Earlier today, the today European Commissionconfirmed that it has approved a conditional marketing authorization pixantrone (Pixuvri?, Cell Therapeutics), also known as BBR 2778, as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas.

Pixantrone is a novel aza-anthracenedione with unique structural and physio-chemical properties. Unlike related compounds, pixantrone forms stable DNA adducts and in preclinical models has superioranti-lymphoma activity compared to other, related antineoplastic compounds. The trial drug was structurally designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite, both of which are the putative mechanisms for anthracycline induced acute and chronic cardiotoxicity. These novel pharmacologic properties allow pixantrone to be administered to patients with near maximal lifetime exposure to anthracyclines without unacceptable rates of cardiotoxicity, and because pixantrone is not a vesicant, allow it to be safely delivered via a peripheral intravenous catheter.

European approval
Pixantrone is the first approved treatment for patients with with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas.

Unmet need
Non-Hodgkin 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 and indolent NHL. Aggressive NHL is a rapidly growing form of the disease that moves into advanced stages much faster than indolent NHL, which progresses more slowly. The World Health Organization’s International Agency for Research on Cancer’s 2008 GLOBOCAN database most recent estimates state that in EU approximately 74,162 people will be diagnosed with NHL and 31,371 are estimated to die from NHL every year.

There are many subtypes of NHL, but aggressive B cell NHL is the most common and accounts for about 60% of cases. Initial therapy for aggressive NHL with anthracycline-based combination therapy cures up to 60% of patients. Of the remaining patients, approximately half will respond to intensive second-line treatment and some are cured by stem cell transplantation. Of those not eligible for intensive second line therapy and those patients who fail to respond or relapse, until the approval of pixantrone, no therapeutic has received regulatory approval for this patient group.

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Conditional Marketing Authorization
Conditional Marketing authorization speeds innovative new therapy to patients with unmet medical needs. Similar to accelerated approval regulations in the United States, conditional marketing authorizations are granted in the EU to medicinal products with a positive benefit/risk assessment that address unmet medical needs and whose availability would result in a significant public health benefit. A conditional marketing authorization is renewable annually. Under the provisions of the conditional marketing authorization for pixantrone, Therapeutics will be required to complete a post-marketing study aimed at confirming the clinical benefit previously observed.

The decision allows Cell Therapeutics to market pixantrone in the 27 Member States of the European Union as well as in Iceland, Liechtenstein and Norway. The company expects to make pixantrone immediately available, initially through a named patient program.

“Pixantrone is a welcome addition in our efforts to control disease progression in these late-stage aggressive NHL patients as it has demonstrated a significant benefit compared to standard treatments used at this stage of disease. By addressing this unmet need, Pixuvri adds an important treatment option for patients,” said Norbert Schmitz, M.D., Ph.D., Head of the Department of Hematology, Askelepios Klinik St. Georg in Hamburg, Germany.

“The European Union’s decision for pixantrone is an important milestone for adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas who currently have no approved option to treat their disease, and we are moving rapidly to make this product available for patients in the EU,” said James A. Bianco, M.D., CEOof
Cell Therapeutics.

Clinical trials
The PIX 301 phase III clinical trial, which formed the basis for the marketing authorization application, demonstrated that a greater proportion of patients achieved a complete response or unconfirmed complete response to pixantrone than a comparator chemotherapy medicine, (20% versus 6%) and patients receiving pixantrone survived for longer without their disease progressing (an average of 10.2 months versus 7.6 months).

Adverse events
The most frequent side effect seen in the clinical studies was suppression of the patient’s bone marrow, resulting in low levels of white blood cells, platelets and red blood cells. Infections were common, but were only serious in a few patients.

At the time of grant of marketing authorization by the European Commission, pixantrone is not yet approved in the United States.

For more information:
NCT00088530 – BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL)
NCT00106600 – Pixantrone (BBR 2778) in Patients With Refractory Acute Myelogenous Leukemia (AML)
NCT00060684 – Dose Ranging Trial for Pixantrone in the FND-R Variant Regimen in Indolent Non-Hodgkin’s Lymphoma

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