Multiple Sclerosis and Related Disorders (2013) 2, 141–146

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Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies against interferon-beta (REPAIR study) Melinda Magyarin, Helle Bach Søndergaard, Finn Sellebjerg, Per Soelberg Sørensen Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Received 19 July 2012; accepted 7 October 2012

KEYWORDS Multiple Sclerosis; Disease modifying therapies; Immunology; Biomarkers; Beta-interferon; Neutralising antibodies

Abstract Background: A major problem in the treatment of multiple sclerosis (MS) patients with interferon-beta (IFN-b) is the development of neutralising antibodies (NAbs). High levels of NAbs block the induction of IFN-b-inducible markers, including Myxovirus Resistance Protein A (encoded by the MX1 gene), resulting in a loss of bioactivity and therapeutic benefit. Objective: The primary objective of this study is to investigate the in vivo biological response to interferon-alpha (IFN-a) in MS patients, who have developed neutralising antibodies (NAbs) against IFN-b. Design/Methods: The study was an open-label phase II study in 10 patients with relapsingremitting MS with persisting NAbs against IFN-b and absent in vivo mRNA MxA response. We used in vivo induction of MX1 mRNA and other IFN-inducible genes as measure of the biological response. The primary endpoint was the in vivo mRNA MX1 response after an injection of IFN-a compared with the response after an injection of IFN-b. Results: In all 10 patients we found high MX1 expression after injection of IFN-a 6 MIU, indicating a preserved in vivo response to IFN-a. We measured the gene expression index of immune system genes in blood cells from the 10 NAb-positive patients after IFN-a treatment and 10 NAb-negative patients after injection of IFN-b. We found a significantly increased expression of a number of genes, including MX1, IFI27, IL10 and TNFSF10 (encoding TRAIL) in the NAb-positive patients treated with IFN-a. Interpretation: IFN-a could be a therapeutic option in patients, who have lost the biological response to IFN-b because of NAbs against IFN-b. ClinicalTrials gov. Identifier: NCT01171209. & 2012 Elsevier B.V. All rights reserved.

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Correspondence to: Department of Neurology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail address: [email protected] (M. Magyari).

2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.10.001

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1.

M. Magyari et al.

Introduction

Treatment of relapsing-remitting multiple sclerosis (RRMS) with interferon-beta (IFN-b) is effective and safe, but a major problem is the development of neutralising antibodies (NAbs) directed against IFN-b (Sørensen et al., 2005;Ross et al., 2000;Perini et al., 2004). The effect of IFN-b is mediated through its binding to its specific cell surface receptor (IFNAR). Via an intracellular signal transduction pathway, receptor-binding leads to an increase or decrease in the expression of a large number of genes. Changes in the expression of IFN-b regulated genes at the mRNA or protein level may therefore serve as markers for bioactivity of IFN-b. In order to investigate the in vivo response to IFN-b, several biomarkers have been studied. Myxovirus Resistance Protein A (MxA, encoded by the MX1 gene) is among the best validated markers and is increasingly used in daily clinical practice. NAbs prevent IFN-b from binding to IFNAR, and thereby reducing, and in high concentrations abolishing, the therapeutic effect of IFN-b (Hesse et al., 2009), not only against the preparation to which NAbs developed, but also to any other IFN-b preparation and, therefore, IFN-b must be replaced with another therapy that may be less effective or have adverse effects (Sørensen et al., 2003). Hence, there is an unmet need for additional treatment possibilities for these patients, many of whom may wish to continue treatment with interferon. Multiferons is a natural human interferon-alpha (IFN-a), and published data indicate that treatment with Multiferons does not induce IFN-a antibodies and is not bound and neutralised by NAbs against IFNb (Myhr et al., 2000). Previous studies have assessed the efficacy and safety of recombinant IFN-a in MS. As both IFN-a and IFN-b are type I interferon that bind to the same interferon receptor (IFNAR), we hypothesised that human IFN-a may induce a secondary treatment response in NAb-positive patients. A full in vivo response to human IFN-a (Multiferons) comparable to that seen after IFN-b induction would suggest that identical therapeutic effect could be obtained. Hence we undertook an open-label, single-centre study on the biological efficacy and safety of IFN-a in MS patients who have developed NAbs against IFN-b and who have lost the in vivo mRNA MX1 response to IFN-b.

2. 2.1.

Material and methods Patient characteristics

The Response to IFN-a in IFN-b Neutralising Antibody Positive Multiple Sclerosis Patients (REPAIR) study was an open-label, single-centre study investigating the biological effect of human IFN-a for the treatment of RRMS. Patients, who had developed NAbs against IFN-b and had no in vivo MX1 mRNA response, were recruited from the Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet Denmark. Eligible patients had relapsing-remitting multiple sclerosis according to the McDonald criteria, were aged between 18 and 55 years, had a disability equivalent to a score of 5.5 or less on the Kurtzke expanded disability status scale (EDSS) (Kurtzke, 1983), had been treated with any IFN-b

preparation for at least 12 months, had been shown to be NAb-positive and without an in vivo MX1 mRNA induction response within the last 12 months, and were required to follow the study protocol for the entire study period. Women of childbearing potential were required to use adequate contraception throughout the study and to have a negative pregnancy test at screening. Exclusion criteria comprised any previous immunomodulatory or immunosuppressive treatment for multiple sclerosis other than IFN-b 6 months prior to the screening visit, and treatment with glucocorticoids within the preceding 2 months. The Ethics Committee, Capital Region (H-3-2009-151) and Danish Regulatory Authorities (1232009) approved the study protocol. The study was undertaken in accordance with the Declaration of Helsinki, the European Medicines Agency Note for Guidance on Good Clinical Practice. The Copenhagen University Hospital GCP-unit evaluated patient safety and benefit–risk profiles. Patients provided written informed consent before initiating study procedures. The trial is registered with EudraCT number: 2009016824-29, and ClinicalTrials.gov, Protocol Record 2009016824-29.

2.2.

Clinical trial procedures

At the screening visit the investigator obtained data on demographic characteristics, medical history, inclusion and exclusion criteria, and previous and concomitant medications (Fig. 1). All disease-modifying treatments taken up to 12 months prior to screening were recorded. At a baseline visit blood samples were drawn for measurement of binding (BAbs) and neutralising antibodies (NAbs) against IFN-b, in vivo response of mRNA MX1 and other markers of IFN bioactivity. A clinical neurological examination including EDSS score and a pregnancy test was performed. Safety laboratory tests, including haematology, serum chemistry and thyroid function tests were performed. A dose of IFN-b similar to the doses before discontinuation of IFN-b therapy was given by the clinical coordinator. In the evening before the IFN-b assessment visit within the next 7 days, the patient administered the IFN-b injection in the evening, and 9–12 h later appeared in the clinic for blood sampling. At the first assessment visit on day 7, blood samples were drawn for measurement of binding (BAbs) and neutralising antibodies (NAbs) against IFN-b and measurement of in vivo response of mRNA MX1 and other markers of IFN. Safety blood tests were analysed. At the assessment visit, blood samples were drawn for measurement of binding (BAbs) and neutralising antibodies (NAbs) against IFN-b and measurement of in vivo response of mRNA MX1 and other markers of IFN. Safety blood tests were analysed. At the second clinical assessment the clinical coordinator dispensed one dose of human leucocyte IFN-a (Multiferons) to be administered within the next 7 days. In the evening before the IFN-a assessment visit, the patient administered the human leucocyte IFN-a (Multiferons) 6 MIU subcutaneously and 9–12 h later the

Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies

143

Fig. 1 Trial profile.

patient appeared in the out-patient clinic where again blood samples were drawn for measurement of binding (BAbs) and neutralising antibodies (NAbs) against IFN-b and measurement of in vivo response of mRNA MX1 and other markers of IFN bioactivity. Safety blood tests were analysed. The primary outcome measure of this study was to compare the in vivo mRNA MX1 response to IFN-a with the in vivo mRNA MX1 response to IFN-b at the baseline visit. The secondary efficacy endpoint was the in vivo response to IFN-a on the expression of other known IFN-b response marker genes: interleukin-10 (IL10), the tumour necrosis factor-related apoptosis-inducing ligand TRAIL (TNFSF10), and the IFN-a-inducible protein 27 (IFI27). An exploratory analysis investigated changes in the expression of a panel of other immune-related genes. We also compared the NAb titre after an injection of IFN-a with the NAb titre at the baseline visit. Adverse events were recorded at each visit. A serious adverse event was any adverse event resulting in death or that was life threatening, required hospital admission, prolonged hospital stay or resulted in persistent and substantial disability.

2.3. Measurement of neutralising—and binding antibodies against IFN-b NAbs were measured using the Luciferase neutralising antibody assay (Lam et al., 2008; Farrell et al., 2008) where NAb titres are calculated based on the Kawade technique (Grossberg et al., 2001a; Grossberg et al., 2001b) and expressed using the tenfold reduction unit. Binding antibodies were measured using a capture enzyme-linked immunosorbent assay (ELISA) (Jensen et al., 2012).

2.4. Isolation of RNA, cDNA synthesis and realtime PCR analysis Total RNA was extracted from whole blood using the PAXgene blood RNA kit (Qiagen). Next, RNA integrity and concentration were assessed on an RNA 6000 nano chip using an Agilent 2100 Bioanalyzer. Synthesis of cDNA was performed with random primers using the high capacity cDNA RT kit (Applied Biosystems). We performed quantitative real-time PCR (qPCR) using the TaqMan array microfluidic card format detecting

24 genes in duplicate per sample in a 384-well set-up (Applied Biosystems). Each loading port contains primer and probe sets to detect 21 genes related to the immune system and 3 genes for use as internal controls. Since the IL10 and IFI27 genes were not on the microfluidic card, they were analysed in a 96-well format. All qPCR reactions were performed on the ViiA7 real-time PCR system (Applied Biosystems) using the fluorescent TaqMan methodology. TaqMan Universal master mix II, no UNG (Applied Biosystems) and cDNA in a 1:5 dilution were used for each microfluidic card qPCR reaction in a final volume of 100 ml. The thermal cycling card conditions comprised 10 min at 94.5 1C and then 37 cycles of 0.05 s denaturation at 97 1C and 30-sec annealing at 59.7 1C as recommended in the user bulletin for rapid gene quantification (Applied Biosystems PN4458317A). For single qPCR reactions, Universal Fast PCR master mix (Applied Biosystems) and standard thermal cycling conditions were used in a final volume of 20 ml. Each gene was analysed in duplicate, normalised against YWHAZ and UBC as reference genes and expressed relative to a calibrator sample consisting of NAb-positive subjects treated with IFN-b. An expression index was calculated by the 2-DDCt method for relative quantification, as described previously (Livak and Schmittgen, 2001). Data were analysed using GenEx v.5 Pro. An additional cohort of 10 NAb-negative RRMS patients were sampled for comparing of gene expression indexes. Blood samples were obtained 9–12 h after an injection of IFN-b.

2.5.

Statistical analysis

SPSS version 18 was used. Paired sample t-test was used to analyse qPCR data for differential gene expression (expression after IFN-b and IFN-a). A p-value below 0.05 was considered statistically significant. PCR gene expression indexes were shown as a ratio of fold induction after IFN-a and were compared with gene expression in the 10 NAb-negative patients by an independent sample test. Data were processed using Microsoft Excel and SPSS.

3.

Results

We screened 13 patients and excluded 3 because the persistence of their NAb negativity and biological response to IFN-b was uncertain. Ten patients with RRMS, who had

144

Table 1

M. Magyari et al.

Baseline characteristics of NAb-positive RRMS patients.

Patient-id

Age

Sex

Onset (Year)

Previous treatment

Treatment at screening

EDSS

1 5 6 7 8 9 10 11 12 13

35 55 45 27 36 25 42 42 32 37

F M M M M F F F F F

1999 1998 2003 2004 2008 2006 2006 1999 2006 2007

Rebif Betaferon Betaferon Rebif Avonex Rebif Avonex Rebif Rebif Betaferon

Rebif 0 Copaxone Copaxone 0 Copaxone Avonex 0 Copaxone Betaferon

1 1.5 2.5 3 2.5 1.5 1.5 0 1 2

Fig. 2 Expression of the genes MX1 (encoding MxA), IFI27, IL10 and TNFSF10 (encoding TRAIL) in blood cells from 10 NAb-positive and 10 NAb-negative MS patients 9–12 hours after injection of IFN-a or IFN-b. 0 = INF-b in NAb-positive patients. A= INF-a in NAbpositive patients. B = INF-b in NAb-negative patients.  Paired t-test 0 vs. A.  Unpaired t-test A vs. B.

sustained presence of high-level NAbs against IFN-b and no MX1 mRNA response, were included in the study. Group baseline characteristics are described in Table 1. In these patients MX1 mRNA expression was significantly increased post-injection with IFN-a, indicating a preserved in vivo response to human IFN-a. (po0.001). The expression of IL10, TNFSF10 and IFI27 also increased after an injection of IFN-a (po0.001). Interestingly, the magnitude of the increases was also significantly higher than the increase observed in the patients treated with IFN-b (Fig. 2). There was no difference in NAb titre after IFN-a treatment compared with baseline (data not shown). To elucidate if there were any differences in expression of immunologically relevant genes after IFN-a treatment of NAb-positive patients we analysed gene expression and the most induced genes are listed in Table 2. Adverse events were mild to moderate. After treatment with IFN-b, mild dizziness, nausea and sensibility disturbances at the injection site were reported. All patients

reported flu-like symptoms, such as fever, chills, myalgia, and arthralgia, after administration of IFN-a. One patient experienced an allergic skin reaction after administration of IFN-a. Abdominal pain was experienced by 2 patients after treatment with IFN-a and headache by 1 patient. There were no unusual or unexpected adverse events and no serious adverse events occurred.

4.

Discussion

In this single centre, open label study investigating the biological effect of human IFN-a, we found a strong induction of MX1 mRNA in all 10 study subjects, and a significant increase in the expression of the other type I IFN-regulated genes, suggesting that IFN-a could be a therapeutic option in patients who have developed NAbs against IFN-b and have therefore lost the biological response to IFN-b. In addition to a significant induction of MX1 mRNA, we observed

Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies

145

Table 2 Gene expression after one injection of IFN-b and one injection of IFN-a in 10 NAb-positive MS patients, and after one injection of IFN-b in 10 NAb-negative MS patients. Gene symbol

IFNG FOXP3 LTA LTB MMP9 TIMP RORC TBX21 HLX EOMES GATA3 IL12A IL27 EBI3 SPP1 TNF TGFB1 IL1B IL23A

IFN-b NAb pos

IFN-a NAb pos

IFN-b NAb neg

Mean

SD

Mean

SD

p-value

1.54 1.03 1.10 1.03 1.43 1.07 1.03 1.10 1.07 1.06 1.07 1.05 1.06 1.14 1.46 1.02 1.03 1.04 1.10

1.90 0.26 0.45 0.27 1.39 0.40 0.30 0.57 0.41 0.41 0.36 0.39 0.40 0.60 1.36 0.22 0.25 0.31 0.43

0.46 0.63 0.43 0.35 2.28 2.17 0.29 0.37 2.99 0.23 0.30 2.49 51.14 2.29 2.65 1.84 3.41 8.38 0.03

0.40 0.13 0.10 0.13 1.48 0.81 0.14 0.18 1.00 0.11 0.13 0.64 15.85 1.99 1.97 0.55 0.52 11.63 0.01

0.145 0.000 0.002 0.000 0.007 0.000 0.000 0.001 0.000 0.000 0.000 0.000 0.000 0.083 0.002 0.001 0.000 0.074 0.005

a

Mean

SD

p-value

1.10 1.27 1.35 1.52 2.09 1.18 0.68 0.91 1.36 0.71 1.03 1.72 8.87 0.93 1.38 1.34 1.37 1.64 0.79

0.64 0.29 0.43 0.45 1.34 0.42 0.31 0.46 0.52 0.38 0.24 0.73 4.06 0.54 1.10 0.23 0.40 0.60 0.43

0.035 0.000 0.000 0.000 0.767 0.003 0.003 0.005 0.000 0.003 0.000 0.025 0.000 0.052 0.096 0.020 0.000 0.084 0.000

b

SD: standard deviation. a Paired t-test IFN-b vs. IFN-a in NAb-positive patients. b Paired t-test IFN-a in NAb-positive patients vs. IFN-b in NAb-negative patients.

increased expression of the type I interferon response biomarkers IL10, TNFSF10, and IFI27 to levels that were even higher than those observed in patients treated with IFN-b. Our results support earlier clinical studies suggesting the clinical efficacy and safety of recombinant IFN-a. Durelli et al., 1995 reported that systemic high-dose recombinant IFN-a-2a reduced exacerbation rate, magnetic resonance imaging (MRI) signs of disease activity, and lymphocyte interferon gamma production in relapsing-remitting multiple sclerosis. In 1996 the same author reported the results of a randomized, double-blind, placebo-controlled pilot trial with 9 million IU IFN-a or placebo intramuscularly every other day for 6 months. Clinical exacerbations or new or enlarging lesions on serial MRI occurred in two of 12 IFN-a treated and in seven of eight placebo treated patients (po0.005) and baseline lymphocyte interferon gamma production decreased (po0.04) in the IFN-a group, whereas production was unchanged in the placebo group. The reduction of clinical MRI signs of disease activity and the immunological effects were temporary and restricted to the period of IFN-a administration (Durelli et al., 1996). Myhr et al. performed a phase II randomized, placebocontrolled study of the effect of recombinant IFN-a-2a on MRI disease activity in ninety-seven patients with RRMS, showing that the median number of lesions at the end of treatment was lower with IFN-a-2a treatment than with placebo (p=0.0004), but the study did not have statistical power to show an effect of IFN-a-2a on clinical endpoints (Myhr et al., 1999; Myhr et al., 2000). Treatment with IFN-b has long been known and shown to have a good safety profile, but NAbs impair the effect of

treatment. Patients fail to respond to IFN-b therapy because of the development of NAbs. Unfortunately, switching to another IFN-b preparation in MS patients who have developed NAbs against one IFN-b is not an option because NAbs are cross-reactive between all IFN-b preparations (Kivisakk et al., 2000; Perini et al., 2001). Cross-reactivity between NAbs to IFN-b-1a or IFN-b-1b and recombinant IFN-a-2a was not found, which suggest that NAbs against IFN-b would not be cross-reactive with human IFN-a. A limitation of the study is the possibility of receptor desensibilization. Determination of gene expression was done after the first administration of human IFN-a, whereas the response to IFN-b was assessed in patients who were on established treatment with IFN-b. The measurements in NAb-negative patients treated with IFN-b were performed at least 6 months after treatment initiation. Since feed-back mechanisms might lead to some reduction in gene expression with repeated administration of type I IFNs, this could contribute to the differences in gene expression observed after one injection of human IFN-a compared with patients treated with IFN-b. Another limitation is the difference in given doses of the type I IFNs. Four first-line disease-modifying drugs are available for treating relapsing-remitting MS today. Their effects are modest, but they showed good safety and long-term benefit. Second-line therapies, such as natalizumab and fingolimod, have better efficacy but increased risks and there is limited long term experience. In the future, additional treatment possibilities will emerge, making the choice of the appropriate treatment

146 more complex, as differences in efficacy and risk has to be taken into consideration for the individual patient. In this context treatment with IFN-a may be a possibility for patients who have developed NAbs against IFN-b, and have no need for therapy escalation.

Conflict of interest Melinda Magyari has served on scientific advisory board for Biogen Idec; has received honoraria for lecturing from Biogen Idec, Merck Serono, Sanofi-Aventis, Bayer Schering; has received support for congress participation from Biogen Idec, Merck Serono, Sanofi- Aventis, Bayer Schering; and has received a grant for research activities from Swedish Orphan International. Helle Bach Søndergaard has nothing to disclose. P.S. Sørensen has served on scientific advisory boards Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, Elan, GSK, has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Genmab, TEVA, GSK, Bayer Schering, and he has received funding of travel for these activities; has served as Editor-in-Chief of the European Journal of Neurology, and is currently editorial board member for Multiple Sclerosis Journal, European Journal of Neurology, Therapeutic Advances in Neurological Disorders and; has received speaker honoraria from Biogen Idec, Merck Serono, TEVA, Bayer Schering, Sanofi Aventis, and Novartis. His department has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. F. Sellebjerg has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis and TEVA and as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec and Sanofi Aventis; has received speaker honoraria from Biogen Idec, Merck Serono, Bayer Schering, ScheringPlough, Sanofi-Aventis and Novartis; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis and Novartis.

Role of funding source This study was sponsor (Per Soelberg Sørensen) initiated and driven, with Swedish Orphan providing a research grant. The protocol was written by the sponsor and the investigator (Melinda Magyari). Data management and analyses were done by the whole research group.

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Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies against interferon-beta (REPAIR study).

A major problem in the treatment of multiple sclerosis (MS) patients with interferon-beta (IFN-β) is the development of neutralising antibodies (NAbs)...
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