By Chris Berrie
PRAGUE, CZECH REPUBLIC -- October 18, 2007 -- Treosulfan appears to be safe and well tolerated, and shows both clinical and radiological efficacy in patients with secondary progressive multiple sclerosis (SPMS), according to a two-center, nonrandomized, noncontrolled, open-label study.
These findings were presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Treosulfan, a cytostatic bifunctional alkylating agent, has been available for the treatment of ovarian cancer for several years, and more recently it has been shown to reduce the severity of autoimmune encephalomyelitis in an animal model. At the same time, it is known to reduce proliferative capacity and increase apoptosis in human peripheral blood mononuclear cells, and to inhibit migration of immune cells.
Heinz Wiendl, MD, Coordinating Investigator and Head, Clinical Research Group, Department of Neurology, University of Wuerzburg, Wuerzburg, Germany, and colleagues evaluated the safety and efficacy of treosulfan in patients with SPMS who have failed or do not qualify for treatment with conventional immunomodulatory agents.
After patient screening, the study design provided an initial induction phase of 3 months with monthly pulses of treosulfan starting at 7 g/m2, with dose escalation to 8 g/m2. This was accompanied by clinical evaluations every 4 weeks, with magnetic resonance imaging (MRI) at baseline and at the end of this induction phase.
This phase was followed by a maintenance phase for 1 year, with 3-monthly pulses of treosulfan, and accompanied by 3-monthly clinical and MRI analyses. In both induction and maintenance, the clinical assessments included expanded disability status scale (EDSS) and MS Functional Composite (MSFC), along with blood and urine analyses.
A total of 21 patients with confirmed SPMS participated in the study, divided according to the safety (n = 11) and efficacy (n = 20) sets. These patients were in a phase of secondary progression of the disease, as seen from the mean duration of SPMS of 4.3 and 4.6 years, respectively. Their mean MS durations since the first manifestation were 16.6 and 17.2 years, respectively, and they were still under active disease according to the number of attacks they had in the previous year (means, 1.4, 1.4). Their mean EDSS scores were 4.95 and 5.05, respectively.
"All of the patients either stabilized or even improved over the observation period of 1 year," Dr Wiendl indicated. The annual relapse rate of 1.5 prior to study entry decreased significantly to 0 by the end of the study year (P <.016).
Within the MRI analyses, there was a trend for a reduction in Gd-enhancing lesions, although, as Dr. Wiendl said, "What we saw by the end of this study was that some of these patients seemed to be having recurring activity, which could be an indication that the 3-monthly maintenance pulses are not sufficient to be anti-inflammatory."
Therefore, the researchers concluded that not only was treosulfan safe and well tolerated, but nine of the 11 patients remained on treosulfan for the complete study period, during which they showed clinical stabilization or improvements, as judged by their EDSS and MSFC scores. Furthermore, no clinical relapses were seen during the treatment period, and the mean numbers and volumes of their T2 and T1 lesions did not change during the year of treatment.
These results have thus moved things forward with the establishing of a randomised phase 2 study, which is currently in recruitment, Dr. Wiendl said.
Funding for this study was provided by Medac GmbH.
[Presentation title: Treatment of Active Secondary Progressive Multiple Sclerosis With Treosulfan. Abstract 75A]
