A Multicenter, Open-Label, Phase II Study Of The Immunogenicity And Safety Of A New Prefilled Syringe (Liquid) Formulation Of Avonex In Patients With Multiple Sclerosis
Phillips JT, Rice G, Frohman E, Vande Gaer L, Scott T, Haas J, Eggenberger E, Freedman MS, Stuart W, Cunha L, Jacobs L, Oger J, Arnold D, Murray TJ, DiBiase M, Jethwa V, Goelz S
Clin Ther 2004 Apr;26(4):511-21
Baylor University Medical Center, Multiple Sclerosis Center at Texas Neurology, 6301 Gaston Avenue, Suite 400 West Tower, Dallas, TX 75214, USA
A new liquid formulation of Avonex (Interferon-beta-1a [Interferon-ß-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with Multiple Sclerosis (MS).
This formulation does not contain Human Serum Albumin (HSA), often added to Interferon (IFN) products for stabilization.
However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFN-ß products.
These kinds of structural changes could lead to the formation of AntiBodies directed against IFN-ß. Some of these Anti-IFN AntiBodies may neutralize the biologic activity of IFN-ß.
This study was designed to determine the Immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with Relapsing MS.
This was a multicenter, single-arm, open-label study. Patients with Relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months.
Immunogenicity and safety were assessed every 3 months.
Serum levels of Neutralizing AntiBodies (NABs) were measured at baseline and every 3 months using a 2-step enzyme-linked Immunosorbent assay and AntiViral Cytopathic effect assay.
A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study.
Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively.
By 18 months, 1 patient (1%) had > or =2 consecutive Titers of > or =20, a level at which the persistent presence of NABs has been shown in some studies to have clinical consequences.
By 24 months, 1 additional patient (total 2%) had > or =2 consecutive Titers of > or =20.
At 18 months, 5 patients (4%) had > or =1 NAB Titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAB Titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA.
The prefilled syringe (liquid) HSA-free formulation of Avonex was well
tolerated and showed a low level of Immunogenicity.
Over 24 months, 2% of patients developed persistent NABs (> or = 2 consecutive Titers of > or =20).
Longitudinal Analyses Of The Effects Of Neutralizing AntiBodies On Interferon-beta-1b In Relapsing/Remitting Multiple Sclerosis
Petkau AJ, White RA, Ebers GC, Reder AT, Sibley WA, Lublin FD, Paty DW
IFNB Multiple Sclerosis Study Group
Mult Scler 2004 Apr;10(2):126-38
University of British Columbia, Department of Statistics, 333-6356 Agricultural Road, Vancouver, British Columbia, Canada V6T 1Z2
We have analyzed data on exacerbation rates, Expanded Disability Status Scale (EDSS) scores, and lesion burdens using the results of two Neutralizing AntiBody (NAB) assays (CPE and MxA).
From the pivotal Relapsing/Remitting Multiple Sclerosis (MS) trial of Interferon-beta-1b (IFN-B) with a longitudinal approach, where the influence of NABs in individual patients is assessed by comparing responses during NAB-positive and NAB-negative periods.
There are apparent influences on exacerbation rate related to dose of IFN-B, Titer level, and duration of positivity.
With the MxA assay, exacerbation rates after switching to NAB-positive status are estimated to be 28% higher [95% confidence interval (CI): (-15%, 92%)] and -2% higher [95% CI: (-21%, 21%)] on the low- and high-dose IFN-B arms, respectively.
When compared with all NAB-negative periods, exacerbation rates during NAB-positive periods are estimated to be 29% higher [95% CI: (0%, 67%)] and 18% higher [95% CI: (0%, 40%)] on the low- and high-dose IFN-B arms, respectively.
When NAB-positive patients again become NAB-negative, no evidence of increased exacerbation rates could then be demonstrated.
More detailed exploratory analyses indicate that the effects are most evident in the approximately 20% of patients developing high Titers.
In these patients, the influence of NABs may be self-limited, as Titers often diminish or NABs become undetectable with time.
The Clinical Impact Of Interferon-beta AntiBodies In Relapsing/Remitting MS
Biasi G, Gallo P
J Neurol 2004 Mar;251(3):305-9
University of Padova, Multiple Sclerosis Centre-First Neurology Clinic, Dept of Neurological & Psychiatrical Sciences, Via Giustiniani, 5, 35128 Padova, Italy
We analyzed the kinetics and clinical impact of Binding AntiBodies (BABs) and Neutralizing AntiBodies (NABs) to three Interferon-beta (IFN-ß) products in patients with Relapsing/Remitting MS (RRMS).
Patients with RRMS received Interferon-ß-1b 8 MIU subcutaneously (SC) every other day, IntraMuscular (IM) Interferon-ß-1a 30 mcg once weekly, or SC IFN-ß-1a 22 mcg three times weekly for up to 4 years.
The changes of BABs and IFN-ß were measured using Enzyme-Linked Immunosorbent Assay (ELISA), and positive BAB samples were then analysed for neutralizing activity using an antiviral cytopathic effect assay.
Patients were considered BAB+ if they had a positive sample with an optical density (OD)>mean + 3SD of the OD of the control sample; high BAB Titers were defined as >1:500.
Patients were considered if they had Titers > or =20 LU/mL, with high NAB Titers defined as >1:100.
The impact of BABs and NABs on relapses and Expanded Disability Status Scale (EDSS) score also was evaluated. Thirty patients were enrolled in each treatment group.
Over the course of the study, 83% of patients developed BABs to Interferon-ß-1b, 13% to IM Interferon-ß-1a, and 47 % to SC IFN-ß-1a.
Forty percent of patients developed NABs to IFN-ß-1b, 6.7% to IM IFN-ß-1a, and 26.7% to SC IFN-ß-1a.
Of 22 patients, 10 patients (45.5%) demonstrated high Titers of both NABs and BABs (20% IFN-ß-1b, 3.3% IM IFN-ß-1a, 10% SC Interferon-ß-1a).
The relapse rate significantly increased after the appearance of high NAB titers (p=0.03); however, an even higher significance level (p<0.001) was observed in patients with high Titers of both NABs and BABs.
In 10 patients with high Titers of both NABs and BABs, an increase in mean EDSS score from 2.2 +/- 0.8 at baseline to 3.6 +/- 1.2 at year 2 (p<0.01) was observed.
NAB- patients showed no significant change in EDSS score at year 2.
These findings demonstrate that high Titers of both BABs and NABs reduce the clinical efficacy of IFN-ß in patients with RRMS, which is important for the long-term efficacy of these drugs.