By Doug Macron
Calando Pharmaceuticals has completed enrollment in a phase I study of its siRNA-based cancer treatment CALAA-01, but an official from parent firm Arrowhead Research said this week that the company has decided to move the drug into a phase Ib trial next, rather than into phase II.
“Some people may be disappointed that we're not moving directly into a phase II at this time, but we believe that spending a small amount of time on a phase Ib will increase the … power and impact of a phase II,” Arrowhead CEO Christopher Anzalone said.
“While we hit our primary endpoints and believe our data are strong, we will expand into a phase Ib because we may be able to push the system further simply by changing the dosing schedule,” he added during a conference call held to discuss Arrowhead's fiscal third-quarter financial results.
CALAA-01 comprises unmodified siRNAs against the M2 subunit of ribonucleotide reductase delivered via Calando's proprietary Rondel cyclodextrin-based polymer technology. It became the first formulated RNAi therapeutic to enter human testing in 2008.
In early 2010, Calando published data in Nature showing that the agent could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism when delivered intravenously (GSN 3/25/2010).
After facing some difficulties finding patients for the study, which prompted Arrowhead to add another site to the trial, the company has wrapped up enrollment, Anzalone said.
He noted that the primary endpoints of the phase I trial, safety and tolerability, have been met, but indicated that certain adverse events were observed. While he didn't disclose the nature of those events, he said that they appeared to be related to CALAA-01's siRNA payload and not the delivery technology.
“In assessing responses from the phase I [trial], we found something very interesting: the adverse effects we saw as we increased dose did not appear to be related to the … delivery system itself, but rather to the natural unmodified siRNA inside,” Anzalone said during the call.
“From our experience with other cyclodextrin-based delivery [agents] and our data with Rondel in non-human primates, we would expect dose-limiting toxicities to be primarily renal in nature,” he explained. “Therefore, we have looked very hard for any signs of renal toxicities as we escalated doses and have not seen anything.
“The [adverse events] we began to see in the phase I [study] were largely consistent with what others have seen stemming from immune responses to natural, unmodified siRNAs and coincide with expected increases in certain cytokine levels,” he said.
Notably, the reactions were transient, “such that if a patient stayed on CALAA-01, the effects and the cytokine responses often subsided,” Anzalone said. Because of this finding, Calando expects that CALAA-01's maximum tolerated dose may be increased through a change in its dosing schedule.
“We have reason to believe that if we pre-treat patients with a lower dose of CALAA-01 for a cycle, we may be able to desensitize them to the natural siRNAs and enable us to increase the dose for further cycles,” Anzalone said. This hypothesis will be tested in the phase Ib, which will enroll up to 12 patients and conclude in 2012.
Anzalone noted during the call that CALAA-01 could have been moved into a phase II using the current dosing regimen, but the phase Ib “will give us more data so we can better design that phase II … and provide us with additional information about Rondel that will inform our future clinical programs,” all of which will use chemically modified siRNAs, he said.
The phase Ib trial is also expected to bolster Calando's ongoing efforts to find an industry partner, he said, though data from the study aren't considered necessary to doing so.
Anzalone had said earlier this year that CALAA-01 would be partnered before the end of 2011 (GSN 5/19/2011). He did not comment on whether that guidance was still valid.
For the three-month period ended June 30, Arrowhead reported no revenues, which is unchanged from last year.
Operating expenses rose to $1.8 million from $1.4 million in the same period the year before, primarily as a result of increased lab and contract services supporting the phase I study of CALAA-01, and greater costs to support Calando's intellectual property portfolio.
Arrowhead's loss from continuing operations in the quarter jumped to $1.9 million, or $0.03 per share, from $84,000, or $0.00 per share, a year earlier.
Arrowhead had $4.3 million in cash at the end of its fiscal third quarter.
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