Cell Therapeutics, Inc. (CTI) announced that the Office of New Drugs (the OND) of the US Food and Drug Administration (FDA) after carefully reviewing the materials CTI submitted in support of its appeal, the reviews of the New Drug Application (NDA) for pixantrone prepared by the FDA staff, the transcript of the March 22, 2010 Oncology Drugs Advisory Committee meeting and consulting with the Centre for Drug Evaluation and Research's (the CDER) Deputy Director of Clinical Science and the Office of Biostatistics, concluded that accelerated approval of pixantrone NDA 022481 may not necessarily be out of reach based on a single controlled clinical trial, provided two key matters can be satisfactorily resolved.
First, the submission of information regarding the circumstances surrounding the decision of stopping the trial early to assure that ongoing results assessment were not dictating the decision to stop and, second, ascertainment of the soundness of the primary endpoint after an additional independent radiologic review. If these two key matters are addressed satisfactorily, then PIX301 could be deemed successful, having achieved its primary and secondary endpoints and a re-review of safety and efficacy would be warranted.
OND denied the dispute appeal request to conclude that the efficacy of pixantrone has been demonstrated, but disagreed with the conclusion in the Complete Response Letter that PIX301 was a failed study, which warranted application of an interim analysis statistical thresholds.
“We are gratified and excited that based on a thorough review of our appeal arguments and NDA review that OND provided us the opportunity to re-submit the NDA for re-review and importantly that an additional clinical trial would not necessarily be required for accelerated approval should the two key matters raised be addressed satisfactorily,” said James A Bianco MD, CEO of CTI. “This was the right decision in the interests of patients with relapsed refractory aggressive NHL beyond second line therapy for whom there are no approved or effective drugs.”
As a result of this important new development, the company plans to move quickly to request a meeting with the appropriate Division of the FDA's Office of Oncology Drug Products and to submit the requested information, as well as all other relevant data requested in the Complete Response Letter, in a re-submission as soon as practical. Under the Prescription Drug User Fee Act (PDUFA) guidelines, the re-submitted NDA would have a 6 month review cycle.
Pixantrone is a novel aza-anthracenedione that has distinct structural and physio-chemical properties that make its anti-tumour activity unique in this class of agents. Similar to anthracyclines, pixantrone inhibits Topo-isomerase II but unlike anthracyclines--rather than intercalation with DNA---- pixantrone 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 pixantrone 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 lymphoma without unacceptable rates of cardiotoxicity.
CTI is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable.