RXi Pharmaceuticals this week held a meeting with investors during which it announced that it has narrowed its therapeutic focus to metabolic, inflammatory, and neurological diseases, and confirmed that it expects to forge its first industry alliance before the end of the year.
During the event, company officials also provided new details about RXi’s recently licensed oral RNAi drug-delivery technology, which the company sees as driving its efforts in inflammatory disease, and hinted that it is developing a new class of RNAi molecules that are distinct from its so-called rxRNAs that are currently under development.
Shortly after going public early this year, RXi announced it had set its sights on amyotrophic lateral sclerosis, a program inherited from its one-time parent firm CytRx (see RNAi News, 11/1/2007), and hypercholesterolemia, as well as programs in neurological disease and cancer (see RNAi News, 3/13/2008).
At the investor event, RXi President and CEO Tod Woolf said that programs in ALS and hypercholesterolemia remain in the company’s in-house pipeline, but have now been joined by Alzheimer’s disease and inflammatory disorders.
The RNAi drug shop’s cancer program, meantime, has been put on hold.
The ALS program, one of RXi’s most advanced, uses local delivery of an RNAi agent to target the gene SOD1, a mutant form of which is responsible for the familial form of the disease. However, familial ALS accounts for only 5 percent to 10 percent of all ALS cases. As such, RXi expects its work in this area will help it expand into other central nervous system indications with greater market potential.
“For local administration, we are focusing on ALS as an entry [point] into the neurologic area,” Pam Pavco, RXi’s vice president of pharmaceutical development, said at the meeting. Ultimately, the company is “aiming to use [our direct delivery approach] for a wider variety of neurologic disease including Alzheimer’s.”
Woolf noted that the Alzheimer’s disease work is “very early-stage,” adding that RXi is not disclosing the targets being considered for this program. Similarly, the company has not disclosed the expected target for its hypercholesterolemia program.
The other newcomer to RXi’s development lineup, inflammatory diseases, stems from the company’s recent acquisition of oral drug-delivery technology from the University of Massachusetts Medical School (see RNAi News, 10/16/2008).
“For local administration, we are focusing on ALS as an entry [point] into the neurologic area … [ultimately] aiming to use [our direct delivery approach] for a wider variety of neurologic disease including Alzheimer’s” disease.
According to Pavco, this technology, called glucan-encapsulated siRNA particles, or GERPs, is based on the activity of M cells, which are specialized cells located in the small intestine.
As part of the body’s defense mechanism, M cells are designed to take up antigens, such as bacteria or yeast, and transcytose them through the intestinal wall so they can be taken up by macrophages, she said.
GERPs “are taken up by the M cells [similarly to] yeast or bacteria because [their] surface … is made out of beta-glucan, which is the same component as the yeast cell wall is made out of,” Pavco said. “So they are recognized and taken up by M cells … trancytosed, and taken up by the macrophages directly.”
Under normal conditions, when a macrophage has taken up an antigen, it begins producing cytokines, which in turn triggers inflammation, she said. “So wherever these macrophages go, you can cause a stimulation of inflammation in that particular area.”
But if treated with an siRNA that inhibits the production of the inflammation, such as with a GERP, “then wherever those macrophages go you would see lessened … inflammation,” Pavco said. “So it’s a very specific way to target different inflammatory sites with oral delivery.”
Pavco noted that RXi hasn’t had much experience with the GERP technology, but has conducted experiments in which macrophages from cynomolgus monkeys were transfected ex vivo with GERPs that had been pre-packaged with fluorescently tagged rxRNA.
“We are really able to efficiently deliver to the macrophages … in cell culture,” she said, “and this is what is expected to happen when you deliver it through the intestines.” She added that proof-of-principle work in animal models has also been done, but that these data are not being released pending their publication in a peer-reviewed journal.
RXi has yet to settle on specific indications it will pursue with the GERP technology, but Pavco noted that it could be applicable to conditions including Crohn’s disease, rheumatoid arthritis, asthma, psoriasis, and type II diabetes.
One notable absence from RXi’s pipeline breakdown was its previously announced efforts in cancer. To date, the company has not provided specific details about this program, and its website states that it has yet to evaluate its RNAi technology in animal models of any form of the disease.
Woolf told RNAi News this week that although RXi has not given up on cancer, the company now intends to only pursue the disease in collaboration with a partner.
“It’s not that we wouldn’t work on it,” he said, but a number of factors complicate the development of a cancer drug, including uncertainty about the efficacy of a target or the level of inhibition needed to obtain a therapeutic response prior to clinical trials.
As such, “we’re looking to partner [on] that,” he said.
As it steps up its in-house drug-development efforts, RXi is also close to signing its first partner, which it expects to do before the end of the year, RXi CFO Stephen DiPalma said during the investor meeting. The company also continues to expect to have secured a second partnership in 2009.
He noted that RXi expects its initial alliances to be structured so that the company would discover potent rxRNAs against gene targets of interest to partners.
“But those will be expandable,” he added. “There will be the opportunity for partners to add additional targets to those programs as they progress. And certainly, we’re going to make all the delivery options that we have to offer available to partners.”
Over time, “we would certainly expect the scope and value of the partnerships to expand in a number of ways,” DiPalma said. “We can simply broaden the scope of the partnership [by] adding more targets or perhaps entire therapeutic areas.”
And as the company develops its oral and other delivery technologies, these too may be included in alliances, he added.
Down the road, RXi anticipates striking “product-oriented” partnerships supported by clinical data, he said. Currently, the company plans to bring its internal programs through phase II development before seeking partners for them.
In line with previous guidance, RXi plans to file its first new drug application with US regulators next year but has yet to disclose the indication. Additionally, in 2009 RXi expects to identify a lead candidate for its second official drug-development program.
Thus far, all of RXi’s drug candidates are based on the company’s rxRNA technology, which involves the use of blunt-ended siRNAs, 25 to 30 nucleotides long, with proprietary modifications on the oligo’s sense strand.
However, Woolf indicated during the investor meeting that a second generation of rxRNAs is being developed. He declined to provide any details on the structure of these molecules or when they may enter the company’s pipeline.