|BBB is the major challenge for Drug Development for Neurology
Drugs, treated as foreign molecules by the blood–brain barrier (BBB) and the blood–retinal barrier (BRB), are unable to pass into brain and retina of eye, respectively. In fact, over 98 per cent of drugs do not show useful activity in the brain due to poor or no penetration of the BBB. The BBB is 4 fold tightener than BRB. BBB and BRB is the barriers that consists of cells that are joined tightly together.Beginning from the late ‘60’s, Palmitoylethanolamide (PEA) is available in the US and Europe as a food supplement, and medicine. It is tested in various clinical trials in over 4000 patients suffering from various neuropathic pain states. Almost all reported significantly reduced pain intensity and an almost complete absence of unwanted effects. However, its efficacy is seriously limited by its low nerve bioavailability. Even if orally administered at high doses, still produces limited systemic and nerve exposure levels, with plasma concentrations remaining in the nM range, and with increases only for a short period of time.
| PPAR gamma
The intended biological target is PPAR gamma. PPAR gamma is a nuclear receptor is activated by a variety of endogenous fatty acid derived compounds (e.g., PEA), and synthetic diabetes drugs (e.g., pioglitazone and rosiglitazone). Our company is the only company that modified the chemical structure of PEA, and improve it brain bioavailability by 83 folds, and thus significant improve the therapeutic window.
|Efficacy of ELB00824 for treating neurological diseases
Since 2015, Prof. Westlund verified the key role of PPAR gamma in neuropathic pain. Then Elixiria decided to use PPARgamma as the target to develop drug for neuropathic pain treatment. Elixiria did computer-assisted drug virtual screening, synthesized the leads, in vitro screen with stable cell lines, and ultimately identified ELB00824 with high in vitro PPARgamma activity, and highest in vivo nerve permeability.
|In preliminary oral dose range-finding/PK studies, ELB00824 was safe when rats were orally administered at a dose up to 450 mg/kg once daily for 2 weeks, equivalent to 150-fold of effective dose, indicating a wide therapeutic window. No significant alterations of neurotoxicity were noticed. In addition, the hematological, blood coagulation and serum biochemistry parameters were analyzed at termination of dosing. No significant changes were observed in any of the values of the 55 parameters studied when compared with controls.|
|1. Trigeminal neuropathic pain: It is the most difficult to treat among all neuropathic pains. At the Prof. W estlund’s lab in the Univ. of New Mexico, sustained relief by ELB00824 was evidenced in animal models of trigeminal neuralgia, given by 3 different routes (i.p., oral, topical) of administration. The figure below indicates how to evaluate pain with von Frey filament to detect whisker pad mechanical threshold.
2. Painful diabetic neuropathy: Elixiria also tested two models of Painful diabetic neuropathy. After 21 day treatment, significant inhibition of pain was detected in mouse and rat models, along with the effect on lowering blood sugar, indicating ELB00824 provides good pain relief. These results encourage us to continue the preclinical development.
3. Alzheimer’s disease: Elixiria treated Alzheimer’s disease mice (APP/PS1) with ELB00824 for 1 month. Improvement in memory of the treated mice was evidenced by significant lower number of reference memory errors. We also isolated brain RNA. ELB00824 was related to clearance of beta-amyloid (evidenced by APOE1, and ABCa1 genes), neuroprotection (Bcl-XL), neuronal and synaptic function (Gng11, and GluN2B), anti-inflammatory response (TNF-a, IL-1b, and TGF-b1), anti-oxidative response (MnSOD, Prx-2 and Klotho).
4. Age-related macular degeneration (AMD): ELB00824 was found to protect retinal-derived neuron and microglia. It readily cross the BRB when applied as ointment on the eye.