This article has been updated from a previous version to clarify Jorgensen’s comments about the company’s plans to test the drug at additional sites, which were intended to stress the importance of confirming the reproducibility of the drug.
As part of its bid to find a partner for an investigational RNAi-based therapy for brain cancer that has already been tested in humans, Senetek has begun taking steps to have the treatment examined in patients at new clinical sites, a company official told RNAi News this week.
However, the company may find itself fighting an uphill battle in looking for a partner given an apparent absence of any animal data on the drug and an ever-growing concern over the possibility that certain RNAi molecules may trigger unintended immune stimulation.
In fact, one RNAi insider familiar with the drug expressed concerns that it may not be working through an RNAi mechanism at all — an issue that has joined delivery as a major hurdle facing RNAi therapeutics (see RNAi News, 9/4/2008).
“There are several other possible explanations [for the drug’s therapeutic effect] besides RNAi.”
Senetek’s drug is a 164 nucleotide-long double-stranded RNA targeting tenascin-C. According to City of Hope researcher John Rossi, the fact that the oligo was prepared using in vitro transcription raises the specter of immune stimulation — an issue on which Rossi and colleagues have previously published.
In vitro transcription “lends itself to tri-phosphate incorporation at the 5’ end,” he said, noting that this is a known trigger of the interferon-inducing RNA helicase protein RIG-I, which has been shown to have anti-cancer properties. Additionally, because long RNAs are typically poorly processed by Dicer, it is unlikely that a sufficient number of siRNAs are produced during Dicing.
As such, “there are several other possible explanations [for the drug’s therapeutic effect] besides RNAi,” Rossi told RNAi News this week.
Importantly, he noted, in vitro transcription can be a dirty process. “You can’t make [an in vitro-transcribed dsRNA] that clean; there is all sorts of stuff in the transcription reaction that you can’t get rid of,” he said. To put this kind of agent into humans “is potentially dangerous.”
To date, 48 patients with the brain cancer glioblastoma multiforme have received the drug at the University of Medical Sciences in Poznan, Poland, according to Jan-Elo Jorgensen, Senetek’s director of research.
And while not all of them have benefited from the therapy, a number are still alive two years after treatment — a significant improvement over the median eight-month survival rate for patients with the disease, he said.
Despite this “very substantial clinical evidence” of the treatment’s efficacy, Jorgensen said that Senetek is aiming to have the drug administered to patients at different sites, most likely in Poland, because “it would be good to see [efficacy] at a site that is not connected to the [drug’s] inventors” in order to confirm the reproducibility and efficacy of the drug.
Jorgensen said positive results from this study could enable Senetek to find a partner to help offset the costs associated with the preclinical work required to begin clinical testing in the US, which the company expects will be the first market it will pursue.
And those costs are likely to be significant since there appears to be no animal data available on the drug, at least none that Jorgensen said he has seen.
A Senetek official had told RNAi News in late 2006 that the company hoped to have found a partner by the end of 2007. Having missed that goal, Jorgensen this week said that the company has ramped up its efforts to forge an alliance, but he declined to provide a new timeline.
Senetek, based in Napa, Calif., acquired the brain cancer drug from the Polish Academy of Sciences in late 2006 as part of its overall strategy of in-licensing technology, supporting its continued development at affiliated research institutes, and then finding a large pharmaceutical or biotechnology partner to help bring the technology to market (see RNAi News, 11/30/2006).
Although focused on skin care products, Senetek picked up the brain cancer drug during negotiations with the Polish Academy of Sciences for three compounds used to treat skin aging, viewing the move into RNAi as a business opportunity, Senetek’s CFO William O’Kelly told RNAi News at the time.
To date, the only publicly available data on the treatment appeared in a 2006 paper in Cancer Biology & Therapy, in which researchers from the Polish Academy of Sciences and the University of Medical Sciences in Poznan reported on the drug’s use in high-grade and low-grade glioma patients.
After surgical removal of their tumors, the researchers injected the RNAi molecule — which they termed ATN-RNA — directly into three to five sites around the areas where the cancer could not be completely removed, according to the paper.
The injection triggered swelling and leaking of the nearby vasculature, which in turn allowed ATN-RNA to penetrate the tumor tissue, the authors wrote, adding that they “did not observe any local or general inflammatory response due to interferon synthesis.”
One of the patients who received ATN-RNA experienced no tumor recurrence after 14 months, the investigators noted. Three other patients experienced tumor recurrence, but only in areas distal from the site of injection.
“The most spectacular result was obtained for [a] patient … with diffuse astrocytoma,” a tumor type that does not allow for “surgical action even in areas where wide resection is possible,” the investigators wrote in Cancer Biology & Therapy. Ten weeks after treatment with ATN-RNA, the glioma in this patient disappeared in the area where the drug was administered, and researchers observed no tumor recurrence after 18 months.
Follow-on cell-culture experiments demonstrated that ANT-RNA specifically knocks down tenascin-C mRNA synthesis in glioblastoma multiforme tissue “with a very high efficiency,” the researchers noted.
“The tumor suppression observed mainly around the sites of ATN-RNA injection but not in remote [areas] can suggest either a short-distance migration of ATN-RNA or short lifetime of dsRNA in human tissues,” they added. “The differences in the observed effects of [the drug in the patients studied] … can be due to the size of … non-removable tumor tissue,” which may require the use of different delivery approaches.
The investigators concluded that “the variable effects induced with ATN-RNA clearly support” tenascin-C as a good target for glioma and the use of dsRNA in treating human glioblastoma.