Technology

We believe nimacimab, a new and distinct class of CB1 inhibitor, has the potential to become a leader in this space. The CB1 receptor is a therapeutic target implicated in several diseases where CB1 receptors are upregulated, including obesity, pulmonary fibrotic diseases, fibrotic liver diseases, and kidney disease. Early generations of CB1 inhibitors experienced challenges due to adverse effects on the central nervous system caused by inhibiting the CB1 receptor in the CNS. Nimacimab is a peripherally-restricted negative allosteric modulator antibody, differentiating it from small molecule CB1 inhibitors. Because it doesn’t readily cross the blood-brain barrier (BBB), it minimizes the risk of psychiatric side effects such as anxiety and depression that have been seen in the past with small-molecule CB1 inhibitors.

Nimacimab has multiple advantages. First, it readily inhibits CB1 signaling when compared to well-established clinical and control compounds. Second, as an antibody, which is a large molecule, nimacimab does not cross the blood brain barrier. This is highlighted in rigorous preclinical studies which demonstrated in cynomolgus and rhesus monkeys that there is no accumulation of nimacimab in the brain and cerebral spinal fluid, even at doses significantly higher than the anticipated effective doses in humans. There was also no nimacimab-related toxicity, including neurological observations, indicating this drug is truly restricted from entering the brain. Phase 1 studies showed no impact on cognitive function or effects of anxiety or depression. In addition, clinical studies showed preferable bioavailability, limited anti-drug antibody formation and PK of nimacimab of approximately 18-22 days. Taken together, these data support the promise of safely and effectively targeting peripheral CB1 receptors to treat disease with nimacimab without potential central nervous system liabilities.

This drug has completed a Phase 1 safety study and is ready for a proof-of-concept Phase 2 study, which is being planned for 2024.

Nimacimab and obesity

The obesity drug market is a global opportunity that is very large and growing. The adoption of the breakthrough GLP-1 drugs has been explosive but also revealed the need and opportunity to enhance the nature of the outcomes of weight loss drugs. Existing approved drugs impact signaling that reduces appetite and increases satiety, but their side effects include nausea, vomiting and diarrhea. Up to 40% of the weight loss can be due to the loss of lean muscle.

Nimacimab’s function of peripherally inhibiting the CB1 receptor outside of the central nervous system offers a promising mechanism of action and therapeutic profile for achieving weight loss. Its ability to target CB1 in adipose tissue, where fat is stored, enables nimacimab to directly affect metabolic processes to “burn” fat. It also indirectly causes signaling to the brain that can decrease hunger. There is validated historical evidence of this mechanism’s ability to reduce weight and also its bias to reduce fat over muscle. CB1 inhibition has in past studies achieved a more favorable side effect profile compared anecdotally to today’s GLP-1 drugs.

Importantly, an issue of the first generation of CB1 inhibitor, which resulted in anxiety, depression, and suicidal thoughts, has been overcome by nimacimab’s distinction of being a large molecule monoclonal antibody rather than a small molecule. Unlike the easier ability of small molecules to pass through the blood-brain barrier into the central nervous system, nimacimab has virtually undetectable penetration into the brain and shown no evidence of neuropsychiatric effects. It is distinct from other peripheral CB1 inhibitors.

The competitive field for CB1 inhibition is limited. This mechanism was the target of one established pharmaceutical company with an approved GLP-1 drug for obesity – they acquired a Phase 2 peer. Skye is starting its Phase 2 study of nimacimab mid-summer 2024. The promise of peripheral CB1 inhibitors as both monotherapies and in combination GLP-1 receptor agonists looks promising and will be substantially explored over the next years.

SBI-100 Ophthalmic Emulsion (“OE”) a novel synthetic prodrug of tetrahydrocannabinol (THC), is a proprietary topical formulation under development for the treatment of glaucoma and ocular hypertension (OHT).

Third party research in humans has shown that THC can reduce intraocular pressure (IOP), which is partly responsible for the crush-like injury to optic nerve cells that can result in blindness associated with glaucoma. Other nonclinical studies have shown the unique potential for THC to also provide neuroprotective benefit – which no other approved drug offers and may be especially important to patients experiencing glaucoma disease progression with normal IOP levels.

The prior research also highlighted the drawbacks of the available methods of THC administration assessed: smoking, oral ingestion, and topical formulations (using mineral oils) applied to the eye. These drawbacks included short duration of effect, toxicity, and psychotropic effects. While local topical administration of THC is alluring, the inherent lipophilic nature of THC and delivery formulations used makes them incompatible with the aqueous nature of the eye, ie oil and water don’t mix. They have not worked.

Skye’s SBI-100 OE consists of chemically-modified THC, resulting in a unique synthetic THC derivative molecule, combined with a proprietary nanoemulsion formulation, both elements designed to enable topical administration and significant penetration into different compartments of the eye. Our objective is to achieve a clinically-validated drug that provides IOP-lowering benefits while minimizing side effects. In the future we would also aspire to characterize neuroprotective benefits of SBI-100 OE that would be unique in the clinical realm.

SBI-100 Ophthalmic Emulsion and glaucoma

Glaucoma is a subset of eye diseases that can cause vision loss and blindness by damaging cells of the optic nerve in the back of the eye. With certain types of glaucoma, damage to the optic nerve is caused by increased IOP due to improper drainage and/or overproduction of fluid in the eye.

According to the Glaucoma Research Organization, glaucoma affects over 60 million people worldwide and is the leading cause of blindness in adults aged 60 and older.

Current therapies attempt to lower IOP by either decreasing fluid production or increasing drainage of fluid. However, nearly 40% of patients will not respond to first-line therapies, and 50% of patients will eventually require taking two or more classes of therapy to manage their IOP, creating a significant opportunity for new and more effective classes of therapy.

In nonclinical studies, Skye’s SBI-100 Ophthalmic Emulsion demonstrated a greater and longer-lasting reduction of IOP compared to leading commercialized drugs in the glaucoma market. These studies also demonstrated:

• SBI-100 Ophthalmic Emulsion is better at penetrating various compartments of the eye than natural THC
• THC in an ex vivo model demonstrated a reduction of biomarkers related to fibrosis and inflammation in conjunction with lowering of IOP, supporting a multimodal mechanism of action.

In the first human study of SBI-100 OE, the drug was deemed safe and well-tolerated, there was little to no exposure of THC in plasma, and significantly less hyperaemia (red eyes) compared to other glaucoma therapies. Minimal discomfort common to topical ocular administration was transient and quickly resolved. The study demonstrated a 23.9% lowering of intraocular pressure in a sub-group analysis of healthy volunteers with a higher baseline IOP compared to the overall group.

Skye owns granted U.S. and foreign patents, and pending US and foreign patent applications, directed to the compositions of matter for the nimacimab antibody and molecular variants and to methods of treatment and uses of nimacimab and its variants for treating a number of diseases responsive to the modulation of the CB1.

Skye has an exclusive “all fields” license agreements for SBI-100 with the University of Mississippi, giving Skye the right to develop theses molecules to treat any disease through any form of delivery. The patents encompassed by these agreements cover composition of matter and methods of use.

Skye intends to continue to seek patent protection for certain of its product candidates, drug delivery systems, molecular modifications, as well as other proprietary technologies and their uses in the U.S. and globally.