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Due to a missed primary endpoint in an open-label study, physicians speculated that Medarex’s Phase III melanoma drug Ipilimumab will likely be rejected by the FDA, Pharmawire reports. The drug is also being developed by Bristol-Myers Squibb.
The open-label trial is one of three pivotal registrational trials to be submitted to the agency for approval as a potential therapy for melanoma, they said.
Dr Antoni Ribas, a melanoma expert and associate professor at UCLA Medical Center said the FDA does not have a track record of approving a drug based on negative results. “In order for the drug to receive agency approval, the study should measure both overall and progression free survival,” he added.
Dr Mark Faires, a physician at the John Wayne Cancer Institute in California added the trial was negative by study design - as it was designed to show a one in ten response rate. “If the primary endpoint of the trial were missed, it seems unlikely the FDA would approve the drug without more data or analysis,” he added.
The primary endpoint in the open-label study was designed to demonstrate an objective response rate of greater than 10% - but was unsuccessful. In the majority of patients receiving the drug, the metastatic melanoma followed its natural disease progression. The observations measured included both complete and partial response.
“It would be disappointing for the drug to have shown responses in less than 10% of patients, even if some of those responses were durable,” said Faires. Although only one out of ten patients respond, the responder did not have a regression of melanoma, added Ribas.
However, open label studies do not have the same significance as randomized studies to the FDA, added a biostatistician.
Faires compared the drug to interleukin-2, which only has strong clinical efficacy in a small patient population. Patients who responded to Medarex’s Ipilimumab experienced tumour shrinkage and generally had stable disease for a long time.
However, this would be a lower rate than with interleukin-2 though it might be possible that the responses were not representative of the efficacy of the drug, explained Faires. “For instance, if some patients had minor progression or had extended stable disease that did not qualify as a response, there may still be some clinical benefit,” he added.
These patients are “seemingly cured” and it is hard to achieve this response in metastatic cancer. However, only a small subset of patients experience a lot of benefit in terms of decreased tumor regression and long-term, relapse-free survival.
However, both Bristol-Myers Squibb and Medarex have not yet disclosed the details of the drug’s additional ongoing trials. Both companies refused to disclose specific patient response rates in the other trials, which includes a double-blind dose response trial - and a randomized double-blind, placebo-controlled study.
Ipilimumab might also be evaluated in combination with other immunotherapies, or if a biomarker was available to select patients more likely to respond, added Faires.
Both companies expect to submit a filing in the first half of 2008.
Medarex and Bristol-Myers Squibb have a current market cap of USD 1.33bn and USD 52.73bn respectively.
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