Novel Glycosylated Delta Opioid Receptor Agonists for Chronic Inflammatory Pain
Small Business Information
51 FOLLEN RD, LEXINGTON, MA, 02421
AbstractDESCRIPTION (provided by applicant): Traditionally, Mu opioid receptor (MOR) agonists have not been given as first line treatments for neuropathic pain due to their significant adverse side effects. Biousian Biosystems Inc, (BBI) is developing novel glycosylated peptide-based delta opioid receptor (DOR) targeted drugs for the treatment of chronic pain. Preclinical profiles for DOR agonists indicate broad-spectrum analgesic efficacy with greatly reduced side effects compared to the currently used MOR opioidanalgesics. The glycosylation of DOR selective peptides also represents a BBI platform technology that improves stability and enhances other PK characteristics of the parent peptide including oral and CNS bioavailability, issues that have impeded the development of peptide- based therapeutics. A successful glycopeptide drug would represent a novel, first in class therapeutic agent with significant advantages, thereby transforming the development of peptide, as well as pain therapeutics. BBI successfully completed its phase I SBIR grant, meeting or exceeding all milestones within the specific aims, and doing so on time and within budget. This included the synthesis of a library of glycosylated deltorphin-based peptides that possess predicted selectivity and efficacy for the delta opioid receptor (DOR). More specifically, a lead candidate emerged (BBI 11008) and backups were identified. These compounds have high affinity (low nM) and functional potency in vitro, and are at least 1000x functionally selective forDOR over MOR and kappa opioid receptors (KOR). Select compounds were advanced into in vivo antinociceptive studies, and demonstrated excellent efficacy in acute thermal nociceptive and sub-acute inflammatory pain models. Additional studies were performedin parallel with Phase I funded RandD efforts in order to begin assessment of safety/side-effect profiles and oral formulation/bioavailability. This phase II SBIR application is a logical extension of the RandD successfully completed in the company's PhaseI award. The proposed studies will further advance the pharmacology of a lead compound (BBI 11008) through a development tract that, if successful, will culminate in a successful IND filing. This will be achieved in Specific Aim 1a by determining and critically evaluating the DMPK properties of BBI 11008 and in Specific Aim 1b by identifying potential safety risks of the lead candidate BBI 11008. In Specific Aim 2, we will assess the potency and efficacy of BBI 11008 in the rat spinal nerve ligation (SNL)model of neuropathic pain. Finally, in Specific Aim 3, the relative side effect advantage of BBI 11008 will be determined compared to drugs used in neuropathic pain. BBI 11008 will be assessed in in-vivo models of respiration, abuse potential, tolerance/dependence and gastric motility and compared to side effects typically associated with traditional MOR agonists, e.g. morphine and/or gabapentin, a drug commonly prescribed for neuropathic pain. The research is complemented by a commercialization plan and the drug development expertise of BBI employees, advisors and collaborators as documented in the grant application, biosketches and support letters. PUBLIC HEALTH RELEVANCE: Traditionally, Mu opioid agonists have not been given as a first line treatment for neuropathic pain due to their significant adverse side effects. Biousian Biosystems, Inc (BBI) is developing novel glycosylated peptide-based, delta opioid receptor-targeted drugs to treat chronic pain with improved efficacy and without the significant side effects of currently used opioid analgesics. BBI plans to continue a successful Phase I program with studies that will further advance the pharmacology of a lead compound (BBI 11008) through a development tract that, if successful, will culminatein a successful IND filing.
* information listed above is at the time of submission.