Skye Bioscience, Inc.

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 Sky Bioscience 2025 fourth quarter financial results and business update call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one a second time. 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. And I would now like to turn the conference over to Puneet 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. C-Beyond established a potential path for namazumab 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 clear high-dose rationale, as well as a feasible cutaneous or subcutaneous path for delivery. And 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. And that is the backdrop for the next question. What has objectively changed over the last two years? Since launching namazumab 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 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, namazamab plus semaglutide delivered a clinically meaningful 3% improvement in weight loss over semaglutide alone with no plateau observed, with a statistically significant improvement 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 plus GLP-1 combination data set, and one of a few dual target approaches that combine a perfectly targeted mechanism with a predominantly centrally driven incretin memetic. Number two, namazumab 200 milligram demonstrated a favorable safety profile with placebo-like tolerability. Through 52 weeks, we also saw no numazumab-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 big weakly underexposed peripheral tissues. That is why we're initiating a Part C expansion study of CB1 to evaluate higher doses, and in parallel, enabling a practical, higher exposure subcutaneous delivery with Halozyme's enhanced 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. The Masomat is designed to improve energy metabolism by inhibiting CB1 in the periphery while minimizing brain exposure. So 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, Puneet. I'll focus on one question, why 200 milligram weekly was a reasonable starting point for Cbion and what the translational data now tell us about the exposure required for robust efficacy. Before phase two, we had robust phase one SADMAD safety and PK data and sufficient drug product. The highest phase one dose, approximately equivalent to 200 milligram weekly, was well-tolerated and showed encouraging trends in MAFLD-related biomarkers. While Phase 1 was not designed to show weight loss, it did provide a high-quality PK dataset. Using that dataset, we modeled Phase 2 steady-state CTROF levels and compared this exposure to the known IC90 concentration for namacimab. We also modeled published phase 1 PK data for NovoNoradus small molecule CB1 inhibitor, Marlunivant, and compared its exposure to its IC90 concentration. On this basis, we projected that 200 milligram weekly namazumab dose to achieve approximately seven times the IC90 concentration in the serum. It's comparable to the 20 milligram once daily mid-dose evaluated in NovoNoradus phase 2 monlunaban study. That made the 200 milligram namazumab dose a reasonable starting dose for our CB1 trial. Despite similar projected levels of serum CB1 inhibition, clinical outcomes diverged. Monlunaban at 20 milligram daily achieved 6.3% weight loss at 16 weeks, whereas namazumab at 200 milligram 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 CbOn started, we have generated biodistribution data in our human CB1 knock-in obese mice. These data show namazumab 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 milligram 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 600 milligrams 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 Even with conservative assumptions for brain penetration, modeled central target engagement remains a fraction of IC90, both at 200 milligrams and 600 milligrams. Maintaining that peripheral versus central separation is fundamental to the Massimab's therapeutic index. So the takeaway is that CB on monotherapy result at 200 milligrams 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 2B. Back to you, Puneet.