By Doug Macron
Silence Therapeutics this week released preliminary results from an ongoing phase I study of its siRNA-based cancer drug Atu027. The drug has been well tolerated at dose levels tested so far, and data from one patient suggests the possibility of therapeutic benefit.
“This is a very exciting data set for the sector as a whole,” Silence CEO Philip Haworth told Gene Silencing News. “There haven't been any clinical studies in which patients had significant amounts of drug in a delivery system without causing problems. So, we're starting to feel, despite the somewhat negative media coverage [about RNAi] … very encouraged.”
Atu027 is a blunt-ended siRNA targeting the protein kinase PKN-3. Originally developed by Atugen, which was later acquired by Silence, the agent entered phase I testing patients with solid tumors in mid-2009 (GSN 7/9/2009). The study is being conducted at Ruhr University Bochum and is expected to enroll 33 patients with advanced or metastatic solid tumors. Single and repeated intravenous infusions of the drug at 11 escalating dose levels will be evaluated, with three to six patients per dose level.
Primary endpoints are the determination of dose-limiting toxicities and maximum tolerated dose. Secondary outcome measures include the collection of pharmacokinetics, clinical safety, and tolerability data, as well as clinical response as determined by standard Response Evaluation Criteria in Solid Tumors, or RECIST, criteria.
During a presentation at the BIO CEO and Investor Conference in New York this week, Haworth said that a total of 157 doses of the drug have been administered so far to 20 patients across seven dose levels. The highest dose administered so far is 0.12 mg/kg, but the trial is designed to test up to .447 mg/kg of Atu027.
In this kind of study, “the things you look for … are cytokine induction and complement activation,” Haworth told Gene Silencing News. “We're very aggressively looking for those things,” but thus far there has been no evidence of cytokine induction. According to his presentation, study investigators have observed “limited Atu027-related transient activation of the alternative pathway of the complement system,” but this was expected given the use of the company's Atuplex liposomal delivery vehicle and was not dose-dependent.
Additionally, the human PK data has shown to be similar to PK data obtained in preclinical testing of Atu027 in non-human primates, Haworth noted.
The phase I trial design does not permit biopsies to be taken from study participants because they are terminally ill and unnecessary surgeries would be ethically “inappropriate,” and so Silence is unable to confirm target gene and protein inhibition in cancer cells, he said.
But experiments in cynomolgus monkeys have shown that protein knockdown occurs in the 0.1 to 0.3 mg/kg range, and the phase I data shows a similar strand concentration in plasma at the 0.072 mg/kg dose as the 0.1 mg/kg dose in the animals.
“The PK is behaving, according to the monkey models, exactly as we want it to,” Haworth said. As such, “we'd expect to see some protein knockdown” in the human patients if biopsies were permitted.
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Perhaps most encouraging is the observation of “remarkable shrinkage of target and non-target lesions,” as much as around 20 percent, in one patient who has thus far received 26 doses — more than any other trial participant — as part of compassionate use therapy, according to the presentation. The patient's disease has also stabilized according to the RECIST criteria.
So, even though Silence has been unable to obtain protein samples from patients, “we are seeing ... remarkable shrinkage of in both the primary tumor and lung metastases,” Haworth said. “We have to be very guarded in over-interpreting this — it's not an efficacy study — but it allows us to say with some confidence that we certainly expect to meet the [trial's] primary objectives.”
More complete data, he added, is expected to be presented at the American Society of Clinical Oncology's annual meeting in Chicago this June.
In the meantime, Silence is working toward completing patient enrollment in the study in October, with an eye toward finding a partner for the Atu027 program by next year.
While securing partnerships with bigger players is a key goal for any small biotech, the cost of conducting human trials of a cancer drug make doing so all the more important for Silence before it moves Atu027 into phase II development.
“A larger company would probably do a better job with [additional clinical] investigations than we'd ever do … [as the necessary] resources typically can't be found in a small company,” Haworth said. “We are in conversations with people now, and obviously they are [asking] for the phase I data when it's complete before they will pull the trigger.”
Still, the company isn't pinning all its hopes on finding a collaborator by the time the phase I trial is complete.
“We're working on the clinical design for phase II [and] the design for a phase Ib,” he said. Drug development “doesn't stop when we finish phase I. What we do ourselves will depend on our ability to finance [the work, but] … we're putting plans into place to move this forward by ourselves for a little longer should we choose to do that.”
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