Optimal Interferon-Beta Dosing in Multiple Sclerosis
Abstracts & Commentary
Sources: The PRISMS study group and University of British Columbia MS/MRI analysis group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 2001; 56:1628-1636; The SPECTRIMS study group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS. Neurology. 2001;56:1496-1504; The EVIDENCE study group. A direct comparative study of rebif versus avonex in relapsing-remitting multiple sclerosis. XVII World Congress of Neurology. London, England, June 22, 2001.
The initial 2-year study data of prevention of relapses and disability by interferon-beta-1a subcutaneously in MS (PRISMS) demonstrated highly significant clinical and MRI benefit for IFN-b, 22 and 44 mcg SC injection 3 times weekly compared with placebo in relapsing-remitting MS (RR MS). In a 4-year extension study, 172 patients initially receiving placebo were randomized in a blinded fashion to either 22 or 44 mcg crossover groups, while the other patients continued blinded treatment at their originally assigned dose (n = 167 in each group). Patients had 3- to 6-month clinical and annual MRI assessments. Annualized relapse rates for 4 years were 1.02 in the crossover, 0.80 in the 22 mcg group, and 0.72 in the 44 mcg group (P < 0.001). The dose-effect approached significance (P = 0.69; risk ratio, 0.88; 95% CI = 0.76-1.01). Crossover groups showed reductions in relapses, MRI activity, and lesion burden accumulation, but the time to sustained disability progression was still prolonged by 18 months in the initial 44 mcg group compared to the crossover group (P = 0.047). The initial 22 and 44 mcg groups maintained a superior reduction in new T2 lesions and and lesion burden compared with the crossover group.
The secondary progressive efficacy clinical trial of recombinant interferon-beta-1a in MS (SPEC-TRIMS) study examined 618 patients older than 3 years of age in either the placebo, 22, or 44 mcg 3 times weekly groups. Time to confirmed progression in all treated patients was not significantly affected, although a subset of patients with the higher prestudy relapse rate appeared to have the most benefit in delaying progression. Significant treatment effects were seen in reduction of relapse rate from 0.71 to 0.50 (P < 0.001), as well as all other clinical and MRI outcomes.
The evidence for interferon dose-response: European-North American comparative efficacy (EVIDENCE) open-label study compared dosing of interferon-beta-1a 44 mcg SC injection 3 times weekly (Rebif) to 30 mcg IM injection once weekly (Avonex) in 677 RR MS patients that were randomly assigned to either group. Patients were assessed by a blinded examining neurologist and by blinded MRI analyses. Interim results at 24 weeks revealed that 25.1% of patients on Rebif experienced a relapse vs. 36.7% of patients on Avonex (odds ratio, 1.9). There was a significant reduction in new clinically unique brain MRI lesions in patients on Rebif compared to Avonex.
The above reports are the latest in a wealth of clinical trials examining the effect of IFN-b applied at different stages of disease or at different dosing regimens. The PRISMS-4 study demonstrated that MS patients treated with IFB-b were less likely to worsen and have more stable disease on brain MRIs, confirming the findings of earlier clinical trials. Additionally, this 2-year extension phase documented that patients on the drug for the full 4 years had less clinical disability and MRI burden of disease, than those who delayed treatment for 2 years and then crossed over to the treatment group. Thus, this trial validates the benefit of early treatment intervention in delaying progression, similar to the outcome in the CHAMPS trial where the drug was started after the first demyelinating event (Apatoff B. Neurology Alert. 2000;19:23).
There has been much controversy surrounding the optimal dosing regimen for IFN-b. The EVIDENCE trial attempts to answer this question, despite some limitations of this brief open-label clinical study. By treating with a four-times higher amount of IFN-b in divided doses, the Rebif patients had a modest advantage in reducing clinical parameters of disease activity. It remains to be seen how significant this advantage is at 48 weeks, and whether the benefits of higher IFN-b dosing are offset by a higher incidence of neutralizing antibodies (Apatoff B. Neurology Alert. 2001;19:39-40). —Brian R. Apatoff