Combo Therapies for MS: In Trials, Some Pairings Fare Better Than Others


For years experts in multiple sclerosis (MS) have been touting the potential benefits of combination therapies for controlling disease progression. The difficulty in finding just the right combination, however, was evident in the mixed nature of findings presented at the Annual Meeting of the American Academy of Neurology (AAN) in Boston, April 28 to May 5.

For years experts in multiple sclerosis (MS) have been touting the potential benefits of combination therapies for controlling disease progression. The difficulty in finding just the right combination, however, was evident in the mixed nature of findings presented at the Annual Meeting of the American Academy of Neurology (AAN) in Boston, April 28 to May 5.


Among the drugs being considered as adjuncts to existing MS therapies is the cholesterol-lowering agent atorvastatin (Lipitor). Researchers from the University of California, San Francisco, made headlines in March 2006 with the online publication of a study in which combined suboptimal dosages of atorvastatin (0.5 mg/ kg/d) and glatiramer acetate (Copaxone) (50 µg) were associated with clinical improvement and reduced inflammation in experimental murine models of MS.1 Findings reported at the AAN meeting, however, suggest that combining atorvastatin with subcutaneous interferon beta 1a (IFN-ß-1a; Rebif) in humans has the opposite effect.2

Twenty-nine patients with relapsing-remitting (RR) MS who had been taking subcutaneous IFN-ß-1a for at least 6 months were randomly selected to receive 6 months of additional treatment with 40 or 80 mg/d of atorvastatin or placebo. Twenty-four patients completed the study. New and enhancing MRI lesions or clinical relapses were observed in 10 of the 15 patients who received the combination therapy (6 high dose, 4 low dose), but in only 1 of the 9 patients in the placebo group.

The results, which are consistent with those presented by the same group at the 2005 annual AAN meeting,3 may reflect an incompatibility specific to interferons. In vitro research from the University of Chicago, Illinois, also presented at the 2007 AAN meeting, suggests that statins block interferons' signaling pathways, thus decreasing their therapeutic efficacy.4


Preliminary analysis of the Avonex Combination Trial (ACT) findings also failed to detect a statistically significant benefit for combining intramuscular IFN-ß-1a (Avonex) with either the chemotherapeutic agent methotrexate or the corticosteroid methylprednisolone.5 Previous studies have suggested that combining IFN-ß-1a with either methotrexate6 or methylprednisolone7 could reduce disease activity in patients with MS.

The ACT study included 313 patients with RRMS from 72 locations. Each patient had demonstrated breakthrough disease activity (relapse or new lesions on MRI) in the previous 12 months and after at least 6 months of treatment with intramuscular IFN-ß-1a. In addition to interferon therapy, patients were randomly selected to receive weekly oral methotrexate (20 mg), pulsed intravenous methylprednisolone (1000 mg/d for 3 days) every other month, both, or placebo.

After 12 months, patients on combination therapy had lower incidences of relapse and MRI lesions than those on monotherapy, with the 3-drug group showing the most favorable outcome. However, the differences between the 4 treatment groups did not achieve statistical significance, according to Jeffrey Cohen, MD, director of the experimental therapeutics program at the Cleveland Clinic's Mellen Center for MS Treatment and Research, and principal investigator of the ACT study.

Similarly, researchers from the University of Calgary, Alberta, found that 9 months of treatment with a combination of glatiramer acetate and the tetracycline derivative minocycline was associated with a trend toward improvement in the number of T1 enhancing lesions, new T2 lesions, and annualized relapse rate compared with treatment with glatiramer acetate and placebo.8 Again, the between-group differences were not statistically significant. Previous research in mice has supported the minocycline-glatiramer acetate combination for treatment of MS.9


More encouraging results involved the peroxisome proliferator-activated receptor gamma agonist pioglitazone (Actos), currently FDA-approved for treatment of type-2 diabetes. In vitro and animal studies have suggested that the drug also may have anti-inflammatory benefits in patients with MS.10 Researchers from the University of Illinois at Chicago randomly assigned 22 patients currently taking IFN-ß-1a to also begin a course of either 30 mg/d pioglitazone or placebo for 1 year.11

The investigators found that lesion volume decreased by 7% from baseline in patients taking pioglitazone but increased by 3% in patients taking placebo. Significantly less gray-matter atrophy was observed in the pioglitazone group compared with the placebo group (3.1% loss vs 5.8% loss).

Researchers from the University of Rochester, New York, reported that functional benefits were observed in a phase 3 trial of the potassium channel blocker fampiridine, administered as adjunctive therapy.12 A clinical response was seen after 14 weeks in 34.8% of the patients who were randomly assigned to receive fampiridine compared with 8.3% patients assigned to receive placebo. Responders in the fampiridine group demonstrated a 25% improvement in walking speed from baseline.


Research related through poster presentations at the AAN meeting support the short-term use of the chemotherapeutic drugs mitoxantrone and cyclophosphamide in MS treatment regimens. Preliminary 2-year follow-up results of a randomized multicenter study revealed that a 90% reduction in MRI lesions could be achieved in patients who received 12.5 months of glatiramer acetate therapy followed by 3 monthly intravenous infusions of mitoxantrone. In comparison, a 70% reduction in MRI lesions was achieved in patients who received a 15-month course of glatiramer acetate monotherapy but no additional chemotherapy.13 Further analysis demonstrated significantly favorable outcomes for the combination-therapy group in terms of T1 and T2 lesion volume and proportion of enhancing lesions that evolved into chronic black holes.14

Another study found that 6 months of cyclophosphamide, given as a monthly 1000-mg dose to patients in whom treatment with IFN-ß-1a or glatiramer acetate had failed, significantly reduced brain atrophy.15 In this study, a 1.3% decrease in cross-sectional normalized brain volume was observed at 3-year follow-up in 31 patients treated with cyclophosphamide. In comparison, a 2.7% decrease in brain volume was observed in 40 patients who received 6 to 12 months of monthly corticosteroids concurrent with IFN-ß-1a or glatiramer acetate therapy.




Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

J Clin Invest.



Birnbaum G, Altafullah I, Reder A. A double blind, placebo controlled trial of atorvastatin in combination with subcutaneous interferon beta 1a in persons with multiple sclerosis.


2007;68(suppl 1):A206-A207.


Birnbaum G, Altafullah I. A double blind, placebo controlled combination trial of interferon beta 1a (Rebif) and atorvastatin (Lipitor) in patients with relapsing-remitting multiple sclerosis.


2005;64(suppl 1):A385.


Dhawan N, Reder A. Statins block interferon signaling in human immune cells: potential loss of the therapeutic effect of IFN-b in multiple sclerosis.


2007;68(suppl 1):A364.


Cohen J, Calabresi P, Eickenhorst T, et al. Results of the Avonex Combination Trial (ACT).


2007;68(suppl 1):A100.


Calabresi PA, Wilterdink JL, Rogg JM, et al. An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS.




Gasperini C, Pozzilli C, Bastianello S, et al. Effect of steroids on Gd- enhancing lesions before and during recombinant beta interferon 1a treatment in relapsing remitting multiple sclerosis.




Metz L, Li D, Traboulsee A, et al. Glatiramer acetate combined with minocycline reduces the number of T1 Gd-enhancing and new T2 lesions compared to glatiramer acetate alone.


2007;68(suppl 1):A84-A85.


Giuliani F, Fu SA, Metz LM, Yong VW. Effective combination of minocycline and interferon-beta in a model of multiple sclerosis.

J Neuroimmunol.



Klotz L, Schmidt M, Giese T, et al. Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients.

J Immunol.



Kaiser C, Shukla D, Stebbins G, et al. Results of a phase I trial of pioglitazone in RRMS patients.


2007;68(suppl 1):A85.


Goodman A, Schwid S, Brown T, et al. A phase 3, multi-center trial of oral, sustained-release fampiridine (4-aminopyridine) in multiple sclerosis.


2007;68(suppl 1):A206.


Vollmer T, Campagnolo D, Panitch H, et al. Reductions in MRI disease activity and relapse rates observed after induction of shortterm immunosuppression with mitoxantrone followed by longterm glatiramer acetate (GA) are maintained at 24 months in patients with relapsing remitting multiple sclerosis (RRMS).


2007;68(suppl 1):A279.


Arnold DL, Bar-Or A, Freedman M, et al. Reductions in Gd enhancing lesions observed with glatiramer acetate following a brief and low dose course of mitoxantrone in patients with relapsing remitting multiple sclerosis (RRMS) are paralleled by favorable effects on MRI markers of disease burden and black hole evolution.


2007;68(suppl 1):A281.


Boster A, Perumal J, Bao F, et al. Short-term exposure to cyclophosphamide is effective in reducing long-term brain atrophy in refractory RRMS.


2007;68(suppl 1):A239.

Related Videos
support group
Dune Part 2
spinal tap
© 2024 MJH Life Sciences

All rights reserved.