Biopharmaceutical company Cell Therapeutics Inc. (CTI) said that the company has voluntarily withdrawn its New Drug Application (NDA) for Pixuvri (pixantrone), a novel aza-anthracenedione for the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) in patients who failed two or more lines of prior therapy.
The NDA was withdrawn because, after communications with the US Food and Drug Administration (FDA), CTI needed additional time to prepare for the review of the Pixuvri NDA by the FDA's Oncologic Drugs Advisory Committee (ODAC) at its February 9 meeting. Prior to withdrawing the NDA, CTI requested that the FDA consider rescheduling the review of the Pixuvri NDA to the ODAC meeting to be held in late March. The FDA was unable to accommodate CTI's request to reschedule, and given the April 24, Prescription Drug User Fee Act (PDUFA) date, the only way to have Pixuvri possibly considered at a later ODAC meeting was for CTI to withdraw and later resubmit the NDA. CTI plans to resubmit the NDA in 2012.
Pixuvri has distinct structural and physio-chemical properties that make its anti-tumour activity unique in this class of agents. Similar to anthracyclines, Pixuvri inhibits Topo-isomerase II but unlike anthracyclines -- rather than intercalation with DNA - Pixuvri alkylates DNA -- forming stable DNA adducts with particular specificity for CpG-rich, hyper-methylated sites. These structural differences resulted in significantly enhanced anti-lymphoma activity compared to doxorubicin in preclinical models.
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 Pixuvri in an effort to prevent the binding of iron and perpetuation of superoxide production -- both of which are the putative mechanism for anthracycline induced acute cardiotoxicity. These novel pharmacologic differences may allow re-introduction of anthracycline-like potency in the treatment of relapsed/refractory diffuse large cell lymphoma without unacceptable rates of cardiotoxicity.