Preclinical Study Provides Potential Mechanisms for Lower Cardiotoxicity in Patients with Multiply Relapsed or Refractory Aggressive B-cell NHL Treated with PixuvriTM Who Received Prior Doxorubicin Therapy
SEATTLE, Dec. 17, 2012 /PRNewswire/ -- Cell Therapeutics, Inc. (CTI) (Nasdaq and MTA: CTIC) today announced the publication of results from a preclinical study of PixuvriTM (pixantrone) in the The Journal of Pharmacology and Experimental Therapeutics providing potential mechanisms for lower cardiotoxicity in patients treated with Pixuvri who received prior doxorubicin therapy. While CHOP-R is considered an effective therapy and is the standard of care in first line treatment of aggressive B-cell non-Hodgkin lymphoma (NHL), exposure to cumulative doses of doxorubicin, an anthracycline contained in this regimen, is associated with increasing the incidence of irreversible, severe, and symptomatic cardiac toxicity. The association with heart damage limits the use of doxorubicin and other anthracyclines beyond first line therapy and in patients with pre-existing cardiac disease.
Pixuvri is a novel anthracenedione that lacks the structural motifs that lead to the formation of reactive oxygen species or long-lived hydroxyl metabolites which are believed to be involved in cardiac damage. Although anthracycline induced cardiotoxicity is complex and multi-factorial, this study provides potential mechanisms by which Pixuvri avoids inducing this serious side effect. The study by Giorgio Minotti, M.D., at the Center for Integrated Research and Drug Sciences, University Campus Bio-Medico, Rome Italy, showed that in a human cardiac tissue model, both untreated and pretreated with doxorubicin, Pixuvri did not form reactive oxygen species or long lived hydroxymetabolites. In doxorubicin pretreated cardiac samples, Pixuvri also inhibited formation of the long-lived hydroxymetabolite of doxorubicin. These results suggest mechanisms for the low incidence of cardiotoxicity seen in clinical trials of Pixuvri in doxorubicin naive or pretreated patients.
"Anthracyclines are an effective therapy in aggressive B-cell NHL patients but their use is limited due to the association with cardiac damage," said Professor Minotti. "Cardiotoxicity complicates the clinical management of patients who relapse after first-line therapy as second or third line non-anthracycline chemotherapeutics might precipitate cardiotoxicity through multiple mechanisms. These data provide a biological rationale for the safety profile of Pixuvri and supports Pixuvri's role in treating multiply relapsed or refractory aggressive B-cell NHL."
The publication by Salvatorelli E., et al., led by Professor Minotti G., titled "The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium; Insight to explain the cardiac safety of pixantrone in doxorubicin treated patients," is available at http://jpet.aspetjournals.org/content/early/2012/12/03/jpet.112.200568.abstract
About Pixuvri (pixantrone)
Pixuvri is a novel aza-anthracenedione with unique structural and physio-chemical properties. Unlike related compounds, Pixuvri forms stable DNA adducts and in preclinical models has superior anti-lymphoma activity compared to related compounds. Pixuvri 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 Pixuvri to be administered to patients with near maximal lifetime exposure to anthracyclines without unacceptable rates of cardiotoxicity.
In May 2012, Pixuvri received conditional marketing authorization in the E.U. as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive NHL. The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy. The Summary of Product Characteristics ("SmPC") has the full prescribing information, including the safety and efficacy profile of Pixuvri in the approved indication. The SmPC is available at www.pixuvri.eu.
CTI is currently accruing patients into a Phase 3 trial comparing Pixuvri and rituximab with gemcitabine and rituximab in the setting of aggressive B-cell NHL.
Pixuvri does not have marketing approval in the United States.
About Conditional Marketing Authorization
Similar to accelerated approval regulations in the United States, conditional marketing authorizations are granted in the E.U. 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 Pixuvri, CTI will be required to complete a post-marketing study aimed at confirming the clinical benefit previously observed.
The European Medicines Agency's (the "EMA") Committee for Medicinal Products for Human Use has accepted PIX306, CTI's ongoing randomized controlled phase III clinical trial, which compares Pixuvri-rituximab to gemcitabine-rituximab in patients who have relapsed after one to three prior regimens for aggressive B‑cell NHL and who are not eligible for autologous stem cell transplant. As a condition of approval, CTI has agreed to have available the PIX306 clinical trial results by June 2015.
About Cell Therapeutics, Inc.
CTI (Nasdaq and MTA: CTIC) is a biopharmaceutical company committed to the development and commercialization of an integrated portfolio of oncology products aimed at making cancer more treatable. CTI is headquartered in Seattle, WA. For additional information and to sign up for email alerts and get RSS feeds, please visit www.CellTherapeutics.com.
This press release includes forward-looking statements that involve a number of risks and uncertainties, the outcome of which could materially and/or adversely affect actual future results and the market price of CTI's securities. Specifically, the risks and uncertainties that could affect the development of Pixuvri include risks associated with preclinical and clinical developments in the biopharmaceutical industry in general and with Pixuvri in particular including, without limitation, the potential failure of Pixuvri to prove safe and effective for the treatment of relapsed or refractory NHL and/or other tumors as determined by the U.S. Food and Drug Administration, that CTI may not market and commercialize Pixuvri in the E.U. as planned, that results in future studies may differ,that CTI may not be able to complete the PIX306 clinical trial of Pixuvri-rituximab compared to gemcitabine-rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B cell NHL and who are not eligible for autologous stem cell transplant by June 2015 or at all as required by the EMA or have the results of such trial available by June 2015 or at all, that CTI may not be able complete a post-marketing study aimed at confirming the clinical benefit observed in the PIX301 trial, that the conditional marketing authorization for Pixuvri may not be renewed, that CTI cannot predict or guarantee the pace or geography of enrollment of its clinical trials or the total number of patients enrolled, that CTI's average net operating burn rate may increase and CTI's ability to continue to raise capital as needed to fund its operations in general, and, including, without limitation, competitive factors, technological developments, costs of developing, producing, and selling Pixuvri, and the risk factors listed or described from time to time in CTI's filings with the Securities and Exchange Commission including, without limitation, CTI's most recent filings on Forms 10-K, 8-K, and 10-Q. Except as may be required by law, CTI does not intend to update or alter its forward-looking statements whether as a result of new information, future events, or otherwise
SOURCE Cell Therapeutics, Inc.