Cell Therapeutics (CTI) intends to appeal FDA’s decision regarding the pixantrone NDA to treat patients with relapsed/refractory aggressive non-Hodgkin lymphoma (NHL). CTI had requested accelerated approval, but the agency issued a complete response letter stating that the firm would need to conduct an additional clinical trial to obtain approval.
CTI expects the FDA decision on the appeal in the fourth quarter of this year. The company continues to prepare for the initiation of an additional pixantrone clinical study in the U.S. that would serve as either a postapproval confirmatory study or as a registration study for approval in the U.S.
Also, CTI expects to file an MAA in Europe before the end of this year. In April it obtained a positive opinion from European regulatory authorities for the proposed filing based on the PIX 301 trial in adults. The EMEA recommended the firm submit an updated Pediatric Investigation Plan (PIP) for development of the drug against hematologic cancers in children. CTI reported submission of the PIP in July; the program will compare pixantrone with doxorubicin in the treatment of lymphoid cancers in pediatric patients aged 6 months to 18 years.
CTI points out that there are no approved or effective therapies for patients with relapsed or refractory aggressive NHL beyond second relapse and that PIX 301 was the first and only randomized trial in this patient group to demonstrate significant improvement in clinically relevant endpoints including complete response rate, overall response rate, and progression-free survival while being safe and effective in this indication.
"After discussions with a number of leading U.S. and international lymphoma experts and leading biostatisticians, all of whom have reviewed the PIX 301 protocol, statistical plan, and trial results, we felt encouraged to appeal the initial decision and have our data reviewed in the context of a trial that achieved statistically and clinically meaningful primary and secondary endpoints in this end-stage patient population for whom there are no approved or effective agents," notes Jack Singer, M.D., CMO at CTI.
CTI will file the appeal under the FDA's Formal Dispute Resolution process, under which it can raise the matter with the supervisor of the office that made the decision.
The company is also investigating additional applications of pixantrone. In May the firm and the North Central Cancer Treatment Group (NCCTG) entered a partnership to conduct a Phase II study of the drug in patients with HER2-negative metastatic breast cancer who have tumor progression after two or three prior chemotherapy regimens.
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. But unlike anthracyclines, rather than intercalation with DNA, pixantrone alkylates DNA, forming stable DNA adducts, with particular specificity for CpG-rich, hyper-methylated sites.
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 to prevent the binding of iron and perpetuation of superoxide production, the company says. These novel pharmacologic differences may allow re-introduction of anthracycline-like potency in the treatment of relapsed/refractory aggressive lymphoma without unacceptable rates of cardiotoxicity, CTI expects.