Development of Estrogen Receptor B Selective Receptor Agonists to Treat Neuropath
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AbstractDESCRIPTION (provided by applicant): Neuropathic pain is a serious neurological disorder affecting approximately 1.8 million people in the United States. It is refractory to standard analgesic therapies, with all current neuropathic pain drugs providing relief to approximately 30% of patients. In addition, these drugs all have significant side effects. Consequently there is a clear unmet medical need for new safe and effective drugs to treat this serious and growing disorder. Acadia Pharmaceuticals has discovered highly selective estrogen receptor beta (ER )-agonists that are highly efficacious in animal models of neuropathic pain. Because of their high selectivity for ER , they do not produce the feminizing side effects attributed to estrogen receptor alpha (ERa) activation and display many desirable attributes for a drug candidate: no apparent cardiovascular liability or mutagenicity risks, and little or no potential for drug-drug interactions. No apparent side effects were seen in rats receiving doses 10x above maximally effective doses. These compounds have good metabolic stability in human liver, suggesting oral dosing in humans is feasible. Further, their bioavailability in rats is high (gt70%) when the compounds are given sublingually. Thus we believewe have several opportunities to develop these compounds as analgesic drugs. In this U44 Translational Research grant we will develop ER agonists as clinical candidates for treating neuropathic pain. In Phase 1, we will take leads, and determine their metabolic profiles in hepatocytes, their in vivo PK characteristics, and their permeability properties across buccal, epidermal, and intestinal (Caco2) cells. The metabolism and PK studies will allow us to predict the bioavailability in humans, and feasibility of oral dosing, while the permeability studies will provide data on the feasibility of buccal/sublingual and transdermal dosing. We will also complete in vitro safety screens for genetic, cardiovascular, or drug-drug interaction liabilities in parallelto the PK studies. We will take the compound with the best overall profile and conduct preliminary in vivo rodent toxicology and cardiovascular safety studies before initiating FDA-compliant GLP studies in Phase 2 SBIR studies. Our goal is to identify 1 ER agonist that can be administered to humans orally, sublingually or transdermally and that has manageable, or ideally no toxicity, including a NOEL at plasma concentrations at least 10-fold above pharmacologically effective concentrations. In Phase 2, the lead compound will be subject to IND-enabling toxicology, cardiovascular and genetic toxicology studies to provide the necessary supporting data for an IND submission. These studies will require GMP-grade material and will include in vitro and in vivo studies for genetic toxicity (Ames assay, chromosomal aberration assay, rat micronucleus), cardiovascular toxicity (hERG channel inhibition, cardiovascular monitoring in conscious, telemetered dogs or monkeys) and repeat dose toxicity studies for 28 days inrodent and non-rodent models. We will then schedule a pre-IND meeting with FDA to discuss the overall development pathway and understand key regulatory issues that may need to be addressed during the clinical program. PUBLIC HEALTH RELEVANCE: Acadia Pharmaceuticals is devoted to the development of novel, safe and efficacious drugs to treat neurological disorders and in this grant we propose to develop drugs targeting estrogen receptor B (ER ) to treat neuropathic pain, a serious neurological disorder that is generally not treated effectively by available medications. We have identified highly selective ER selective agonists and have conducted extensive preclinical testing with these prototypical drugs and found they were highly effective in a numberof animal models of neuropathic pain and they had many desirable pharmaceutical properties with no apparent side effects in rodents. Our goal in this grant is to optimize our ER agonists and conduct standard IND enabling studies including toxicology to be able to begin clinical development of our ER selective agonists for treating neuropathic pain.
* information listed above is at the time of submission.