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April 29, 2014; 82 (17) Article

Natalizumab in progressive MS

Results of an open-label, phase 2A, proof-of-concept trial

Jeppe Romme Christensen, Rikke Ratzer, Lars Börnsen, Mark Lyksborg, Ellen Garde, Tim B. Dyrby, Hartwig R. Siebner, Per S. Sorensen, Finn Sellebjerg
First published March 28, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000361
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Abstract

Objective: Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive multiple sclerosis (MS). The objective of the study was to examine the effects of natalizumab in progressive MS.

Methods: In an open-label phase 2A study, 24 patients with progressive MS were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60.

Results: Seventeen patients completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34–96 ng/mL; p = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain.

Conclusions: Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration.

Classification of evidence: This study provides Class IV evidence that in patients with progressive MS, natalizumab reduces biomarkers of intrathecal inflammation.

GLOSSARY

CI=
confidence interval;
DTI=
diffusion tensor imaging;
EDSS=
Expanded Disability Status Scale;
GdEL=
gadolinium-enhancing lesion;
GM=
gray matter;
MBP=
myelin basic protein;
MMP9=
matrix metalloproteinase-9;
MS=
multiple sclerosis;
MTR=
magnetization transfer ratio;
NAWM=
normal-appearing white matter;
NFL=
neurofilament light chain;
PBVC=
percentage brain volume change;
PPMS=
primary progressive multiple sclerosis;
RRMS=
relapsing-remitting multiple sclerosis;
SPMS=
secondary progressive multiple sclerosis

Primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) are characterized by gradual development of irreversible neurologic disability with limited treatment possibilities.1,2 The pathogenesis of progressive multiple sclerosis (MS) is complex and unresolved, but axonal damage is thought to underlie the development of irreversible disability.2 Pathology studies have established that SPMS and PPMS pathologies are comparable and that the degree of inflammation in progressive MS brains correlates with axonal damage and clinical disease activity.3,–,5 However, it remains controversial whether systemic inflammation contributes to intrathecal inflammation and tissue damage in progressive MS.

Natalizumab is a humanized monoclonal antibody directed against α4-integrin molecules on leukocytes that blocks the transmigration of systemic immune cells to the CNS.6 Using an open-label phase 2A study design, we aimed to assess the safety and efficacy of natalizumab treatment in patients with progressive MS. We were particularly interested in clarifying whether systemic immune cells contribute to intrathecal inflammation and tissue damage in progressive MS. Because standard MRI endpoints used in MS trials do not reflect several aspects of progressive MS pathology, we chose to explore the use of CSF biomarkers, which mirror progressive MS pathology and are stably increased in patients with SPMS over a 1-year period.7,8

METHODS

Primary research question.

We examined whether natalizumab treatment reduces CSF biomarkers of intrathecal inflammation in patients with progressive MS. This study was an open-label phase 2A trial design and provides Class IV evidence for the primary research question.

Standard protocol approvals, registrations, and patient consents.

The study was initiated and driven by the investigators. The protocol was in accordance with the Declaration of Helsinki, approved by the local ethics committee and Danish regulatory authorities, and registered in clinicaltrials.gov (NCT01077466). All patients signed written informed consent before inclusion.

Patients.

Patients were recruited from Rigshospitalet beginning February 2010, and the last patient visit was completed in January 2012. Inclusion criteria included a diagnosis of SPMS or PPMS according to the McDonald criteria,9 age 18 to 55 years, Expanded Disability Status Scale (EDSS) score of ≤6.5, and progression the last 2 years of ≥1 EDSS point (≥0.5 if baseline EDSS score was ≥5.5). Exclusion criteria included relapse the previous month and immunomodulatory treatment 3 months or immunosuppressive treatment 6 months before the inclusion (complete inclusion and exclusion criteria are presented in appendix e-1 on the Neurology® Web site at Neurology.org).

Study design and procedures.

Study visits and procedures are shown in figure e-1. Included patients received open-label treatment with IV natalizumab 300 mg every fourth week for 60 weeks. The 60-week duration was chosen to evaluate possible pseudoatrophy during the first 12 weeks. Lumbar punctures were performed at baseline and week 60. CSF samples were handled and analyzed using commercial ELISA and colorimetric assays (Human Osteopontin, CXCL13 and MMP-9 Quantikine ELISA Kit, Total Nitric Oxide and Nitrite/Nitrate Assay [all from R&D Systems, Minneapolis, MN], NF-Light Neurofilament ELISA [UmanDiagnostics, Umeå, Sweden], and Myelin Basic Protein ELISA [Beckman Coulter, Brea, CA]) as described previously.8 Samples were analyzed on the same assay plate, and mean intra-assay coefficients of variance were ≤6.1%. MRI scans were performed using a 3T Siemens Trio scanner (Siemens, Erlangen, Germany) to acquire 3-dimensional whole-brain scans using T1-weighted (pre- and postgadolinium), T2-weighted, fluid-attenuated inversion recovery, magnetization transfer, and diffusion sequences. MRI scans were acquired at baseline, week 12, and week 60. Processing of MRI data is described in appendix e-2 and summarized as follows: cortical gray matter (GM) and normal-appearing white matter (NAWM) were segmented based on T1 images using SIENAX. Longitudinal assessment of percentage brain volume change (PBVC) was based on T1 images and estimated with SIENA. Lesions were delineated on fluid-attenuated inversion recovery with support of T2 and T1 images using a semiautomated contouring tool. Magnetization transfer ratio (MTR) was calculated as a ratio between magnetization transfer images with and without a saturation pulse.

Endpoints.

Primary efficacy endpoint was CSF concentration of osteopontin. Secondary CSF endpoints included biomarkers of inflammation (CXCL13 and matrix metalloproteinase-9 [MMP9]), axonal damage (neurofilament light chain [NFL]), demyelination (myelin basic protein [MBP]), and oxidative stress (total nitric oxide metabolites). Secondary MRI endpoints included number of gadolinium-enhancing lesions (GdEL), number of new or enlarging T2 lesions, T2 lesion volume, PBVC, change in NAWM and GM volume, changes in MTR, and diffusion tensor imaging (DTI) indices (fractional anisotropy, mean, axial, and radial diffusivity in NAWM, GM, and T2 lesions).

Secondary clinical endpoints were EDSS, MS Impairment Scale, MS Functional Composite, and the 36-Item Short Form Health Survey.10,–,12

Statistical analysis.

Target sample size was estimated from data on natalizumab treatment effects on CSF biomarkers in relapsing-remitting MS (RRMS).13 Using a 5% significance level for paired t test and a power of 80% to detect a treatment effect of 30% reduction in CSF osteopontin, the estimated size of each subgroup was 9. Accounting for dropouts, we recruited 12 patients with SPMS and 12 with PPMS.

All patients completing the trial were included in the analysis of primary and secondary endpoints using paired analyses to test statistical significance of changes. Unpaired tests were used for group-wise comparisons. We applied parametric and nonparametric statistic tests when appropriate and used bootstrapping to generate estimates of the confidence intervals (CIs) for data not fitting to the normal distribution. We used Pearson correlation for correlation analyses. Statistical analyses were performed using IBM SPSS version 19 (IBM Corp., Armonk, NY), and graphs were made with GraphPad Prism version 6 (GraphPad Software, Inc., La Jolla, CA).

RESULTS

We screened 30 patients and included 12 patients with SPMS and 12 with PPMS (figure 1). Baseline characteristics are shown in table 1. Seven patients did not complete the study, 4 because of development of anti-natalizumab antibodies and 3 because of inconvenience of the study visits in relation to their daily life.

Figure 1
Figure 1 Diagram of the recruitment and completion of the study

PPMS = primary progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis.

View this table:
Table 1

Baseline characteristics

Thirty-two adverse advents occurred in 18 patients. Three were severe (ureteral stone, venous thrombosis, and pneumonia); none were judged to be related to natalizumab treatment.

The primary endpoint, CSF osteopontin, was significantly reduced from the mean baseline value 322 ng/mL (95% CI 257–387) by a mean of 65 ng/mL (95% CI 34–96; figure 2) at week 60. The decrease in CSF osteopontin was significant when testing the subgroups of PPMS (n = 10; p = 0.02) and SPMS (n = 7; p = 0.006), patients without relapses the last 5 years (n = 14; p = 0.002), and patients without GdELs at baseline (n = 13; p = 0.007) alone.

Figure 2
Figure 2 CSF biomarker endpoints

Change in the concentration of CSF markers of inflammation (osteopontin, CXCL13, and matrix metalloproteinase-9 [MMP9]), axonal damage (neurofilament light chain), demyelination (myelin basic protein [MBP]), and oxidative stress (total nitric oxide [NOX]) from baseline to 60 weeks after initiation of natalizumab treatment. The p values represent paired t tests for osteopontin, neurofilament light chain, MBP, and NOX, while significance was tested for CXCL13 and MMP9 using Wilcoxon signed-rank test. Black squares = primary progressive multiple sclerosis; black triangles = secondary progressive multiple sclerosis; green symbols = baseline values for noncompleting patients.

Secondary inflammatory CSF endpoints also decreased: CXCL13 from baseline 30.5 pg/mL (95% CI 10.7–53.9) by a mean of 28.6 pg/mL (95% CI 9.1–51.8; p = 0.02) and MMP9 from baseline 0.28 ng/mL (95% CI 0.18–0.40) by a mean of 0.13 ng/mL (95% CI 0.002–0.25; p = 0.046). CSF markers of axonal damage and demyelination decreased concomitantly: NFL from baseline 657 ng/L (95% CI 389–925) by a mean of 243 ng/L (95% CI 23–462; p = 0.03) and MBP from baseline 1.1 ng/mL (95% CI 0.92–1.35) by a mean of 0.21 ng/mL (95% CI 0.003–0.43; p = 0.047). A significant decrease in CSF mononuclear cells was also observed (table 2). Exploratory analyses of the contribution of subgroups to the treatment effects showed no difference between patients with SPMS and those with PPMS in change in the CSF endpoints (figure e-2). In addition, we explored the relation between intrathecal inflammation and axonal damage and found a correlation between percentage change in CSF osteopontin and NFL (0.68; p = 0.003).

View this table:
Table 2

CSF routine and clinical endpoint data

MRI scans were scheduled to account for pseudoatrophy, which has been reported in patients treated with natalizumab and estimated to occur during the first 3 to 6 months.14,15 Accordingly, atrophy measures were analyzed from week 12 to 60. PBVC decreased by −0.55% from week 12 to week 60, and annualized rates of atrophy during the first 12 weeks and last 48 weeks of the trial did not differ (table 3). NAWM volume decreased from week 12 to week 60, while GM volume did not change. Four patients had GdELs on the baseline scan while none were observed at week 60.

View this table:
Table 3

MRI endpoints

MTR data were available for all 3 time points for 10 patients. MTR increased significantly from baseline to week 60 by 0.55 in NAWM and 0.63 in GM. To explore whether MTR changes were related to CSF biomarkers, we performed correlation analysis of percentage change in MTR and CSF endpoints and found changes in CSF NFL and MTR to correlate in NAWM (−0.73; p = 0.003) and GM (−0.66; p = 0.01), while we observed a nearly significant correlation between changes in CSF osteopontin and MTR in NAWM (−0.51; p = 0.06).

DTI-based indices of brain microstructure revealed a significant increase in fractional anisotropy in the NAWM and a near-significant increase in axial diffusivity from baseline to week 60, while mean and radial diffusivity were unchanged. Within T2 lesions, fractional anisotropy was stable, while we observed significant increases in mean, axial, and radial diffusivity.

None of the patients completing the study deteriorated in EDSS or had relapses. EDSS change was analyzed by using the average of screening and baseline EDSS as baseline, because this measure is more accurate than single measurements.16 The EDSS and MS Impairment Scale scores decreased significantly from screening/baseline to week 60 (table 2). MS Functional Composite and its components were stable from baseline to week 60. The 36-Item Short Form Health Survey score was unchanged, but the Physical Component Summary score increased significantly.

DISCUSSION

This open-label study of natalizumab treatment of patients with progressive MS used a novel approach to study treatment effects in patients with progressive MS and demonstrated a beneficial effect on intrathecal inflammation and tissue damage by blocking the recruitment of systemic immune cells to the CNS.

Development of treatments for progressive MS has so far been disappointing, which may partly be attributed to incomplete understanding of the complex pathogenesis of progressive MS.2 Pathology studies show that progressive MS is characterized by cortical and slowly expanding white matter lesions along with inflammation in the meninges and diffuse inflammation in the NAWM. This is thought to be more chronic in contrast to the transiently active focal white matter lesions characterizing RRMS.3,–,5 These features of progressive MS pathology are poorly reflected by the MRI endpoints frequently used in RRMS trials.7 In addition, progressive MS phase 3 studies are challenged by the use of EDSS progression as clinical endpoint, which, because of a low event rate and fluctuation in scores, necessitates costly phase 3 trials with long duration and large sample sizes.12

To circumvent this problem, we designed an open-label proof-of-concept study, which to our knowledge is the first using a CSF biomarker as primary endpoint. We chose CSF osteopontin as primary endpoint. Osteopontin is a pleiotropic proinflammatory cytokine that is abundantly expressed in MS and experimental autoimmune encephalomyelitis lesions, and is associated with the development of a progressive disease course.17,–,19 In MS, CSF osteopontin is a sensitive and dynamic marker of intrathecal inflammation, is associated with disease severity, and is stably increased over time in SPMS.8,20,21 CXCL13, NFL, and the other secondary CSF biomarkers have also been studied as biomarkers in MS.8,22,23 We recruited both patients with PPMS and patients with SPMS because the diseases are comparable in pathology and disease activity, irrespective of relapse activity.1,4,24

Using this approach, we demonstrate a beneficial effect on intrathecal inflammation as reflected by CSF osteopontin, which was corroborated by a concomitant decrease in other CSF biomarkers of inflammation, axonal damage, and demyelination. It is noteworthy that these treatment effects were comparable in PPMS and SPMS, suggesting that the 2 disease courses may be equally amenable to treatment. Furthermore, the decrease in CSF osteopontin remained significant when excluding patients with relapses and GdELs from the analysis, suggesting a treatment effect beyond an effect of relapses and GdELs. The findings of reduced intrathecal inflammation and tissue damage in the CSF were corroborated by MTR and DTI data. MTR and DTI have been used in MS to assess the tissue integrity on a macromolecular level, and MTR values are reduced in both NAWM and GM of patients with progressive MS and predict future progression, while DTI fractional anisotropy is decreased in the NAWM of patients with MS.25,–,27 The increased MTR in GM and NAWM and the increased fractional anisotropy in NAWM may indicate increased integrity of myelin and neurons or reduced microglial activity.27,28 The correlation between MTR and CSF NFL changes supports that the MTR increases are related to decreased axonal damage.

The MTR findings are in agreement with an MTR study of natalizumab treatment in RRMS, while the DTI findings are contrasted by a study that found decreased NAWM fractional anisotropy and axial diffusivity in natalizumab-treated patients with RRMS.29,30 Because patients with progressive MS have more inflammation in the NAWM than patients with RRMS, this discrepancy in the NAWM DTI data could reflect a treatment effect distinct to progressive MS.3 The increased mean, axial, and radial diffusivity observed in lesions may indicate a decreased tissue integrity in lesions and consequently that lesion pathology may be relatively unaffected by natalizumab treatment.28,30 However, the unchanged lesion fractional anisotropy and MTR do not support this conclusion, which therefore requires further exploration.

The PBVC in this study matches the PBVC in patients with untreated progressive MS, but also in patients with RRMS during the first year of natalizumab treatment.14,31 Because the annualized PBVC the first 12 weeks and the last 48 weeks was similar, the PBVC might be attributable to true tissue loss rather than pseudoatrophy. However, our findings of a significant decrease in NAWM but stable GM volume imply that atrophy in natalizumab-treated patients with progressive MS is driven by NAWM changes, and because GM volume is unaffected by pseudoatrophy, delayed pseudoatrophy of NAWM may contribute to the PBVC. Because GM atrophy in untreated MS is more pronounced than NAWM atrophy and because GM atrophy is a better predictor of progression, the observed stabilization of GM volume may indicate a beneficial treatment effect.15,32 Considering that SIENAX is an indirect method associated with substantial noise in longitudinal estimates of GM and NAWM changes and that there was no control group, these results should be interpreted with caution.

The primary mechanism of action of natalizumab is blocking the migration of immune cells into the CNS.6 Therefore, the effects on inflammation and tissue damage indicate that systemic immune cells contribute to progressive MS pathogenesis. Indeed, inflammatory cells in progressive MS lesions originate from the systemic immune compartment,4,33 and patients with progressive MS have increased systemic inflammation.34 However, the decreases in osteopontin, NFL, and MBP were only partial compared with effects observed in RRMS.13,35 Because the intrathecal sources of osteopontin are microglia, macrophages, astrocytes, macrophages, and T cells, while CXCL13 and MMP9 are expressed by cells most likely to be blood-derived leukocytes, and patients with progressive MS have substantial microglia activation in slowly expanding lesions, GM, and NAWM, these findings could indicate that residual inflammation is mainly caused by brain-resident microglia or macrophages.17,36,–,38 Whether residual inflammation and tissue damage will decrease further with longer treatment duration or by treatments targeting microglia and macrophages are important questions to be addressed in future studies.

The blockage of systemic immune cells by natalizumab could theoretically reduce inflammation necessary for tissue repair and remyelination. Although osteopontin has been suggested to be involved in tissue repair and remyelination, this role is redundant in experimental autoimmune encephalomyelitis.39 Furthermore, natalizumab treatment results in decreased proinflammatory cytokines and increased anti-inflammatory cytokine expression in CSF cells.13 In line with these findings, the increased MTR in GM and NAWM during natalizumab treatment indicates that remyelination is not likely to be decreased by natalizumab treatment.

There are several limitations in the present study, mainly the lack of a placebo control group, and uncertainty that the effects on biomarkers and clinical endpoints will translate into robust clinical effects.

A single-arm phase 2 design confers a risk of both false-positive and -negative results but can be considered for screening drugs for further development, especially when there are no effective standard therapies.40 Being a preliminary proof-of-concept trial using CSF endpoints, this approach was chosen to reduce the sample size and duration of the trial. Although the primary endpoint, CSF osteopontin, is not likely to be affected by placebo effects, this design still involves a risk that some of the changes observed are not attributable to direct treatment effects. This is particularly relevant for the clinical endpoints that are susceptible to placebo effects. While CSF and MRI endpoints are not influenced by placebo effects, both regression to the mean and effects related to the natural course of the disease or technical limitations potentially may influence the endpoints. That we found the CSF biomarkers to be stably increased during a 1-year period in a previous study in SPMS argues against these possibilities.8 Furthermore, the correlations between changes in CSF biomarkers and MTR demonstrate consistency of treatment effects when using different technical approaches. The high dropout rate confers risk of bias and reduces the power of the study. Because 4 patients left the study as a result of developing anti-natalizumab antibodies and the remaining 3 for personal reasons related to convenience, we do not suspect that these patients differ from the patients who completed the study.

Collectively, natalizumab treatment in patients with progressive MS reduces CSF and some MRI measures of intrathecal inflammation and tissue damage and produces improvements in clinical outcomes. These results support that systemic immune cells contribute to progressive MS pathogenesis and encourage the initiation of placebo-controlled clinical trials with natalizumab for both SPMS and PPMS.

AUTHOR CONTRIBUTIONS

Study concept and design was done by J. Romme Christensen, P.S. Sorensen, and F. Sellebjerg. Acquisition of data was planned and done by J. Romme Christensen, R. Ratzer, L. Börnsen, E. Garde, H.R. Siebner, P.S. Sorensen, and F. Sellebjerg. Analysis and interpretation of data was done by J. Romme Christensen, L. Börnsen, M. Lyksborg, T.B. Dyrby, E. Garde, H. Siebner, P.S. Sorensen, and F. Sellebjerg. J. Romme Christensen drafted the first version of the manuscript and all authors contributed with suggestions and commentaries to the finally submitted manuscript. All authors have approved the final version.

STUDY FUNDING

Supported by Biogen Idec, Danish MS Society, Danish Council for Strategic Research (grant 2142-08-0039), and Brdr. Rønje Holding.

DISCLOSURE

J. Romme Christensen has received speaker honoraria from Genzyme and TEVA, consultant honoraria from Biogen Idec and Royalty Pharma, and has had travel expenses reimbursed by Merck Serono. R. Ratzer has had travel expenses reimbursed by Merck Serono, TEVA, Biogen Idec, Genzyme, and Sanofi-Aventis. L. Börnsen has received support for congress participation from Novartis. M. Lyksborg reports no disclosures relevant to the manuscript. E. Garde and T. Dyrby have received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec. H. Siebner has received honoraria as reviewing editor for NeuroImage, as speaker for Biogen Idec and Genzyme, and as scientific advisor from Lundbeck. P. Sorensen has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, Elan, and GSK, has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Genmab, TEVA, GSK, and Bayer Schering, and he has received funding for travel for these activities; has served as editor-in-chief for the European Journal of Neurology, and is currently an 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, 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, Schering-Plough, Sanofi-Aventis, and Novartis; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis, and Novartis. Go to Neurology.org for full disclosures.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received September 19, 2013.
  • Accepted in final form January 22, 2014.

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