From the American Academy of Neurology 59th Annual Meeting: Sequential and combination drug therapies for MS associated with fewer lesions, reduced relapse rates

Key Points

Novel strategies for the treatment of relapsing remitting multiple sclerosis (RRMS) incorporate multiple agents used sequentially or in combination to suppress the development of new brain lesions and reduce relapse rates.

One such strategy involves the use of the immunosuppressive agent mitoxantrone prior to immunomodulating therapy with glatiramer. The effect of this approach on several MS disease parameters was the subject of numerous presentations at the American Academy of Neurology 59th Annual Meeting that was held April 28 to May 5, 2007, in Boston, Massachusetts.

"It is possible to take current therapies and use them in tandem in a rational way to get much bigger effects that will help prevent brain injury early on, so that patients have more cranial reserve later in life, and will be more functional and less likely to be disabled," said Timothy Vollmer, MD, director of the neuroimmunology program, Barrow Neurological Institute, St. Joseph's Hospital, Phoenix, Arizona. "Preserving brain function up front is key," he said.

Preliminary clinical studies have demonstrated that immunosuppression with mitoxantrone prior to glatiramer treatment is safe and is more effective than glatiramer alone in suppressing the development of gadolinium (Gd)-enhancing lesions and in reducing annual relapse rates.

In a multicenter, randomized, single-blind study, 40 patients with RRMS were assigned to either induction therapy with mitoxantrone preceding glatiramer treatment or to glatiramer without induction therapy. To be eligible, patients had to have ≥1 Gd-enhancing lesion at screening (identified by magnetic resonance imaging [MRI]) and an Expanded Disability Status Scale [EDSS] score of ≤6.5. Mitoxantrone was administered as 3 monthly infusions of 12 mg/m² followed by a 2-week washout before the administration of glatiramer 20 mg/d.

The superiority of mitoxantrone induction prior to glatiramer over glatiramer alone in reducing Gd-enhancing lesions extended to a 24-month follow-up, which included 28 of the 40 patients enrolled in the study, Dr Vollmer said.

The reductions in Gd-enhancing lesions with mitoxantrone plus glatiramer at 15 months are paralleled by favorable effects on MRI markers of disease burden and tissue damage, according to Douglas L. Arnold, MD, Montreal Neurological Institute, Canada.

In the assessment of brain MRIs, significant differences favoring the mitoxantrone plus glatiramer group were observed in the change from baseline in the volume of T2-weighted lesions (P=.0139), the volume of T1-weighted lesions (P=.0303), and the proportion of Gd-enhancing lesions that evolved into chronic black holes (areas of lost brain tissue where lesions once were) (P=.0023), Dr Arnold said.

The mean volume of T2-weighted lesions was reduced from 10.35 mL at baseline to 8.77 mL at Month 15 in the mitoxantrone plus glatiramer group (P=.0103) but was essentially unchanged in the glatiramer-only group (7.25 mL at baseline vs 7.63 mL at Month 15). Approximately 0.01% of Gd-enhancing lesions evolved into black holes in patients assigned to mitoxantrone plus glatiramer, compared with 0.20% in patients assigned to glatiramer only. "Prevention of chronic black holes may slow disease progression by avoiding permanent tissue destruction," Dr Arnold said.

The findings "suggest that induction of rapid anti-inflammatory activity with mitoxantrone followed by immunomodulation with glatiramer may have a place in the treatment algorithm for active RRMS," he said.

This use of mitoxantrone followed by glatiramer may serve as an effective "rescue option" in patients who experience ongoing relapses despite interferon therapy, said Jason Ramtahal, MD, University of Liverpool and the Walton Center for Neurology and Neurosurgery, United Kingdom.

Dr Ramtahal examined the use of mitoxantrone plus glatiramer in a cohort of 18 patients with continuing relapse activity with interferon beta-1a treatment. EDSS scores stabilized or improved in 16 of the 18 patients at the most recent follow-up (mean, 31 months). However, 14 patients had EDSS scores >3.5, which indicate significant disability caused by continuing relapse activity during interferon administration, Dr Ramtahal said.

"It's difficult to justify keeping patients on beta interferon if they've had a relapse and lost use of their legs," Dr Ramtahal said. "We use mitoxantrone-glatiramer both for interferon failure and in treatment-naEFve patients who have accrued disability or have frequent relapses or other poor prognostic factors." Markers for poor prognosis while patients are taking interferon beta are a high lesion load (>10 lesions) on MRI, early motor or ataxic brain stem relapses, or incomplete recovery from a relapse.

MINOCYCLINE AND GLATIRAMER

Early data also demonstrate promising results with the addition of minocycline to treatment with glatiramer in patients with RRMS. This combination therapy resulted in strong trends towards reductions in the total number of T1-enhancing lesions, the number of new T2 lesions, and the risk of relapse compared with glatiramer alone, said Luanne Metz, MD, department of clinical neuroscience, University of Calgary, Canada.

Forty-four patients with ≥1 T1-enhancing lesions on their screening MRI were randomized to minocycline 100 mg twice daily plus glatiramer 20 mg/d, or glatiramer 20 mg/d plus placebo. Forty patients completed the study. At Months 8 and 9, the number of T1-enhancing lesions was reduced by 63% (P=.08) and the number of new T2 lesions was reduced by 65% (P=.06) in the glatiramer plus minocycline group compared with glatiramer plus placebo.