SR Pharma announced this week the completion of preclinical toxicology studies for Atu-027, an siRNA-based cancer drug being developed by the firm’s subsidiary Atugen, opening the door for the initiation of the final toxicology work required by US regulators before clinical trials of the compound can begin.
With the news, Atugen said it expects a phase I trial of Atu-027 will begin around the middle of 2007 — a minor adjustment of the company’s previous guidance that the study would begin in the first half of the year.
As reported by RNAi News late last year, Atugen had expected that its phase I study would be only in patients with pancreatic cancer and would be followed by a second phase I trial enrolling patients with a variety of gastrointestinal malignancies (see RNAi News, 11/2/2006).
However, Atugen CSO Klaus Giese told RNAi News this week that the company now expects to run a single phase I trial in GI cancers, including pancreatic cancer.
This approach, he said, would allow Atugen to follow up the study with phase II trials of the drug in pancreatic cancer and possibly lung cancer. He noted that Atugen is also considering using another formulation of Atu-027 called Atu-093 in the lung cancer trial, but that a decision on this will be made based on the phase I data.
“As we run [the phase I trial], we will make decisions,” Giese said.
Atu-027 is designed to inhibit the growth of new blood vessels feeding tumors by targeting PKN-3, a protein kinase that Atugen researchers have linked to tumor growth and metastases.
The drug incorporates Atugen’s proprietary siRNA molecules, which are 19-mer duplexes that lack 3' overhangs and have been chemically stabilized with alternating 2'-O-methyl sugar modifications on both strands. Atu-027 also uses company’s so-called lipoplex delivery technology that comprises a mixture of cationic and fusogenic lipids.
Earlier this year, Atugen researchers published data in Gene Therapy showing that its blunt-ended siRNAs can trigger an RNAi effect in the vasculature of mice when delivered using the lipoplex technology. The researchers showed that the company's formulated siRNAs could be used to inhibit tumor growth and metastases in xenograft mouse models, apparently through anti-angiogenesis, by targeting CD31. Follow-on work in rodent cancer models demonstrated that Atu-027 could inhibit tumor cell growth and proliferation with no adverse effects.
According to Giese, preclinical toxicology studies designed to determine a maximum tolerated dose of the drug and dose ranges to be used in additional experiments have been successfully completed by an independent contract research firm.
In the studies, Atu-027 was given to rodents and non-human primates as a “reconstituted lyophilized material” via 4-hour continuous intravenous infusions in escalating doses. The drug was administered every third day over a period of 15 days.
Now, Atugen is clear to begin full toxicological evaluation of Atu-027 in the 28-day toxicity studies required by US regulators prior to human testing. Giese noted that this toxicity work has just begun in rodents, and that the non-human primate portion of the effort is slated to start by the end of February.
At the same time, Atugen is preparing for its planned phase I study in GI cancers. Patients enrolled will receive intravenous infusions of Atu-027, Giese said, although the time period over which the drug will be administered has yet to be determined.
“It could be a fast bolus, it could be a 2-hour infusion, it could be a 4-hour infusion,” he said. “We have all these options in our preclinical program covered, [and] we are very flexible. The sponsors of the clinical trial will most likely determine with us” which approach is taken.
Slow Progress on Partnerships, M&A
Although Atugen remains on-track with its research and development efforts, the company has missed two of its corporate-development goals for 2006: the establishment of at least one “significant” partnership, and the acquisition of a product or company.
“We are open-minded [and] do not suffer from the not-invented-here syndrome. We are always looking for other technologies that might work better in other tissues.”
As for the first, Giese said this week that Atugen has “made progress,” and has been the subject of increased interest since Merck closed its acquisition of RNAi drug shop Sirna Therapeutics late last year (see RNAi News, 1/4/2007). However, the company yet to sign any deal.
“We are in … late-stage discussions” regarding therapeutic collaborations,” Thomas Christely, Atugen’s CEO and SR Pharma’s COO, told RNAi News this week, adding that the company is “quite confident” it will have something finalized “in the first half of 2007.”
Christely, however, stressed that this timeline could change depending on the breadth and scope of any deal, and Giese noted that it is still unclear exactly what kind of collaboration Atugen forge.
“We have three options” when it comes to partnerships, he said. “We have … a platform technology, we have a pipeline, and we have a lead program. So there are many options for [potential] partners right now.”
Additionally, the ongoing negotiations are not just centered on the company’s oncology research, which is thus far the company’s primary area of interest. Christely offered respiratory disease as an example of an indication beyond cancer where Atugen’s technology might be applied.
With regards to Atugen’s other goal for 2006 — acquiring a product or company — Christely said that while the company continues to search for a promising acquisition target, it has yet to find one.
He also offered some insight into the kind of acquisition Atugen is hoping to make, noting that “we’re looking for good … delivery technologies and opportunities.”
Although Atugen’s delivery technology works well, “we are open-minded [and] do not suffer from the not-invented-here syndrome,” he said. “We are always looking for other technologies that might work better in other tissues. Delivery is clearly our focus.”