Pixuvri could be made available to patients prior to sanction based on an expanded access program.

Following the advice of its oncologic drugs advisory committee (ODAC), FDA has asked Cell Therapeutics (CTI) to perform an additional trial to demonstrate the safety and effectiveness of Pixuvri™ in relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). The FDA did, however, give the company the option to make the drug available to patients. Cell Therapeutics has decided to pursue an expanded access program while it conducts additional clinical work in aggressive NHL.

In its response letter FDA cited that its primary reason for delaying approval was the concerns previously raised by the ODAC on March 22. The panel voted 9–0 against the approval of Pixuvri, sending the firm’s stock price from $0.91 on March 22 to open the next day at $0.40. The company opened today at $0.66.

Cell Therapeutics’ NDA was based on the PIX 301 Extend (expanding the reach of anthracyclines with pixantrone in relapsed or refractory aggressive NHL disease) single-agent trial, which enrolled 140 patients. The study achieved its primary endpoint—higher rate of complete remissions—and patients treated with pixantrone experienced a statistically significant improvement in median progression-free survival.

Yet both ODAC and FDA were vary of the therapy’s side effects. Those receiving the drug had a low incidence of severe neutropenia complicated by either fever, infections, severe vomiting, or diarrhea. Pixantrone patients also had a higher incidence of leucopenia and numerically more severe cardiac events. Only one cardiac event was considered to be related to the study drug, according the company.

Commenting on FDA’s decision to offset sanction until more clinical data is available, Stanley M. Marks, M.D., director of clinical services and CMO for the University of Pittsburgh Cancer Centers, says “I was disappointed that an agency charged with providing treatment hope for patients with life threatening diseases like relapsed/refractory NHL would ignore clinically meaningful improvements in overall response rate and progression-free survival, let alone complete responses, something we all wish for our patients, but with existing treatments rarely achieve.” Dr. Marks presented at CTI’s investor and analyst meeting that focused on Pixuvri.

The company will meet with the FDA to discuss design of the follow-on study as well as the expanded access program for patients who are not participating in the clinical trial. “On the basis of discussing the PIX 301 clinical trial results with directors of more than 50 of the largest academic and community-based lymphoma treatment centers across the U.S., we expect enrollment in a follow-up combination therapy study in a similar population could be rapid and occur predominantly within the U.S.,” notes Jack W. Singer, M.D., CMO of the company.

“We have had preliminary discussions on the subsequent trial design with a leading statistician and potential lead investigators who believe the study will be positively received by the lymphoma treatment community on the basis of the PIX 301 clinical trial results and the lack of satisfactory alternative therapies for their patients with multiple relapsed aggressive non-Hodgkin lymphoma.”

Cell Therapeutics is in the process of preparing its MAA and expects to submit the application to the EMEA in the third quarter of this year. Pixantrone is an aza-anthracenedione that has distinct structural and physio-chemical properties that make its antitumor activity unique in this class of agents, according to CTI.

Similar to anthracyclines, pixantrone inhibits topo-isomerase II. Unlike anthracyclines, though, rather than intercalation with DNA, pixantrone alkylates DNA to form stable DNA adducts with particular specificity for CpG rich, hyper-methylated sites.

In addition, the structural motifs on anthracycline-like agents that are responsible for the generation of oxygen-free radicals and the formation of toxic drug-metal complexes have also been modified in pixantrone. These changes prevent the binding of iron and perpetuation of superoxide production, both of which are putative mechanisms for anthracycline-induced acute cardiotoxicity.

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