SBI-100 OPHTHALMIC EMULSION: RECENT DEVELOPMENTS

 

SBI-100 is a pro-drug of Tetrahydrocannabinol (THC), which is being evaluated as a topical agent in ophthalmic suspension form.

For further information on marijuana in glaucoma, please follow the link below:

https://ourgsc.blogspot.com/search?q=marijuana

The agent could be useful in the treatment of glaucoma and ocular hypertension.

The agent has undergone a Phase 1 study with 2 cohorts each of 8 patients.

Skye Bioscience, Inc., the parent company, has received positive recommendation following a pre-specified data review by the safety review committee (SRC). The SRC has recommended that the trial continue without modification. The company shall be recruiting the third cohort soon.

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

Previous preclinical studies have shown the potential for THC to also provide neuroprotective benefit, which may be especially important to patients with glaucoma who are experiencing disease progression with normal IOP levels.

One of the major drawbacks of previous studies concerning the use of THC for glaucoma was that they relied on inhalation or ingestion of THC. These systemic routes of drug administration cause negative side effects like psychotropic changes and potentially decreasing blood pressure, which resulted in the American Academy of Ophthalmology determining that the adverse effects of systemic cannabis administration/consumption outweighed its therapeutic benefit.

Skye has chemically modified THC to create a unique synthetic molecule with the intent to safely realize the known positive effects of THC. The molecule enables enhanced local delivery in the eye, reduced systemic side effects, and the potential for neuroprotection for the treatment of ocular diseases.

HIGHLIGHTS:

SBI-100 OE is a cannabinoid receptor type 1 (CB1R) agonist delivered topically into the eye. It is a synthetic cannabinoid derivative to treat glaucoma and ocular hypertension. SBI-100 OE possesses a “novel molecular structure and formulation that was rationally designed to enable better penetration of ocular tissue and effective topical delivery of a CB1R agonist.”

https://skyebioscience.com/

BETA BLOCKERS: MECHANISMS OF ACTION

 

β-adrenergic receptors are found in many different tissues (vascular, cardiac, pulmonary, and ocular). The receptors in the heart and blood vessels are primarily β1, whereas those in the lung are primarily β2.

Agents that block both β1- and β2-receptors are classified as nonselective, whereas agents that primarily block β1-receptors are classified as cardio-selective or simply as selective β1. Blockade of β1-receptors in the heart can induce or exacerbate heart block, bradycardia, and cardiac failure. Blockade of β2-receptors can precipitate bronchospasm, dyspnea, and respiratory failure, especially in patients with asthma or chronic obstructive pulmonary disease.

β-adrenergic antagonists competitively (reversibly) inhibit the binding of catecholamines at the β-adrenoreceptor.

In the eye, the sites for receptor interaction of these drugs are suggested to be β-adrenergic receptors in the iris and ciliary body.

The highest density of receptors was reported in the ciliary processes (180 fmol/mg of protein), whereas the density of receptors in the iris (98 fmol/mg of protein) and ciliary body (42 fmol/mg of protein) is notably lower.

Most of the β-adrenergic receptors in the human iris-ciliary body are of the β2 subtype. β2-adrenergic receptors have also been detected in cultured human trabecular cells and in the human trabecular meshwork.

The most commonly accepted theory of the mechanism of IOP reduction by topical β-adrenergic antagonists is that by blocking the β-receptors in the ciliary epithelium, aqueous production is suppressed, thereby lowering IOP.

It has been suggested by Mishima that β-adrenergic antagonists lowered IOP by reducing aqueous humor formation.

Timolol does not appear to be effective in sleeping human participants during which time the aqueous flow is normally less than half the daytime flow rate. However, timolol does lower aqueous flow at night in humans receiving systemic epinephrine. Based on these clinical observations in certain diseases known to affect the sympathetic nervous system and normal physiologic conditions, the precise mechanisms by which the sympathetic system regulates aqueous humor dynamics is complex and not fully understood.

Although the outflow facility is not apparently affected by beta-blockers there is a school of thought which points to the presence of β-receptors in the trabecular meshwork which could play a role in enhancing aqueous outflow through the conventional pathway.

A histologic study of the outflow apparatus in human eyes treated with timolol before enucleation for malignant melanoma revealed no morphologic changes suggestive of a pressure-lowering action by the drug. However, the trabecular meshwork in primates after long-term timolol therapy revealed degeneration of the trabecular cells, partial destruction of the beams, rarefaction of the meshwork, and disconnection of the trabecular lamellae from the ciliary muscle fibers.

In experiments conducted by Neufeld, topically applied timolol did not increase cyclic adenosine monophosphate (cAMP) levels in the aqueous humor of rabbit eyes or stimulate cyclic AMP formation by ocular tissues, indicating that the drug has no intrinsic β-adrenergic agonistic activity. He postulated that timolol may cause vasoconstriction of blood flow to the ciliary body, thus decreasing aqueous humor production.

The possible effect of ß-blockers on ocular blood flow is complex and involves consideration of the various vascular beds, including the ciliary, retinal, choroidal, and retrobulbar vessels located within their respective tissues. There are conflicting effects of the topical ß-blockers on ciliary systolic perfusion pressure.

Van Buskirk experimentally confirmed that topical β-blockers, namely timolol maleate and betaxolol hydrochloride, cause substantial, localized constriction in the arterioles that supply the ciliary processes. However, Millar and Wilson found no change in vascular resistance in arterially perfused bovine eyes after administration of timolol.

Experiments by Crook and Riese showed that Timolol, propranolol, and betaxolol inhibited the cotransport of the ions in ciliary epithelial cells, suggesting that aqueous humor production decreases due to the inhibition of Na+/K+/Cl- cotransport. Inhibition of Na+/K+/Cl- cotransport also inhibits cAMP formation, indicating that β-adrenergic antagonists may inhibit cAMP formation in ciliary epithelial cells.

Maren did confirm that aqueous humor production was reduced with timolol, but did not find similar reduction of sodium transport from plasma to aqueous humor as seen with carbonic anhydrase inhibitors.

Kiland et al. studied the mechanisms of timolol on aqueous suppression and ultrafiltration and confirmed that timolol does decrease the formation of aqueous humor, but does not enhance filtration or increase the outflow facility of aqueous humor through the trabecular meshwork. Kiland found that timolol does not affect levels of ascorbate in the aqueous humor indicating that timolol may not inhibit the Na+/glucose transporter.

VITAMIN B3 TREATMENT FOR GLAUCOMA

 

• Increasing age and high intra-ocular pressure (IOP) interact to drive neurodegeneration.
• An experiment was conducted by a group of researchers using DBA/2J (D2) mice, a widely used model of chronic, age-related, inherited glaucoma to analyze the effect of vitamin B3.

https://pubmed.ncbi.nlm.nih.gov/28209901/

• RNA-sequencing (RNA-seq) was utilized to elucidate age and IOP-dependent molecular changes within retinal ganglion cells (RGCs) that precede glaucomatous neurodegeneration.
• Emerging evidence suggests that imbalances in the relative proportions of mitochondrial proteins encoded by nuclear and mitochondrial genomes negatively impact mitochondrial function.
• Differential expression of genes encoding mitochondrial proteins, and significant enrichment of differentially expressed (DE) genes in the mitochondrial dysfunction and oxidative phosphorylation pathways further point to mitochondrial abnormalities.
• Electron microscopy (EM) studies in the experiment revealed abnormal mitochondria with reduced cristae volume in the dendrites of D2 RGCs, but not in those of control RGCs.
• A number of studies demonstrate that mitochondrial perturbations are among the very first changes occurring within RGCs during glaucoma.
• Retinal levels of nicotinamide adenine dinucleotide (NAD+; a key molecule in energy and redox metabolism) decrease with age, and render aging neurons vulnerable to disease-related insults.
• The current study reported early decreases in metabolites that are central to healthy mitochondrial metabolism and protection from oxidative stress (NAD+ and NADH [total NAD; NAD(t)], GSH and GSSG [total glutathione; glutathione(t)]).
• RGCs go through a period of mitochondrial stress and metabolite depletion, potentially moving towards fatty acid metabolism. Fatty acid β-oxidation can increase generation of free radicals/reactive oxygen species (ROS).
• Oral supplementation of vitamin B3/nicotinamide (NAM; a precursor of NAD) has been successfully used to correct disturbances in NAD+ metabolism in two mouse models of pre-eclampsia.
• In this experiment NAM was administered to D2 mice, initially at the same dose (550 mg/kg/d, NAMLo). NAM administration in drinking water prevented the decline of NAD levels through to 12 months (a standard end stage for assessing neurodegeneration in this glaucoma model).
• Supporting the neuronal vulnerability hypothesis, NAMLo did not alter IOP, but protected from glaucoma. NAM was protective both prophylactically (starting at 6 months, prior to IOP elevation in most eyes) and interventionally (starting at 9 months, when the majority of eyes have had continuing IOP elevation).
• NAM significantly reduced the incidence of optic nerve degeneration, prevented RGC soma loss and retinal nerve fiber layer thinning, and protected visual function as assessed by PERG.
• NAM administration was sufficient to inhibit the formation of dysfunctional mitochondria with abnormal cristae and also limited synapse loss that occurs in this model.
• Attempting to further decrease the probability of glaucoma, a higher dose of NAM was administered (2000mg/kg/d; NAMHi). NAMHi was extremely protective with 93% of treated eyes having no optic nerve damage. The degree of protection afforded by administering this single molecule is unprecedented and unanticipated.
• Although NAMLo demonstrates a clear neuroprotective effect (no effect on IOP), NAMHi lessens the degree of IOP elevation.
• This indicates that NAM can protect against age-related pathogenic processes in additional cell types to RGCs. Therefore vitamin B3/NAM, a single molecule that protects against both IOP elevation and neural vulnerability, has great potential for glaucoma treatment, however human studies are needed.