Monday, June 09, 2008
Mark J. Tullman, MD
New data from key clinical trials of disease-modifying therapy were presented at the 60th Annual Meeting of the American Academy of Neurology. The results of some of these studies, along with the potential clinical implications of those results, are presented below.
Efficacy of Interferon Beta-1b and Glatiramer Acetate in Patients With Relapsing-Remitting Multiple Sclerosis: The BEYOND Trial
Results of the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose (BEYOND) trial, which was funded by Bayer Healthcare Pharmaceuticals, were presented in a late-breaking session by Paul O'Connor, MD. This trial was designed to compare the efficacy of 250 micrograms (mcg) and 500 mcg of interferon beta-1b given subcutaneously (SC) every other day in patients with relapsing-remitting multiple sclerosis (RRMS). The efficacy of these two doses of beta interferon-1b was also compared with glatiramer acetate (20 mg SC administered daily).
The trial randomized treatment-naive patients with RRMS with Expanded Disability Status Scale (EDSS) scores equal to or less than 5. Patients also had to have at least one relapse in the year prior to entry into the study. A total of 2244 patients were randomized in a 2:2:1 ratio to the 500-mcg dose of beta interferon-1b (n = 899), the 250-mcg dose of interferon beta-1b (n = 899) or to the 20-mg dose of glatiramer acetate (n = 448) for a period of 104 weeks or longer. Patients underwent clinical evaluations every 3 months and brain magnetic resonance imaging (MRI) scans annually.
The trial's primary endpoint was relapse risk. A per-protocol analysis and an intent-to-treat analysis were performed on the data. The clinical efficacy of each of the 3 treatment groups (beta interferon-1b 250 mcg, beta interferon-1b 500 mcg, and glatiramer acetate 20 mg) was similar in each of the analyses.
There were several supportive endpoints, including relapse rate, proportion of relapse-free patients, and time to first relapse. Secondary outcome variables were time to confirmed EDSS progression and T1 black hole development. Other endpoints of interest included the number and volume of T2 lesions. The annualized relapse rate fell by nearly 80% compared with the year prior to enrollment in the study, but there were no significant differences among the treatment groups.
There were some MRI endpoints that showed statistically significant differences between the treatment groups. The cumulative number of T2 lesions up to the last scan was significantly higher in the group receiving glatiramer acetate compared with the groups receiving 250 mcg (P = .17) or 500 mcg (P = .001) beta interferon-1b. Additionally, patients receiving 250 mcg or 500 mcg beta interferon-1b had a significantly lower increase in T2-lesion volume compared with the group receiving glatiramer acetate (P < .001 and P = .001, respectively). The authors note that it is unclear whether there is any long-term clinical significance to these findings.
All 3 treatments were generally well-tolerated. Dropout rates for 250 mcg interferon beta-1b, 500 mcg interferon beta-1b, and glatiramer acetate were 13%, 19%, and 17%, respectively. It is important to note that although this was a double-blind study for the interferon beta-1b groups (ie, they were unaware which dose they were receiving), this was not a double-blind trial for the patients who received glatiramer acetate. This may explain the higher dropout rate in the group receiving glatiramer acetate (17%) compared with the group receiving 250 mcg interferon beta-1b (13%) because the patients receiving interferon beta-1b were aware that there was a 50% chance that they could be receiving the higher, and potentially more effective, dose of interferon beta-1b.
The adverse events observed were similar to the known adverse event profiles of these compounds. Flulike symptoms were more common with interferon beta-1b and injection-site reactions (eg, pain, pruritis) were more common with glatiramer acetate.
The Results of the BEYOND trial are similar to the recently presented results from the REGARD trial that compared interferon beta-1a 44 mcg SC 3 times a week to glatiramer acetate. In these 2 studies, more than 2000 patients were randomized to either high-dose interferon or glatiramer acetate. Patients did very well and there were no major differences in terms of efficacy between the therapies. Unfortunately, the 500-mcg dose of interferon beta-1b was no more effective than the 250-mcg dose. In the absence of clear superior efficacy data between the high-dose interferons and glatiramer acetate, it seems to me that a high-dose interferon and glatiramer acetate are both reasonable initial treatment options for most patients with RRMS. Patients should be well informed and part of the treatment decision process. Some patients may prefer starting with a daily injection with fewer side effects and others would rather take a medication that has fewer injections but the potential to cause more side effects and requires periodic blood work.
Furthermore, for patients on a high dose interferon of glatiramer acetate who experience persistent side effects, switching from one agent to the other might improve tolerability and enhance quality of life without sacrificing efficacy.
Efficacy of Glatiramer Acetate in Delaying Conversion to Clinically Definite Multiple Sclerosis: The PreCISe Trial
Results from the Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS of Subjects Presenting With a Clinically Isolated Syndrome (CIS) (PreCISe) trial, were presented in a late-breaking session by Giancarlo Comi. The PreCISe trial was a randomized, double-blind, placebo-controlled, multicenter, 3-year study designed to evaluate the efficacy of early treatment with glatiramer acetate in delaying the progression to clinically definite MS (CDMS) in patients with clinically isolated syndromes (CIS), which are considered to be first events suggestive of MS.
The study randomized 481 patients who had a minimum of 2 T2-weighted brain lesions at least 6 mm in diameter shown on MRI and who had experienced a first clinical event to receive glatiramer acetate 20 mg/day SC (n = 243) or placebo (n = 238). Only patients with a unifocal disease manifestation were included. Key baseline characteristics were: age (31.1 ± 6.9 years), time from first event to randomization (74.0 ± 14.9 days), and corticosteroid use for first attack (64% of patients). There was no difference between the study arms in EDSS (1.0 ± 1.0), number (31.5 ± 30.7) and volume (6.0 ± 6.2ml) of T2 weighted lesions, and number (1.5±2.9) and volume (0.3 ± 0.6ml) of gadolinium enhanced lesions.
The primary endpoint of the study was time to CDMS based on a second clinical attack. The trial was stopped prematurely by the data and safety monitoring committee after a preplanned interim analysis. The group initially receiving placebo was then switched to active treatment on an open-label basis. At this point, about 80% of the planned drug exposure had been given, and CDMS had developed in about 43% of those patients in the placebo group compared with just 25% in the glatiramer acetate group. The odds ratio for progression to CDMS was 0.41 (P < .0001) and the hazard ratio for progression to CDMS was 0.55 (95% CI 0.40-0.77; P = .0005) in the group taking glatiramer acetate compared with the placebo group. This translates in to a 45% risk reduction for progression to CDMS in the group on active treatment compared with the group on placebo. Additionally, the 25th percentile time to CDMS was prolonged from 336 days in the placebo group to 722 days (115% increase in time to CDMS onset) in the group receiving glatiramer acetate.
The results of MRI scans also favored the group receiving glatiramer acetate compared with the group receiving placebo. The mean number of new T2-weighted lesions was reduced by 61% in the patients receiving glatiramer acetate compared with the patients receiving placebo (P < .0001). Similarly, patients receiving glatiramer had a 61% reduction in new T1 gadolinium-enhancing lesions compared with the group receiving placebo (P < .0001).
Glatiramer acetate was well tolerated, and side effects were similar to those previously reported in patients with CDMS, including local injection-site reactions and transient postinjection reactions including chest pain, flushing, dyspnea, palpitations, and anxiety.
The open-label extension phase of the study will continue to a 5-year follow-up to evaluate the potential for glatiramer acetate to prevent or delay clinical progression of the disease. Patients will receive glatiramer acetate and will be followed until the development of CDMS.
The PreCISe study results are really not surprising. However, we now have strong evidence that the interferons and glatiramer acetate are effective when initiated after a first MS attack in patients with at least minimally abnormal brain MRI. The 5-year PreCISe data may provide additional evidence that early treatment with MS immunomodulatory therapy prevents the development of disability.
This activity is supported by an independent educational grant from Teva Neuroscience.