It is important to note that the comparator arm did not contain treatment with a class of drugs known for cardiac side effects (with the exception of 4/68 patients who received mitoxantrone). Thus the only way to put the safety data with pixantrone in perspective is to provide, solely for illustrative purposes, the numerical events of CHF (irrespective of relationship to drug) by total doxorubicin equivalent exposure, and see how it would stack up based on literature review.

Here’s some background relevant literature:

JCO 1995, 13:2530-2539, Sonnenveld et al. Study of CNOP Vs CHOP in 148 elderly patients >=60 years of age with aggressive NHL. Only 31% (23 patients) of CNOP and 45% (33 patients) of CHOP patients received all 6 cycles of therapy (for CHOP that would be 300mg/m2 of doxorubicin). LVEF declines of >=15% occurred in 10/22 CHOP patients treated with 300mg/m2 who had LVEF’s measured, and who got 6 cycles (300mg/m2 of dox). 4/33 patients who received 6 cycles of CHOP developed CHF (12%). On intent to treat 4/74 = 5.5%. Thus at standard CHOP exposure of 300mg/m2 – 5.5% develop CHF on an intent to treat basis.

NEJM 1998, 319:745-752 Speyer et al. Study of FDC (flurouracil, doxorubicin, cyclophosphamide) with or without ICRF-187 (an investigational cardio-protectant agent) in 92 women with metastatic breast cancer. LVEF declines of 7% from baseline were observed in the 250mg/m2 to 399mg/m2 group, with 16% declines in the group receiving between 400mg/m2 and 499mg/m2. CHF developed in 11/46 patients (24%). Their median doxorubicin exposure was 397mg/m2.

Cancer 2003, 97:2869-2879, Swain et al. CHF in patients with doxorubicin treatment- retrospective meta-analysis of 3 trials. In this publication women with metastatic breast cancer treated with FDC in 3 separate trials were reviewed and combined to examine the dose-dependent increase in CHF at various levels of total doxorubicin exposure. Overall 178,500mg/m2 was administered to 630 patients (283mg/m2 dox exposure), 32/630 patients developed CHF (5.1%). These data are consistent with the other studies reporting approximately 5% rates of CHF in the standard CHOP dose of 300mg/m2. As noted in Swain, the majority of CHF events occurred at or above a total of 500mg/m2. Using a Kaplan Maier estimation, Swain developed a table estimating 5% incidence at 400mg/m2, 16% at 500mg/m2, 26% at 550mg/m2 and 48% at 700mg/m2.

Importantly in each of these reviews (and well documented in all the literature as well as the doxorubicin drug label), cardiac toxicity is a linear cumulative life-time dose dependant side effect of this class of agents.

Since PIX301 was not a randomized trial against standard doxorubicin, and given that patients had a median of ~300mg/m2 of prior doxorubicin exposure before starting on pixantrone, these patients, based on the literature cited, would be expected to have a significant frequency of CHF events given the median cumulative doxorubicin equivalent exposure of 535mg/m2 (>26% CHF and >50% declines in LVEF >20% from baseline according to historical literature) if this were standard doxorubicin.

The table presented at BIO (and noted in our press release) was an illustrative representation of the number of reported CHF events at various total cumulative doxorubicin equivalent exposure for standard 300mg/m2 levels upward to in excess of 650mg/m2. We do not present this as definitive clinical evidence of lower cardio toxicity, and we agree with your notes that a randomized comparison to doxorubicin would be the gold standard for demonstrating a lower incidence of cardiac damage. Such a trial has completed its 2 year follow up period (CHOP-R Vs CPOP-R, n=124 patients). This study extensively measured (every 2 cycles x 6 cycles, then every 3 months for 2 years) cardiac function which is evaluated by an independent cardiologist blinded to treatment assignment. These data will be included in the NDA safety update, and we hope to have it presented at this year’s ASH meetings.

We hope this information, and the new efficacy and safety information being presented at ASCO will further clarify the unique risk-benefit profile pixantrone has over standard anthracyclines and the impressive efficacy in patients with relapsed/refractory aggressive NHL.