ECTRIMS highlights
Efficacy results
Monitoring and safety issues
Commentary by Dr. Paul S. Giacomini, Associate Director, MS Clinic, Montreal Neurological Hospital and Institute, Assistant Professor, Department of Neurology and Neurosurgery, McGill University
Natalizumab and alemtuzumab are the two high-efficacy monoclonal antibodies typically used to treat aggressive multiple sclerosis and patients with an inadequate response to prior therapies. New data on the use of these agents were presented at the 31st congress of the European Committee for Treatment and Research in MS (ECTRIMS). The following summarizes some of the research addressing efficacy, mode of action and safety considerations.
Natalizumab: Efficacy was demonstrated in the phase III trials AFFIRM and SENTINEL (Polman et al. N Engl J Med 2006;354:899-910; Rudick et al. N Engl J Med 2006;354:911-923); the latter was stopped early due to the emergence of progressive multifocal leukoencephalopathy (PML). While no trial extensions were done, long-term data are being collected in the ongoing Tysabri Observational Program (TOP) and a five-year interim analysis has been published (Butzkueven et al. J Neurol Neurosurg Psychiatry 2014;85:1190-1197; free full text at www.ncbi.nlm.nih.gov/pmc/articles/pmid/24532785/).
TOPS data have now been analysed to determine the risk of disability confirmed at 24 and 48 weeks in patients completing at least two years on treatment (median 40 infusions) (Butzkueven et al. ECTRIMS 2015; abstract P1092). The cumulative probability of 24-week confirmed EDSS worsening of ≥1.0 point at week 96 was 9%, and 18.5% at week 288. EDSS worsening was higher in patients with relapses compared to those relapse-free (23.6% vs. 15.0%), suggesting that early EDSS worsening is largely attributable to relapse-related deficits. This contrasts with the findings in secondary-progressive MS (SPMS): in the recently reported ASCEND trial of natalizumab, treatment was ineffective in slowing disability unrelated to relapses (www.businesswire.com/news/home/20151021005273/en/Biogen-Reports-Top-Line-Results-Phase-3-Study).
For the Canadian cohort of TOP (n=339), ARR declined from 1.68 at baseline to 0.19 after a mean of 2.4 years (Bhan et al. ECTRIMS 2015; abstract EP1333). EDSS scores remained stable from baseline (3.5) to year 3 (3.1). The incidence of serious adverse events was 8.3%, most commonly infections (2.9%). There were three cases of PML (0.9%), which was substantially higher than the rate (0.4%) reported in the TOP 5-year data (Butzkueven 2014) or current risk estimates (0.12 if JCV index < 1.5).
A population-based study in Sweden reported sustained efficacy with natalizumab at five years (Johansson et al. ECTRIMS 2015; abstract 599). Mean EDSS scores declined from 3.27 at baseline to 2.86 at month 60. The most common serious adverse event was neoplasms, but the incidence was low (0.5%). There were eight cases of PML (0.3%).
Alemtuzumab: Efficacy was demonstrated in two phase III trials comparing alemtuzumab versus interferon-β-1a s.c. in de novo patients (CARE-MS I) and previously-treated patients (CARE-MS II) (Cohen et al. Lancet 2012;380:1819-1828; Coles et al. Lancet 2012; 380:1829-1839). Over 90% of patients completing the core studies entered long-term extensions and results at five years are now available.
In CARE-MS I, 68% of patients required only two treatment courses (Havrdova et al. ECTRIMS 2015; abstract 152). The annualized relapse rate (ARR) in year 5 remained low (0.15) and 80% had no sustained accumulation of disability. Overall, 69% had stable/improved EDSS scores, including 33% with a six-month sustained reduction in disability. In years 3-5, >70% of patients had no new MRI activity (Arnold et al. ECTRIMS 2015; abstract P1100). Among patients with no evidence of disease activity (NEDA) at year 2, 61% had sustained NEDA through year 5. In the IFNβ cohort switched to alemtuzumab for the extension phase, ARR declined from 0.39 during the core study (on IFNβ) to 0.11 for years 3-5, and the proportion relapse-free increased from 60.1% to 72.1% (Hartung et al. ECTRIMS 2015; abstract P1096). Over 80% of patients had stable (67.2%) or improved (13.3%) EDSS scores after switching to alemtuzumab. The mean number of gadolinium-enhancing T1 lesions declined from 0.31 with IFNβ in year 2, to 0.04 with alemtuzumab in year 4, and 81.7% were free of new MRI activity (Rovira et al. ECTRIMS 2015; abstract P1088). The mean brain volume loss from baseline to year 4 was 30% lower in patients initially randomized to alemtuzumab compared to the IFNβ/alemtuzumab switch group.
In CARE-MS II, 60% of patients did not require re-treatment (Fox et al. ECTRIMS 2015; abstract P1102). ARR was 0.27 at the end of the core study, remained stable (0.21) through years 3-5, and >80% in each year of follow-up were relapse-free. A total of 49% had no MRI activity in years 3-5 (Traboulsee et al. ECTRIMS 2015; abstract 1103). Over five years, 76% of patients had no six-month confirmed disability progression, including 43% of patients with improved EDSS scores (Fox 2015). Overall, 25% of patients had a ≥1-point EDSS improvement. In the subgroup with NEDA at the end of the core study, 48% had sustained NEDA at five years. In the group switching from IFNβ to alemtuzumab, ARR declined from 0.52 in year 2 (on IFNβ) to 0.14 for years 3-5; the proportion relapse-free increased from 46.1% to 73.7%; and 75.6% had stable or improved EDSS scores (Cohen et al. ECTRIMS 2015; abstract P1101). The rate of NEDA doubled from 31.6% in year 2 with IFNβ, to 67.2% in year 2 of alemtuzumab (Wiendl et al. ECTRIMS 2015; abstract P637).
Long-term data are available from the Cambridge cohort of patients participating in open-label studies from 1999-2015. The median follow-up was 10.1 years for RRMS patients (n=86), and 19.8 years for patients with secondary-progressive MS (SPMS; n=36) (Brown et al ECTRIMS 2015; abstract P1504). Dosing differed from what is now used: alemtuzumab 12-20 mg/day x 5, a three-day cycle (12-20 mg/day) at month 12, and further cycles for patients with relapses or new lesions. The mean ARR for the RRMS cohort was 0.14/year; median EDSS at 10 years was unchanged from baseline. A larger proportion of patients had a six-month sustained reduction in disability rather than an accumulation of disability (52.2% vs. 40.2%). Treatment had no effect on disability progression in SPMS patients.
Natalizumab: Regular assessments of JC virus antibody status and the JCV index have been proposed to mitigate the risk of PML (Plavina et al. Ann Neurol 2014;76:802-812).
A French study of 192 natalizumab-treated patients reported that the JCV index remained stable during follow-up (Matthias et al. ECTRIMS 2015; abstract P1111). In the group with JCV index 0.9-1.5 at baseline, the JCV index remained below 1.5 in 78.6%; the index crossed the 1.5 threshold in the remaining 21.4%. Patients with a high JCV index at baseline remained >1.5 in 95.4% of cases.
Similarly, the JCV index was generally stable in a small study in Germany (Salmen et al. ECTRIMS 2015; abstract P1128). Anti-JCV seroprevalence was 63.7%; an additional 11% of patients seroconverted after a mean of 7.6 months of natalizumab exposure. A high index was evident 2-3 years prior to PML (median 3.7 at PML diagnosis). For patients with an antibody index >3.0, the odds ratio for PML was 14.5. Rising antibody titres were not seen prior to PML, which may be due to reaching the saturation level of the assay, as previous studies have reported (Vennegoor et al. Mult Scler 2015; epublished October 21, 2015).
A separate study found that among anti-JCV Ab-positive patients, 39% crossed the index threshold of 1.5 during three-year follow-up (Cambron et al. ECTRIMS 2015; abstract EP1337). In the group with a baseline index >0.9, 53.3% crossed the threshold of 1.5 during the observation period.
The relationship between lymphocyte counts and the JCV index was examined in a two-year study of 51 MS patients (Carotenuto et al. ECTRIMS 2015; abstract P1124). Natalizumab was associated with significant increases in WBC count, total lymphocytes and CD19+ B cells, and a decrease in CD4+ T cells in peripheral blood. Of interest was that the CD4/CD8 ratio was positively correlated with anti-JCV antibody levels at months 0, 12 and 24, suggesting that a rising CD4/CD8 ratio may be a useful PML risk marker.
Alemtuzumab: Lymphocyte recovery following alemtuzumab administration was analysed from data obtained in CARE-MS II (Gilmore et al. ECTRIMS 2015; abstract P1045). CD4+ T cells were reduced in peripheral blood mononuclear cells (PBMC) at all time points from months 3-24. The proportion of FoxP3+ regulatory T cells increased at month 5 and remained elevated, suggesting that the reconstituting immune response favours a regulatory rather than pathogenic response. CD8+ T cells, B cells and natural-killer cells demonstrated repopulation at month 5. There were also modest increases in pro-inflammatory cells producing interferon-gamma and interleukin-17A; the authors speculated that this may reflect homeostatic repopulation.
Immune thrombocytopenic purpura (ITP) with alemtuzumab was first reported in the phase II trial (CAMMS Trial Investigators et al. N Engl J Med 2008;359:1786-1801). The incidence in the CARE-MS trials was 1%. The updated incidence of ITP in the clinical development program is 2.3%, or 0.44 events/100 patient-years of exposure (Cuker et al. ECTRIMS 2015; abstract P590). Most cases had received two treatment courses. The mean time from last alemtuzumab dose to ITP was 17 months.
Two studies have now reported on pregnancy outcomes in patients treated with alemtuzumab. In the clinical development program, female subjects were required to have a pregnancy test prior to treatment initiation, and were required to use contraception for six months following each treatment course. To date, there have been 193 pregnancies resulting in 110 live births (Achiron et al. ECTRIMS 2015; abstract P120). No congenital abnormalities or birth defects have been observed. The rate of spontaneous abortion was 22.2%, which is within the range reported in the general population (Nybo Anderson et al. BMJ 2000;320:1708-1712). The rate of elective abortions was 11%. There was one stillbirth occurring four years after the last dose of alemtuzumab that was not necessarily attributable to therapy. In the Cambridge cohort, there were 18 healthy births from 20 pregnancies (McCarthy et al. ECTRIMS 2015; P553. Two women had miscarriages but subsequently had two successful pregnancies each.
Dr. Paul Giacomini: These latest data from ECTRIMS 2015 support the growing body of evidence demonstrating the sustained efficacy of monoclonal therapies, but also the need for ongoing clinical surveillance and vigilance with these agents.
The advent of the JCV index has enabled physicians to better risk stratify their patients on natalizumab, and provide more accurate PML risk estimates to guide clinical decisions. However, the aforementioned studies underscore that the JCV index is a dynamic measure that can increase while patients are on therapy, even over short intervals, and alter a patient’s risk profile. These data suggest that the JCV index needs to be frequently monitored to best guide clinicians in balancing the risks and benefits of natalizumab.
The recent, encouraging alemtuzumab extension data from ECTRIMS 2015 support the perception that alemtuzumab seems to fundamentally alter the disease course in MS, with efficacy maintained even years following the last infusion. Gaining a better understanding of how immune cell profiles differ following reconstitution may provide valuable insight and clues as to why secondary autoimmune disorders (such as thyroid disorders and ITP) occur, and if these risks can be mitigated.