Palifosfamide lacks resistance, side effects of forebears

November 16, 2009 – 9:12 am by Colette Pilkus

Cancer drugs have come a long way and work very effectively today, but they create a tremendous expense for patients because treatment requires them to be admitted to the hospital. Drugs such as doxorubicin, ifosfamide, and cyclophosphamide can have severe side effects, including brain, kidney, and bladder issues, diminishing the benefit of the treatment.

Palifosfamide is a new molecular entity that appears to avoid such pitfalls. Ziopharm Oncology recently announced Phase II results of palifosfamide in patients with unresectable or metastatic soft tissue sarcoma in the first-line and second-line setting. Patients were randomized either to doxorubicin or to palifosfamide in combination with doxorubicin.

“What we showed was that palifosfamide caused an increase in benefit of progression-free survival of at least 50%, and when this was looked at by several experts and the medical advisory board of Ziopharm, the recommendation was to stop enrolling in the trial,� says Dr. Jonathan Lewis, CEO and chief medical officer, Ziopharm. “The reason for that was as we looked very carefully there was a strong benefit, much stronger than we had imagined. As we looked at the two different arms, there was no difference in toxicity and the drug was very easy to tolerate and to give.�

Palifosfamide delivers the cancer-fighting component of ifosfamide and is expected to overcome the resistance seen with ifosfamide and cyclophosphamide, two of the most commonly used alkylating drugs used to treat certain cancers. Palifosfamide does not have the toxic metabolites of ifosfamide that cause the debilitating side effects of encephalopathy and severe bladder inflammation. Palifosfamide is also easily administered as an outpatient treatment.

“The experience so far with palifosfamide has been that it’s very easy to administer and the side effects have been very few,� Dr. Lewis says. “The requirement of readmission is very little. It’s much easier to give with much fewer side effects. The other advantage is that in the research lab, it works in the setting of resistance of tumors that are resistant to a lot of other drugs and seems to work quite effectively.�

The company plans a formal end of Phase II meeting with FDA in the beginning of next year and expects to start trials in the first half of next year. Ziopharm also expects to file an investigational new drug application for an oral capsule version of palifosfamide in the first half of 2010. The company is looking into treating other indications such as pediatric cancer and breast cancer.

According to Dr. Lewis, no new drugs have been approved in the last 30 years for first-line and second-line sarcoma. Although there are drugs in development for certain rare subsets of sarcoma, he says some of those have hit a few bumps in the road. “We see this as wide open right now, and our model with this [program] is we want to keep the cost down,� Dr. Lewis tells R&D Directions. “We envision low-cost, oral, and global [drug formulations], and even though sarcoma is a small indication, [we want to] be able to distribute this globally. We want to move from mature markets to emerging markets and do the same not just with sarcoma, but other cancers as well.�

Ziopharm believes that palifosfamide will compare favorably with other approved cancer treatments. The company estimates that product sales for treating sarcoma could reach $250 million, and for other indications, such as lymphoma, product sales could reach $400 million.

Palifosfamide, under the code name ZIO-201, was selected one of R&D Directions’  100 Great Investigational Drugs of 2008 for soft tissue and bone sarcomas and ovarian and pediatric cancers. In 2006, Ziopharm’s darinaparsin, under the code name ZIO-101, also made the list for solid tumors, hemotologic cancer, and myeloma.

Darinaparsin is a novel organic arsenic being developed for the treatment of various hematologic and solid cancers. Preclinical and clinical studies have demonstrated that darinaparsin is less toxic than inorganic arsenic, particularly with regard to cardiac toxicity. Phase I and Phase II testing of the intravenous form of darinaparsin in solid tumors and hematological cancers has been completed or is nearing completion. Ziopharm expects to advance into a registration trial in peripheral T-cell lymphoma as early as the first half of 2010.

According to Dr. Lewis, the most important thing about darinaparsin is that it seems to be effective while providing limited doses that have limited toxicity. While using the drug, patients noted that they felt really well, several reporting that they felt the best that they’ve felt since they started any kind of treatment, especially after being on multiple kinds of treatment. The drug also seems to work in several different cancers where people have failed many other treatments.

Tags: cancer, darinaparsin, palifosfamide, Ziopharm