A Multiple Sclerosis disease-modifying therapeutic that activates the PPARγ pathway expressing both anti-inflammatory and neuroprotective bioactivities

Multiple sclerosis (MS) affects 2.5 million people worldwide, of which 400,000 are in the USA and 500,000 in the EU. According to Cleveland Clinic estimates, MS-related health care costs exceed $10 billion per year in the United States. Despite being the most common demyelinating disease of the CNS, there are as yet no satisfactory treatments for MS. A clear need exists for the development of agents able to treat this progressive disorder.MS is a demyelinating and neurodegenerative disease of the CNS, which is one of the main causes of irreversible neurologic disability in young adults. MS is notoriously heterogeneous in terms of its clinical manifestations and evolution, as well as in terms of its immunopathological substrates.

Pathogenesis of Multiple Sclerosis

MS pathogenesis involves inflammatory demyelination and axonal degeneration. Myelin-specific degeneration auto-reactivates T-cells that infiltrate the CNS and activate other inflammatory cells, which drive MS inflammatory processes. Microglial activation contributes to MS pathology through antigen presentation and secretion of pro-inflammatory mediators. In addition, macrophages and microglial cells participate in demyelination and phagocytosis of the degraded myelin. Demyelination and axonal damage produce MS clinical symptoms such as functional impairment, neuropathic pain, and disability.

Multiple Sclerosis Drugs

Although MS is currently considered ‘incurable,’ many different approaches to therapy have been proposed, with different degrees of effectiveness and risk. Newer immune-modifying biologics (Tysabri), while highly effective, carry significant risks, e.g. progressive multifocal leukoencephalopathy (PML) that has required recent re-labeling by the FDA as a potential serious adverse effect. Other medications include beta-interferons, glatiramer acetate, Gilenya, and mitoxantrone. Recently, two new additional disease-modifying agents, teriflunomide (Aubagio) and dimethyl fumarate (Tecfidera, Biogen) were also approved by the FDA for treating relapsing-remitting MS (RRMS). These small-molecules, orally available mechanism-based therapies represent the ‘next wave’ of highly specific and selective biological response modifiers, which have greater potency, effectiveness and fewer ‘off-target effects.’

Cannabidiol (CBD)

CBD has multiple activities on key molecular targets involved in neuroinflammatory and neurodegenerative diseases. We plan to utilize a proprietary enabling technology platform [US Patents] to nanoencapsulate CBD into a final drug product in order to enhance the oral bioavailability of this first in class compound and bypass first-round metabolism in the liver, thereby improving its safety and increasing therapeutic efficacy. This is a green technology that has been previously used to nanoencapsulate 9-THC without using organic solvents [US Patent]. Cannabinoids are a group of chemicals exemplified by Δ9-tetrahydrocannabinol (Δ9-THC), Cannabigerol (CBG) and Cannabidiol (CBD) the main components of Cannabis sativa. Phytocannabinoids like Δ9-THC and CBD show a beneficial effect on neuroinflammatory and neurodegenerative processes through cell membrane cannabinoid receptors (CB1 and CB2) dependent and independent mechanisms. In fact, Sativex®, a botanical drug containing equal proportions of Δ9-THC and CBD, has been approved in EU and Canada for treatment of spasticity in MS. Moreover, Δ9-THC, CBD, and other cannabinoids have been shown to mediate their anti-inflammatory effects through the activation of PPARγ and CB2 pathways. The safety and toxicological profile of cannabinoids combined with their lipophilic structure and good penetration across the blood-brain barrier make them good candidates for the development of drugs for neuroinflammatory diseases. Our CBD product will differ significantly from Sativex® (GW Pharmaceuticals), a cannabinoid medicine, which was recently approved as a second-line treatment in Canada, New Zealand, and 8 European countries for the treatment of spasticity due to MS. Sativex® contains the psychotropic Δ9-THC and the non-psychotropic cannabidiol (CBD) and has alcohol content in its formulation. By comparison, our CBD product will be formulated in aqueous-phase nanoparticles for oral administration and is non-psychotropic and only palliative for MS.

Orally Bioavailable Nanotechnology Formulation

APH-1403 is a nanotechnology formulation of CBD designed to increase its oral bioavailability. APH-1403 is manufactured using an environmentally friendly enabling technology platform to nanoencapsulate CBD in biodegradable polymer nanospheres [US Patents]. This nanoformulation enhances the oral bioavailability of this first-in-class compound which bypasses first-round metabolism in the liver, thereby improving its safety and increasing therapeutic efficacy. This green nanotechnology platform has been previously used to nanoencapsulate a similar molecule class without the use of organic solvents [US Patent]. If successful, the introduction of CBD as an orally available biological response modifier will allow earlier and simpler treatment for MS flares, and prevent progression of disability and primary/secondary progressive MS (PPMS/SPMS).