By utilizing its expertise in RNAi compound design and delivery, RXi initially intends to identify lead compounds in neurology, metabolic disease and oncology. After identifying compounds, RXi intends to begin pre-clinical development in these focus areas as appropriate.
NEUROLOGY:
Market opportunity
ALS (amyotrophic lateral sclerosis, commonly known as Lou Gehrig's Disease) is a progressive neurodegenerative disease that attacks nerve cells in the brain and spinal cord resulting in muscle weakness and eventual paralysis. The mortality rate is high: 80% of individuals with ALS die within five years of diagnosis. There are over 120,000 cases of ALS worldwide, and over 5,000 new cases are diagnosed in the United States annually. Approximately 90% of ALS cases are sporadic, and the remaining 10% are familial. Twenty to thirty percent of the familial forms of ALS have been linked to dominant mutations in the SOD1 gene that result in defective protein products that aggregate in cells, causing progressive motor-neuron degeneration. RXi plans to address this medical need by seeking to develop an RNAi compound as a therapy for this disease.
RXi ALS Program
RXi is generating RNAi compounds that we believe target the form of ALS caused by a dominant defect in the SOD1 gene. Mice expressing a human SOD1 mutant gene and developing the symptoms of ALS are available and widely used as a laboratory model for human ALS. Early pre-clinical studies in this mouse model conducted by RXi advisors Dr. Rana and Dr. Xu at the University of Massachusetts Medical School showed promising results in animals using an RNAi compound to selectively inhibit the production of SOD1. In a series of studies using this model, Dr. Xu administered a proprietary chemically modified RNAi compound into the cerebral spinal fluid of the mice with an implantable pump. This strategy resulted in significantly reduced levels of expression of SOD1 mRNA and protein. RXi is refining and extending this work and, if successful, intends to move into formal pre-clinical development.
As part of RXi’s neurology program, the company intends to optimize further its advisors' RNAi chemistry and local delivery techniques to extend to other diseases of the central nervous system. For example, in addition to ALS, many neurodegenerative diseases exist for which no effective therapies are available, including Alzheimer's Disease. In many of these cases, molecular targets have been identified that are difficult to access by conventional small molecule or antibody based approaches. RXi believes that the knowledge gained in its discovery and development activities related to ALS may allow the company to rapidly pursue additional related therapeutic areas.
METABOLIC DISEASE:
Market Opportunity
Obesity and type 2 diabetes are major health problems and affect hundreds of millions of people worldwide, with a growing global market of over $27 billion. The World Health Organization estimates that, on a worldwide basis, there are more than 300 million cases of obesity and 159 million cases of type 2 diabetes. The American Obesity Association, or AOA, states that there are currently more than 60 million cases of obesity in the United States, and the American Diabetes Association reports that there are more than 16 million cases of type 2 diabetes in the United States. According to the AOA, obesity increases the risk of illness from about 30 serious medical conditions and has been found to be the largest environmental influence for the prevalence of diabetes in a population.
RXi Obesity/Type 2 Diabetes Program
RXi scientific co-founder and scientific advisory board member Dr. Michael Czech is a leading researcher in the area of metabolic disease. Dr. Czech has studied gene expression linked to obesity and diabetes. RXi has in-licensed intellectual property discovered by Dr. Czech on a database of genes which appear to be important regulators of metabolism and may target these genes in future development programs for obesity and type 2 diabetes. One of the genes identified by Dr. Czech, RIP140, appears to be a master-regulator of metabolism. Studies have shown that inactivation of RIP140 can convert fat cells from a fat storage to a fat burning phenotype. For example, in studies using a "knock-out" mouse model for diabetes and obesity, the deletion of the RIP140 gene results in mice that remain lean and non-diabetic even when maintained on a high fat diet. RIP140 is a member of a protein class that does not appear to be effectively treatable with traditional small molecule approaches; however, it may be treatable with an RNAi approach. RXi has acquired exclusive rights to develop RNAi products targeting the RIP140 gene from the University of Massachusetts Medical School and the Imperial College of London.
ONCOLOGY:
Market Opportunity
RNAi compounds have the potential to target any gene. In contrast, traditional small molecule or antibody based approaches can access only some of the known targets, resulting in a large number of so-called “non-drugable” genes. Unfortunately, many of these non-drugable genes have been implicated in the multi-step process driving the development of malignant cancers. An example of such a group of genes includes the Bcl-2 family of genes. Many of these genes are known to regulate responses to conventional chemotherapy drugs, but the conventional technologies have so far not been able to control this group of genes directly. Treatment with RNAi compounds that inhibit gene expression, if successfully developed, have the potential to be useful in concert with existing chemotherapeutics. Selecting targets from such families could potentially offer a significant competitive advantage over non-RNAi based approaches. Additionally, RNAi reagents targeting multiple genes could be developed to treat cancers originated from malfunctioning of multiple intracellular pathways.
RNAi may potentially be employed at several facets of cancer development. Delivery of RNAi compounds to tumors and silencing of oncogenes or drug resistance genes in animal models has been demonstrated in the literature. RNAi compounds may potentially also be delivered to endothelial cells in the tumor vasculature in order to potentially inhibit angiogenesis. Additionally, RNAi may be used to inhibit cell division in non-cancerous tissues which are damaged by chemotherapy in order to protect these cells from chemotherapy. RNAi screening methods may potentially also be used to rapidly prioritize molecular targets within large gene families by conducting in vitro experiments to identify which gene family members are the most appropriate targets to pursue.
RXi Oncology Program
Studies to date indicate that it is highly unlikely that non-formulated, non-modified RNAi compounds will be effective as therapeutics in oncology. Key characteristics of the molecule that will need to be developed to increase efficacy include metabolic stability and potency in vivo while maintaining an appropriate therapeutic index. Medicinal chemistry and formulations can achieve these characteristics to a limited extent. RXi has access to proprietary delivery technology which has demonstrated increased RNAi efficacy in normal mice. This technology has yet to be evaluated in animal models of cancer. RXi is currently working to establish nanotransporter formulations appropriate for oncology targets.
OTHER THERAPEUTIC AREAS:
Although RXi’s near-term focus will be on ALS, type 2 diabetes, obesity and cancer, the company plans to leverage its experience related to local delivery of RNAi therapeutics to develop RNAi-based treatments for neurodegenerative diseases other than ALS. For example, in addition to ALS, many neurodegenerative diseases exist for which no effective therapies are available, including Alzheimer’s and Huntington’s diseases. In many of these cases, molecular targets have been identified that are difficult to access by conventional small molecule- or antibody-based approaches. RXi believes that the knowledge gained in its discovery and development activities related to ALS may allow it to rapidly pursue additional related therapeutic areas.
RXi may also pursue pre-clinical studies in several additional disease areas, with the goal of creating multiple clinical development programs. For example, one of RXi’s founding scientists and scientific advisors, Dr. Greg Hannon, is a leader in the understanding of tumor-suppressor and oncogene pathways. RXi expects that Dr. Hannon’s involvement with RXi will provide insight into potential cancer therapeutic targets. Many well-studied targets exist for numerous diseases that RXi believes will be difficult to target with normal medicinal chemistry. RXi intends to focus on combining its expertise in RNAi with existing disease models through collaborative interactions with academic, biotech and pharmaceutical industry scientists.
Alliance Partners in Therapeutic Areas:
RXi is actively seeking to leverage its technology platform by working with larger pharmaceutical and biotechnology partners in the partners' fields of interest. Furthermore, the RXi team has experience targeting genes in virtually every major therapeutic area. With the pioneering work being done in developing the RXi technology platform, RXi believes it will discover many more drug candidates than can be advanced in-house. For research on target genes in the RXi portfolio that are not funded internally, RXi will seek to work with partners in the discovery and development process these areas to build its development pipeline.
