As a developer of antisense-based cancer treatments, OncoGenex was naturally interested in RNA interference when it came onto the scene. But despite having significant success using RNAi for target validation work, the company decided the gene-silencing technology was not quite ready for therapeutic applications, and opted for a next-generation antisense approach in its latest drug program.
“We do use [RNAi] from a perspective of validating targets,” OncoGenex President and CEO Scott Cormack told RNAi News this week. “And as everybody finds, it’s an absolutely fabulous tool for that because it’s very powerful — very low quantities [of oligos] … achieve very good down regulation of the target in the in vitro model systems.”
But when OncoGenex researchers evaluated RNAi as a possible therapeutic modality in model systems, Cormack said the results were not encouraging. “I think our results are similar to what others are seeing,” he said. “Generally, we’re not getting [significant] down regulation in vivo … [and] are seeing some non-specific down regulation of other genes.”
On top of this, Cormack said that RNAi is simply not at the point where systemic delivery is easily achieved. As such, OncoGenex opted to use a second-generation antisense technology known as 2’ MOE, licensed from Isis Pharmaceuticals, in its drug-development program targeting Insulin-like Growth Factor Binding Protein-2 and Insulin-like Growth Factor Binding Protein-5.
According to the company, IGFBP-2 and IGFBP-5 are involved in regulating growth signals that cause tumor growth and lead to the development of metastatic cancer. Cormack said this program, which is developing a drug named OGX-225, is specifically focusing on hormonally regulated cancers such as breast cancer and prostate cancer.
“OncoGenex is a therapeutics company, so our primary goal is taking drugs, moving them into people, and ultimately developing therapeutics,” Cormack said. “When we look at RNAi, even though it is working in vitro, it’s difficult [to use] in vivo, certainly from a systemic perspective. We think it still has more development to go in chemistry.”
As for antisense, it’s “already there,” he added. “We can move it forward.”
Cormack cited data from a clinical study in which prostate cancer patients were treated once a week for five weeks with the antisense drug OGX-011, which targets clusterin. The drug, which is being jointly developed by OncoGenex and Isis, is delivered intravenously in buffered saline and also uses the 2’ MOE technology, he noted.
“We surgically removed prostates in the sixth [week], and we looked at drug concentration and down regulation of the target in prostate cancer and in lymph nodes,” Cormack said. “We got [much] higher concentrations of drug in tumor tissue, and we got 91 percent suppression of the target in prostate [tissue] and 98 percent in lymph nodes.”
According to Cormack, questions of delivery and efficacy have surrounded the antisense field since its inception, and those “had never appropriately been answered before in humans. Now we look at [the field] and are saying, ‘A once a week IV administration getting 90 percent plus [down regulation] in both lymph node and tumor tissue — [antisense is] doing what it’s supposed to do … and way better than anybody every expected,’” he said.
Cormack said that OncoGenex is not at this point pursuing further development of RNAi for therapeutic applications, but this doesn’t mean that the company has ruled out the technology for good.
“We’re kind of watching the field to see if anybody is getting there, and [we’re] watching the papers and presentations,” he said. In addition, “we continue to use RNAi in the lab, we continue to patent our targets in respect to that technology, and when it gets to the point of being a systemic human reality, we may well end up with a second-generation drug that’s RNAi.”
Cormack remains optimistic that this second-generation RNAi drug could be reality sooner rather than later, given the lessons learned from antisense.
“It took 20 years of development … to get through the chemistry issues to make [antisense] a therapeutic reality and I think we have it,” he said. “I don’t think RNAi will go through the same timeline, however. There’s so much money and so many people working on it — and I hope they’ve learned a lot of the lessons … from the antisense experience — that the timeline will compress significantly.”
— DM