Poster Number-32 - Enkephalin as a Novel Analgesic: Efficacy and Safety in Pre-Clinical Models

Enkephalin as a Novel Analgesic: Efficacy and Safety in Pre-Clinical Models

Purpose: Enkephalin is an endogenous peptide with central analgesic properties that binds to the delta opioid receptor and has been shown to spare typical mu-opioid toxicities. There are 2 main forms of the molecule, methionine- and leucine-enkephain (M-ENK and L-ENK). Unfortunately, enkephalins are subject to rapid metabolism and degradation and to date have not been successfully developed for use as analgesics. Using a novel encapsulation method known as Molecular Envelope Technology (MET), we have developed a "protected" form of leucine enkephalin. MET is composed of a modified chitosan derivative also known as GCPQ (N-palmitoyl-N-monomethyl-N, N-dimethyl-N, N, N-trimethyl-6-Oglycolchitosan). Delivered intranasally, MET promotes L-ENK delivery through the olfactory nerve, across the blood brain barrier, and into the CNS. 
We were awarded a cooperative research and development agreement (CRADA) with the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) to support Good Manufacturing Practices (GMP) production of drug substance and drug product, as well as to support Good Laboratory Practices (GLP) toxicology, safety studies and preclinical efficacy studies. Our goal was to characterize the safety and efficacy of the MET-LENK formulation.

Methods:

A range of pharmacologic, toxicology and efficacy studies were carried out. Using a rat model, we assessed the distribution of MET and L-ENK in the blood, cerebrum, cerebellum olfactory bulb, nasal cavity, and systemic organs following intranasal administration. Following MET/L-ENK dosing, rats were sacrificed at 0, 2, 10, 20, 30, 45, 60, 120, or 240 minutes, and blood, cerebrum and olfactory bulb were harvested for LENK biodistribution using LC-MS/MS.
14-day dose range toxicity studies were performed in both rats and dogs. Anti-hyperalgesic efficacy assessments in rats were performed using a chronic pain spared spinal nerve ligation (SNL) model.

Results: Dose range finding (DRF) studies were performed in rats and dogs, with no treatment related clinical signs or mortality noted.
Analysis of L-ENK concentrations in plasma showed peak levels at 10 minutes post-dosing, after which LENK values began to plateau at 20-30 minutes. L-ENK concentrations in the olfactory bulb were highest at 45 minutes post-dosing. 
In preclinical efficacy studies, animals dosed with MET-LENK showed a strong anti-nociceptive response versus control in multiple assays of evoked pain. A dose-response with intranasal MET-LENK was noted in a Complete Freund’s Adjuvant (CFA) anti-hyperalgesia model versus intranasal placebo and subcutaneous morphine. No analgesic tolerance was noted. 

Conclusion:

There is a significant unmet need for effective analgesics with limited or no abuse potential. We sought to investigate the preclinical safety and efficacy of a novel L-ENK formulation. No significant safety signals were noted, and data suggests an analgesic response when the MET/L-ENK formulation was delivered intranasally. This compound warrants additional investigation and advancement through further clinical trials. If data confirms analgesic benefit without respiratory depression or addiction, this enkephalin formulation may represent a potential broad-spectrum molecule to treat multiple types of acute and chronic pain and potentially other CNS disorders.  

 

References: Godfrey L, Iannitelli A, Garrett NL, Moger J, Imbert I, King T, Porreca F, Soundararajan R, Lalatsa A, Schätzlein AG, Uchegbu IF. Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. J Control Release. 2018 Jan 28;270:135-144.