Skye Bioscience’s 2025 Q4 Call: ENHANZE Readiness, Dose Selection, and Delivery Method Claims Clash

Date of Call: Mar 10, 2026

Guidance:

• Anticipated catalysts in Q1 2026: Interim CVON extension data reported; FDA Type C meeting minutes received; CVON expansion study initiated; ENHANZE compatibility and in-use study completed.
• Q2 2026: Cohort two enrollment initiated; enrollment completes for both cohorts; additional preclinical bioconjugation data shared; high concentration formulation feasibility work completed.
• Q4 2026: Top-line clinical data from expansion study expected; Phase 2b final study design and execution readiness planned, including final protocol and operational plan completion.
• Cash runway extended through Q4 2026.

Business Commentary:

Clinical Progress and Development Strategy:

• Skye Bioscience reported meaningful 3% improvement in weight loss when nimacimab was combined with semaglutide over semaglutide alone at 26 weeks, with no plateau observed.
• The company initiated a Part C expansion study to evaluate higher doses due to the 200 mg weekly dose underexposing peripheral tissues.

Regulatory and Formulation Advancements:

• The company received written feedback from the FDA regarding their Type C meeting request, which is helping to sharpen their Phase 2b clinical trial design.
• Skye Bioscience is advancing the development of a high concentration nimacimab formulation and a co-formulation using Halozyme's ENHANZE technology for subcutaneous delivery.

Mechanistic and Preclinical Insights:

• Nimacimab demonstrated a favorable safety profile with placebo-like tolerability and no neuropsychiatric signal through 52 weeks.
• The mechanism of action was found to be primarily orthogonal to incretins, providing a strong rationale for combination therapy.

Financial and Operational Management:

• Skye Bioscience ended 2025 with $25.7 million in cash equivalents and short-term investments, managing their operating plan to extend their runway through Q4 2026.
• The company focused on aligning their cost structure with their most critical work, ensuring financial discipline.

Sentiment Analysis:

Overall Tone: Positive

• Management expressed confidence in progressing nimacimab's development, citing 'three key learnings' from clinical data showing meaningful combination weight loss, favorable safety, and a solvable exposure issue. They highlighted 'very exciting' new antibody-peptide conjugate platform data and stated the company's 'conviction is strong' with a 'clear dose response' and 'comfortable' safety profile. The tone focused on moving from a 'promising signal to a more coherent development case' and addressing an 'important void' in the obesity landscape.

Q&A:

• Question from Jay Olson (Oppenheimer): Can you talk about your plans to share data from the higher dose cohorts above 200 milligrams? 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 2b?
  Response: Expect higher exposure data from the Part C expansion study before end of 2026/Q4 2026, which will validate the dose rationale. ENHANZE co-formulation work is ongoing, expected to be ready for Phase 2b; delivery will be via mix-and-deliver subcutaneous method, with auto-injector intended for Phase 3.

• Question from Ted Tenthoff (Piper Sandler): 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?
  Response: The selected doses provide the necessary peripheral exposure for target engagement with a comfortable safety margin; higher doses are possible but current two doses are sufficient to achieve the desired efficacy and safety profile for Phase 2b selection.

• Question from Ted Tenthoff (Piper Sandler): 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?
  Response: The antibody-peptide conjugate (APC) platform is a long-term optionality, not a near-term lead; it serves as an exciting proof-of-concept for a broader combination platform, offering potential dosing simplification and exploring multi-mechanism metabolic combinations beyond incretins.

• Question from Michael DiFiore (Evercore ISI): 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?
  Response: Adipose tissue and liver are key for monotherapy to drive lipid metabolism and glycemic control. In combination therapy, engagement in adipose and liver compartments may be more relevant, with appetite regulation less critical as incretins handle that.

• Question from Michael DiFiore (Evercore ISI): Why are you 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?
  Response: IV provides the cleanest and fastest way to generate high exposure PK and safety data; it is not the end-state. ENHANZE subcutaneous path is being built in parallel for the Phase 2b study.

• Question from Andy Hsieh (William Blair): One is, I see that you kind of mentioned that 400 milligram IV is equivalent to 600 or 700 milligram subcutaneous. I'm just curious about what is that based on? 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.
  Response: The conversion is based on a past bioavailability study showing subcutaneous dose has ~56% relative bioavailability vs. IV; the correct equivalent is closer to 700 mg subcutaneous. IV infusion will take about an hour; initial doses require longer on-site safety monitoring, with subsequent doses taking a couple hours total.

• Question from Albert Lowe (Craig-Hallum): What do you see as the bar for success from the expanded study as far as the dose to be taken forward for monotherapy?
  Response: Success is primarily PK and safety validation, not an efficacy readout; the expectation is that monotherapy activity at higher exposure validates the model, helping finalize and reshape Phase IIb dosing with confidence.

• Question from Albert Lowe (Craig-Hallum): Do you still plan to share the full extension data with the 300 mg monotherapy patients?
  Response: The 300 mg dose data will be shared to improve PK model sensitivity, but it is not expected to define the commercial efficacy zone; expectations are anchored to the higher doses planned for Phase IIb.

Contradiction Point 1

ENHANZE Formulation Readiness for Phase 2b

Timeline for subcutaneous formulation availability for Phase 2b.

Jay Olson (Oppenheimer) - Jay Olson (Oppenheimer)

2025Q4: ENHANZE co-formulation work is ongoing and expected to be ready in time for the Phase 2b study. - [Tu](COO)

Can you discuss your plans to share data from higher dose cohorts above 200 milligrams, the status of your formulation work using Halozyme technology and potential use of a subcutaneous self-administered pen in future studies, and whether the formulation needs to be available at higher doses before proceeding to Phase 2b? - Catherine (Citizens for John Wolleben)

20251111-2025 Q3: The focus is on... demonstrating a clear dose-response relationship. The company is still evaluating the optimal dose range, with 1,000 mg not ruled out. - [Punit Dhillon](CEO) and [Puneet Arora](CFO)

Contradiction Point 2

Sufficiency of Phase 2b Dose Selection

Whether the planned Phase 2b doses are adequate for efficacy.

Ted Tenthoff (Piper Sandler) - Ted Tenthoff (Piper Sandler)

2025Q4: The selected doses... are consistent with modeled peripheral target engagement needed for Phase 2b. - [Punit Dhillon](CEO)

Given the low brain penetration and likely safe CNS, are you considering higher doses of nimacimab beyond those outlined, and is there a reason to explore this further? - Michael DiFiore (Evercore ISI)

20251111-2025 Q3: The hope is to see a clear separation in weight loss trends between combination and monotherapy arms. - [Christopher Twitty](CSO)

Contradiction Point 3

Purpose of Monotherapy Dose Extension Data

The value and expected utility of the 300 mg monotherapy extension data.

What are your thoughts on the company's earnings performance this quarter? - Albert Lowe (Craig-Hallum)

2025Q4: The 300 mg dose data will not anchor efficacy expectations. - [Punit Dhillon](CEO)

Will you share the full extension data for the 300 mg monotherapy patients? - Catherine (Citizens for John Wolleben)

20251111-2025 Q3: The goal is to improve PK/PD understanding and see if higher doses can achieve the target efficacy (over 5% weight loss at 26 weeks). - [Punit Dhillon](CEO) and [Puneet Arora](CFO)

Contradiction Point 4

Intended Delivery Method for Phase 2b Study

Contradiction on whether Phase 2b will use IV or subcutaneous delivery.

Michael DiFiore (Evercore ISI) - Michael DiFiore (Evercore ISI)

2025Q4: ENHANZE-ready formulation will be used for Phase 2b. - [Punit Dhillon](CEO)

What is the rationale for using IV in Part C of the study instead of ENHANZE reconstituted at the site? - Edward Andrew Tenthoff (Piper Sandler)

2025Q2: The Arecor partnership aims to... enable less frequent dosing. - [Punit S. Dhillon](CEO)

Contradiction Point 5

Characterization of Arecor Formulation Program

Contradiction on whether the formulation program is a separate track or integrated with clinical development.

Jay Olson (Oppenheimer) - Jay Olson (Oppenheimer)

2025Q4: ENHANZE co-formulation work is ongoing and expected to be ready in time for the Phase 2b study. - [Tu](COO)

Can you discuss your plans to share data from higher dose cohorts above 200 milligrams, the status of your formulation work using Halozyme technology and a subcutaneous self-administered pen, and whether this formulation needs to be available at higher doses before proceeding to Phase 2b? - Edward Andrew Tenthoff (Piper Sandler)

2025Q2: This is a separate R&D track and does not interfere with clinical development. - [Punit S. Dhillon](CEO)