Lymphoma drug pixantrone (Pixuvri) needs more safety data: US FDA tells Cell Therapeutics

Cell Therapeutics’ experimental lymphoma drug pixantrone dimaleate (Pixuvri) would require additional trial data to establish safety and efficacy, US FDA said.

US FDA has given Cell Therapeutics, Inc a Complete Response Letter regarding its New Drug Application (NDA) for Pixuvri (pixantrone dimaleate) for relapsed or refractory aggressive non-Hodgkin’s lymphoma (NHL).

US FDA cited as its primary reason for the action its concerns previously raised at the Oncologic Drugs Advisory Committee (ODAC) meeting on March 22, 2010 and recommended the company conduct an additional trial to demonstrate the safety and effectiveness of its product.

US FDA’s ODAC presentation provided the committee and the company with alternative options to consider to make investigational drugs available to patients if drugs need to be studied further prior to approval.

Cell Therapeutics has decided to pursue expanded access programme for pixantrone while it conducts an additional study in aggressive NHL.

“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 centres across the US, we expect enrolment in a follow-up combination therapy study in a similar population could be rapid and occur predominantly within the US,” noted Jack W Singer, chief medical officer of the company.

The company plans to request a meeting with the US FDA on both the design of the follow-on study as well as expanded access program for patients who are not participating in the company’s clinical trial.

Later this month, Cell Therapeutics is scheduled to meet with its clinical expert and the co-rapporteurs as it prepares to submit its Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) for review. Based on their feedback and guidance, Cell Therapeutics expects to submit the application in the third quarter of 2010.

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 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 aggressive lymphoma without unacceptable rates of cardiotoxicity.

What is non-Hodgkin’s lymphoma?

Non-Hodgkin’s lymphoma is caused by the abnormal proliferation of lymphocytes, cells key to the functioning of the immune system.

It usually originates in lymph nodes and spreads through the lymphatic system. NHL can be broadly classified into two main forms–aggressive non-Hodgkin’s lymphoma is a rapidly growing form of the disease that moves into advanced stages much faster than indolent NHL, which progresses more slowly.

According to the National Cancer Institute’s SEER database, on January 1, 2006 there were approximately 419,533 people in the U.S. living with a history of non-Hodgkin’s lymphoma.

The American Cancer Society estimated that 65,980 people would be diagnosed with NHL in 2009 with 19,500 estimated to die from this disease.

Non-Hodgkin’s lymphoma is the fifth most common cancer in the United States.

There are many subtypes of non-Hodgkin’s lymphoma, but aggressive NHL is one of the more common types of NHL and accounts for about 60% of cases. Initial therapy for aggressive non-Hodgkin’s lymphoma with anthracycline-based combination therapy cures up to 50 percent of patients.

Of the remaining patients, approximately half will respond to second-line treatment, but few are cured and there is no effective therapy for patients relapsing after or refractory to second-line treatment.

Headquartered in Seattle, Cell Therapeutics is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable.