Stacy Oswald, BS, MSQR Coorinator–Barrow Neurological Institute; and Timothy Vollmer, MD, Chief, Neuroimmunology Section–Division of Neurology and Director–Barrow MS and Related Diseases Clinic and Research Center, Phoenix, AZ

Rebif® is the most recent of three interferon drugs to be FDA-approved for use in slowing the progression of multiple sclerosis (MS) disease-related disability. The other approved interferon drugs are Avonex® (interferon beta-1a) and Betaseron® (interferon beta-1b). Although these three drugs work in a similar manner, the difference between interferon beta-1a (IFN beta-1a) and Interferon beta-1b (IFN beta-1b) is that their biochemical make-up is slightly different. IFN beta-1a is more like human interferon than IFN beta-1b. Rebif, also an IFN beta-1a, is essentially the same drug as Avonex, however, Avonex is approved for a dosage of 30 micrograms injected intramuscularly once per week and Rebif has been approved for a dosage up to 44 micrograms injected subcutaneously three times per week.

These drugs are called immunomodulators. Unlike complete immunosuppressant agents, immunomodulators only inhibit selective portions of the body’s immune response. The drug alters how portions of the immune system interact with one another (Confavreux & Vukusic, 2004).

Evidence shows that the higher doses given more frequently have a better effect in most cases (Antonetti et al.,2002; Deisenhammer et al., 2000). In a study by Munafo et al. (1998) the safety and efficacy of the method of delivery between Rebif and Avonex was compared using identical doses (in mass) through subcutaneous versus intramuscular administration. They found that there was no significant difference in how safe the drugs were and no difference in how the drugs were metabolized when administered either by subcutaneous or intramuscular injection (Munafo et al., 1998).

PRISMS Study

The PRISMS study was a double blind, placebo-controlled trial in patients with relapsing remitting MS (RRMS) designed to investigate the treatment effect of subcutaneous IFN beta-1a. Five hundred and sixty patients were enrolled from 22 centers in nine countries. Criteria included a clinical diagnosis of RRMS, having had at least two clinical relapses in the past 2 years, and an Extended Disability Status Scale (EDSS) score between 0 and 5.0. The study participants were randomly assigned to three treatment groups; 22 micrograms of IFN Beta-1a (Rebif), 44 micrograms of Rebif, and placebo for subcutaneous injection three times per week for 2 years.

For safety and efficacy purposes, neurological exams were done every 3 months and MRI scans were taken twice per year.

Patient retention during the study was very good. Of the initial 560 patients enrolled in the study 533 were still in the study at the end of 1 year (95%) and 502 patients were still in the study by the end of year 2 (90%) (PRISMS Study Group, 1998).

All patients had proton density (PD) and T2-weighted MRI scans (PD/T2) twice each year, while a subset of 205 patients completed monthly PD/T2 and T1-weighted gadolinium scans over the first 9 months of the study.

The relapse rate was slightly lower at 1 and 2 years with both of the treatment groups compared to placebo. The mean number of relapses per patient was reported as follows: The time to first relapse was prolonged by 3 months for the 22-microgram group and by 5 months for the 44-microgram group. The proportion of relapse-free patients improved significantly in both treatment groups as compared to the placebo group. The number of active lesions was lower in each therapy group than for patients on placebo as well.

Rebif was shown to be effective in relapse rate, defined disability, and all MRI outcome measures related to dose level. The drug was also well tolerated and neutralizing antibodies appeared significantly less frequently in the 44-microgram group than in the 22-microgram group.

Safety and efficacy was demonstrated by the PRISMS study, but follow-up would be needed to determine what the long-term effect on MRI and clinical outcomes would be.

SPECTRIMS Study: Clinical Results

This multi-center, randomized, parallel-group, placebo controlled study tested two treatment groups with doses of 22 or 44 micrograms of Rebif compared to a placebo group. The study drug was given by subcutaneous injection three times a week for a total of 3 years. The 618 patients with secondary progressive MS (SPMS) were assessed every 3 months and a total of 506 (82%) completed the 3 years of treatment (SPECTRIMS Study Group, 2001).

The primary outcome was the time to confirmed progression of disability. This was defined as the time it took for each patient to progress by one full EDSS score (or 0.5 if the patient started at 5.5). The study did not show a significant difference in time to disability progression between either treatment group and the placebo group. However, there was a significant effect of therapy on exacerbations and other positive treatment-related outcomes became apparent upon analysis.

Compared to the placebo group, the patients who had pre-study relapses in the two active treatment groups had an average per-year relapse rate of 0.57 (22 micrograms) and 0.67 (44 micrograms) while on the study. The per-year relapse rate for the placebo group was 1.08 during the 3-year study. Overall, the mean exacerbations per person, per year were the following:

Records of adverse events reported by study patients showed that Rebif was well tolerated. Elevated liver enzyme levels were more common in the patients randomized to the two active treatment groups, however, these instances were all quite mild.

Patients were also tested for developing interferon-neutralizing antibodies while on the study. It was clear that the patients who did develop antibodies against interferon had significantly less treatment benefit.

After some analysis, an unexpected efficacy related to the sex of the patient was discovered. When a separate analysis was conducted, researchers noted that women responded better to the drug in terms of relapse rate. The drug effect was also greater for those patients who had at least one relapse in the 2 years prior to enrolling in the study (SPECTRIMS Study Group, 2001).

SPECTRIMS Study: MRI Results

This portion of the SPECTRIMS study looked at the MRI results. The patients with SPMS had to have progressed on the EDSS scale by at least one point over the previous 2 years. The EDSS scores fell between 3.0 and 6.5.

The total number of patients were divided into two cohort groups. Cohort 1 included all 618 patients who were to have seven semiannual PD/T2 scans. Cohort 2 consisted of a 283- patient subset who were to undergo 11 monthly PD/T2 scans and T1-weighted scans with gadolinium enhancement (T1-Gd).

There were three means of MRI analysis carried out. The first was called Burden of Disease (BOD), which is defined as the total area of all MS lesions as identified on slices of a PD/T2 scan. The second efficacy outcome was active lesions on a T2 MRI. In this case, an active lesion was defined as any new, recurrent, newly enlarging, or persistently enlarging lesion. The third outcome measure (applied to Cohort 2 only) was call combined unique (CU) activity. The PD/T2-weighted MRIs were analyzed and compared to T1-Gd scans. Any lesions that appeared on both scans in the same location were only counted once. Lesions unique to either the PD/T2 scans or the T1-Gd scans were counted and combined with the number of common lesions. This number represents the number of active CU lesions.

Results for Cohort 1

BOD increased in the placebo group by 10%, whereas it decreased in the 22-microgram group by 0.5% and in the 44-microgram group by 1.3% (Li, Zhao, Paty, the University of British Columbia MS/MRI Analysis Research Group, & the SPECTRIMS Study Group, 2001).

Of the 480 patients who received all seven scheduled scans during the study, the placebo group showed a steady increase in median percentage change in BOD compared to their baseline, while the two treatment groups showed a reduction in BOD or no change.

The T2 scan activity also showed a strong treatment effect in the median number of active lesions per patient, per scan. As compared to how the placebo group did, the 22-microgram group showed a reduction of 70% and the 44-microgram group had a 75% reduction in median number of T2 active lesions.

Over one third of the treated patients displayed no T2 activity on their scans during the 3 years of the study.

Results for Cohort 2

Baseline scans were taken twice, at 1 month and within 48 hours before administration of the first dose. The baseline MRI activity did not differ between the three different treatment groups.

The CU activity in Cohort 2 was determined at baseline and at the conclusion of the study. The percent of placebo patients who had active CU lesions when they started the study was 48%. The 22-microgram group had 55% with active CU lesions at baseline and the 44-microgram group had 51% with active CU lesions.

Compared to the placebo group, the active treatment groups both showed a reduction in the number of active CU lesions per patient, per scan. The median number was reduced by 78% in the 22-microgram group and reduced by 89% in the 44-microgram group.

The sex-related treatment effect analyses showed that, as was apparent by the relapse data, women responded somewhat better to treatment than men. This was particularly clear in the number of active lesions on T2 scans. The patients who had at least one relapse in the 2 years prior to enrolling in the study also had a lower number of active lesions on T2 scans than patients who did not have definite relapses (Li et al., 2001).

The SPECTRIMS trial failed to support its primary outcome of reduction of time to confirmed
progression of disability by either dosage level, but a significant reduction in exacerbations was clear as compared to the placebo group. MRI data also demonstrated a clear dose-dependent treatment effect in both active treatment groups. In addition, a trend in sex-related treatment effect was discovered, as well as a greater efficacy in patients with SPMS who experienced clinically definite relapses.

EVIDENCE Trial

The EVIDENCE trial was a randomized comparative study of two different IFN Beta-1a treatment regimens. This study compared the efficacy and safety of 44 micrograms of Rebif given subcutaneously three times per week compared to 30 micrograms of Avonex given intramuscularly once per week. Six hundred and seventy-seven patients with RRMS were enrolled at 15 sites in Europe, 5 sites in Canada, and 36 sites in the United States. The primary outcome of the study was the proportion of patients who stayed relapse-free by the end of 24 weeks. In addition, MRI results were analyzed for the number of active lesions per patient, per scan taken at 24 weeks. All patients were followed for a total of 48 weeks.

A total of 339 patients were randomized into the Rebif group and 338 patients into the Avonex group. At the conclusion of the study, 75% of patients in the Rebif group remained relapse-free, and 63% of the Avonex group remained relapse-free through the 24 weeks. MRI scans, with and without gadolinium enhancement, were taken at the screening visit, at the first dosing visit, and every 4 weeks through Week 24. A final scan was done at Week 48 without gadolinium. As with the SPECTRIMS trial’s MRI data, active CU lesions were identified as evidence of disease progression. At 24 weeks, 48% of patients in the Rebif group did not have any new MRI activity and 33% of patients in the Avonex group did not have any active CU lesions (Panitch et al., 2002).

Blood samples were collected at Week 48 to determine whether patients had developed any neutralizing antibodies. Twenty-five percent of patients in the Rebif group tested positive for neutralizing antibodies and 2% of patients in the Avonex group had neutralizing antibodies in their blood.

The safety of the two drugs was determined through laboratory tests and clinical exams conducted during each study visit. Both treatments were fairly well-tolerated. In three areas, the Rebif group appeared to have a significantly larger number of adverse events as compared to the Avonex group. Injection site reactions were reported by 83% of the Rebif group and only 28% of the Avonex group. This may be due to the fact that the Rebif treatment required three times as many injections, and they are done subcutaneously as opposed to intramuscularly. At the same time, the higher dose and higher injection frequency has been associated with the greater efficacy displayed by the results in the Rebif group as compared to the Avonex group.

Elevated liver enzymes were also reported as an adverse event twice as often in patients of the Rebif group compared to the Avonex group (18% vs 9%, respectively). All elevated levels were corrected either spontaneously, by adjusting dosing levels, or by interrupting treatment for a time.

Abnormal white blood cells were reported in 11% of Rebif patients and 5% of Avonex patients. The majority of cases, however, were considered mild.

In all, the percentage of patients who discontinued therapy due to adverse events was similar between the two treatment groups. Sixteen Rebif patients (4.7%) and 14 Avonex patients (4.2%) left the study because of adverse events they experienced. The low per-group percentage and similarity between treatment groups supports the claim that most adverse events were mild and manageable (Panitch et al., 2002).

This relatively short study showed an increased treatment effect on relapse rate using IFN beta-1a delivered subcutaneously three times a week (Rebif) as compared to IFN beta-1a delivered intramuscularly once per week (Avonex).

Long-Term Follow-Up of PRISMS Study

This PRISMS study was a long term observational follow-up of the original PRISMS cohort. Analyses of MRI BOD showed a long-term benefit of high-dose, high-frequency therapy with IFN Beta-1a (Rebif) in RRMS.

As presented at this year’s American Academy of Neurology Conference, results of the follow-up to the PRISMS cohort demonstrate a sustained efficacy when using 44 micrograms of subcutaneous injections of Rebif three times per week.

The long-term data was collected from patients 7 to 8 years following enrollment in the PRISMS study. The patients who were examined for the long-term follow-up may or may not have continued taking any immunomodulating therapy since they completed the original PRISMS study. For instance, patients who were randomized to placebo in the original study could have started taking an immunological therapy after they left the study. Nevertheless, the patient’s increase in BOD, as analyzed during the follow-up, was representative of the original treatment group they were randomized to up to 8 years prior. The follow-up distribution of percentage increase in BOD was 5.0% for those originally randomized to the 44-microgram group, 17.4% for those in the 22-microgram group, and 24.5% for those originally in the placebo group (Li & Abdalla, 2004).

The results of this long-term follow-up study clearly make a case for patients with RRMS to get early high-dose, high frequency treatment in order to prevent the accumulation of lesion damage over time. Complete results of this study will be published at a later date.

References

Confavreux, C., & Vukusic, S. (2004). Non-specific immunosuppressants in the treatment of multiple sclerosis. Clinical Neurology and Neurosurgery, 106, 263-269.

Deisenhammer, F., Mayringer, I., Harvey, J., Dilitz, E., Gasse, T., Stadlbauer, D., et al. (2000). A comparative study of the relative bioavailability of different interferon beta preparations. Neurology, 54(11), 2055-2060.

Li, D., & Abdalla, J. A. (2004). Long-term observational follow-up of the PRISMS cohort: Analysis of MRI BOD shows benefit of high dose, high-frequency IFN beta-1a (Rebif®) [Abstract]. American Academy of Neurology Abstracts, P02.118.

Li, D. K. B., Zhao, G. J., Paty, D. W., the University of British Columbia MS/MRI Analysis Research Group, & the SPECTRIMS Study Group (2001). Randomized controlled trial of secondary interferon-beta-1a in secondary progressive MS: MRI results. Neurology, 56(11), 1505-1513.

Munafo, A., Trinchard-Lugan, I., Nguyen, T. X. Q., & Buraglio, M. (1998). Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. European Journal of Neurology, 5, 187-193.

Panitch, H., Goodin, D. S., Francis, G., Chang, P., Coyle, P. K., O’Connor, P., et al. (2002). Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology, 59(10), 1496-1506.

Patten, S. B., Metz, L. M., & SPECTRIMS Study Group (2002). Interferon [beta]1a and depression in secondary progressive MS: Data from the SPECTRIMS trial. Neurology, 59(5), 744-746.

PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998). Randomised doubleblind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. The Lancet, 352, 1498-1504.

Secondary Progressive Efficacy Trial of Recombinant Interferon beta-1a in MS (SPECTRIMS) Study Group (2001). Randomized controlled trial of interferon beta-1a in secondary progressive MS: Clinical results. Neurology, 56(11), 1496-1504.

This entry was posted on Saturday, September 4th, 2004 at 3:49 pm and is filed under All Articles, Clinical Trials. You can follow any responses to this entry through the RSS 2.0 feed.