Hugh J. Willison, MD, PhD, Glasgow Biomedical Research Centre, Room B330, 120 University Avenue, Glasgow G12 8TA, Scotland, UK. Tel: +(44)141-330-8287; Fax: +(44)141-330-4600; E-mail: Hugh.Willison@glasgow.ac.uk
Human and animal studies on antibody-mediated neuropathy implicate complement in pathogenesis. In animal models complement inhibition is therapeutically beneficial. The monoclonal antibody, eculizumab (Soliris™, Alexion Pharmaceuticals, Cheshire, CT), prevents cleavage of C5 and thus inhibits terminal complement activation. In an open label study, 13 multifocal motor neuropathy patients received eculizumab for 14 weeks, 10 of whom were concomitantly receiving intravenous immunoglobulin. The primary outcome was safety of eculizumab, and the secondary outcomes included change in intravenous immunoglobulin (IVIg) dosing frequency, performance, and electrophysiological parameters. Adverse events were minor during the study. Nine of 10 patients on IVIg maintenance continued to require IVIg. IVIg dosing interval was not different between the run-in and the treatment period. There were improvements in patient-rated subjective scores and selected clinical and electrophysiological measurements. Overall, a small treatment effect occurred in some patients that appeared supplementary to and independent of the IVIg treatment effect, and occurred more frequently in patients with higher baseline motor function.
Intravenous immunoglobulin (IVIg) remains the only therapeutic option in multifocal motor neuropathy (MMN); however, its effects are temporary and weakness slowly progresses despite regular therapy (Terenghi et al., 2004). No other immunomodulatory therapies have shown enough benefit to be routinely recommended alone or as an adjunct to IVIg.
The safety and efficacy of eculizumab in complement-mediated disorders have been shown in clinical trials of patients with paroxysmal nocturnal haemoglobinuria (Hillmen et al., 2006). However, eculizumab has yet to be trialed in any putatively MAC-dependent neurological disorders, and its administration and safety in patients who are concurrently receiving intravenous immunoglobulin have not yet been studied. In this study, we sought to find out whether co-administration of eculizumab with high dose IVIg was safe and tolerable in MMN patients, and whether eculizumab remained pharmacologically active during co-administration with IVIg. Secondary aims were to assess patients for possible therapeutic benefit of eculizumab.
Materials and Methods
Patients fulfilled European Federation of Neurological Societies (EFNS) electrodiagnostic criteria for MMN (Joint Task Force of the EFNS and the PNS, 2006; van Schaik et al., 2006). Patients had a current or past history of IVIg responsiveness and met other inclusion and exclusion criteria (Table 1). At enrollment, all were vaccinated with tetravalent meningococcal vaccine (ACWY Vax®, Glaxo Smith Kline, Uxbridge, Middlesex, UK). The trial protocol and supporting documentation were approved by the Regional Ethics Committee and conducted in keeping with the Declaration of Helsinki. The trial is registered on EudraCT database (unique no. 2008-005748-18). The study was investigator led and co-sponsored by the University of Glasgow and NHS Greater Glasgow and Clyde. Financial support and supply of drug were provided by Alexion Pharmaceuticals, Cheshire, CT, USA.
Table 1. Inclusion and exclusion criteria.
IVIg, intravenous immunoglobulin.
1. Slowly progressive or stepwise progressive, asymmetric limb weakness, or motor involvement having a motor nerve distribution in at least two nerves, for more than 1 month.
2. Absent or minor sensory symptoms or objective abnormalities.
3. Predominant upper limb involvement.
4. Documented conduction block in at least one nerve segment, classified by EFNS criteria.
5. Clinical improvement following IVIg treatment (current or historical).
6. Able to complete the self-evaluation functional rating scale weekly.
7. Agreement to vaccination against meningococcal infection.
8. Willing and able to give written informed consent.
1. Upper motor neuron signs.
2. Prominent focal or diffuse sensory impairment on routine sensory testing.
3. Below the age of 18.
4. Pregnancy, planned pregnancy, or lactation.
5. Inability to comply with study related procedures or appointments.
6. Unresolved Neisseria meningitidis infection or history of meningococcal infection.
7. Any condition that in the opinion of the investigator could increase the patient's risk by participating in the study or confound the outcome of the study.
8. Known hypersensitivity to eculizumab, murine proteins, or to any of the excipients.
9. Known or suspected hereditary complement deficiencies.
Patients entered the trial at baseline visit, run-in day zero (Fig. 1), which was timed to coincide with their next scheduled IVIg infusion. Patients not receiving regular IVIg entered the trial at a convenient date. Baseline clinical, functional, and electrophysiological assessments (Table 2) were measured immediately prior to IVIg infusion in those receiving IVIg. The next dose of IVIg was withheld until criteria for reaching their individualised deterioration point (DP) met self-evaluated functional rating (SEFR) score increase by 2 points from baseline plus at least one of the following: Medical Research Council (MRC) sum score decrease by at least 1 point; pinch/palm grip decrease by at least 10%; 9-hole peg test time increase by at least 10%; 10-m walk time increase by at least 2 s or patient/clinician feels deterioration has occurred. This allowed determination of the IVIg inter-treatment interval. Upon reaching this DP, the run-in period ended and the 14-week treatment period began. If no DP was reached or the patient did not receive IVIg, then the run-in period ended at week 8. In the treatment period, all patients received eculizumab by intravenous infusion 600 mg at weeks 0, 1, 2, and 3, then 5 doses at 900 mg every 2 weeks, up to week 12. IVIg was given at DP, as assessed by the investigator. Clinical assessments were repeated at weeks 4, 8, and 14 and electrophysiology repeated at week 14.
Table 2. Assessments and deterioration point criteria.
Clinical and functional assessments
Deterioration point (DP) criteria
1. Medical Research Council (MRC) sum score: total of 10 muscle groups from two affected limbs
SEFR score increase by 2 points from baseline
2. Muscle strength force (MSF) sum score: total of five muscle groups from two affected limbs, using myometry
Plus at least one of the following (a)–(e)
3. Hand grip strength: using hydraulic dynamometer
(a) MRC sum score decrease by at least 1 point
4. Palm and pinch strength: using vigirometer
(b) Pinch/palm grip decrease by at least 10% (either side)
5. Nine-hole peg test: time to completion in seconds
(c) 9-hole peg test time increased by at least 10%
6. 10-m walk time to completion in seconds
(d) 10-m walk time increase by at least 2 s
7. Self-evaluated functional rating scale (SEFR)
(e) Patient/clinician feels deterioration has occurred
8. Overall neuropathy limitation scale (ONLS)
9. European quality of life scale (EQ5D)
The primary outcome was safety as assessed by the frequency of adverse events (AEs) and serious adverse events (SAEs) occurring during the treatment period compared with the run-in and run-out period. The secondary outcomes were: (1) IVIg inter-treatment interval (in days), excluding the three patients who were not receiving IVIg; (2) clinical and functional efficacy measurements between the baseline (run-in day zero) and treatment and run-out periods (Table 2); and (3) electrophysiology parameters at baseline and treatment period week 14.
Self-evaluated functional rating scale (SEFR)
In addition to investigator-assessed functional scorings, a self-rated score was completed by patients weekly (Leger et al., 2001). Each patient identified five tasks of daily living affected by MMN. Performance on these tasks was graded on the perceived level of difficulty from 0 (normal) to 5 (impossible). The baseline SEFR score was used as a reference point throughout the trial. An increase in SEFR score by 2 points beyond this baseline score indicated a DP and triggered clinical assessment by the investigator to assess if DP criteria were reached (Table 2).
Motor nerve conduction studies and electromyography were carried out in at least one affected nerve segment and muscle group, respectively, at baseline and again at the end of the treatment period. Temperature of the limbs was maintained above 30°C. The trial neurophysiologist was not involved in any other trial assessments. Data for distal latency (DL), compound muscle action potential (CMAP) amplitudes and durations, conduction velocity, and F-wave latency were collected. Needle electromyography recordings of voluntarily contracting muscle activity were scored by a panel of five qualified neurophysiologists to assess any difference in the recruitment density pattern between baseline and the end-of-treatment period. The recordings were presented in pairs (pre- and post-treatment) and assessors were blinded to the patient details and the ordering of the recordings.
Blood tests were taken prior to each eculizumab dose, and assays were performed for pharmacokinetics (serum drug concentration) and pharmacodynamics, as measured by terminal complement functional assay (percentage of red cell lysis using patient serum as complement source). Anti-GM1 glycolipid antibodies were measured at baseline by enzyme-linked immunosorbent assay (ELISA) (Willison et al., 1999).
Because the study was not designed to test efficacy, no power calculation was performed, and the number of patients enrolled was a convenience sample.
Task scores, speeds or values were summarised by median and inter-quartile range (IQR) values for each time point or period, and presented as box-and-whisker plots. The myometry or muscle strength/force (MSF) recordings were summed across all five selected muscles for each patient to make a total MSF score. All electrophysiology results were transformed to z-scores, except % conduction block. The Wilcoxon signed-rank test was used to test whether the median differences in the intra-patient scores or speeds between the measurement points or periods and baseline (run-in day zero) were statistically significantly different from zero. The Mann-Whitney U-test was used to compare the medians between unpaired groups. A p-value <0.05 was considered to be significant and all tests were two-sided.
Twenty-two patients with a diagnosis of MMN were screened and considered eligible. One patient was excluded from recruitment as he required air travel to reach hospital. One other patient was diagnosed with metastatic cancer of unknown primary during the screening period and was excluded from recruitment. Seven of 20 patients declined enrollment due to (1) perceived risks of the trial drug and/or (2) already receiving perceived full benefit from IVIg.
The remaining 13 patients were recruited to the study with informed consent. Basic clinical data are listed in Table 3. At the time of inclusion, 10 of 13 patients were regularly attending for cycles of intravenous IVIg 1 g/kg administered over 1–5 days and repeated on average at 4 weekly intervals (Table 3). The remaining three patients were not currently on treatment.
Table 3. Clinical features.
IgM, Immunoglobulin M; IVIg, IQR, inter-quartile range; intravenous immunoglobulin.
Clinical features, n = 13
Age at start of trial
55 years (IQR 51–65)
Years affected by start of trial
19 years (IQR 10–29)
Upper limb onset
Lower limb involvement
Affected limbs only
IgM anti-GM1 antibody positive
IgM anti-GM1 antibody titre
1/9,000 (IQR 1/1,275–1/12,500)
Current IVIg treatment
Duration of IVIg treatment
9 years (IQR 5–14)
Current IVIg inter-treatment interval
4 weeks (IQR 3.0–4.75)
Average IVIg dose in year before trial
840 g/year (IQR 300–1,000)
Primary outcome – safety and tolerability
No patient discontinued the study medication due to an AE. One patient had an aborted infusion due to an allergic response, which was managed with prophylactic steroid and anti-histamine before subsequent doses. No unexpected treatment emergent signs or symptoms were noted. No bacterial or other infections were identified.
There were 52 AEs during the treatment period (Table 4), which were either mild (73%) or moderate (27%). Headache was the most common AE, accounting for 33% of all AEs during the treatment period. Almost two-thirds (11 of 17; 65%) of the headaches were in the first 4 weeks of eculizumab treatment.
Table 4. Adverse event data.
AEs, adverse events.
The rate of AEs (expressed as the proportion of weeks per period where an AE was experienced) was significantly higher (median 14%; IQR 7%–21%) during the treatment period than in either the run-in (median 0%; IQR 0–0%; p = 0.004) or the run-out periods (median 0%; IQR 0%–3%; p = 0.011).
There were two SAEs during the treatment period comprising headache and vomiting following co-administration of IVIg and eculizumab treatment. These led to overnight admission for medical management. One was diagnosed as aseptic meningitis and the other as treatment-related headache.
Median serum eculizumab concentration had increased to above the 35 µg/ml minimum therapeutic level by treatment period week 1, and it was maintained above this level throughout the treatment period (Fig. 2A). Before eculizumab treatment the median % haemolysis was 95% (IQR 77.5–98), whilst by week 1 this had reduced to 5% (IQR 2.75–19.5) (Fig. 2B).
Patients receiving IVIg had significantly lower median eculizumab concentration (78.7 µg/ml, IQR 55–108) compared with those not receiving IVIg (119.7 µg/ml, IQR 95–147) (Fig. 2C). Complete terminal complement inhibition in serum was achieved in both groups, with no difference between the median haemolytic complement activity in both groups (2% and 1%, respectively) (Fig. 2D).
Secondary outcomes – efficacy
Intravenous immunoglobulin requirements
During the treatment period, 9 of 10 patients receiving IVIg as maintenance therapy continued to require IVIg at regular intervals, as indicated by reaching their DP. Patient 012, who did not require IVIg during the treatment period, had been receiving IVIg at 10 week intervals for 2 years prior to the trial. The three patients not receiving IVIg were excluded from this analysis.
There was no significant difference between the IVIg dosing interval between the run-in period (median 30.5 days), the treatment period (median 34.5 days), or the run-out period (median 34 days). There was a difference when comparing the historical pre-trial IVIg interval (median 28 days) to the treatment interval (p = 0.006) (Fig. 3).
Muscle strength measurements
The MRC sum score did not differ significantly in any of the trial periods (Fig. 4A). The MSF (myometry) score steadily increased at each successive assessment point (Fig. 4B). Although a trend to improvement in myometry can already be seen in the run-in period, this was not significant, but became significantly higher than baseline (median 35 kg, IQR 25–42) at treatment week 8 (median 43 kg, IQR 38–52) and week 14 (median 44 kg, IQR 31–59), and run-out week 8 (median 44 kg, IQR 30–48). This suggests a generalised increase in patient muscle strength with eculizumab treatment, which was sustained into the run-out period. Median pinch grip strength showed small but significant changes at week 4 in both sides, but this difference was not seen at any other time point. There was no significant change in median palm grip strength throughout all periods.
The timed walk speed did not differ from baseline throughout the treatment period. There was significant increase in the speed of completion of 9-hole peg test using the right hand at all time points, and the left hand at week 4 only. This suggests a possible learning effect for the right hand.
Overall, there were improved SEFR scores (i.e., numerically reduced) week by week throughout the treatment period. There was a significant improvement from the baseline SEFR only at week 8 (median change −1 point, p = 0.03) and week 14 (median change −3 points, p = 0.02). There was no significant change in SEFR between the treatment and run-out periods. In a post hoc exploratory analysis, patients that had at least a 2-point decrease in the lowest SEFR score at any time during the treatment period compared with the run-in period were retrospectively classed as “subjective responders.” Using this criterion, 7 of 13 patients were subjective responders: of these 5 of 7 had subsequent worsening of SEFR by at least 2 points (i.e., score increase) during the run-out period.
In the EQ5D visual analogue scale, the median baseline response was 70% (IQR 60–81) and significantly increased to 75% (IQR 70–90) at week 4 only. The EQ5D health utility showed no change in the median score throughout the treatment period compared with baseline (median 0.71 throughout). The overall neuropathy limitation scale (ONLS) remained the same throughout all time points (median 4 points).
There was a small yet significant net decrease in the median percentage conduction block across all nerves studied of 6.5% (IQR 2.5–11.5) (Fig. 5). There was no significant change in the median distal CMAP amplitudes or conduction velocity of the whole group.
Electromyographical assessment of a maximum voluntary contraction was carried out in 22 muscle groups. Of 22, only 6 muscle groups received unanimous scorings, 4 showing increased motor unit recruitment and 2 showing decreased recruitment following treatment.
The primary aim of this open label single arm study was to test the safety and tolerability of eculizumab in MMN patients receiving IVIg. We found a significant increase in AE incidence during eculizumab treatment when compared with the run-in period. Many of the AEs reported are known side effects of IVIg treatment (Orbach et al., 2005). The three patients not receiving IVIg experienced mild AEs, indicating that eculizumab alone is associated with side effects. None of the AEs throughout the study were severe, bacterial infections were not encountered in this study, and no patients experienced a worsening of disease.
Pharmacological assays demonstrated that terminal complement function was fully inhibited in plasma in all patients, regardless of concomitant IVIg use, and thus there was no major neutralising effect of IVIg upon eculizumab. However, we do not know whether terminal complement inhibition was completely achieved within the endoneurial compartment, which is separated from plasma, relatively protected by the blood-nerve barrier, and may contain cells that synthesise C5.
This study shows a continuing benefit from IVIg treatment, even while complement blockade in the plasma has been achieved, as 9 of 10 patients continued to require and respond to IVIg during the treatment period. Thus, the acute mechanism of IVIg action in MMN is likely due to immunomodulatory or pharmacological mechanisms other than terminal complement inhibition over this short period of time.
We did observe some improvements in secondary outcomes. Overall, there was a trend towards an improvement in patient-rated subjective scores and increased muscle strength as measured by myometry. However, objective clinical measurements did not show any clear trends, even when responders and non-responders were considered separately in post hoc analysis.
There were improvements on individual electrophysiological measurements in some patients and deterioration in others. When considered as a group there was a small but significant net decrease in the degree of conduction block across all nerves studied. Following only 14 weeks of eculizumab treatment, a small improvement is noteworthy.
Overall, in this short duration open label study we observed that eculizumab was well tolerated and safe in MMN when administered in conjunction with IVIg. A small improvement was seen in selected objective motor performance measures and in conduction block. Ideally, a longer term study of terminal complement inhibition, looking for a more gradual cumulative effect or an arrest of disease progression, should be conducted in MMN and related disorders. When considering future studies, placebo-controlled trial designs would be preferable to the current un-blinded study in order to control for test performance variability, learning effects, and operator and patient-related assessment bias.
We gratefully acknowledge the contribution of the following parties: Dr. Donald Grosset, Consultant Neurologist, Institute of Neurological Sciences, Southern General Hospital Glasgow, DMC Chairman. Professor Richard Hughes, Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, DMC member. Professor Iain McInnes, Glasgow Biomedical Research Centre, University of Glasgow, DMC member. Consultant Neurophysiologists, Department Clinical Neurophysiology, Institute of Neurological Sciences, Southern General Hospital, for blinded MUR assessments. Ward 68 nursing, secretarial and administrative staff. Research nurses from Glasgow Clinical Trials Unit (CTU), Tennent Institute, NHS Greater Glasgow and Clyde, patient care and IV drug administration. Audrey Lush and Elizabeth Douglas, Trial Pharmacy, NHS Greater Glasgow and Clyde, storage and supply of eculizumab. Neuroimmunology Diagnostic Laboratory staff, Southern General Hospital for assistance with sample collection and storage. Data management and IT staff in the Robertson Centre for Biostatistics, University of Glasgow.