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Play Cytrx 'Albumin' Stereo: Drug Hits Glioblastoma, Too?

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By Randy Osborne
Staff Writer

Cytrx Corp.'s decision to stop in May its Phase IIb trial with the synthetic retinoid tamibarotene for non-small-cell lung cancer turned investor eyes to aldoxorubicin, an improved, albumin-binding form of the chemotherapy drug doxorubicin at the same stage of testing in first-line soft-tissue sarcoma (STS).

But it was preclinical results in glioblastoma with the new, more potent and apparently safer chemo agent that provided a nice hop for the Los Angeles-based firm's stock (NASDAQ:CYTR), which closed Tuesday at $2.66, up 46 cents, or 21 percent, after trading as high as $3.20.

The statistically significant efficacy in animals with aldoxorubicin in the fast-moving brain cancer will be detailed this fall at the European Society for Medical Oncology meeting in Amsterdam. Meanwhile, a Phase IIb trial in STS goes on.

"It's the first time we've been able to show that this drug does collect very specifically at the site of the [brain] tumor and not at normal tissue," said Steven Kriegsman, president and CEO of Cytrx. "That would be extrapolation to [the STS trial]."

Daniel Levitt, chief medical officer, explained the mechanism further. "Doxorubicin is conjugated with a specific linker molecule," he said, and one side of the linker is acid-sensitive. "This part of the molecule is cleaved, and free doxorubicin is then released and can enter the cell. The other side of this linker molecule will attach very rapidly and very specifically to circulating albumin," by way of a covalent tie that causes the drug to "only enter tissues that have a leaky vasculature, which tumors do."

A "Trojan-horse" effect is created, Levitt told BioWorld Today. "Tumors need albumin for various nutrients, so they take it up very avidly, and by doing so, they bring in this toxic agent, doxorubicin, which then, in the low pH environment of the tumor, is cleaved," he said. "So you get a concentration effect of doxorubicin, basically, inside the tumor, and then the release. You bring in a gift, which is albumin, and attached to it is something lethal."

Setbacks and delays faced by others developing STS drugs could end up putting Cytrx in the pole position. In March, New York-based Ziopharm Oncology Inc.'s Phase III trial with the alkylating agent palifosfamide for first-line, metastatic disease failed to meet the primary endpoint of progression-free survival (PFS). (See BioWorld Today, March 27, 2013.)

At the start of this month, Threshold Pharmaceuticals Inc., of South San Francisco, disclosed a protocol amendment to its pivotal Phase III trial with TH-302 in advanced STS. Projected enrollment will increase from 450 to 620 patients, and the PFS futility analysis has been removed. The changes, to which the FDA gave its agreement, mean that survival interim data will not likely appear until the first half of 2014 (instead of the end of 2013, since 235 events are required as compared with the previous 175). Final survival outcomes would be available in the first half of 2015, instead of the end of 2014. The FDA has given Cytrx the go-ahead for a Phase III trial in first-line STS in the first quarter of 2014.

Levitt said the research that led to aldoxorubicin came out of Louisiana State University Medical School. "Basically, it was [the result of] our suggestion to a collaborator there, Om Prakash," who started work at the end of 2011 , he said. "We inject our drug, and within minutes, it binds to albumin in the circulation" – a possibility first demonstrated by Felix Kratz at Tumor Biology Center in Freiburg, Germany. Cytrx owns the rights to the technology.

Further work with aldoxorubicin in glioblastoma "may move very quickly," Levitt said, whereas the large Phase III trial in STS may take a while to enroll. The "huge need" in brain cancer could allow that program to catch up with STS, he said, predicting that "they'll probably run pretty much neck and neck."

CEO Kriegsman said Cytrx is exploring options with "numerous big pharma and big biotech" firms regarding a possible global partnership, though "right now, we're going on the assumption that we will continue to internally develop the drug," and start the pivotal Phase III in STS.

"If the Phase IIb data are positive, we would start a Phase III there, and continue along in brain," he said. "We always keep our options open. Anything's possible, at this point. We're open to what's best for the company." Other tumor types in which aldoxorubicin might prove worthy include gastric, small-cell lung, gastric and multiple myeloma. "There are a lot of different cancers we'd like to attack," he said.

At last report, Cytrx had about $30 million in cash and no debts, with a burn rate of $1 .6 million to $1 .7 million per month, Kriegsman told BioWorld Today. "That will increase, but for the foreseeable future, we're fine," he said, adding that a financing could happen but, "more likely than not, a major partnership. We have a nice runway."