InMed Pharmaceuticals provided an update on the preclinical results from its INM-088 drug development program that indicate a potential neuroprotective effect of cannabinol (CBN) on nerve cells located in the eye. INM-088 is being developed as a potential treatment option for ocular diseases, such as glaucoma, where neuroprotection may provide an added therapeutic benefit.
The first in vitro preclinical study evaluated the neuroprotective effects of several individual cannabinoids, including CBN, tetrahydrocannabinol (THC) and cannabidiol (CBD), on differentiated retinal ganglion cells, or RGCs, that form a thin layer of neurons responsible for relaying visual signals in the eye. This particular study examined the effects of cannabinoids on RGCs under normal atmospheric pressure and elevated pressure conditions as a model of raised IOP. Elevated pressure mimicking high IOP had a cytotoxic effect on the RGCs. However, the combination of CBN and elevated pressure, within the same time period, resulted in a high level of cell survival in a dose dependent fashion. CBN was superior to both CBD and THC under identical testing conditions. This data indicates a potential neuroprotective effect of CBN in ocular disease, according to InMed Pharmaceuticals.
Next, using the same in vitro model described above, InMed examined the potential effect of CBN on reducing or preventing natural RGC cell death, or apoptosis. Data indicate that CBN has a significant anti-apoptotic effect on differentiated RGCs subjected to elevated pressure conditions. Exposure of RGC to high pressure for a period of 6 hours led to apoptosis ranging from 30-60%, whereas the addition of CBN resulted in a significantly higher level of cell survival.
Elevated IOP in glaucoma is often attributed to decreased aqueous humor outflow through the trabecular meshwork of the eye. Additionally, the cytokine TGF-β2 has been found to be aberrantly elevated in correlation with increased TM outflow resistance. Therefore, the company evaluated CBN exposure to primary TM cells under these simulated glaucoma condition through either increased pressure conditions or by elevating TGF-β2. TM cells exposed to CBN under a range of conditions, including normal pressure or elevated pressure or TGF-β2 exposure, for a duration of 72 hours, demonstrated deceased expression of protein markers associated with reduced TM outflow. These results suggest that CBN may have potential to reduce IOP through improvement in the aqueous humor outflow in the TM.
InMed also conducted several in vivo experiments to understand the pharmacokinetics and effect of CBN in the eye. The first of these studies was designed to specifically measure CBN levels in the eye and plasma following direct bilateral intravitreal (IVT) injection into the fluid of the central cavity of the eye. Following IVT delivery, systemic plasma levels of CBN were found to be below detectable limits, whereas CBN levels in the eye were shown to persist for an extended period of time with a projected half-life (t1/2) of approximately 33 hrs. These results present the prospect of high CBN localization at the site of intended treatment.
In addition, InMed conducted an in vivo efficacy study to evaluate neuroprotective and IOP lowering effects of CBN following IVT injection in the recognized episcleral vein laser photocoagulation model for glaucoma. Biological function of the neurons was assessed through pattern electroretinogram (pERG) measurement of neuronal electrical activity in response to light. Results demonstrated reduced IOP and improvement of pERG function when CBN was delivered by IVT injection after episcleral laser photocoagulation.
“Results from these preclinical in vitro and in vivo studies, which also served as the basis for our recently filed PCT patent application, highlight the potential for CBN to contribute an independent neuroprotective effect in addition to the standard IOP reduction approach to treating glaucoma,” Dr. Eric Hsu, InMed’s Senior Vice President of Preclinical Research and Development. “We are now well positioned to advance towards selection of a suitable topical formulation for CBN delivery to the eye and anticipate commencing IND-enabling toxicology studies with INM-088 in the latter half of 2020”.