Nimacimab + tirzepatide combination results in 30% weight loss

Skye Bioscience's novel CB1 antibody, nimacimab in combination with the dual GLP-1/GIP agonist, tripeptide, resulted in greater than 30% weight loss. Nimacimab alone demonstrated 23.5% weight loss, comparable to monlunabant and tirzepatide alone (Figure 1).

Figure 1 - DIO model to interrogate combination of nimacimab and tirzepatide

Skye also shared new in vitro potency data demonstrating that nimacimab’s non-competitive allosteric binding to CB1 provides for a differentiated and potentially advantageous mechanism of inhibition versus small molecules like monlunabant, which must compete with CB1 agonists.

In this study, potency of nimacimab and monlunabant (Figure 2) were assessed against two concentrations of the CB1 agonist CP55940. The first condition evaluated potency of each drug with a lower concentration of CP55940 (50nM or EC80), while the second condition evaluated potency against an elevated concentration of CP55940 (2000nM or 40X EC80). These two conditions serve as a model of a physiological versus a pathological state where conditions such as obesity can promote an increase in the CB1 ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and thus competition for the CB1 receptor.

“These data demonstrate for the first time how nimacimab’s allosteric binding to the CB1 receptor is differentiated from the small molecules which bind to the receptor’s active orthosteric site. We know that in a disease state such as obesity, the CB1 receptor as well as its natural ligands, AEA and 2-AG, are upregulated. In this diseased state, there may be significant competition for the active binding site. In our in vitro experiment we aimed to recreate this potential situation,” said Dr Chris Twitty, Chief Scientific Officer of Skye. “The biological impact of these data suggests that when there is significant competition for CB1 binding, the activity of small molecules like monlunabant can be significantly impacted. Clinically this could result in impacting the relationship between pharmacodynamics and pharmacokinetics of the drug, ultimately requiring more of the small molecule to overcome the competition. Alternatively, nimacimab does not compete for the same site as the natural ligands, and our data show that as a result of this allosteric binding, the potency is minimally impacted regardless of the concentration of competing molecules.”

These data demonstrated that while nimacimab’s potency remained relatively stable, the activity of monlunabant when challenged with a higher concentration of a CB1 agonist was significantly impacted.

Figure 2 - Comparison of potency between monlunabant* and nimacimab** * Monlunabant’s potency dropped significantly at high agonist levels due to direct competition for the receptor’s orthosteric site. ** Nimacimab’s potency was preserved due to its allosteric binding mechanism that avoids direct competition.

“This new preclinical study highlights that a truly peripherally-restricted CB1 inhibitor, nimacimab, effectively drives weight loss in a diet-induced obesity (DIO) model. Nimacimab compared favourably to and provided significant additive weight loss when combined with GLP-1-targeted drugs like tirzepatide,” said Punit Dhillon, CEO of Skye. “Using higher doses, this study builds on our previous preclinical DIO data in human CB1 knock-in mice that showed significant dose-dependent weight loss. Biomarker analyses demonstrated that nimacimab-driven weight loss was associated with beneficial changes in key hormones, glycaemic control, and inflammatory markers. Skye believes nimacimab shows potential both as a monotherapy and in combination with a GLP-1 targeted drug to address unmet needs in obesity with the potential to change weight loss standards of care. Initial data from Skye’s Phase 2a study in obesity is expected in late Q3/early Q4 2025.”