Study Reveals No Increase in Anthracycline-Induced Heart Damage With Pixantrone
Wednesday November 19, 2:16 am ET
Preclinical Study Supports Preliminary Clinical Data Suggesting Pixantrone Is Safe in Anthracycline Pre-Treated Patients
MILAN, Italy, Nov. 19 /PRNewswire-FirstCall/ -- Novuspharma SpA (Nuovo Mercato: NOV.MI and NOV IM), a biopharmaceutical company focused on developing new cancer therapeutics, today announces preclinical results which demonstrate that Pixantrone does not significantly increase existing anthracycline-induced heart damage, while repeat treatment with traditional anthracyclines leads to significant deterioration in heart tissue. These results suggest Pixantrone is safe to use in patients heavily pre-treated with existing anthracyclines; the same conclusion that has been reached in clinical trials for Pixantrone in relapsed aggressive non-Hodgkin's lymphoma (NHL). The results together with results from three other studies with Pixantrone, were presented in a poster session at the AACR-NCI-EORTC, International Conference on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts, on Tuesday November 18, from 12:30 to 19:30 local time.
Pixantrone is an investigational drug that is being developed by Novuspharma to improve the activity and safety of anthracyclines. Anthracyclines form an important treatment for a number of malignancies but their utility is often limited by their potential to cause irreversible heart damage, which often prevents them being used in repeat therapy. Pixantrone was specifically designed to eliminate the cardiac toxicity associated with these agents. It is currently undergoing a number of clinical trials in NHL with the aim of providing a highly active anthracycline-like agent, which could be safely used in patients previously treated with traditional anthracyclines (such as mitoxantrone and doxorubicin).
Pixantrone does not increase existing anthracycline-induced heart damage in preclinical models
Results were presented in Boston from a preclinical model designed to mimic the administration of Pixantrone to relapsed patients, which have previously been treated with the traditional anthracyclines. In this experiment, doxorubicin pre-treated mice were administered Pixantrone, doxorubicin, mitoxantrone or vehicle (inactive injection), following a six-week treatment-free period. Damage to the heart tissue was scored using the Bertazzoli method, which runs from 0 (normal) to 10 (severe damage). The results demonstrate that animals which received a second cycle of treatment with Pixantrone had a mean cardiotoxicity score that was not significantly different from animals receiving vehicle alone (2.6 with Pixantrone in the second cycle, compared to 2.7 with vehicle (p=0.91)). In contrast, a second cycle of treatment with mitoxantrone or doxorubicin led to a statistically significant difference in cardiac damage compared to vehicle treated animals (mean score of 5.7, with doxorubicin (p=0.0029) and 8.4 with mitoxantrone (P<0.0001)). Results were also statistically significant when animals receiving Pixantrone in their second cycle were compared to those receiving doxorubicin (p=0.0011) and mitoxantrone (p<0.0001)*.
These results therefore suggest it would be safe to use Pixantrone in patients which have been heavily pre-treated with the traditional anthracyclines; a similar conclusion has been drawn from the clinical studies conducted for Pixantrone in relapsed patients to date.
In contrast to Pixantrone, doxorubicin appears to induce the expression of p21 in heart tissue; a response associated with cellular stress
Novuspharma has conducted a large number of experiments confirming that Pixantrone causes no meaningful heart damage in anthracycline naive animals, while the traditional anthracyclines are markedly cardiotoxic. At the congress, results were presented from an experiment where the gene expression profile of mouse heart tissue was monitored during treatment with Pixantrone or doxorubicin. As expected, doxorubicin treatment led to significant cardiac damage, while no injury was detected in Pixantrone treated animals. The experiment also revealed that doxorubicin modified the expression of several genes, including the induction of p21, which is indicative of cellular stress. Pixantrone did not induce the expression of p21 and only slightly affected gene expression, with results similar to those observed with vehicle alone.
In total, 4 presentations were made at AACR-NCI-EORTC on November 18, from 12:30 to 19:30 local time:
-- The aza-anthracenedione Pixantrone (BBR 2778) confirms its reduced
cardiotoxic potential vs. reference standards also in mouse
pre-treated with anthracyclines. L. Crippa et al.
-- Molecular and histopathological evaluation of lack of Pixantrone
induced cardiotoxicity as compared to Doxorubicin in mice. M. Cassin
et al.
-- Investigation of Pixantrone's mechanism of action on HS-Sultan human
non-Hodgkin's lymphoma cells by cDNA microarray technology. M. Cassin
et al.
-- Population pharmacokinetics of Pixantrone in cancer patients.
A. Bernareggi et al.
# These results were achieved using a daily doxorubicin dose of 4.6 mg/kg in both cycles but similar conclusions can be drawn from animals treated at 7.5mg/kg of doxorubicin. |
