Despite promising results of the Phase II Helping to Evaluate Rituxan® in Relapsing–Remitting Multiple Sclerosis (HERMES) trial in RRMS patients, and positive subgroup analyses of the OLYMPUS trial in primary progressive MS (PPMS) patients (discussed later), the B-cell-depleting, chimeric anti-CD20 mAb RTX is currently not being further developed for MS therapy – possibly as patent protection will expire in the USA between 2015 and 2018, and in the rest of the world in 2013 (not taking into account potential patent term extensions). However, two newer generation anti-CD20 mAbs, ocrelizumab (OCRE) and ofatumumab (OFA), with different pharmacological profiles completed, entered Phase II trials for RRMS, helping to further develop the promising therapeutic concept of B-cell depletion in MS patients (see later). Theoretically, humanized or fully human antibodies might provide advantages over a chimeric antibody due to a lower immunogenicity, possibly translating into improved tolerability and efficacy.
The OLYMPUS Trial
The Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS) trial was a 96-week, double-blind, placebo-controlled Phase II/III study, investigating the efficacy and safety of RTX in 439 patients with PPMS according to the McDonald criteria. Its protocol was reported in the 2008 review.
At inclusion, patients were aged 18–65 years (mean 49.9 years, standard deviation 8.9). The percentage of males was higher in the RTX (52.1%) than in the placebo (44.9%) group; however, gender differences did not affect the outcome of this trial. This is important to note as in the Glatiramer Acetate in Primary Progressive Multiple Sclerosis (PROMiSe) trial a trend for a treatment effect in males, possibly due to faster disease progression in males, was noted in an originally unplanned post hoc analysis.[83,84] All patients in the OLYMPUS trial had a disease duration of longer than 1 year (mean 9.1 years since onset, standard deviation 6.6), a baseline Expanded Disability Status Scale (EDSS) score between 2.0 and 6.5 points and disabling motor symptoms, which were defined as a Functional Systems Scale score of at least 2.0 for the pyramidal system or gait impairment due to lower-extremity dysfunction. In fact, the median baseline EDSS score was 5.0, corresponding to a maximal continuous walking distance between at least 200 m and less than 300 m. Evidence for intrathecal IgG synthesis as an indicator of chronic CNS inflammation was furthermore required for inclusion. Of note, 24.5% of patients had Gd-enhancing MRI lesions at baseline, indicating acute inflammatory disease activity. This was a higher rate than in the PROMiSe trial, where only 14.1% of study participants had Gd-enhancing lesions at baseline. Furthermore, it is interesting that 35.1% of the study participants had previously received therapy with an IFN-β preparation or glatiramer acetate, although these treatments are only approved for relapsing forms of the disease. This may also provide some indirect evidence for rather high inflammatory disease activity in this cohort. Baseline age, disease duration, prior therapy, EDSS and various MRI parameters were comparable between RTX and placebo patients. Together, the baseline data indicate that the OLYMPUS trial investigated a rather old cohort of significantly disabled PPMS patients with relatively long-standing disease and evidence for rather high inflammatory disease activity.
Patients were randomized in a 2:1 ratio to receive intravenous infusion cycles of either 2 × 1000 mg RTX (n = 292) or 2 × placebo (n = 147) 2 weeks apart every 24 weeks for a treatment period of 96 weeks, corresponding to four cycles in total. In total, 84.4% of the placebo and 82.5% of the RTX patients completed 96 weeks. The percentage of patients with EDSS progression sustained over 12 weeks at the end of the 96-week treatment period was prespecified as the primary end point. It was 38.5% in the placebo and 30.2% in the RTX group, which did not reach statistical significance (p = 0.1442). Changes in T2 lesion volume and total brain volume from baseline to week 96 were defined as secondary end points. RTX patients experienced significantly less increase in T2 lesion volume (mean: +1507 mm3) than placebo patients (mean: +2205 mm3; p < 0.001), while the decrease in brain volume did not differ significantly between RTX (mean: -10.8 mm3) and placebo patients (mean: −9.9 mm3; p = 0.62). Preplanned subgroup analyses for the primary end point indicated that in patients both aged younger than 51 years and with at least one Gd-enhancing MRI lesion at baseline (n = 72) RTX significantly reduced the risk of disease progression by two-thirds (hazard ratio: 0.33; p = 0.0088), while in patients younger than 51 years without enhancing lesions (n = 143) and in patients of at least 51 years of age with enhancing lesions (n = 37) the beneficial effect of RTX did not reach statistical significance. However, a significant effect was independently observed in the overall groups of patients aged younger than 51 years or with enhancing lesions. An early separation of response curves concerning time to confirmed EDSS progression during the first year of treatment was only observed in patients fulfilling both criteria, but not in those fulfilling only one criterion, additionally supporting the interpretation that patients fulfilling both criteria triggered the effect observed in the overall cohorts of patients fulfilling only one criterion to a relevant extent. Significant effects on the timed 25-foot walk indicated that the beneficial effect on EDSS progression was primarily due to effects on walking ability, as one would expect in a cohort of patients with a baseline EDSS score of median 5.0 (see previous for definition). This clinical measure may mainly reflect spinal cord disease activity, usually poorly correlated to cranial MRI scans where RTX, therefore, independently showed a beneficial effect regarding the secondary end point of T2 lesion volume. Younger age and enhancing lesions also predicted a favorable RTX response concerning total cranial MRI T2 lesion volume.
The 96-week treatment period was followed by a 26-week safety follow-up. However, at week 122, when the study ended, only 35% of RTX-treated patients had recovered peripheral B-cell counts, leaving the safety data partially incomplete. During weeks 0–122, all RTX and placebo patients, except one patient within the RTX group, reported adverse events (AEs), leading to study drug discontinuation in 0.7% (one out of 147) of the placebo and 3.1% (nine out of 292) of the RTX patients. Serious AEs were reported in 13.6% of the placebo and 16.4% of the RTX patients. This difference was attributable to RTX patients experiencing multiple serious AEs. Infusion-associated AEs were more frequently observed in RTX than in placebo patients during the first three treatment cycles, with an overall decreasing frequency over time, and were comparable between both groups during the fourth cycle. They were reported in 67.1% of the RTX and 23.1% of the placebo patients after the first infusion, and in 22.6 versus 15.1% after the second infusion 2 weeks later. Infusion-associated AEs in less than 5% of patients and more frequently observed in RTX than in placebo patients included nausea, dizziness, various influenza-like symptoms, throat irritation or pain and various skin symptoms. Their frequency ranged from 0 to 8.2% (hypotension) in placebo and from 7.5 to 18.5% (pruritus) in RTX patients. Infection-related serious AEs were reported in 0.7% (one out of 147) of the placebo and 4.5% (13 out of 292) of the RTX patients. Pneumonia occurred in 0.7% (one out of 147) of the placebo and 1.4% (four out of 292) of the RTX patients. Three patients died: the placebo patient experiencing pneumonia, one RTX patient with pneumonia and a history of brainstem lesions and aspiration and one RTX patient from cardiopulmonary failure.
In conclusion, RTX did not meet its prespecified primary end point, as it did not significantly reduce the risk of disease progression over 96 weeks, despite a favorable trend. However, a subgroup analysis strongly suggested that in younger patients with MRI evidence for inflammatory disease activity RTX might substantially reduce the risk of disease progression. From a clinical perspective, this is an important finding, considering that there is no proven disease-modifying therapy for this small proportion of MS patients to date. Overall, RTX appeared to be safe and – with the exception of infusion-related AEs after the first infusion – well tolerated in this cohort of PPMS patients over 122 weeks.
Clinical Trials in RRMS
Results of the double-blind, placebo-controlled Phase II trial HERMES in 104 patients with RRMS were summarized in the 2008 review. As reported, the total number of Gd-enhancing MRI lesions at weeks 12, 16, 20 and 24, which was prespecified as the primary end point, was reduced by 91% (mean: 0.5 vs 5.5; p < 0.001) in the RTX in comparison to the placebo group. Here it should be added that according to the final publication of the trial, a number of MRI baseline data differed significantly between patients receiving RTX and those treated with placebo. In contrast to the baseline clinical disease activity, which did not differ between the groups, patients receiving RTX had higher baseline MRI disease activity than those receiving placebo, which may have affected the primary end point in either of two directions: it seems conceivable that the RTX treatment effect on MRI disease activity was overestimated in this trial due to a statistical phenomenon called regression to the mean; or the relative effect of RTX in comparison to placebo might have been underestimated as the total number of Gd-enhancing lesions could have been higher in a placebo cohort with higher baseline MRI disease activity. However, different MRI baseline activity does not generally question a strong effect of RTX on MRI disease activity in this trial.
A 72-week, open-label, multicenter Phase I trial in 26 patients with RRMS investigated the safety of two courses of 2 × 1000 mg RTX 6 months apart. No serious AEs were recognized during this study. The trial included cranial MRI scans at weeks 4, 8, 12, 23, 28, 36, 48 and 72. While the mean number of Gd+ lesions was 1.31 at baseline, it decreased to 0.73 at week 4, 0.05 at week 48 and 0 through week 72, confirming the strong RTX effect on MRI disease activity observed in the HERMES trial in an uncontrolled, open-label setting.
Anti-chimeric Antibodies to RTX
During the 122-week safety period of the OLYMPUS trial, 7.0% (20 out of 286) of patients receiving RTX and 6.3% (nine out of 143) of patients receiving placebo tested positive for human anti-chimeric antibodies (HACA). There was no apparent association between HACA positivity and adverse effects or clinical efficacy observed in the OLYMPUS trial. In the HERMES trial, 24.6% (16 out of 56) of RTX-treated patients developed HACA, but none of the placebo patients. Again there was no apparent association between HACA positivity and AEs or clinical efficacy. In conclusion, there is no positive evidence in MS patients to date that HACA influence the therapeutic effect of the B-cell-depleting mAb RTX. As outlined later, this matches the limited experience with anti-idiotypic antibodies against newer anti-CD20 mAbs in RA patients. The RTX data may indicate that a potentially higher immunogenicity of the chimeric mAb RTX in comparison to humanized or fully human anti-CD20 mAbs is not clinically relevant in MS patients.
RTX in Neuromyelitis Optica
Neuromyelitis optica (NMO) is an immune-mediated, demyelinating disease of the CNS, mainly affecting optic nerves and spinal cord. Serum antibodies against the water channel aquaporin-4, which is expressed on astrocytic end feed, may serve as a moderately sensitive and highly specific biomarker helping to establish a diagnosis of NMO. Importantly, there is accumulating evidence for a central pathogenic relevance of these antibodies, which most likely trigger a destructive perivascular immune reaction within the CNS.[87–89] B-cell depletion might therefore be a promising therapeutic approach in patients with NMO. In a first prospective open-label study including eight NMO patients who were treated with RTX for 6–18 months, no further relapses were observed in six patients during RTX treatment. High therapeutic efficacy was also suggested by a retrospective case series including 25 patients. As of February 2010, there were no NIH-registered Phase II or III trials further developing the promising therapeutic concept of anti-CD20 therapy in NMO.
Expert Rev Neurother. 2010;10(5):791-809. © 2010 Expert Reviews Ltd.
Cite this: Treating Multiple Sclerosis with Monoclonal Antibodies: A 2010 Update - Medscape - May 01, 2010.