Staff Writer

The happy gist of Ziopharm Oncology Inc.'s interim Phase II news with palifosfamide for soft-tissue sarcoma came as little surprise, but details disclosed at a scientific meeting proved enough to tickle the stock again by 12 percent, and should lend strength to partnering talks.

"We're in dialogue with several right now, and obviously the interest level has gone even higher," said Jonathan Lewis, who serves as CEO and chief medical officer for the New York-based firm, which plans to sign a partner "either before or as we're going into Phase III" trials in the first half of next year.

If it continues to work, palifosfamide (to be sold under the brand name Zymafos, if approved) could replace the familiar doxorubicin, often known simply as "doxo," the last drug that was approved for sarcoma by the FDA - and that was about 30 years ago. Physicians and patients have long been waiting for a better, safer compound.

Last month, New York-based Ziopharm said the trial was stopped early after hitting key efficacy and safety goals, and shares soared by 24.6 percent. But full data didn't come until Friday at the annual meeting of the Connective Tissue Oncology Society in Miami Beach. (See BioWorld Today, Oct. 15, 2009.)

Speaking from the conference, Lewis cited "many considerations and options" for partnering. "The ideal thing would be to do a regional deal in Europe first, with someone who's very good at manufacturing, retaining rights in the U.S. and then go from there," he told BioWorld Today. "The clinical-development part we're quite good at."

Apparently so. Chrystyna Bedrij, analyst with Griffin Securities, said her phone was ringing off the hook after the poster session that disclosed the full results. "It's pretty amazing, really," she said. "This is not just a good Phase II trial with palifosfamide - this is a good cancer trial," with powerfully convincing results against a well-validated endpoint. Ziopharm, she added, "has always had the best of the best [scientists] behind its programs."

Patients with unresectable or metastatic disease in the front-line or second-line setting were randomized to get either doxo or doxo plus palifosfamide, "the classic A vs. A-plus-B" scenario, Lewis noted.

As of the Oct. 5 cutoff date, 67 patients had entered, with 65 treated and 61 eligible for analysis. The 61 were evaluated for progression-free survival - which Lewis called "the most biologically relevant endpoint in sarcoma" and was the subject of a talk at the CTOS meeting - with 20 documented PFS events.

Doxo alone netted 14 events; the combo with palifosfamide recorded 6. Analyzing all randomized and eligible patients, the hazard ratio added up to 0.63, favoring the combo and proving that palifosfamide prolonged PFS by at least 50 percent.

The median PFS for doxo is 4.4 months, while the median PFS for the combination has not been reached; the first quartile PFS was 1.5 months for doxo as compared to 3.5 months for the combo.

Adding palifosfamide does not add to the toxicity of single-agent doxo, the trial found, and only fairly benign side effects surfaced in both arms of the study: neutropenia and fatigue, hypokalemia, nausea, anemia, leucopenia and alopecia.

Intravenous palifosfamide is easily administered as an outpatient treatment, but there's an oral version in the works, too. "We've finished the preclinical, and we're ready to file an IND," Lewis said, adding that capsules already have been made. "We wanted to be very sure the I.V. works, and we wanted to control our spend, but we're ready to go now," Lewis said. Once we're through partnering, we'll pull the trigger on Phase I."

Since palifosfamide is the functional active metabolite of ifosfamide - a standard of care for treating not only sarcoma but also lymphoma plus testicular cancer and others - Ziopharm with a partner likely will try the drug against other tumors.

Just in sarcoma, the revenues could mean as much as $500 million per year, by Bedrij's estimates. "That's a decent franchise," she said. "I haven't modeled [the other tumor types], and I'm not going to model them" until Ziopharm and its eventual partner disclose which cancers they will target next.

Ifosfamide and cyclophosphamide are two of the most commonly used alkylating drugs to treat certain cancers, but patients often develop resistance. Along with efficacy, palifosfamide's upside includes lack of the toxic metabolites of ifosfamide that can lead to encephalopathy (sometimes known as "fuzzy brain") and severe bladder inflammation.

Soft-tissue sarcoma - a cancer that begins in the muscle, fat, fibrous tissue, blood vessels or other supporting tissue of the body - doesn't get many headlines, since it represents only about 5 percent of tumors. "There are people walking around who are actually cured of their disease, if it's diagnosed early" and attacked with surgery, Lewis said.

But early diagnosis is the trick, since the tumors often escape notice and metastasize. At that point, "there are some options, but not a lot," he said. In the U.S., the prevalence of sarcoma is about 100,000 annually. Of those, 30,000 to 50,000 are getting chemotherapy.

Also in the Ziopharm pipeline are Zinapar (darinaparsin), an organic arsenic for blood and solid cancers that has proven positive in Phase II, and Zybulin (indibulin), an oral tubulin-binding agent that targets mitosis and cancer cell migration. Zybulin is undergoing a Phase I/II study at Memorial Sloan Kettering.

Palifosfamide is considered the crown jewel, but "all three programs are compelling," Bedrij said.

Ziopharm's stock (NASDAQ:ZIOP) closed Friday at $3.44, up 37 cents, after trading as high as $3.60.

Published  November 9, 2009