Mitoxantrone as Induction Followed by Interferon Beta-1b Versus Interferon Beta-1b: Presented at ECTRIMS

By Chris Berrie

PRAGUE, CZECH REPUBLIC -- October 18, 2007 -- Mitoxantrone induction in combination with methylprednisone prior to interferon beta (IFNbeta) treatment in patients with aggressive relapsing-remitting multiple sclerosis (RRMS) reduces the risk of developing fixed disability and increases relapse-free periods when compared with IFNbeta prior to methylprednisone.

These findings are from a multicentre, randomised, prospective, controlled, study presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The study's principal investigator, Gilles Edan, MD, and Professor of Neurology, Istitut des Neurosciences Cliniques de Rennes, Rennes, France, presented the findings on behalf of the French-Italian Mitoxantrone-Interferon-beta-1b Study Group.

Although IFNbeta-1b can reduce relapse frequencies and new lesions on magnetic resonance imaging (MRI), the magnitude of these effects remains small, providing around 30% benefit. Furthermore, in the longer term of 3 to5 years, these beneficial effects can be lost, particularly for the 35% of patients with RRMS who develop neutralizing antibodies while under IFNbeta treatment.

"Mitoxantrone has a strong, rapid and sustained impact on the inflammatory processes, but its potential toxicity limits the duration of its prescription," Dr. Edan said. Therefore, Dr. Edan and colleagues conducted a study to determine whether the use of mitoxantrone induction prior to IFNbeta-1b therapy can provide further clinical benefits.

The main inclusion criteria were age 18 to 45 years, confirmed diagnosis of MS using Poser criteria and as defined by MRI. For disease status of aggressive RRMS, there was the requirement for two or more relapses in the preceding 12 months, at least one Gd+ lesion on MRI, and an expanded disability status scale (EDSS) score of 2.5 to 5.5 (significant disability).

Exclusion criteria were pregnancy and breast feeding, nonuse of efficient contraception, previous global immunosuppression, use of other specific agents, and associated disease.

The primary endpoint was time to 1 or greater-point increase on the EDSS during the 3 years of the study. There were also secondary endpoints of relapse frequency, relapse-free patients, time to first relapse after inclusion, and safety.

Of 123 patients randomized in the study, 109 were treated and analyzed, constituting the intention-to-treat population. The study design provided randomization to one of two treatment arms after 12 months of followup.

The 55 patients in the first arm started at baseline with mitoxantrone 20 mg/month plus methylprednisone 1 g/month for the first 6 months of treatment. They then had a 3-month break from treatment (months 7-9), followed by interferon 250 mcg SC every other day from months 10 to 36.

The 54 patients in the second arm started at month 0 with methylprednisone 1 g/month in combination with IFNbeta-1b. As with group 1, methylprednisone was stopped after 6 months, while IFNbeta-1b continued for the full 36 months of the study.

Patients in the two groups had similar mean ages (33.2 vs 32.2 years, respectively) and gender distribution (male 34.6% vs 33.3%, respectively).

At baseline, the disease characteristics across treatment groups 1 and 2, respectively, were not significantly different, including duration of MS (6.6 vs 5.1 years), time from last relapse to M0 (3 vs 3 months), annual relapse rate (2.65 vs 2.83) and EDSS score (4.1 vs 3.8).

The primary endpoint was time for a 1-point increase in EDSS (acquisition of fixed disability) within the 36 months of the trial. "This time was clearly longer in the group of patients using mitoxantrone and interferon beta," Dr. Edan said, and thus, there was mitoxantrone group obtained significant benefit compared with group 2 (P =.008). As only five of the total 19 patients who acquired this fixed disability by month 36 were in group 1, this represented a significant 65% reduction in clinical worsening in the mitoxantrone-pretreated patients (P <.024).

When variations in EDSS score were analyzed from baseline to the last recorded scores during the treatment period, the mitoxantrone group saw a small but significant decrease in mean EDSS score from 4.1 to 3.6 (P <.006), whereas in the absence of mitoxantrone there was no significant change (from 3.8 to 3.7).

For the annual relapse rate under study treatment, there was again a large, 61.5%, significant benefit with the use of mitoxantrone (annual relapse rate: group 1, 0.44; group 2, 1.14; P <.003). When further analyzed as annual relapse rate during the IFNbeta-1b alone treatment, benefits for mitoxantrone were again seen compared with treatment without mitoxantrone (group 1, 0.50; group 2, 1.14; P <.007).

Patients in the mitoxantrone group also had significantly improved time to first relapse from baseline (P <.002). Similarly, there was a significant increase in the percentage of relapse-free patients in group 1 over group 2 (53% vs 26%; P =.01).

Finally, the researchers also tested mitoxantrone benefits at the patient disability levels. Although not a pre-planned analysis, this was achieved in a subgroup analysis of EDSS at baseline, divided according to an EDSS of 4.0, and demonstrated a significant benefit for both the use of mitoxantrone and an EDSS score less than 4 at baseline (P <.02).

The safety analysis showed significantly more adverse events in the mitoxantrone group compared with the group not treated with mitoxantrone. These comprised upper respiratory tract infection (45.4% vs 24.1%, respectively; P <.02), leucopenia (36.4% vs 16.7%, respectively; P <.02) and nausea (21.8% vs 7.4%, respectively; P <.02).

"However, these [adverse effects] are exactly what you might expect from adding mitoxantrone to this treatment, and there was no serious adverse effect in this study," added Dr. Edan.

Thus, he concluded, this induction treatment of mitoxantrone combined with methylprednisone provides clinical benefits for patients with aggressive RRMS that include decreases in both acquisition of fixed disability and relapse rates.


[Presentation title: Comparison of Two Therapeutic Strategies in Aggressive Relapsing-Remitting MS: Mitoxantrone as Induction for 6 Months Followed by Interferon Beta-1b Versus Interferon Beta-1b. A 3-Year Randomised Trial. Abstract 74]

Rituximab in Adults With Relapsing-Remitting Multiple Sclerosis: Presented at ECTRIMS

By Chris Berrie

PRAGUE, CZECH REPUBLIC -- October 17, 2007 -- A single course of rituximab is safe and well tolerated, and compared with placebo, significantly reduces magnetic resonance imaging (MRI) and clinical evidence of inflammatory activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to a multicenter, randomized, placebo-controlled, phase 2 trial.

The findings were presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

"For a decade or more, people have mostly looked at treatment that affects T cells in MS, although within the past 10 years there has actually been increased interest in B cells and their products," said principal investigator Emmanuelle Waubant, MD, PhD, Associate Professor of Neurology, Department of Neurology, University of California at San Francisco, San Francisco, California.

Past research has shown that the action of the genetically-engineered chimeric monoclonal anti-CD20 antibody rituximab, in its depletion of pre-B and B cells via binding to their CD20 antigen, could provide an alternative approach in the modulation of MS pathophysiology.

"So this is a proof-of-concept study, to determine whether, in human MS, targeting B cells has an impact on the course of the disease," Dr. Waubant said. The design aim was to evaluate the safety and efficacy of a single treatment cycle of rituximab over 48 weeks in patients with RRMS.

Study subjects were 18 to 55 years old and had a confirmed diagnosis of MS, at least one relapse in the previous year, and an expanded disability status scale (EDSS) score of 0 to 5. They were excluded if they had secondary progressive, primary progressive, or progressive-relapsing MS, and patients who had received various previous treatments were also excluded.

The 104 patients with RRMS enrolled were randomized to placebo (n = 35; mean age, 41.5 years; male, 17.1%) or rituximab 1,000 mg IV infusion on days 1 and 15 (n = 69; mean age, 39.6 years; male, 24.6%).

The primary endpoint was the total number of Gd-enhancing T1 brain lesions on serial MRI scans at weeks 12, 16, 20, and 24. A series of exploratory efficacy outcome measures were used as secondary endpoints: proportion of patients relapsing; annualized relapse rate; total number of new Gd-enhancing T1 lesions; and annualized relapse rate and T2 lesion volume change.

Baseline clinical characteristics between placebo and rituximab treatment groups were essentially the same with respect to number of relapses in the previous year (about 75% of patients had one relapse), mean EDSS score (2.7 vs 2.8, respectively), MS therapy in the previous 2 years (generally glatiramer acetate, interferon beta-1a, and methylprednisone), and lesion counts and volumes.

When compared with the placebo group, rituximab treatment satisfied the primary endpoint, with a significant 91% reduction in mean total Gd-enhancing lesion counts at weeks 12, 16, 20, and 24 (5.5 vs 0.5, respectively; P <.001). Significance was reached at week 12 (P =.003) and continued through the full 48 weeks of monitoring (P <.0001).

For the secondary endpoints, rituximab significantly reduced the number of new Gd-enhancing lesions at weeks 12, 16, 20, and 24, as compared with placebo (P <.001). From week 12, rituximab significantly reduced the number of new Gd-enhancing lesions at each assessment (P =.002 to P <.001).

Rituximab treatment also showed a trend in these patients towards lower annualized relapse rates that reached significance compared with placebo by week 24 (0.84 vs 0.37, respectively; P =.04), although this significance did not carry through to week 48.

For the safety assessments, while all other safety aspects examined were the same across the treatment groups, after the first infusion there were significantly greater infusion-associated adverse events with rituximab than placebo (78.3% vs 40.0%, respectively). However, this effect was reversed after the second infusion (40.0% vs. 20.9%, respectively).

Overall, rituximab was safe, well tolerated, and efficacious through the full 48 weeks of follow-up.

"We demonstrate a very rapid effect of depletion of B cells on the course of MS, measured by MRI, and clinical course, which suggests that it is probably not an effect that is promoted by interfering with the antibodies or immunoglobulin in MS, but it's more likely to be through B cells and their direct cellular effects on T cells and cytokines," Dr. Waubant indicated.

Funding for this study was provided by Genentech Inc.


[Presentation title: Safety and Efficacy of Rituximab in Adults With Relapsing-Remitting Multiple Sclerosis: Results of a Phase 2, Placebo-Controlled, Multicentre Trial Through 48 Weeks. Abstract P554]