Interesting news in Pharmaland today as we hear that Pfizer has decided to voluntarily withdraw gemtuzumab ozogamicin (Mylotarg) from the market and the FDA declined to grant Ziopharm an SPA for their phase III trial with palifosphamide (palifosfamide for those reading in American English) in soft tissue sarcoma.
The first is unexpected, the second interesting.
In 2000, Wyeth (now part of Pfizer) were granted accelerated (fast track) approval in AML for Mylotarg, an anti-CD33 monoclonal antibody, on the basis of response rates, with the intent that survival data would provide evidence for full approval. Unfortunately, like Iressa's situation in lung cancer, that did not happen so polite withdrawal is the only option in this situation. Perhaps the only surprise is that it took a decade for it to happen.
It's not a big loss for elderly AML patients, given the drug never showed any major efficacy benefit and the side effect profile of fevers, chills, nausea and vomiting severely impacted quality of life for many frail people. Many AML patients are over 60 and in much less robust health compared to younger, fitter patients who might be candidates for high dose chemotherapy and a transplant. This is where Mylotarg was supposed to offer hope, given the limited options. In this setting, the ideal drug would be a targeted therapy without too many debilitating adverse events. Early toxicities with Mylotarg, however, were not pleasant:
"… among all patients evaluable for early toxicity the
fatal induction toxicity rate was significantly higher in
subjects given the combination of standard induction chemotherapy
and Mylotarg than in those treated with chemotherapy alone."
I always look at sales as a good indicator of whether physicians like a drug or not. At around $35M annually, Mylotarg clearly wasn't a popular option. Sometimes we need to focus on what matters – response rates per se (around 10-13% complete responses) don't mean much in isolation, but extending lives does, hopefully without too much collateral damage. In this situation, Pfizer made a good call.
Ziopharm's management team have been very bullish and brimming with confidence lately, however, such sentiments can sometimes turn out to be irrational exuberance. The phase II PICASSO trial with palifosfamide and doxorubicin versus doxorubicin alone has completed enrollment with initial promising interim results in metastatic or unresectable soft tissue sarcoma and the company were clearly hoping to negotiate an SPA with the FDA for the phase III trials, but it seems negotiations have broken down on that front, with concomitant fall in the share price.
The trial design is interesting for several reasons.
Firstly, the current standard of care for treatment of soft tissue sarcoma is ifosfamide plus doxorubicin but there's no comparator arm with ifosfamide, an old chemotherapy now available generically.
According to the company:
"Palifosfamide (ZIO-201) is a proprietary stabilized metabolite of ifosfamide."
Meaning it's a second generation version of the generic, but is it any better than ifosfamide? We won't know with the proposed design. Of course, the current reimbursement structure means that oncologists will make more revenue from a branded drug (6% of $1000 is more than 6% of $100), whereas in the old scheme, there was more usage of generics because the spread was greater than for newer, more expensive therapies.
Secondly, the big sticking point for the FDA was the proposed primary endpoint, ie PFS rather than overall survival (OS). One does not always follow the other, but seriously, accepting OS as the goal may well have been an easy win-win for Ziopharm. It seems a little odd that they chose not to go there in the initial discussions with the FDA:
"In a recent communication, FDA has indicated that the Company could conduct the pivotal trial as designed without SPA and that approvability would be determined by the data, balanced with risks and benefits. FDA presently considers the endpoints as designated for the proposed pivotal trial as not supportive of SPA in this disease setting, although they would grant SPA with modified endpoints."
If changing the endpoint from PFS to OS is all that is needed for garnering an SPA, I think I would grab it and go. It's much easier to gain approval if you meet the criteria for a pre-negotiated SPA, as Roche/Genentech have shown with Tarceva several times, even with marginal, yet significant improvements, based on well powered studies. Going it alone without agreement with FDA is a recipe for disaster down the road, as many small biotechs have discovered to their dismay over the last 18 months.