Although neutralizing antibodies (NAbs) receive a lot of attention in the treatment of multiple sclerosis (MS), measuring their effect in relation to treatment with interferon beta has not been determined. In fact, there is no sufficient evidence that demonstrates there is any clinical benefit to even measuring NAbs in a patient taking interferon beta.
Understanding the effect of NAbs on treatment is an important issue. A recent study investigated the dynamics of NAbs during treatment with Betaseron® (interferon beta 1b). The researchers measured NAbs every 6 months for a minimum of 3 years and looked for a pattern in the development of NAbs. They found that out of 192 patients who did not have NAbs (NAb-negative) at 12 and 18 months, 93.1% remained without NAbs after a treatment period of 3 years. Of these patients, 87.5% remained without NAbs after 4 years. One hundred and twelve patients tested positive for NAbs; however, many of these patients later went back to having no NAbs. Among these 112 patients with a NAb-positive status, 20.2% had two consecutive negative tests at 4 years and 34.8% of these patients tested negative for NAbs at 5 years. Some patients, however, showed a fluctuation in their NAb status. The remaining 108 patients tested both positive and negative for NAbs at different times during the trial.
This study emphasized that NAbs often do not develop during treatment. The study also showed that patients testing NAb-positive often become NAb-negative over time. In comparing NAb status among patients treated with Betaseron versus those treated with Avonex® or Rebif® (interferon beta-1a), the researchers found that significantly more patients treated with Betaseron converted to NAb-negative status throughout the course of the study (41% vs 0% and 8.3%). Also, only a small number of NAb-positive patients on Betaseron remained so throughout the study (31%), while more NAb-positive patients on Avonex and Rebif remained NAb-positive (100% and 88%, respectively). Such results reinforce the thinking that MS therapy should be evaluated in terms of patient response and effectiveness of the medication and not necessarily on the presence of NAbs.
Sorensen PS, Koch-Henriksen N. Dynamics of neutralizing anti-interferon antibodies in multiple sclerosis patients during interferon-beta therapy. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract P05.055.
Combination therapy for MS may offer hope
For patients with MS who take Betaseron® (interferon beta-1b) but still have had one or more relapses, combination therapy with another medication may offer help. Dr. Peter Calabresi and his colleagues investigated how well combination therapy with Betaseron and Imuran® (azathioprine) would work for these patients. Imuran is an immunosuppressant medication often used with other drugs to treat autoimmune disorders. These results were presented at the American Academy of Neurology’s 56th annual meeting held earlier this year.
The goals of the study were to establish the safety of the combination therapy and determine the most effective dose. Fifteen patients, who were already taking Betaseron, were given Imuran. The dose of Imuran was gradually increased during the 6 months of the study. The results of the study were determined by gadolinium-enhancing (or contrast-enhancing) MRIs. Contrast enhancement enables lesions to show up more clearly on MRI scans.
Twelve patients completed the 6-month trial, and the results showed a significant reduction (63%) in contrast-enhancing lesions for the patients on combination therapy. No serious adverse events occurred throughout the 6-month trial.
Of the 3 patients who discontinued treatment, one did so because of severe nausea, one because of gastrointestinal side effects and headaches, and one because of depression and a lack of compliance. Out of the 12 patients who completed the 6 months of combination therapy, the most common side effect was gastrointestinal problems.
The final results of this trial have not yet been published. However, the results so far may mean that combination therapy with Betaseron and Imuran—with careful monitoring of white blood cell count and liver chemistries—may help many patients who do not completely respond to single-drug therapy.
Calabresi PA, Bash CN, Costello K, et al. Optimization of the safety and efficacy of interferon beta-1b and azathioprine combination therapy in multiple sclerosis. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract P06.089.
Combination therapy offers hope for patients with secondary-progressive MS
Some patients with secondary-progressive MS (SPMS) do not do well on single-drug therapy. Unfortunately, patients with SPMS often progress to severe, continuous disability. Thus, finding better treatment options for patients with SPMS who do not respond well to single-drug therapy is an important issue. This problem was addressed earlier this year at the American Academy of Neurology’s 56th annual meeting in San Francisco.
A medical team based in Italy investigated whether combination therapy with Betaseron® (interferon beta-1b) and the chemotherapy drug Endoxana® (cyclophosphamide) could benefit patients with SPMS. The study consisted of 14 patients with SPMS being treated with Betaseron and Endoxana for 24 months. A group of 13 patients with SPMS were treated only with Betaseron and the 2 treatment groups were compared.
Endoxana is commonly used to treat chronic lymphocytic leukemia, lymphomas, ovarian cancer, and bladder cancer. Previous clinical studies have shown that Endoxana may be effective for SPMS.
Investigators analyzed expanded disability status scale (EDSS) changes to assess combination therapy with Betaseron and Endoxana. They found that disease activity in the patients on combination therapy stabilized. This was demonstrated by an unchanged EDSS score at 12 and 24 months of treatment.
In addition, more patients treated with combination therapy were free of progression of disability compared with the patients treated with single-drug therapy (92.9% vs 69.2%). No serious adverse events were reported throughout the entire 2 years of the study. Overall, the study showed that therapy with Betaseron and Endoxama was beneficial to patients with SPMS who were previously not responding well to single-drug monotherapy with Betaseron.
Reggio E, Nicoletti A, Fiorilla T, Politi G, Reggio A, Patti F. The combination of cyclophosphamide and interferon beta is able to stabilize deteriorating secondary progressive multiple sclerosis patients. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract P06.094.
Double dose of Betaseron shows hope for patients with relapsing-remitting MS
The BEYOND study (Betaseron® Efficacy Yielding Outcomes of a New Dose) is one of the largest MS studies ever conducted, including more than 2000 patients. BEYOND compares the standard dose of Betaseron (interferon beta-1b) with a double dose of Betaseron, and with Copaxone® (glatiramer acetate). Recently, the American Academy of Neurology declared that the efficacy of inteferons may depend on the dose. Since then, researchers have started to look at the effects of a higher dose of Betaseron. Data from the BEYOND study were presented earlier this year at the 56th annual meeting of the American Academy of Neurology in San Francisco. The results look promising, showing that a higher dose of Betaseron may have more therapeutic value than other treatments available for MS.
The BEYOND study compares the normal dose of Betaseron—250 ?g every other day—with a double dose, or 500 ?g every other day in patients with relapsing-remitting MS (RRMS). In addition, BEYOND evaluates the effectiveness of Copaxone 20 mg administered subcutaneously every day.
In September 2003, BEYOND investigators announced the safety results from the first phase of the trial, and showed that the standard and the double dose of Betaseron were well-tolerated, with no new or unpredictable side effects.
MRI results indicated that the group receiving the double dose of Betaseron showed a greater treatment effect compared with the standard dose. The average number of active lesions decreased 90% with the 500-?g dose and 70% with the 250-?g dose. The initial data—the higher dose showing a positive treatment effect as well as being well-tolerated—show that the BEYOND study will be an important tool in the future treatment of patients with MS.
Arnason BGW and the BEYOND Study Steering Committee. BEYOND—Betaseron® Efficacy Yielding Outcomes of a New Dose. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract P06.086.
8 years after EUSPMS Betaseron patients show positive results
In 2001, results from the European Study of Interferon beta-1b (EUSPMS) were published, showing that Betaseron® (interferon beta-1b) delayed neurological degeneration in patients with secondary-progressive multiple sclerosis (SPMS). The original study looked at 718 patients, and 222 of those patients entered a long-term follow-up study. This follow-up study ultimately showed 8 years of evidence on Betaseron in SPMS patients.
Preliminary data from the 8-year follow-up study were released earlier this year at the 56th annual meeting of the American Academy of Neurology. The results showed less disability in the patients who received Betaseron instead of placebo. The study also examined the safety of Betaseron treatment, and how well patients adhered to treatment over time.
At the end of the study, the average change in expanded disability status scale (EDSS) versus the EDSS score at the beginning of the study was lower in the patients who took Betaseron than those who took placebo—and this difference persisted throughout the 8 years of follow-up. At the end of 8 years, more than half (56%) of the patients remained on a disease-modifying therapy. About three quarters (74%) were still taking Betaseron.
This study revealed the sustained benefit of long-term Betaseron therapy. It also demonstrated the ability of patients to stay on such medication over the long term—and to benefit from such therapy.
Kuhle J, Hardmeier M, Hooghe MD, et al. 8-year follow-up of the European Study of Interferon Beta-1b (EUSPMS) in Secondary Progressive MS. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract P06.084.
What can MRI lesions predict about patients with relapsing-remitting MS taking Betaseron?
Magnetic resonance imaging (MRI) scans are useful for evaluating multiple sclerosis (MS) disease activity. Some research has shown that the degree of cognitive impairment is reflected in the results of MRI scans. The objective of this trial was to determine the predictive value of MRI contrast enhancement in patients with relapsing-remitting MS (RRMS) before and during treatment with Betaseron® (interferon beta-1b). This was a 3-year study, and the results were presented at the 56th annual meeting of the American Academy of Neurology earlier this spring.
The investigators looked at the development of T1 black holes over a 1-year period. In MS, black holes, or hypointense lesions, are dark areas that indicate a loss of myelin and nerve fibers, or axons. On an MRI, these areas look like “black holes” and the darker the spot, the more extensive the tissue loss. Black holes are totally inactive areas where a lesion has been repeatedly reinflamed.
The MRI scans were conducted before the study and then at 1-year intervals. During this period, the 20 patients enrolled in the study were taking Betaseron. The investigators found that the number of contrast-enhancing lesions at the first year did not predict change in black hole volume with treatment. The investigators found, however, that the number of contrast-enhancing lesions seen on the first 3 monthly scans after the first year of treatment predicts the change in black holes over the next 2 years. This means that patients who had no contrast-enhancing lesions after 1 year of Betaseron treatment did not develop a significant change in T1 black hole volume over the next 2 years. In contrast, those patients with at least 1 contrast-enhancing lesion after 1 year of treatment showed a significant increase in T1 black hole volume over the next 2 years.
This study demonstrates that the development of contrast-enhancing lesions during treatment with Betaseron predicts an increase in T1 black hole volume. More studies are needed to determine the clinical implications of this information.
Morgen KE, Crawford ALT, Bagnato F, et al. Contrast-enhanced MRI lesions during treatment with interferon beta-1b predict increase in T1 black hole volume in patients with relapsing-remitting MS. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract S46.005.
Do MRI measures in Betaseron trials tell an accurate story about MS progression?
Although MRI scans are often used to evaluate the effectiveness of drugs in multiple sclerosis (MS) trials, the validity of scans is still not clear. Recent data suggest that lesions (detected by MRI) may precede relapses, but there is still no definitive evidence.
This study looked at 2 MRI parameters in 2 clinical trials of Betaseron® (interferon beta 1b) in relapsing-remitting MS (RRMS): T2 lesion burden of disease and number of active T2 lesions after 1 year of observation. The question remains: Are MRI results usable as a marker of MS progression?
The researchers found that the MRI results provided some information, but not a complete picture of disease progression. The researchers proposed that active T2 lesions may prove a better indicator for clinical relapses; active T2 lesions may represent new central nervous system inflammation.
Although the study’s investigators supported the continued use of MRI parameters in MS clinical trials, they recommended further research before coming to a definitive conclusion.
Tremlett H, Traboulsee A, Li D, Paty D. Validity of MRI measures as surrogate markers in clinical trials of beta-interferon in relapsing-remitting multiple sclerosis. Presented at the 56th American Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May 1, 2004. Abstract P04.041.
OPTIMS study: higher doses of Betaseron may improve MRI outcomes
Patients with relapsing-remitting multiple sclerosis (RRMS) who do not completely respond to therapy with Betaseron® (interferon beta-1b) may find inspiration from the latest research. The 1-year OPTIMS (OPTimization of Interferon for MS) study evaluated patients with RRMS who either experienced relapses or showed signs of disease activity on monthly MRIs. The results of the study were presented at the American Academy of Neurology’s 56th annual meeting earlier this year.
In the OPTIMS study, all 76 patients studied were given Betaseron 250 ?g subcutaneously every other day for 6 months. Approximately half of these patients were then given an increased dose of Betaseron 375 ?g subcutaneously every other day.
Patients with RRMS who received the higher dose of Betaseron showed significant improvement in both MRI scans and relapse rate. The group who had the higher dose of Betaseron experienced significantly reduced monthly MRI activity in terms of fewer new T2 or gadolinium-enhancing lesions.
The higher dose of Betaseron was well tolerated and safe; there were no novel or unpredicted adverse events. In fact, the OPTIMS study investigators found that the frequency of side effects was reduced, including flu-like symptoms, which diminished in many of the patients. Another unexpected finding was that neutralizing antibody (NAb) count decreased in the patients who received the higher dose.
The results of this study raise the possibility that changing the dose of Betaseron may be helpful for patients with RRMS. The OPTIMS study is one of the first to look closely at the benefits of higher-dose Betaseron.
Durelli L, Verdun E, Barbero P, et al. The OPTimization of Interferon
for MS (OPTIMS) study: a multicenter trial comparing two different doses
(250 and 375 ?g) of interferon beta-1b. Presented at the 56th American
Academy of Neurology Annual Meeting; San Francisco, Calif; April 24-May
1, 2004. Abstract P02.116.
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