Tuesday, October 10, 2006

Safety and Tolerability of Mitoxantrone for Worsening Multiple Sclerosis Appears Stable in Long Term

Presented at ECTRIMS

By Bruce Sylvester

MADRID, SPAIN -- October 2, 2006 -- Researchers report that the safety and tolerability of Novantrone (mitoxantrone) in long-term treatment of worsening multiple sclerosis appears to be consistent with its known safety profile.

The findings were presented here on September 29th at the 22nd Congress of the European Committee for Treatment and research in Multiple Sclerosis (ECTRIMS).

"In a large sample of patients followed prospectively, we found that the risk/benefit ratio is in keeping with prior knowledge about this drug," said lead investigator Edward Fox, MD, PhD, clinical assistant professor, University of Texas Medical Branch, Austin, Texas.

Mitoxantrone is currently being evaluated for long-term safety and tolerability in patients with worsening relapsing-remitting multiple sclerosis, progressive relapsing multiple sclerosis and secondary progressive multiple sclerosis in the ongoing, multicenter, open-label Registry to Evaluate Novantrone Effects in Worsening MS (RENEW).

Dr. Fox reported data on 509 patients in the RENEW trial who initiated Novantrone 12 mg/m2. Patients were excluded from the study if they showed signs of primary progressive MS, history of congestive heart failure, and left ventricular ejection fraction < 50% and if they had received previous treatment with mitoxantrone, other anthracenediones or anthracyclines.

The investigators evaluated subjects every 3 months during treatment for a total of 3 years and for an additional 2 years for safety evaluation.

Data were collected from April 2001 to Jan 2006. Mean cumulative dose was 67.5 mg/m2 (8.0-148.6 mg/m2) and mean treatment duration was 1.4 years (0.0-4.0). Sixteen subjects reached the recommended maximum cumulative dose of 140 mg/m2. A total of 355 (70.0%) patients have received concomitant medications for MS.

Treatment was discontinued by 80% of 508 subjects with validated data. Follow-up data is being collected on 361 subjects regardless of treatment status -- the 104 patients receiving mitoxantrone plus the 257 patients who discontinued mitoxantrone.

There were 301 relapses during treatment of 221 subjects. Median time to first relapse was 155 days (range: 3-1215).

Adverse events were reported in 95 patients, who experienced 158 events. The most frequently reported serious adverse events were infectious (34%) and cardiac events (23%). Congestive heart failure occurred in 8 patients, and left ventricular ejection fraction <50% in 4.7% of 340 patients with postbaseline tests.

Also, 9 of 46 patients with serious infections were severely neutropenic (absolute neutrophil count <500).

"There have been 7 deaths, 5 unrelated and 2 possibly related to treatment. One therapy-related leukemia case has been reported," the authors wrote in their poster.

The results, which reflect treatment at higher cumulative mitoxantrone doses (mean: 67.5 mg/m2), appear consistent with the known safety profile, they noted. "Continued patient observation will provide important longer-term safety and tolerability data for mitoxantrone use in clinical practice," they wrote.

"Since FDA approval in 2000, there is no new safety information except, importantly, that cardiac function should be tested before each dosing," Dr. Fox noted.

[Presentation title: Ongoing Evaluation of the Safety and Tolerability of Novantrone (Mitoxantrone) Worsening Multiple Sclerosis: The RENEW Study. Abstract P759]