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Silence Presents Phase I Data on siRNA-based Cancer Drug at ASCO, Touts Safety of Delivery System

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By Doug Macron

Silence Therapeutics this week released additional data from an ongoing phase I trial of siRNA-based cancer drug Atu027, reporting that the drug has proven well tolerated in all dosing cohorts up to 0.18 mg/kg, with hints of positive responses in certain patients.

The data also indicate that Silence's lipid-based delivery technology, dubbed AtuPlex, can be used to safely administer siRNA payloads at therapeutically relevant doses, which the company hopes will garner attention from potential industry partners interested in using the technology with their own RNAi candidates, Silence CEO Philip Haworth told Gene Silencing News.

“This is the first time we can distinguish our delivery system from what's out there in terms of its safety risk,” he said, noting that other siRNA delivery approaches, including the lipids used by Alnylam Pharmaceuticals with its phase I liver cancer drug ALN-VSP02, require patients first be treated with an immunosuppressant.

“We're the only one that doesn't require pre-treatment, and that is going to be a big benefit … going forward,” Haworth said.

Atu027 is a blunt-ended siRNA targeting the protein kinase PKN-3, which is associated with cellular morphology and locomotion in endothelial and cancer cells.

According to the phase I data, which were presented at this year's American Society of Clinical Oncology meeting in Chicago, a total of 24 patients with a variety of solid tumors, including ones of the colon, breast, cervix, and pancreas, received intravenous infusions of the drug at doses ranging from 0.001 mg/kg to 0.18 mg/kg. Of those, twenty completed treatment, while four dropped out of the study due to disease progression.

Nine of the patients achieved stable disease after repeated treatment with Atu027, with six of the cases confirmed after three months. Three other patients continue to receive treatment under compassionate use.

Of the patients with stable disease, one with neuroendocrine cancer showed partial regression of pulmonary metastases, while one patient with breast cancer showed a “slight regression” in liver metastases.

No dose-limiting toxicities were observed with Atu027 treatment, nor was there evidence of cytokine induction, according to Silence. “Favorable pharmacokinetic data showed dose-dependent increases in siRNA and lipid levels, suggesting no evidence of drug accumulation during repeat treatment.”

Notably, the maximum tolerated dose has not been reached in the study, which is designed to examine doses up to 0.447 mg/kg.

Haworth said that although Silence will continue dosing patients up to the highest dose under the trial's protocols, “we now have a circulating concentration [exceeding 0.3 mg/kg], which causes [target] knockdown in primates, so we believe we are at or above the efficacious dose” for man.

He cautioned that Silence is making no assumptions in this regard given the differences between non-human primates and humans, and because it is impossible to biopsy patients in the ongoing trial due to the severity of their conditions. But at the 0.18 mg/kg dose tested in the trial, “from our point of view, we've achieved a dosing level that will work.

“We continue with the phase I study to see what, ultimately, the maximum tolerated dose will be,” he added. However, “our view is that the drug has shown safety at this point and even if we don't finish any more cohorts, we will continue to develop” it.

Should Silence dose all 11 cohorts as set forth in the trial's design and still not reach the maximum tolerated dose, the question is whether dose escalation should continue, or if the company should “declare victory and move on," Haworth said.

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“You'd like to know how high you can take the dose, but you'd also like to finish the study and move to the next one,” he explained. “It's still a debate we have internally that we haven't resolved, and we'll see what things look like when we get to cohort 11.”

The phase I trial is expected to be completed before year end, with a phase Ib study in a single tumor type slated to start in 2012. A phase II trial is expected in 2013.

In addition to providing Silence with further confidence in Atu027, the data presented at ASCO are also expected to give Silence an edge when it comes to negotiations with companies on the lookout for effective RNAi delivery technologies, Haworth said.

Not only does the AtuPlex technology appear to be safe and effective, “we don't suppress these patients with dexamethasone … [which] just seems like a risk for patients who have cancer already,” he said. “So the safety hurdle, we believe, has been met.”

“We're not going to claim we have efficacy [based on phase I data], but we're very encouraged by the way patients are responding,” he added.

With the compassionate treatment patients having received over 30 doses with “no signs of lipid accumulation in the liver … [we] think this [delivery system] can be used quite aggressively” against the numerous other endothelial targets that are relevant to cancer, he said.


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