By Doug Macron
Researchers from Calando Pharmaceuticals this week published phase I data in Nature showing that the company's lead siRNA-based cancer drug CALAA-01 could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism when delivered intravenously.
The data, which were generated in collaboration with a team from the California Institute of Technology, "demonstrate that RNAi can occur in a human from a systemically delivered siRNA, and that siRNA can be used as a gene-specific therapeutic," the investigators wrote in the paper.
For Calando's parent firm Arrowhead Research, the publication marks an important milestone in the company's efforts to secure a partner for the program and its proprietary delivery technology, dubbed Rondel.
"There are literally hundreds of delivery strategies that are out there preclinically," Arrowhead CEO Christopher Anzalone told RNAi News this week. "Now, we can show [these] data and show that we're capable of [achieving an RNAi effect] in the clinic. … We view these data and the anticipation of more clinical data as our big separator" from other technologies in the field.
Earlier this year, Anzalone said that Arrowhead had put negotiations with potential Calando partners on hold in anticipation of the publication of the CALAA-01 data (see RNAi News, 2/18/2010).
"We wanted this paper to come out [first], and then start to have some sort of discussions based on [the data] … because we didn't want to threaten the publishability of the data," he said this week. "Now that it's out … we expect to start having at least loose partnership discussions fairly soon."
As far as the kinds of deals Arrowhead would consider, Anzalone said that the firm is not going to enter discussions "with any preconceived notions. We're going to wait to see how those pan out."
Product-specific deals, platform licenses, and a merger or acquisition are possibilities, he noted. "We're just going to see what looks best as we go down that road."
One thing he said that is not a likely possibility is Calando fully developing CALAA-01 on its own. "We do not expect that you will see a drug on the market that is marketed by Calando," Anzalone said. "We don't see that as a viable model for us — to bring this all the way through the clinic and to sell this under our own label. Short of that, everything is on the table."
Anzalone also said that Calando would consider taking CALAA-01 into phase II on its own if it cannot find a partner by the end of phase I development.
He declined to offer any guidance on how long it might take for Arrowhead to consummate a deal, but added that "the good news is that we're not waiting for this to happen. We will continue to dose patients [in the ongoing phase I study] and continue to generate more data on higher doses, and of course expand the number of patients who have been treated."
Importantly, Calando has not achieved the maximum tolerated dose in the phase I trial, and that "we are not yet dosing at the highest dose of our protocol." He added that the company will "likely" amend the study's protocol to include doses higher than initially planned.
Anzalone declined to specify how many patients have thus far been treated in the trial. He also said that Arrowhead was not providing guidance on when the study may wrap up.
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Meanwhile, a moratorium on in-house research and development not related to CALAA-01 remains in effect at Calando. In late 2008, Arrowhead announced that the subsidiary would not advance any of its preclinical programs pending the signing of a cash-generating deal (see RNAi News, 12/18/2008).
Right now, we are personally not actively involved in moving [other pipeline candidates] down the field," Anzalone said this week. "However, we are working with partners to move some of those projects."
He declined to comment on the structure of those arrangements. He did, however, state they include both academic and industrial partners, and characterized them as basic "exploratory" R&D arrangements in which Calando retains the full rights to the drug candidates.
"Once we feel more comfortable about our resources and what CALAA-01 needs, we can look to devote some resources back to those [programs] internally," he added.
CALAA-01 comprises a linear, cyclodextrin-based polymer decorated with a human transferrin protein targeting ligands on its surface, which are designed to engage transferrin receptors on the surface of cancer cells; polyethylene glycol to promote stability in biological fluids; and an siRNA payload targeting the M2 subunit of ribonucleotide reductase, an established cancer target.
In the phase I trial of CALAA-01, patients with solid cancers refractory to standard-of-care therapies were treated with one of three doses of the drug on days 1, 3, 8, and 10 of a 21-day cycle by 30-minute intravenous infusion, according to the Nature paper.
Biopsies from melanoma patients enrolled in the study not only showed the presence of the nanoparticles inside of the tumors, but that they also accumulated in a dose-dependent manner. Additionally, "a reduction was found in both the specific messenger RNA and the protein levels when compared to pre-dosing tissue," the researchers wrote.
"Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the sire predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles," they added.
"When taken together, the data … provide the first, to our knowledge, mechanistic evidence of RNAi in a human from an administered siRNA," the paper states. "Moreover, these data demonstrate the first example of dose-dependent accumulation of targeted nanoparticles in human tumors. The reduction of the RRM2 mRNA and protein by the RRM2 specific siRNA is observed, and the results from 5'-RACE analyses show that the delivered siRNA engages the RNAi machinery.
Anazalone this week declined to comment on whether Calando had made any observations of efficacy in the trial, and cautioned that "it's dangerous to start speculating on efficacy in a phase I, particularly a phase I that is not yet done."
Still, he pointed out that the Nature paper indicates that patients receiving the highest dose of CALAA-01 "had stable disease between the two [treatment] cycles. I don't want to read too much into that because cancer … becomes stable sometimes … but that is one data point that is out there."