Skye Bioscience (NASDAQ:SKYE) executives used the company’s fiscal 2025 fourth-quarter call to outline how new translational work and longer-duration clinical follow-up from its CBeyond study are shaping the next stage of development for nimacimab, its peripherally targeted CB1 antibody being developed in obesity. Management also announced a Part C expansion of CBeyond to test higher exposures, discussed formulation work with Halozyme’s ENHANZE technology, and shared early preclinical results from an antibody-peptide conjugate (APC) program intended to combine CB1 inhibition with GLP-1 activity in a single molecule.
CBeyond combination results and 52-week durability
Chief Executive Officer Punit Dhillon said the company believes CBeyond established “a potential path for nimacimab alongside existing incretin therapies,” pointing to additive weight loss, durability, and tolerability. He emphasized that the program has moved “from a promising signal to a more coherent development case,” including additional 52-week combination data and work toward a feasible subcutaneous delivery path.
On safety, Dhillon said nimacimab at 200 mg showed “placebo-like tolerability” through 52 weeks, with no nimacimab-associated neuropsychiatric signal and no additive gastrointestinal burden when combined with semaglutide.
Why monotherapy underperformed and the rationale for higher dosing
Chief Scientific Officer Chris Twitty focused on why the 200 mg weekly dose was selected for CBeyond and what subsequent modeling suggests about exposure requirements. He said the starting dose was supported by Phase 1 safety and pharmacokinetic (PK) data and modeling that projected 200 mg weekly would reach roughly seven times the IC90 concentration in serum, similar to exposures evaluated in published Novo Nordisk small-molecule CB1 inhibitor work.
However, Twitty said clinical outcomes diverged: a published small-molecule CB1 inhibitor regimen achieved 6.3% weight loss at 16 weeks, while nimacimab 200 mg weekly produced a 1.5% reduction at 26 weeks in CBeyond. He attributed the difference to distribution, arguing that antibodies and small molecules can have similar serum target engagement but different tissue exposure.
Skye said it generated biodistribution data in human CB1 knock-in diet-induced obese (DIO) mice indicating nimacimab distributes to peripheral tissues relevant to metabolic efficacy (including adipose tissue, liver, GI tract, and muscle) while maintaining minimal central nervous system exposure, consistent with the clinical safety profile. Integrating DIO dose-response and biodistribution into a compartmental model, Twitty said the company believes 200 mg weekly underexposed peripheral tissues and that a “half log increase” to approximately 600 mg would allow full tissue engagement and more robust inhibition of CB1 signaling, while modeled central target engagement would remain a fraction of IC90.
Management repeatedly framed the monotherapy result as “an exposure question, not a pathway question,” and said the next step is to confirm PK and safety at higher exposures before finalizing Phase 2b dose selection.
Part C expansion: new IV cohorts to generate higher-exposure PK and safety data
Chief Operating Officer Tu stated the company initiated a CBeyond Part C expansion that adds new intravenous (IV) cohorts intended to “rapidly generate safety and PK data at higher exposures,” while specifically monitoring for neuropsychiatric events and continuing safety oversight through an independent data monitoring committee.
Participants will enroll into one of two cohorts:
- 400 mg nimacimab or placebo IV once weekly
- 600 mg nimacimab or placebo IV once weekly
Tu said each cohort will be randomized 3-to-1 (six active, two placebo) for 16 weeks. He added that relative to subcutaneous dosing, the 400 mg and 600 mg IV doses correspond to approximately 700 mg and 1,000 mg subcutaneous doses, respectively, based on a prior bioavailability study showing subcutaneous relative bioavailability of about 56% versus IV.
During the Q&A, management said IV administration was chosen to obtain “the cleanest and fastest” high-exposure PK and safety readout and that using ENHANZE would have slowed initiation of the expansion. Tu said infusion time is expected to be about one hour, with longer on-site observation for the first few doses and shorter visits (generally within a couple hours) thereafter.
Dhillon said the company expects to share the higher-exposure data when available and guided to top-line expansion study data in Q4 2026. When asked about the bar for success, Dhillon said Part C is primarily a PK and safety study rather than an efficacy readout, though he added that any directional monotherapy activity at higher exposure would be meaningful in validating the company’s model and informing Phase 2b dosing.
Formulation and regulatory updates: Halozyme ENHANZE and FDA feedback
Tu said Skye is working under a research and collaboration agreement with Halozyme to develop a nimacimab co-formulation using ENHANZE (recombinant human PH20) to enable high-volume subcutaneous injections in a planned Phase 2b study. He said the company expects the ENHANZE-related work to be ready in time for Phase 2b and described an initial “mix-and-deliver” approach in which components are mixed at the clinical site and administered subcutaneously by the participant or site staff.
Tu also said the company is advancing a high-concentration nimacimab formulation (up to 200 mg/mL) and sees a longer-term opportunity for a next-generation extended half-life version via Fc domain modifications. On device strategy, management said an auto-injector format is intended from a commercial standpoint, but the auto-injector work would be targeted for Phase 3 rather than Phase 2b.
On regulatory progress, Tu said the company received written FDA feedback from a Type C meeting request, including comments on proposed Phase 2b design and questions related to a potential registration path and combination development with GLP-1s. While still reviewing the minutes, management said the feedback helped “sharpen” dose, duration, endpoints, and inclusion criteria planning and provided insight into expectations for combination therapies.
Off-therapy follow-up and body composition signals
Tu also highlighted additional CBeyond follow-up examining weight regain among participants who did not enter the extension and went off therapy. He said participants who had been on semaglutide alone regained 38.7% of weight over 13 weeks, which he noted aligned with prior observations from the STEP 1 extension study. In contrast, participants previously on nimacimab plus semaglutide regained 17.8% over the same period.
In that same off-therapy follow-up group, Skye evaluated body composition and said the main driver of weight regain in the combination cohort was lean mass gain, while fat mass loss was maintained. Management presented this as supportive of nimacimab’s “orthogonal” mechanism and its potential role as a complementary add-on for GLP-1-experienced patients, particularly where durability, persistence, and body composition outcomes matter.
Early preclinical APC data and platform expansion
Skye also shared early data from a first-generation antibody-peptide conjugate designed to combine nimacimab’s mechanism and half-life with a GLP-1 receptor agonist peptide in a single unimolecular therapeutic. Twitty described a study in which nimacimab and the APC were dosed at 75 mg/kg every three days; the APC also delivered 1 µmol/kg of a GLP-1 peptide on the same schedule. Control arms included vehicle, semaglutide, and Skye’s conjugation-engineered GLP-1 peptide (SBI-403).
Management said nimacimab alone produced approximately 14% vehicle-adjusted weight loss, while semaglutide and SBI-403 produced 21% and 23%, respectively. Twitty said both a mixed combination arm and the APC arm produced “highly encouraging additive weight loss,” and that the APC dosed every three days achieved efficacy equivalent to a daily combination regimen in that experiment.
Dhillon characterized the APC result as a proof point for a broader bioconjugation-enabled platform and said the company intends to continue using nimacimab as an initial scaffold while applying a candidate selection framework before advancing programs into formal preclinical development. Executives stressed that APC work is longer-term optionality and not intended to distract from near-term clinical milestones for nimacimab.
Cash position, runway, and 2026 catalysts
Dhillon said Skye ended 2025 with $25.7 million in cash, cash equivalents, and short-term investments, and that the company has been managing its operating plan to extend runway through Q4 2026, including the newly planned CBeyond expansion data set.
Management outlined anticipated catalysts through 2026, including completion of ENHANZE compatibility and in-use work, enrollment progress for Part C cohorts, additional bioconjugation data and formulation feasibility work, and, in Q4 2026, top-line clinical data from the expansion study alongside a finalized Phase 2b design and operational readiness materials.
About Skye Bioscience (NASDAQ:SKYE)
Skye Bioscience, Inc is a clinical-stage biotechnology company focused on the development of novel, selective cannabinoid type 1 (CB1) receptor modulators for the treatment of ocular diseases. Headquartered in Sunnyvale, California, Skye Bioscience leverages proprietary chemistry and formulation expertise to design and optimize compounds with high potency, tissue selectivity and favorable drug-like properties. The company’s lead product candidate is being evaluated for the treatment of glaucoma and other ophthalmic conditions characterized by elevated intraocular pressure.
Skye Bioscience’s pipeline centers on synthetic cannabinoids engineered to avoid central nervous system side effects commonly associated with traditional cannabinoid therapies.
