populations we can study and how we can define them. I think that with data in hand.
Sorry, I can tell you someone's cut off. Thanks again for taking my questions. This was really great. Thank you.
Operator (participant)
Your next question comes from the line of Jay Olson of Oppenheimer. Your line is open.
Jay Olson (Analyst)
Oh, hey, thanks for providing this update. Can you please remind us about your findings from the DIO model on body composition and how nimacimab may help preserve lean muscle mass in combination with GLP-1? I guess, looking ahead longer term, just how are you thinking about the magnitude of the commercial opportunity for nimacimab in combination with GLP-1 versus nimacimab monotherapy? I had a follow-up, if I could, please.
Punit Dhillon (CEO)
Hey there, Jay. I'm acting as operator right now, so I'm going to let Chris take that first question. Then maybe that's teed up really well for Tu, who's been handling all the commercial assessments. After Chris, Tu can give you a response in the second part of your question.
Chris Twitty (Chief Scientific Officer)
Thanks, Punit. And thanks for the question, Jay. Actually, just to clarify, the combination data was around tirzepatide, so in combination and alone with tirzepatide. In terms of body composition, we did see when we look at nimacimab monotherapy, similar to what we saw in the previous repeated studies, which, by the way, I'll just note, those were done with independent labs and we see very reproducible data. We see body composition where significant reduction in fat mass with preservation of lean mass. We see that to a lesser extent with tirzepatide, tirzepatide alone, still significant, but it's trending up toward less fat mass. In combination with nimacimab, we see the greatest amount of reduction. They're all fairly notable. There's not a huge shift, but we do see that, in fact, in combination, it looks like there's even more fat mass there.
It really sets the stage for combination. If we look at the weight loss, we see this nice additive effect, partially additive effect. This, again, gets back to some of the mechanism where there is some overlap in the anorexogenic driver compartment, if you will. The caloric intake both can impact that pathway. There are additional pathways that CB1R inhibition with nimacimab touch on. We feel that's where we get this additive nature of weight loss. And Tu, do you want to take the next piece?
Tu Diep (COO)
Yeah, happy to. Jay, would you mind just repeating your question?
Jay Olson (Analyst)
Oh, yeah, just how you're thinking about the relative magnitudes of the commercial opportunity for the combination of nimacimab plus GLP-1, GLP-1 GIP versus the magnitude of the opportunity for nimacimab monotherapy.
Tu Diep (COO)
Yeah, thanks for that question, Jay. We've been modeling sort of our commercial opportunity. As Punit said, we've been doing a lot of sort of commercial assessment of the nimacimab in terms of what the target populations really are. As Punit highlighted, we think we do have that opportunity both as a monotherapy and in combination monotherapy, most likely in the area where patients are intolerable or unresponsive or have a contraindication to GLP-1s, which we think is probably a much larger opportunity than some people may have originally thought. In terms of the combination opportunity, again, I think this is a potentially large opportunity where you have a class of patients who do require some significant weight loss.
Again, looking at that 20%-25% plus weight loss, likely in that class three obese population, where maybe, again, they're not tolerable to the higher doses of, let's say, tirzepatide and can achieve those higher weight losses, or they need just additional weight loss on top of the tirzepatide or other GLP-1 class. When we look at sort of what those commercial opportunities are between the monotherapy and combo, they're relatively equal, I think, at least at this point in terms of how we're seeing the market. They both are quite large and they are billion-dollar size markets. One hasn't necessarily differentiated itself, at least at this point, as we've been going through the analysis.
Jay Olson (Analyst)
Okay, great. Thank you. That's super helpful. If I could squeeze in one last follow-on question. Have you guys done any work on the co-formulation of nimacimab with GLP-1 or GLP-1 GIP? Is a fixed-dose combination technically feasible? Can you comment on any potential IP advantages or lifecycle management advantages of doing a fixed-dose combination?
Punit Dhillon (CEO)
Yeah, that's a great question there, Jay. The opportunity for us in terms of co-formulation, obviously, exists, but that has not been something that we have explored yet. The first proof of concept is going to be just in terms of the dosing happening at the same time in the current trial. Instead, there has been interest from a fixed-dose perspective. We definitely see an advantage being a biologic, being an antibody, that there is really a future where you can be a CB1R plus story. Stay tuned. I think first things first is we want to demonstrate nimacimab's advantage as a monotherapy and highlight this data. It has been well supported by the preclinical evidence. We expect that later this year, once we get through the clinical data, we can start highlighting what that pipeline looks like as a CB1R plus story that includes fixed dose.
Jay Olson (Analyst)
Okay, great. Thank you so much for taking all the questions.
Operator (participant)
Your next question comes from the line of Albert Lowe of Craig-Hallum. Your line is open.
Albert Lowe (Analyst)
Hi, guys. Thanks for taking my questions. Maybe the first one, I saw that there's some stage reviews that have not raised any concerns. I was just wondering if there are any other reviews planned and would any severe or serious neuropsychiatric AEs be raised in these reports? Thanks.
Punit Dhillon (CEO)
Dr. Arora, you want to take that question?
Puneet Arora (Chief Medical Officer)
Sure. We are actually holding these unblinded reviews on a quarterly basis. The independent DMC meets every quarter, and they are provided with unblinded data on safety in order to review. Now, what we have told you, and as you were mentioning, was that they've reviewed that data and told us that there were no concerns moving forward with the study. They are provided with a list of all the adverse events that are reported in the study and the serious adverse events. We also report any neuropsychiatric events that may occur in the study as adverse events of special interest. Those are also channeled into the DMC. They get to review all of this, and they are doing it on a quarterly basis, and no concerns have been raised so far.
The next review is scheduled for July the 18th, and they will be ongoing from there on until the study ends.
Albert Lowe (Analyst)
Okay. So it sounds like the review board has some, I guess, discretion over, I guess, what weren't a concern. Is that right?
Puneet Arora (Chief Medical Officer)
Yes. I mean, they get all of the data that's available for the study, and we have on that review board two psychiatrists, actually, and we have people who have experience both with CB1R and with obesity studies in general. So it's a very experienced set of people who understand exactly how these studies run, what this data looks like, and what they're looking for.
Albert Lowe (Analyst)
Okay. Thanks. Maybe one follow-up question. I just want to be sure I still kind of understand what's the expectations for would be a strong separation from placebo and monotherapy at 26 weeks. Would this still be 8%?
Punit Dhillon (CEO)
Yeah, Albert. Yeah, that's an excellent question. The primary endpoint is for 8% at 26 weeks, based on what has been kind of shared now. When we put that number out, we did not have the benefit of 16-week data from Monlunaban, which showed 5.7% placebo adjusted, if I recall. For us, we are expecting to see separation between placebo and active. Obviously, we're targeting over 5%. The study has a design based on 8%.
Albert Lowe (Analyst)
Okay. All right. Thank you. If I can just squeeze in one last one with this follow-up here or start with this. Are you still planning to—sorry. I can see with this open label extension for the 26 weeks, it looks like there may be some gaps in the treatment period. I was just wondering, I guess, if you have plans on how to interpret this data to, I guess, account for some variations here and potential weight changes during these gaps.
Punit Dhillon (CEO)
Yeah, there is a rollover period that we've had to account for because naturally, there's an operational kind of updates that come along with adding an extension that wasn't previously a part of the protocol. I mean, the data will be collected based on weight and other parameters at the start of the extension as well. We don't know if there's going to be variability, but if there is variability, it'll be collected in terms of the data, and we can discuss that once we have all that information.
Albert Lowe (Analyst)
Thank you.
Operator (participant)
Your next question comes from the line of Ted Tenthoff of Piper Sandler. Your line is open.
Ted Tenthoff (Analyst)
Great. Thank you very much, and thanks for the update. I wanted to get a sense. I know you guys extended the CBION study phase II to 52 weeks. What is the incremental benefit from going from 26 weeks to 52 weeks, considering you still have the primary efficacy readout at 26 weeks? How does this impact potential timing for a phase IIB start? Would you have to wait for the full 52-week data set for CBION? I just wanted to get a sense for how you're thinking about that. Thank you.
Punit Dhillon (CEO)
Hey, Ted. Thanks. That's a pretty important question. As we talked about in the last learnings call, what we really wanted to try to do is maximize what we could from the current trial. One, having the trial up, the phase IIA up and running with the primary endpoint based on 26 weeks, it did allow us the flexibility to leverage a study that's already there, patients already enrolled, and then generate another data point that allows us to have broader efficacy, safety data, other information that we're collecting from the trial. That's been one of the key factors. It's always been important for us to eliminate any white space between any of our development objectives.
At the moment, this extension actually slots in really well before the phase IIB starts and allows us to take the phase IIA data, able to have a productive discussion with the agency about what a phase IIB would look like, and at the same time, continue collecting information based on this extension before that phase IIB begins and perhaps even inform the phase IIB to some extent. At the moment, it has not created any extra time. In fact, it is slotted really well operationally, and we have the drug product to be able to get that additional data point. The last thing I would say is that the 52-week data point is another important thing to continue to build confidence on the broader safety that we want to see with this mechanism.
I think that's been another important factor, as well as the tolerability information. Dr. Arora, do you want to expand on anything I missed?
Puneet Arora (Chief Medical Officer)
Yeah. No, I just think you covered a lot of it. I just want to add a couple of small things. In the monotherapy arm, because it's an open label arm, we are able to continue to refine our PK/PD models as the study goes on beyond 26 weeks, and that will help us in picking the correct dose range for the phase IIB study. That data will be helpful. Of course, as Punit pointed out, the safety data is invaluable because we are treating longer and being able to show that nimacimab is safe and tolerable. There is also a second arm to this study. We are also extending the combination dose. The combination dose isn't currently being tested in the proposed phase IIIB, which will be a dose ranging for the monotherapy.
For the combination dose, we're getting this additional 52-week data, which just adds to what happens when you dose these drugs together and what happens to the curves and the trajectories of weight loss. We think that data will be really useful both for safety and for efficacy.
Ted Tenthoff (Analyst)
Gotcha. So you think the phase IIB would have to be a monotherapy study, or could there be combo arms?
Puneet Arora (Chief Medical Officer)
At the moment, the phase IIB is planned and proposed as a monotherapy study because what we need to do is to do a proper dose ranging, right? We need to understand what the optimal dose for nimacimab is. It does not preclude the idea that we could do a study with the combination or do other work, but it is necessary to find that optimal dose in order to go to phase II.
Ted Tenthoff (Analyst)
Yep. Perfect. Thanks, guys.
Operator (participant)
Your next question comes from the line of Kristen Kluska of Cantor Fitzgerald. Your line is open.
Kristen Kluska (Analyst)
Hi, everyone. Based on some of these preclinical studies that you've conducted, the ones that are ongoing, I'm wondering if this has changed the way you're thinking about how the trial is powered. Perhaps are you walking away with greater conviction in the % that you've provided us with, or essentially, if any of your parameters or thought process has changed? Outside of just the monotherapy, same thing with the combination. Thank you.
Punit Dhillon (CEO)
Yeah. Kristen, that's a really great and important question that you've raised. The data generated so far preclinically wasn't something that we had when we launched the program. This demonstrates that we've now, I think there are three important takeaways here. We've demonstrated this robust inhibition of CB1R across multiple assays. That information is available in the deck, and that shows the potency relative to or the differentiation relative to small molecules. We've continued to benefit from a really strong safety profile, right? We had this previous work of multiple biodistribution studies done in NHPs that didn't show any CNS penetration. We've achieved now monotherapy of 16-23.5% weight loss in several studies and repeat studies as monotherapy and now shown over 30% in a combo model. Across the board, it checks a lot of boxes. How does that translate to human?
Of course, it gives you this aspect of, well, we feel more confident around the mechanism, and there's this component that comes along with it that we expect it to translate into the clinic. To be at the same time transparent, these are my studies. We have to put that in one aspect. The only other confident thing that we can leverage is that the DIO models across the landscape have been, interestingly, a very good tool, a very good tool in the therapeutic area across different mechanisms. The DIO models have translated to some degree in the clinical setting. That's kind of our broad take. Chris, do you want to take any different approach on answering Kristen?
Chris Twitty (Chief Scientific Officer)
No, I think you touched really all the key points. I might just add a very small detail, and that relates to, and this is sort of the translatability and how well, in terms of confidence, do we feel these DIO models will predict what we see in the clinic? I think you touched on some of the key areas. One other aspect is we are dosing. When we look at our DIO dosage, it looks relatively high, and it's worth noting that we have a very different behavior in terms of the PK profile in the mouse than we do in the human. We are very mindful of looking at exposures, not necessarily a Cmax.
It's really when you understand the whole area of the curve analysis and what the exposure and engagement looks like in these DIO models and keeping in mind that these are obviously very short duration relative to what we're doing in the clinic. When you look at that all together, you really start to appreciate how we're matching exposure, and we're looking at doses that we feel very translatable. We've seen some success with predicting efficacy in the ingredient space and arguably looking at the CB1R space with Novo's data set, which we feel is actually a pretty significant data set. This is actually, I think, a very strong data set. They too had DIO data that looked pretty strong. We reproduced that in our own lab.
Coming back to this idea of translating, we do feel pretty confident that we're going to have an active drug in the clinic. I'll just add that piece. That's all.
Punit Dhillon (CEO)
Thanks, Chris.
Kristen Kluska (Analyst)
Thank you.
Operator (participant)
Your next question comes from the line of Andy Hsieh of William Blair. Your line is open.
Andy Hsieh (Analyst)
Great. Thanks for taking our questions. Maybe from the outside world, can you kind of talk us through some of the discussions that you will be having with the FDA in terms of the protocol amendment? Just what are some steps that you need? Do you need to have a meeting with the FDA, the kind of logistical part of that? The second question I have, I just wanted to make sure. Chris, you mentioned about all the preclinical data that really kind of accentuates the clinical differentiation of nimacimab. Was that also a part of the April 15 disclosure? I just want to see if there's any overlap, or is there any new data that you disclosed today? Thank you.
Punit Dhillon (CEO)
Yeah. Thanks, Andy. We haven't disclosed any new data today. What we expect is updates to these data sets that we've shared recently in upcoming scientific meetings. We'll keep some of that information close to our vest until we get there. There'll be an update at those meetings. What we're committed to, as what Chris kind of pointed to earlier, is we now have multiple efforts underway, domestic and international, where we are going to continue to build on the understanding of the mechanism and support our clinical activities and biomarker activities and other stuff. Because of that workflow, that is allowing us a much larger data set to work with and continue to support our clinical activities. I'll turn it over to Dr. Arora, and then Chris, you can elaborate on anything after Dr. Arora.
Puneet Arora (Chief Medical Officer)
Yes. Your question was about regulatory infractions. As you know, with the protocol amendments, the FDA does not ask for and does not grant actual meetings. We have submitted the protocol amendment to the FDA. They have asked us for some minor clarifications at this point, and we have already sent them the responses for that. It is our expectation that we will be able to sort out the minor issues that have been raised, and we will be able to start rolling patients into our extension. It is very unlikely that they will ask for any kind of actual meeting around the protocol amendment.
Operator (participant)
Your next question comes from the line of Jon Willoben of Citizens JMP. Your line is open.
Jon Wolleben (Analyst)
Hey, thanks for taking the question. I'm wondering if you guys have looked at blinded baseline data and specifically wondering if you have any concerns like we've seen with some of the anchor teams about reduced efficacy in larger individuals and also in the Hispanic population, if there's anything in the demographics that caught your eye when you take a look at that.
Punit Dhillon (CEO)
Jonathan, we're still blinded to the data, so we don't really have access to anything. Dr. Arora, do you want to take a stab at anything that you want to provide context from your experience?
Puneet Arora (Chief Medical Officer)
Yeah. So we have, I think we've managed to get a pretty good representative population recruited for this trial. We do have some Hispanic representation, and we also have a pretty good weight range to my mind. Once we unblind, to the extent that some analysis is actually possible based on these parameters, we will be able to do that. At the moment, as Punit pointed out, we are blinded. It's hard to know right now whether or not there's any correlation or whether any of these individual parameters are making a difference.
Jon Wolleben (Analyst)
How do you think about managing discontinuations in the combination arm? Are you allowing dose adjustments for patients on semaglutide?
Puneet Arora (Chief Medical Officer)
That is one of the reasons that we've kept the rollover gap small, as we do not want patients off semaglutide for any extended period. They are limited to being off their drug for only four weeks. This will only account for the few initial patients who will be able to join the rollover extension when we are able to begin it and have recently finished. After that, everyone who rolls over will rollover directly. There will be no gap, and we will not need to do any dose adjustments for the semaglutide because they are already on effective doses of semaglutide. For the few patients who will have this small gap, we have made some allowance to be able to go back a little bit on dose and be able to, if they require to, readjust to the semaglutide.
We know that these people can tolerate the effective dose of semaglutide because they will all have completed 26 weeks of treatment on it.
Jon Wolleben (Analyst)
Got it. All right. Thanks, guys.
Operator (participant)
With no further questions, ladies and gentlemen, this concludes today's conference call. You may now disconnect.