Mabthera-RA 2010

Introduction

This section focuses on safety data collected during the clinical development programme for MabThera^® in rheumatoid arthritis (RA) and from post-marketing surveillance up to January 2010. An overview of the key clinical trials can be found here.

Overview of the long-term safety population

The safety and tolerability of MabThera^® given with methotrexate (MTX) was studied in six double-blind, randomised, controlled clinical trials (five Phase III trials and one Phase II trial) and one open-label, controlled Phase II trial in patients with RA (Figure 1). More than 3000 patients received at least one treatment course of MabThera^® (2 x 500 mg or 2 x 1000 mg), with safety follow-up ranging from 6 months to 9 years.¹

The MabThera^® all-exposure population (n=3189) includes all patients randomised to MabThera^® at baseline as well as patients initially randomised to placebo who received MabThera^® as rescue therapy or part of an open-label extension. The placebo population (n=818) comprises all patients who received a placebo infusion who had not been exposed to MabThera^®, and includes pre-exposure data from patients who were subsequently exposed to MabThera^®.

A total of 2417 patients received two or more courses of treatment, 1392 patients received four or more courses of treatment and 656 patients received six or more courses. Total duration of observation at the time of reporting was 9342 patient years (Figure 1).¹

Figure 1. Pooled safety data from RA patients treated with MabThera^® plus MTX in the global clinical trial programme¹

Overview of adverse events

Table 1. Summary of adverse drug reactions reported in patients with RA receiving MabThera^® in clinical trials or during post-marketing surveillance²

The overall rate of adverse events (AEs) in patients receiving MabThera^® plus MTX was similar to that observed in patients receiving placebo plus MTX (309.4 vs. 353.1 events per 100 patient years of exposure, respectively) (Table 2). In addition, the rate of serious AEs (SAEs) in the MabThera^® plus MTX group was comparable with that observed in the placebo plus MTX population (16.2 vs. 15.5 events per 100 patient years of exposure) (Table 2). The overall rate of AEs and SAEs in MabThera^®-treated patients remained stable over multiple treatment courses (Table 3).¹

Table 2. Long-term safety: all-exposure and placebo populations¹

Table 3. Rate of adverse events by treatment course¹

Infections

The overall rate of infection in patients receiving MabThera^® plus MTX was comparable with that observed in patients receiving placebo plus MTX (94.3 events per 100 patient years of exposure vs. 100.8 events per 100 patient years of exposure, respectively) (Table 4). The most common infections included upper respiratory tract infections and urinary tract infections. Serious infection rates were similar between treatment groups with 4.35 events per 100 patient years of exposure for those receiving MabThera^® plus MTX compared with 4.29 per 100 patient years of exposure for patients receiving placebo plus MTX (Table 4). The rate of serious infections did not increase over time (Figure 2) and was stable over multiple treatment courses.¹

Within the clinical trial programme there have been no reported cases of hepatitis B viral reactivation, tuberculosis or atypical mycobacterial infections. One case of opportunistic Pneumocystis jiroveci infection occurred in each of the MabThera^® and placebo groups.¹

Table 4. Infections: all-exposure and placebo populations¹

Figure 2. Rate of serious infections over time¹

Progressive multifocal leukoencephalopathy

Very rare cases of progressive multifocal leukoencephalopathy (PML) with fatal outcome have been reported following use of MabThera^® for the treatment of autoimmune diseases, including RA.²

In the MabThera^® clinical trial safety population there was one case of PML in a patient who had received four courses of treatment. The last dose of MabThera^® was administered 18 months prior to diagnosis with PML. The patient had received chemotherapy and radiotherapy for cancer 9 months prior to PML diagnosis.¹

In the post-marketing setting, very rare cases of PML have also been reported.²

Infusion reactions

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of MabThera^®.² In the safety population, AEs associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 23% of patients during the first infusion of the first course of MabThera^® (Figure 3). The most common reactions were headache, pruritis, throat irritation, hot flushes, rash, urticaria, hypertension and pyrexia. The incidence of serious infusion reactions was 0.5%. Most infusion events were mild to moderate in severity and none were fatal.^1,2 Reactions were usually reversible with a reduction in rate or interruption of MabThera^® infusion. If required, other treatment options include administration of an antipyretic, an antihistamine and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.² Premedication with glucocorticoids can significantly reduce the incidence and severity of infusion-related AEs (data from the DANCER study).

In general, the proportion of patients experiencing any infusion-related reaction was higher following the first infusion of any treatment course than following the second infusion. Subsequent infusions were better tolerated than the initial course (Figure 3).¹

Figure 3. Incidence of infusion-related reactions (IRR) by treatment course¹

Immunoglobulin levels

Immunoglobulin G (IgG), immunoglobulin M (IgM) and immunoglobulin A (IgA) levels were analysed over multiple treatment courses in 2454 patients from the MabThera^® all-exposure population.³ Overall, median Ig levels remained above the lower limit of normal (LLN) across five treatment courses and over 6 years of follow-up. During the course of treatment serum Ig levels decreased, with 23% of patients developing IgM levels below the LLN on at least 1 visit at any time during post-baseline follow-up. In a similar fashion, 5% of patients had IgG levels below the LLN on at least one visit, with 1% of patients having sustained levels below the LLN for at least 1 year and 2 consecutive visits; five patients had very low IgG levels (<3 mg/ml). A small proportion of patients (<1%) developed IgA levels below the LLN at any time.

Serious infection rates were similar before and after the detection of low IgG or IgM (Table 5). A numerical increase in the serious infection rate was observed following the development of low IgG, but this increase was not statistically significant. The sample size of patients with low IgA was too small for analysis.³

Table 5. Serious infection rate by IgM and IgG level³

Immunisation

The safety of immunisation with live virus vaccines following MabThera^® therapy has not been studied. Therefore, vaccination with live virus vaccines is not recommended while on MabThera^® or while depleted of B cells. Patients treated with MabThera^® may receive non-live virus vaccinations but may have a reduced response to the vaccine. In a randomised study, patients with RA treated with MabThera^® and MTX had similar response rates to tetanus recall antigen (39% vs. 42%) and reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least two pneumococcal antibody serotypes) and to KLH neoantigen (47% vs. 93%) when vaccinated 6 months after MabThera^® compared with patients receiving only MTX.² In the overall experience of MabThera^® repeat treatment over 1 year, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.²

Cardiovascular safety

The rate of myocardial infarction (MI) in the MabThera^® all-exposure population was consistent with that observed in the pooled placebo population and the general RA population. The rate of MI (95% CI) in the MabThera^® all-exposure population was 0.49 events per 100 patient years compared with 0.31 events per 100 patient years in the placebo population. Comparative rates in the general RA population range from 0.47 to 0.59 per 100 patient years.¹ MI was the most common serious cardiac event in the pooled analysis. The majority of patients experiencing MI had one or more conventional risk factors for MI.¹

Malignancies

Patients with RA appear to be at higher risk of malignancies, particularly lymphoma, compared with the general population.⁴ Concerns have also been raised regarding the use of biologic therapies in the treatment of RA, with an increased risk of malignancies noted in clinical trials.⁵ MabThera^® is indicated for the treatment of patients with non-Hodgkin’s lymphoma, and was first licensed for use in patients with non-Hodgkin’s lymphoma in the USA in 1997 and the rest of the world in 1998.

The rate of malignancy observed in the MabThera^® all-exposure population was consistent with that of the general population (Table 6). Excluding non-melanoma skin cancer and non-malignant events (n=77), the rate of malignancy observed in MabThera^®-treated patients was 0.82 events per 100 patient years of exposure. The age- and sex-adjusted standardised incidence ratio (SIR) among patients treated with rituximab, compared with the general population in the SEER database was 1.06 (95% CI 0.83–1.32).¹

Table 6. Rate of malignancy in the MabThera^® all-exposure population and observational studies¹

Safety of RA therapies after discontinuation of MabThera^®

Given the numerous available RA therapies with different mechanisms of action, the safety of switching among different biologics, particularly with regards to rate of infection, is an important consideration in RA treatment.

A study was conducted to assess the safety of biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients with RA following MabThera^® therapy.⁶ The study investigated 283 patients in the MabThera^® clinical trial programme who were previously treated with one or more courses of MabThera^® and subsequently received another biologic DMARD during the safety follow-up. The majority of these patients (81.3%) received a tumour necrosis factor (TNF) inhibitor and 83.0% had peripheral B cell depletion at the time of initiation of another biologic agent. Serious infection rates following initiation of another biologic DMARD were consistent with rates subsequent to MabThera^® therapy and prior to biologic DMARD initiation (4.97 events per 100 patient years vs. 6.01 events per 100 patient years, respectively) (Table 7). These data suggest that treatment with a biologic DMARD following MabThera^® therapy was not associated with an increase in the rate of serious infections.⁶

Table 7. Serious infection rate in patients who received treatment with a biologic DMARD after MabThera^® treatment⁶

1. Van Vollenhoven et al. Ann Rheum Dis 2010; 69(Suppl. 3):66
2. MabThera^® (rituximab) Summary of Product Characteristics. Roche Registration Limited. April 2010
3. van Vollenhoven et al. J Rheumatol 2010;37:558–567
4. Smitten AL, et al. Arthritis Res Ther 2008;10:R45
5. Khraishi M. J Rheumatol Suppl 2009;82:25–32
6. Genovese MC, et al. EULAR 2010, Oral presentation OP0048