Looking to take early advantage of a recently acquired oral drug-delivery technology, RXi Pharmaceuticals has named an undisclosed program in inflammatory disease as its lead drug-development effort, according to a US Securities and Exchange Commission filing published last week.
The pipeline changeup is at least the third for RXi since it was spun out of one-time RNAi player CytRx in early 2007 (see RNAi News, 1/11/2007) and marks the apparent departure of neurological disease as a near-term focus.
In the filing, RXi noted that initial targets within its inflammatory disease program include validated genes related to the tumor necrosis factor-alpha pathway, "which is involved in many diseases including … rheumatoid arthritis, Crohn’s disease, and psoriasis." Follow-on targets in the program, meanwhile, include those associated with diseases such as atherosclerosis and type II diabetes.
The decision to focus on inflammation comes as little surprise given RXi's enthusiasm for its new oral-delivery technology, which company officials have highlighted at various investor and scientific meetings since it was licensed from the University of Massachusetts Medical School last fall (see RNAi News, 10/16/2008).
The technology, called glucan-encapsulated siRNA particles, or GERPs, is based on the activity of specialized cells, called M cells, located in the small intestine. Specifically, GERPs are "hollow, porous, micron-sized shells that can be filled with one or more types of RNAi compounds," RXi noted in the SEC filing. After ingestion, "these shells are believed to be taken up by [M cells] … and then transferred to immune cells residing in the underlying gut-associated lymphatic tissue" where they are phagocytosed by macrophages and other cells.
"Once in the macrophage, the RNAi compounds are presumed to be released from the GERP shell into the cytoplasm where they would silence the specific target gene," the company added.
Under normal conditions, when a macrophage has taken up an antigen, it begins producing cytokines, which in turn triggers inflammation. But a macrophage treated with an anti-inflammatory siRNA would, in theory, lessen inflammation as it migrates from the intestine to other tissues in the body.
Just weeks after announcing that it had picked up the rights to the delivery technology, RXi was touting GERPs as a major driver of its decision to expand into inflammatory disease (see RNAi News, 10/23/2008). At that time, however, the company had not yet positioned the program as its top drug-development priority.
But the decision to step up its efforts in inflammation seemingly isn't the only change for RXi, given the noticeable absence of a program in neurological disease from an overview of the company's research and development activities presented in the filing.
During an investor meeting last October, RXi had announced that it had sharpened its therapeutic focus onto metabolic, inflammatory, and neurological disorders, including a longstanding effort in amyotrophic lateral sclerosis inherited from CytRx and a new program in Alzheimer's disease.
Last week's SEC filing, however, suggests that RXi has put its neurological disease work on the backburner.
"We are focused on the discovery and potential development of a pipeline of RNA-based therapeutics to address inflammatory and metabolic diseases using our proprietary … compounds and delivery technologies," the company said in the filing. "Our lead program targets genes involved in inflammation using our GERP delivery technology, and our metabolic disease program is focused on genes involved with high cholesterol and other metabolic diseases."
In breaking out its metabolic disease work, RXi highlighted as a key target RIP140, a ligand-dependent transcriptional repressor originally licensed by CytRx from Imperial College London that has been shown to play a role in fat burning in animals and fat cells (see RNAi News, 9/9/2005).
"We are currently designing RNAi compounds targeting RIP140 as a potential treatment for obesity and obesity-related type II diabetes," the company said.
But no mention was made of any efforts in other indications.
RXi noted that since RNAi holds promise in targeting genes not amenable to "conventional medicinal chemistry … [it] may also pursue additional disease areas with the goal of creating multiple clinical-development programs," but it fell short of naming any of those.
Late last year, RXi President and CEO Tod Woolf had confirmed to RNAi News that the company had put an oncology program on hold until it could be partnered. Company officials were not available this week for comment on the future of the neurological disease work.
Partnering Problems?
As with most every company developing RNAi-based therapeutics, securing industry alliances has been a key goal for RXi.
During last year's investor event, RXi CFO Stephen DiPalma had said that the company was close to signing a deal with its first partner and expected to do so before the end of 2008. At the same time, RXi anticipated forging a second deal sometime in 2009.
To date, RXi has made no announcements regarding partnerships, but in last week's SEC filing the company indicated that it continues to seek "partnerships with large pharmaceutical and biotechnology companies to leverage our intellectual property and expand our development pipeline."
Such partnerships "may include traditionally structured drug-development and -commercialization licenses, discovery and development collaborations, research and technology collaborations, and intellectual property licenses," the company stated.
RXi did not indicate in the filing when it expects to sign a partnership agreement. The company did, however, note that it plans to handle the development of "a limited number of RNAi drug candidates" using its own capital resources.
"We intend to develop drugs in [inflammatory and metabolic diseases] internally to establish significant value, at which point we may seek to partner them," it added.