SBIR-STTR Award

We have discovered that Esculentoside A (EsA) has potent anti-inflammatory effects including specific COX2 inhibition. Our preliminary studies and the associated patent apply to the use of EsA for the prevention of radiation-related inflammation (IR). We found that EsA was more effective than Celebrex at preventing and reducing acute radiation dermatitis and late soft tissue fibrosis, and EsA was as effective as dexamethasone at reducing radiation-induced brain edema. Side effects were similar or less than Celebrex(r). Studies in a standard model of inflammation are needed to establish the utility of EsA for autoimmune (e.g. rheumatoid arthritis) and other inflammatory disease (e.g. osteroarthritis). In our IR studies, the drug was administered i.p., and we need to confirm that EsA can be delivered effectively by other routes. Likewise, the therapeutic index must be determined. These basic requirements precede others required by the FDA before phase I and phase II testing can commence. We will focus on the following aims in Phase I: 1) test for beneficial anti-inflammatory effects of EsA in a standard arthritis model; 2) demonstrate that oral and other administrative routes have utility, and determine the optimal dose and ED50; and 3) measure the therapeutic window and side effect profile of EsA in mice. The study should broaden our knowledge of EsA and lay the foundation for development of this naturally existing anti-inflammatory agent. Relevance: While there is high demand for COX2 inhibitors, the recent observation that Vioxx(r) increases heart attacks and strokes has resulted in a great public health need for a new, less toxic and less expensive NSAID of the selective anti-COX2 class. Our preliminary studies indicate that EsA should not predispose patients to vascular events. While the leading COX2 inhibitor, Celebrex(r), has allergic cross-reactivity to sulfonamides, EsA should not.

Eva Pharmaceuticals, STTR Phase II Application, April 2007, Abstract Since their discovery, COX-2 inhibitors have dominated the market for non-steroidal anti-inflammatory agents (NSAIDs). In 2004, Vioxx(r), a major COX-2 inhibitor, was removed from the marketplace due to thromboembolic toxicity. Celebrex(r), the other major COX-2 inhibitor, now has almost no competition and therefore can remain inhibitively expensive. Celebrex also has a lower but still measurable rate of thromboembolic complications. There is therefore a powerful need for a new, less toxic, and less expensive NSAID. We have recently discovered that Esculentoside A (EsA), a saponin isolated from Phytolacca esculenta, has multifactorial anti-inflammatory activity and specifically inhibits COX-2 but not COX-1. Initial in vivo studies were aimed at reducing inflammation from ionizing radiation (IR), a common side effect of cancer treatment for which there is no satisfactory agent for prevention, mitigation, or therapy. Among the most common and symptomatic complications of therapeutic radiation are toxicity to the skin and to the lung. The impact of EsA, and its aglycoside analog, h-EsA, on IR induced inflammation is dramatic and substantially better than Celebrex. To the best of our knowledge there are no comparable modifiers of intermediate or late lung toxicities after irradiation. Thus h-EsA could prove to have substantial impact on public health. Animal experiments performed under the Phase I portion of this STTR confirmed that EsA has anti-inflammatory utility. Additionally we found that administration of EsA and h- EsA in mice reduced radiation-related pneumonitis and pulmonary fibrosis, in addition to reducing radiation effects in other soft tissue such as brain and skin. Our goals with this Phase II STTR are to develop the Good Laboratory Practices and Good Manufacturing Practices, quantify the benefit with respect to delay and alleviation of pulmonary toxicity (eg. dose modifying factors), determine the dose schedules for h- EsA, and establish the no adverse effect level (NOAEL dose). The proposed studies will provide the remaining components required for our FDA IND submission. Eva Pharmaceuticals STTR Phase II Grant Request Project Narrative We are pursuing the goal of commercializing EsA, a drug that, based on sound experimental data, promises to reduce the harmful side effects of nuclear radiation on people. There is currently nothing else available anywhere that has the equivalent combination of (a) efficacy on lungs, brain and skin tissue, (b) ease of storage, handling and oral consumption, and (c) most importantly, effectiveness when taken after the exposure. The potential value to society is huge, especially for the estimated 325,000 people yearly who receive radiation treatments for cancerous tumors, but also for the nation's first responders and for our armed services.

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