MU 1140
BackgroundOur lantibiotic, MU1140, was discovered by Dr. Hillman in the course of developing SMaRT Replacement Therapy™. MU1140 is a potent antibiotic that is naturally produced by the parent of the SMaRT strain, and we have produced a synthetic version of MU1140 known as MU1140-S. MU1140 is active against all Gram positive bacteria against which it has been tested, including those responsible for a variety of healthcare-associated infections, or HAIs. The key technology that enables our production of MU1140-S is our Differentially Protected Orthogonal Lanthionine Technology, or DPOLT™, which is a patented, novel organic chemistry synthesis platform developed by our scientific team. We reported the successful, analytical scale synthesis of MU1140-S using DPOLT in October 2008, and thus achieved what we believe will lead to the first-ever synthetic route to commercial-scale production of lantibiotics.Market OpportunityThe most common HAIs are caused by drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, or MRSA; vancomycin-resistant Enterococcus faecalis , or VRE; and Clostridium difficile, or C. diff . According to the Centers for Disease Control and Prevention, or CDC, HAIs are estimated to occur in 5% of all acute-care hospitalizations, based on the 35 million patients admitted to 7,000 acute-care institutions in the United States, with an annual incidence of approximately 1.7 million cases, which result in 99,000 deaths. The CDC also estimates that the total direct medical cost to the U.S. healthcare system from HAIs is between $35.7 billion to $45 billion annually. HAIs are estimated to more than double the mortality and morbidity risks of any admitted patient in a U.S. hospital, which is the equivalent of 350,000 years of life lost annually. The critical care market for antibiotics is approximately $7 billion in the United States alone. Cubicin, a Gram positive lipopeptide antibiotic which was recently introduced by the biotechnology company Cubist, had 2009 sales of $562 million in the United States.The need for novel antibiotics is increasing as a result of the growing resistance of target pathogens. The CDC estimates that bacteria resistant to known antibiotics cause 44% of HAIs, and individual hospitals have resistance rates as high as 70% for many Gram positive infections. HAIs are not exclusively a problem in the United States as the rest of the world has also seen a dramatic rise in HAIs during the last decade. Vancomycin, which was introduced in 1956, has served as the last line of defense against certain life-threatening infections, and, more recently, Cubicin has also served in this capacity, but bacterial resistance to these drugs has been growing at an increasing rate. Novel antibiotics have become increasingly scarce as major pharmaceutical companies have focused more research and development resources on lifestyle drugs and fewer resources on specialty pharmaceuticals such as antibiotics. Between 1983 and 1987, 16 new antibiotics were approved by the FDA. Twenty years later, from 2003 to 2007, only five new antibiotics were approved, of which only two possessed a novel mechanism of action. Lantibiotics such as MU1140 are highly modified peptide antibiotics made by a small group of Gram positive bacterial species. Approximately 50 lantibiotics have been discovered since 1927 when the first lantibiotic, nisin, was discovered. Lantibiotics are known to be potent antibiotic agents, however, all attempts to investigate their usefulness have met with uniform failure due to the inability to produce sufficient pure amounts of any of these molecules to be able to test them as a therapeutic agent for the treatment of infectious diseases. Standard fermentation methods, such as those used to make a variety of other antibiotics, typically result in production of only minute amounts of the lantibiotic. In cases where large amounts of a lantibiotic are made, such as with nisin, the unique chemical structure of lantibiotics has prevented the necessary purification needed for clinical testing. Our SolutionMU1140 has demonstrated activity against a wide variety of disease-causing Gram positive bacteria, including MRSA, VRE, C. diff., Mycobacterium tuberculosis, or M. tuberculosis, and anthrax. We have performed extensive preclinical testing on MU1140, which has demonstrated the molecule’s novel mechanism of action. In order to produce sufficient quantities for our clinical trials and commercialization efforts, we intend to use a synthetic version of MU1140, known as MU1140-S.We created MU1140-S using our patented, novel organic chemistry synthesis platform known as DPOLT. We believe that DPOLT will enable large-scale, cost-effective production of clinical grade MU1140-S. We reported the successful, analytical scale synthesis of MU1140-S using DPOLT in October 2008, which we believe will lead to the first-ever synthetic route to commercial-scale production of a lantibiotic. In addition, we believe that DPOLT will allow us to synthetically produce any of the 50 known lantibiotics due to the shared chemical structure features of this class of molecule. We intend to use DPOLT to create a pipeline of lantibiotics for therapeutic use. Regulatory StatusWe have performed extensive preclinical testing using native MU1140, which demonstrated the following features: Bactericidal activity against Gram positive strains and against both replicating and non-replicating M. tuberculosis; Unusual chemical structure, which makes it extremely stable; No immune response in a variety of animal models, even with the use of strong adjuvants and carriers; Negligible toxicity when supra-therapeutic doses were tested in yeast, and fibroblast and kidney cell lines; In vivo efficacy in mouse and rat models, in which animals were infected intraperitoneally with MRSA (60xLD50) and MU1140 was administered intravenously at doses well below its maximum tolerated dose; Novel mechanism of action that involves binding to and abducting Lipid II, which is required for cell wall biosynthesis; No spontaneous, genetically stable resistant mutants to MU1140; Synergy with an aminoglycoside; and Good pharmaceutical properties. We expect to conclude the preclinical testing of MU1140-S, including toxicity testing in rodent and non-rodent animal models, at the end of 2011. We then intend to file an Investigational New Drug, or IND, application with the FDA in mid-2011. We estimate that, once commenced, the regulatory process will require at least four years of clinical testing and the application and FDA approval of a New Drug Application, or NDA, before MU1140-S would be commercially available. We have engaged Celerion (formerly known as MDS Pharma Services) on a fee-for-service basis to represent us in regulatory meetings with the FDA, and to perform the first-in-human trials with MU1140-S. Our StrategyWe intend to develop MU1140-S through Phase 1 clinical trials. If MU1140-S successfully completes Phase 1 trials, we believe that its value will substantially increase, and we would then seek to license MU1140-S to or partner with a major pharmaceutical company. If we are unable to consummate an acceptable licensing or partnership arrangement, we may pursue Phase 2 clinical trials independently.Analysis of the 50 known lantibiotics suggests that there are possibly six to ten subclasses of lantibiotics as classified by known mechanisms of action, spectra of activity, or structural characteristics. In addition to MU1140-S, we intend to utilize DPOLT to synthesize additional lantibiotics of interest in the future. ManufacturingWe have retained Almac Sciences, a leading contract manufacturer, to refine and scale-up GMP production of MU1140-S. We expect to have sufficient amounts of MU1140-S by second half of 2010, which will enable preliminary testing to demonstrate equivalence between the synthetic and native molecule. |
