Expert Commentary

Robert M. Herndon, MD, Department of Neurology, University of Mississippi VA Medical Center, Jackson, Mississippi

Interferon beta products are currently the most effective treatment for patients with relapsing-remitting multiple sclerosis (MS). Since MS is a chronic condition, it is essential that treatment options possess both sustained tolerability and safety in addition to efficacy, with long-term administration. However, it is still unclear whether the commercially available interferon beta products (interferon beta-1a, Avonex; interferon beta-1a, Rebif; and interferon beta-1b, Betaseron) differ substantially in their adverse event and tolerability profiles during long-term therapy. Arguments regarding the relative merits of the available interferon preparations relate to the significance of neutralizing antibodies, dose effects and side effects.

Differences in propensity to induce neutralizing antibodies remain substantially different for the various preparations. Specifically, 28 to 47% of patients develop neutralizing antibodies to Betaseron,^1-3 12 to 28% develop neutralizing antibodies to Rebif,^3-7 and 2 to 6% develop neutralizing antibodies to Avonex.^7-10 There is convincing evidence that neutralizing antibodies differentially reduce the efficacy of interferon beta in patients with MS. Patients who were treated with Betaseron and developed neutralizing antibodies had a statistically significantly higher annual relapse rate and mean number of enlarging T2 lesions than did neutralizing antibody-negative patients.² Similar statistically significant findings were observed for patients who developed neutralizing antibodies to Rebif 44 mcg in PRISMS-4.⁵ Patients who received Avonex and developed neutralizing antibodies showed an increase in mean gadolinium-enhancing lesions and annualized relapse rates compared to neutralizing antibody-negative patients but these differences did not reach statistical significance,⁸ possibly due to the small numbers of patients neutralizing antibody-positive to Avonex. Therefore, the potential for the development and persistence of neutralizing antibodies to interferon beta and its significance on reducing clinical efficacy warrants continued vigilance by the clinician during the assessment of interferon beta therapy.

The initial advantage of Rebif over Avonex which is presumably due to the more frequent dosing and higher dose of Rebif in the EVIDENCE trial largely disappeared after the first 24 weeks since there was no difference in attack rate between the two drugs in the second 24-week period. This is likely due to the effect of antibodies in reducing the effectiveness of Rebif since 25% of the Rebif patients were antibody positive at 24 weeks. Unfortunately, the magnetic resonance imaging (MRIs) done at 48 weeks were done without contrast so only cumulative lesion load is available for analysis and no information regarding comparative current MRI activity is available at this time.

At the recent 17th Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) held May 28-June 1, 2003 in San Diego, California, data were presented that continue to support the safety and efficacy of long-term treatment with Avonex; both as single-agent and combination therapy with corticosteroids.

Continued Tolerability and Low Incidence of Neutralizing Antibodies with Avonex: 8-year Data

Robert M. Herndon, MD, from the University of Mississippi VA Medical Center, Jackson, Mississippi presented the results of a safety-extension study evaluating the long-term safety profile of Avonex over 8 years of treatment in patients with relapsing-remitting MS.¹¹ An additional secondary objective of the study was an assessment of the development and incidence of neutralizing antibodies. Overall, Avonex was well tolerated for up to 8 years with only 2% of patients discontinuing treatment due to adverse events. Consistent with previous studies, the incidence of neutralizing antibodies in patients who were neutralizing antibody-negative at baseline was approximately 5%.¹²

A total of 382 patients with relapsing-remitting MS were enrolled in the 6-year safety-extension study, of which 218 had participated in the original phase III trial.¹³ Of the remaining 164 patients, 140 were previously treated with Betaseron and 24 were interferon beta-naпve. All patients were administered Avonex 30 mcg intramuscularly once weekly for 6 years, for treatment duration of up to 8 years. Safety was evaluated by assessing the incidence of adverse events and the analyses of blood chemistry, hematology, and urine testing results. Assessment of neutralizing antibodies included measurement at baseline, every 3 months during the first 2 years of treatment and every 6 months thereafter. During the study, use of intravenous methylprednisolone served as a surrogate measure of the clinical efficacy of Avonex in preventing relapses.

Of the 382 patients enrolled in the safety-extension study, 275 (72%) patients completed treatment. Of the 107 (28%) patients who discontinued treatment, 38 (10%) voluntarily withdrew from treatment, 20 (5%) withdrew due to perceived worsening of MS, and only 8 (2%) withdrew due to adverse events. Other reasons for discontinuation included loss to follow-up (4%), alternative therapy (3%), noncompliance (2%), and other (2%). A total of 86 patients were treated with Avonex for the full 8 years.

The incidence and types of adverse events observed over the safety-extension study were similar to those observed in the original phase III trial.¹³ The most commonly reported adverse events were flu-like symptoms (74%), headache (58%), muscle aches (48%), and cold symptoms (46%) all of which declined over time. No new treatment-emergent adverse events were observed. The incidence of severe adverse events (defined by the FDA to include any event requiring hospitalization for any reason) was 27% (21 patients with exacerbation of MS, 13 patients with accidental injury).

The incidence of neutralizing antibodies in patients at risk for developing neutralizing antibodies (titers ≥20) is illustrated in Table 1. Neutralizing antibodies developed after 6 months of treatment and reached a plateau at 12 months. Of the 281 patients who were neutralizing antibody-negative at baseline, 15 (5%) tested positive for neutralizing antibodies at some time during the 6-year safety extension study and no more than 4% were positive at any given time point.

The incidence of neutralizing antibodies was assessed in 140 patients who had received prior treatment with Betaseron but had not participated in the original phase III trial. Neutralizing antibodies that developed during treatment with Betaseron disappeared in 68% within six months and in 85-91% of the patients after several years of treatment with Avonex (Figure 1).

At the start of the safety-extension study, 18 patients were positive for neutralizing antibodies to Betaseron. At 2 years, only 2 of 15 patients were neutralizing antibody-positive; at 5 years, 1 of 11 patients was neutralizing antibody-positive. Although preliminary and in a limited number of patients, the investigators suggested that patients who develop neutralizing antibodies to Betaseron may consider Avonex as an acceptable alternative treatment option. This process took from six months to two years to occur and during this time, individual patients that were still neutralizing antibody-positive would not receive the full benefit of the interferon beta therapy.

The data on the incidence of neutralizing antibodies associated with Avonex are not only in concordance with the previous published studies, but also provide compelling evidence of the low immunogenicity of Avonex in the long-term treatment of relapsing MS patients.

The treatment effect of Avonex on relapses, as measured by intravenous methylprednisolone use, was durable for up to 8 years of treatment. The rate of methylprednisolone use decreased from 0.56 courses/patient/year during Year 1 to 0.33 courses/patient/year during Year 6. Table 2 illustrates methylprednisolone use for patients who participated in both the phase III trial and the 6-year safety-extension study.

Patients who had originally received placebo in the phase III trial had a 51% reduction in the number of methylprednisolone courses/patient/year over 6 years of treatment.

Break-through Treatment Option with Avonex and Continuous Low-dose Corticosteroid

Heidi Lee, MD, of the Indiana Center for Multiple Sclerosis and Neuroimmunopathologic Disorders, Indiana University School of Medicine, Indianapolis, Indiana presented the results of a study evaluating the combination of Avonex and continuous low-dose corticosteroid (prednisone) for the treatment of relapsing-remitting and relapsing-progressive MS.¹⁴ To date, there are no studies addressing the risk/benefit ratio of continuous treatment of MS patients with low-dose corticosteroid.

The primary objectives of the study were to document relapse rate and disease progression, using Expanded Disability Status Scale (EDSS), and the incidence of side effects associated with combined immunomodulatory-immunosuppressive treatment of Avonex and low-dose prednisone.

A total of 177 patients with MS were treated with intramuscular 30 mcg Avonex once weekly and prednisone (0.10 mg-0.20 mg/kg/day; 7.5 mg-15 mg/day) for 4 to 74 months (median duration 39 months). Relapses with worsening in the EDSS rating, exceeding two points, were treated with intravenous methylprednisolone (total dose not exceeding 3,500 mg); and those relapses not exceeding two EDSS points were treated with oral prednisone (1 mg/kg/day) for five days. Subsequently, prednisone was gradually titrated to the daily maintenance dose.

The investigators established 69 instances of a clinical relapse representing an annualized relapse rate of 0.11. A significant decline in the disability rating was observed from baseline (2.98 ± 1.33 to 2.37 ± 1.61; P<0.001).

Thirty-seven patients (20.9%) experienced elevations in blood pressure that were effectively treated. Seven patients (3.9%) were effectively treated for diabetes (3 patients were diagnosed as diabetic before study entry).

These findings demonstrate that the combination of Avonex and continuous low-dose of prednisone (average dose not exceeding 0.12 mg/kg/day) is well tolerated. Moreover, continuous low-dose prednisone offers the clinician an alternative to pulse therapy with high-dose intravenous methylprednisolone. Potential side effects are manageable with effective treatment. Patients on long-term corticosteroids, even at very low doses need to have their blood sugar monitored periodically and need to be monitored for osteoporosis.

The EVIDENCE Study: 63-week Data

Hillel Panitch, MD, of the Department of Neurology, University of Vermont, Burlington, Vermont presented an analysis of 63-week data of the EVIDENCE Study.¹⁵ The EVIDENCE Study was a randomized, multicenter, assessor-blinded study that compared subcutaneous Rebif 44 mcg three times weekly to intramuscular Avonex 30 mcg once weekly.⁷ The study enrolled 677 patients with relapsing-remitting MS from 56 multinational centers and was conducted in two 24-week phases.

The primary outcome measure was the proportion of relapse-free patients. Secondary outcome measures included relapse rate and change in T2 lesion activity on MRI. Tertiary outcomes included percentage of T2 active scans, proportion of patients with no T2 active scans, and time to first relapse, relapse severity and corticosteroid use. Baseline patient characteristics of both treatment arms were well matched. Baseline MRI characteristics were also similar; however, the Avonex treatment arm had 20% more combined unique lesions at baseline.

Of the 339 patients randomized to subcutaneous Rebif 44 mcg three times weekly, 315 (93%) continued in the study and 299 (88%) continued on treatment until study completion; 319 of 338 patients (94%) randomized to intramuscular Avonex 30 mcg once weekly continued in the study and 306 (91%) completed treatment. Discontinuation due to adverse events was noted in 19 and 18 patients in the Rebif and Avonex treatment arms, respectively.

The proportion of relapse-free patients treated with Rebif 44 mcg was 56% compared with 48% for Avonex-treated patients (adjusted odds ratio 1.5; 95% Confidence Interval (CI), 1.1-2.0; P = 0.023) an absolute difference of 8% (Table 3). This difference appears to lessen over time as the absolute difference at 24 weeks was 12% and at 48 weeks was 10%. The results suggest that the beneficial treatment effect seen with Rebif compared to Avonex is demonstrated most clearly in Months 0 to 6 and declines over time.

The annualized relapse rate for Rebif-treated patients was lower than Avonex-treated patients, 0.54 versus 0.65, respectively (P = 0.033), although there was not a significant difference at 48 weeks (Table 4). Time to first relapse was 13.5 months for Rebif-treated patients compared to 6.7 months in Avonex-treated patients (hazard ratio 0.70; 95% CI, 0.56-0.88; P = 0.002). Mean T2 active lesion count was 0.9 in Rebif-treated patients compared with 1.4 for Avonex-treated patients (P<0.001). Mean T2 active lesion count was 0.9 for Rebif-treated patients and 1.4 for Avonex-treated patients (P<0.001); mean proportion of active scans per patient was 27% and 44%, respectively (P<0.001); and proportion of patients with no active scans was 58% and 38%, respectively (P<0.001).

Persistent neutralizing antibody titers (defined as at least 2 consecutive positive tests of titers ≥20) were observed in 21% of Rebif-treated patients compared to 3% of Avonex-treated patients (P<0.001) (Table 5). Neutralizing antibody-negative patients had significantly fewer T2 active lesions than neutralizing antibody-positive patients. This incidence is consistent with previously reported results and it remains low for Avonex.

Injection-site reactions were significantly higher with Rebif administration (84.7% vs 33.2%; P<0.001) (Table 6). The incidence of inflammation and rash was 34.8% and 17.7% in Rebif-treated patients versus 8.6% and 2.7% in Avonex-treated patients, respectively (both P<0.001). Liver function abnormalities occurred in 18% and 9.8% of Rebif- and Avonex-treated patients, respectively (P = 0.003). White blood cell (WBC) abnormalities were significantly higher with Rebif than with Avonex (13.6% vs 5.3%; P<0.001).

The results of the 63-week data were determined at a randomly selected timepoint. Given that studies of Rebif have demonstrated that the presence of neutralizing antibodies had an effect on increasing T2 lesion activity over 4 years of treatment (P<0.001) and further appeared to negate the effect of Rebif on relapse during Years 3 and 4 of treatment (P = 0.0002),⁵ firm conclusions concerning the study's primary endpoints (MRI activity and relapse) appear to be premature at 63 weeks, relative to results of previous Rebif studies. Further study of these patients over a greater period of time is needed to clarify these observations.

The majority of the advantage observed with Rebif is found in the first 24 weeks of treatment. Subsequently, the benefit diminishes (% relapse free and relapse rate). During the second 24 weeks of the study, the relapse rate was not significantly different between Avonex and Rebif.

An additional complication in interpreting the data is the open-label aspect of the study design. Patients may have been influenced by the extensive media promotion of the 24-week results suggesting that Rebif was more effective than Avonex. In an open-label trial, this may bias a patient's reporting of relapses.

References

1. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655-661.
2. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1996;47:889-894.
3. Bertolotto A, Malucchi S, Sala A, et al. Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry. 2002;73:148-153.
4. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing-remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352:1498-1504.
5. PRISMS-4: long-term efficacy of interferon beta-1a in relapsing MS. The PRISMS (Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis) Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 2001;56:1628-1636.
6. Rice GPA, Francis GS, and the PRISMS Study Group. Further evidence of dose effect of interferon beta-1a based on neutralizing antibody status. Poster presentation at the 11th Annual Meeting of the European Neurological Society, April 21-25, 2001, Paris, France.
7. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS. The EVIDENCE Trial. Neurology. 2002;59:1496-1506.
8. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Neurology. 1998;50:1266-1272.
9. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898-904.
10. Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology. 2002;59:1507-1517.
11. Herndon RM, Bennett R, Riester K, Zhang H, Toal M. Eight-year experience with interferon beta-1a in subjects with multiple sclerosis. Presented at the 17th Annual Meeting of the Consortium of Multiple Sclerosis Centers, May 28-June 1, 2003, San Diego, California. Poster S16.
12. Avonex prescribing information [package insert]. Biogen, Inc. Available at http://www.avonex.com. Accessed June 30, 2003.
13. Jacobs JD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39:285-294.
14. Lee H, Arbona JA, Baurle JA, et al. Continuous combined treatment of MS with Avonex and prednisone. Presented at the 17th Annual Meeting of the Consortium of Multiple Sclerosis Centers, May 28-June 1, 2003, San Diego, California. Poster S11.
15. Panitch H. The EVIDENCE Study - final 16-month comparative data. Presented at the 17th Annual Meeting of the Consortium of Multiple Sclerosis Centers, May 28-June 1, 2003, San Diego, California. Presentation P25.