Microbial biosynthesis of opioid antagonists a novel low cost method for producing addiction pharmacotherapies

Abstract Medicinal opioids are essential medicines for treating pain but exhibit addictive properties The United States has committed significant resources to curb opioid dependence and overdose The nal opioids a suite of antagonist and mixed partial agonist opioids are an important group of pharmacotherapies used in drug addicted patients for treating overdose managing symptoms during detoxification and maintenance by blocking reward responses In pain management patients nal opioids are used in combination with opioids to prevent addiction and abuse and to reduce side effects Current production methods for nal opioids are inefficient expensive and rely on the farming of a drug crop The raw starting materials for nal opioid synthesis are natural opiates that are extracted from opium poppy and subsequently chemically modified through a series of inefficient reaction steps As a result of the costs associated with this process nal opioids command a substantially higher price than opiates that have not been chemically modified For example natural morphine active pharmaceutical ingredient API retails for $ kg whereas naloxone and buprenorphine cost $ kg and $ kg respectively Antheia s technology will produce nal opioids efficiently and at a fraction of the cost of the current production methods The novel technology allows for total biosynthesis of nal opioids by yeast fermentation thereby removing the reliance on drug crop farming and changing the way these life saving therapeutics are manufactured Antheia will leverage its existing technology for producing opioids in yeast and extend the biosynthetic capabilities of these strains to include precursors of the nal opioids and ultimately the end products naloxone naltrexone and buprenorphine Technoeconomic models indicate that Antheia s unique technology will result in greater than a fold reduction in the cost of producing these compounds The objective of this Phase I SBIR project will be to develop engineered yeast strains that produce high levels of noroxymorphone the direct precursor for the nal opioids naloxone and naltrexone through whole cell biocatalysis First a yeast strain capable of high level oxycodone biosynthesis will be constructed by the addition and optimization of two enzymatic steps to Antheia s existing opioid production strains Second two novel O demethylase and N demethylase enzyme activities will be developed with enzyme evolution and a high throughput colorimetric screening assay Finally the O and N demethylase activities will be combined with the optimized oxycodone producing strain to deliver a novel bioproduction system for noroxymorphone This project will address major technical barriers to the microbial production of nal opioids and support the commercial viability of this technology By addressing much of the technical risk this SBIR project will enable investor funded development and scale up and Antheia s entry into a new product line to help combat growing opioid abuse and addiction Narrative Nal opioids such as naloxone naltrexone and buprenorphine are pharmacotherapies that save and rebuild lives by treating chemical dependence on opioids However these active pharmaceutical ingredients demand a premium price due to their complex production process in which molecules extracted from opium poppy are tailored to exhibit antagonist properties Antheia s unique microbial production technology will dramatically decrease the price of producing nal opioids and provide a secure sustained supply for drug addiction treatment