Health Articles

00_annrheumdistoc.indd

Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial Peter C Taylor, 1 Emilia Quattrocchi, 2 Stephen Mallett, 2 Regina Kurrasch, 3 Jørgen Petersen, 4 David J Chang 3 ▶ An additional supplementary ABSTRACT
human CD20 molecule, distinct from the epitope table is published online only.
Objectives To evaluate the effi cacy and safety of
recognised by rituximab 1 or by other anti-CD20 To view this fi le please visit intravenous ofatumumab, a fully human anti-CD20 mAb. 2 3 The membrane proximity of this epitope the journal online at ( http://ard.
monoclonal antibody, in biological-naive, active probably accounts for the high effi ciency of B-cell rheumatoid arthritis (RA) patients despite methotrexate killing observed with ofatumumab in both in-vitro 1 Kennedy Institute of and in-vivo preclinical studies. 4 – 7 Rheumatology Division, Imperial College, London, UK Methods In this double-blind, placebo-controlled, phase
In animal models, ofatumumab induced selec- 2 GlaxoSmithKline Clinical III study, active RA patients on stable methotrexate tive and prolonged B-cell depletion primarily Development, Stockley Park, UK were randomly assigned to one course of two infusions mediated by effective complement-dependent 3 GlaxoSmithKline Clinical of ofatumumab 700 mg (n=130) or placebo (n=130), cytotoxicity and antibody-dependent cell-mediated Development, Upper Merion, Pennsylvania, USA 2 weeks apart. The primary endpoint was the ACR20 cytotoxicity. 8 9 Effective complement-dependent 4 Genmab, Copenhagen, response at week 24. Secondary endpoints included cytotoxicity may depend on the distance between ACR50/70, EULAR response, disease activity score based the plasma membrane and the constant parts of the on 28 joints using C-reactive protein, adverse events (AE) sensitising antibody thus enabling the effi cient and Correspondence to
and immunogenicity. rapid engagement of complement activation. 10 Professor Peter Taylor, Kennedy Institute of Rheumatology Results At week 24, a greater proportion of patients
A phase I/II study of ofatumumab, administered Division, Imperial College, on ofatumumab compared with placebo achieved an as two intravenous infusions of 300, 700 or 1000 mg ACR20 response (50% vs 27%, p<0.001) and a good or 2 weeks apart, in active rheumatoid arthritis (RA) [email protected] moderate EULAR response (67% vs 41%, p<0.001). All patients with an inadequate response to disease- Accepted 17 July 2011 other key secondary effi cacy endpoints were signifi cantly modifying antirheumatic drugs (DMARD), dem- Published Online First improved on ofatumumab. Effi cacy observed by 8 weeks onstrated signifi cant clinical benefi t and reasonable was sustained throughout the study. The most common tolerability (improved after the implementation of AE for ofatumumab versus placebo were rash (21% vs premedication) at all doses investigated when com- <1%) and urticaria (12% vs <1%), mostly occurring pared with placebo, with the 700 mg dose consid- on the fi rst infusion day. Overall, fi rst-dose infusion ered to be optimal. 11 reactions were 68% for ofatumumab and 6% for placebo, To characterise further the effi cacy and safety mostly mild to moderate; second-dose infusion reactions profi le of ofatumumab we conducted a placebo- markedly declined (<1% and 0%). Serious AE were controlled phase III trial in patients with active RA reported in 5% of ofatumumab versus 3% of placebo who had an inadequate response to methotrexate patients. Infection rates were 32% and 26% (serious therapy and no previous biological treatment expo- infections <1% and 2%), respectively. One death sure. This trial was also designed to investigate the (interstitial lung disease), unrelated to study drug, was effects of ofatumumab on the extent and duration reported on ofatumumab. No antidrug antibodies were of B-cell depletion, biomarkers of clinical response, detected in ofatumumab patients. patient-reported outcomes and immunogenicity. Conclusions Ofatumumab signifi cantly improved
all clinical outcomes in biological-naive, active RA
patients with no detectable immunogenicity at week 24. Study design and objectives
No unexpected safety fi ndings were identifi ed. This was a multicentre, randomised, double- Trial Registry clinical trials.gov registration number blind, placebo-controlled, parallel group, phase III trial. Patients were enrolled at 36 sites in west-ern Europe, eastern Europe, South America and Asia Pacifi c. The trial is registered at clinicaltrials.
Ofatumumab (HuMax-CD20) is a human IgG1ĸ gov number NCT00611455. The fi rst patient was lytic monoclonal antibody (mAb) that specifi cally enrolled in January 2008 and the last visit for the binds to the human CD20 antigen inducing potent double-blind phase was in June 2009. The trial B-cell lysis. The CD20 antigen is expressed only was conducted in accordance with good clinical by B lymphocytes from the pre-B to the plasma- practice and the Declaration of Helsinki. All par- cytoid immunoblast stage. Ofatumumab recogn- ticipating sites received approval from national, ises a unique membrane-proximal epitope on the regional, or investigational centre ethics committee Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:42 PM or institutional review boards; each patient provided written therapy, other autoimmune diseases, signifi cant concurrent, informed consent. uncontrolled medical conditions, neutrophils less than 2×10 9 /l, The trial included a 24-week double-blind, placebo-controlled platelets less than 100×10 9 /l, IgG less than 6.94 g/l (below lower period followed by a 120-week open-label extension and a safety limits of normal), and positive serology for HIV, hepatitis B or follow-up. This paper summarises results from the completed, C infection. Patients were screened for JC virus using PCR for JC placebo-controlled, 24-week double-blind phase only. viral DNA (Quest Diagnostics, Van Nuys, CA, USA and Heston, Eligible patients were randomly assigned (1:1) to receive two Middlesex, UK ) and were excluded if tested positive. infusions of either ofatumumab 700 mg or placebo 2 weeks apart (one course), added to their stable background methotrexate Assessments
dose. Randomisation was stratifi ed by rheumatoid factor (RF) Clinical assessments of disease activity were performed at seropositivity/negativity and region. GlaxoSmithKline prepared baseline and every 4 weeks to week 24 and included an evalu- a computer-generated randomisation schedule and randomisa- ation of the 68-joint tender joint count and 66-joint swollen tion was handled centrally through an interactive voice response joint count conducted by an independent assessor (blinded to system. An unblinded pharmacist at each site prepared the infu- patient-rated outcomes), patient's pain assessment (visual ana- sions; ofatumumab and saline (placebo) infusions were indis- logue scale (VAS) 0–100 mm), patient's and physician's global tinguishable. Other study personnel and patients were blinded assessment of disease activity (VAS 0–100 mm), HAQ-DI and to treatment allocation until the double-blind period was com- levels of acute-phase reactants (ESR and CRP). From these data, plete. Premedication with antihistamine (certirizine 10 mg or ACR20, ACR50 and ACR70 response rates, mean change in equivalent), oral paracetamol 1000 mg and intravenous meth- DAS28–ESR and DAS28–CRP and EULAR response were deter- ylprednisolone 100 mg was administered 30 min to 2 h before mined. FACIT-F and SF-36v2 were assessed at baseline, week each infusion. Patients who did not respond were allowed non- biological DMARD rescue treatment from week 16; however, Laboratory investigations included levels of peripheral the use of rescue treatment precluded subsequent entry into B lymphocytes measured by fl uorescence-activated cell sorting the open-label period. Breakthrough pain management such as analysis by the surrogate marker CD19, peripheral T lympho- analgesics, non-steroidal anti-infl ammatory drugs and one intra- cytes measured by CD3, CD4 and CD8 markers, immunoglob- articular corticosteroid injection in one joint per 6-month period ulins (IgA, IgM, IgG), RF and immunoglobulins to RF (IgM–RF, were allowed. The joint receiving an intra-articular injection IgG–RF and IgA–RF), anticyclic citrullinated peptide antibodies was scored as both swollen and tender in joint count assess- (anti-CCP), acute phase serum amyloid A, interleukin 6 (IL-6) ments during the following 12-week period. (all performed by Quest Diagnostics) and antibodies to ofatu- The primary objective was to evaluate the effi cacy of ofa- mumab measured using a validated electrochemiluminescence tumumab compared with placebo based on the proportion of meso-scale discovery immunoassay. Positive samples from the patients achieving an American College of Rheumatology (ACR) binding antibody assay were tested in a neutralising antibody 20 12 response at week 24. Secondary endpoints included propor- assay (Clinical Immunology, Biopharm R&D, GlaxoSmithKline, tions of patients achieving ACR50, ACR70, European League King of Prussia, PA, USA). Against Rheumatism (EULAR) good or moderate responses, 13 Adverse events (AE) and serious adverse events (SAE) were and mean changes in the disease activity score based on 28 collected throughout the study and coded using the Medical joints (DAS28) using C-reactive protein (CRP), 14 health assess- Dictionary for Regulatory Activities (MedDRA) version 12. ment questionnaire disability index (HAQ–DI), Infusion-related events occurring during study drug infusion and health survey (SF-36v2) and functional assessment of chronic ill- up to 24 h after completion of the infusion (and likely to repre- ness therapy–fatigue version 4 (FACIT–F) 16 at week 24. sent clinical signs and symptoms characteristic of ofatumumab infusion reactions in patients with RA) were identifi ed by a safety review team before unblinding. Low CD19 cell counts Patient population
were not reported as AE and hospitalisation for completion of Male and non-pregnant, non-lactating female patients 18 years an infusion was not reported as a SAE. Infections were deter- and older, diagnosed with active RA according to ACR 1987 mined using the MedDRA system organ class ‘infections and criteria 17 (RA functional class I, II or III) of 6 months or more duration were eligible to participate. Active RA was defi ned as eight or more swollen and eight or more tender joint counts, based on 66/68 joint count; either CRP of 1.0 mg/dl or greater or Sample size estimation
erythrocyte sedimentation rate (ESR) of 22 mm/h or greater; and A sample size of 124 subjects per group was estimated to pro- DAS28 based on ESR of 3.2 or greater. Patients were required to vide at least 90% power to detect differences in the proportions have an inadequate response to methotrexate and to be receiv- of patients achieving an ACR20 response at week 24 between ing methotrexate 7.5–25 mg/week for at least 12 weeks, and at ofatumumab versus placebo, at a 5% level of signifi cance. This a stable dose for at least 4 weeks, before baseline. All patients was based on a χ 2 test comparing two binomial proportions. underwent a washout period of at least 4 weeks for all DMARD (lefl unomide ≥12 weeks or administration of cholestyramine Statistical analysis
treatment for washout according to the manufacturer's instruc- For categorical endpoints, the effi cacy of ofatumumab ver- tions) but maintained their concomitant stable methotrexate sus placebo was analysed using the Cochran Mantel Haenszel therapy, along with folic acid of 5 mg/week or greater. Oral test, adjusting for baseline stratifi cation factors, RF status and corticosteroids (≤10 mg/day of prednisolone equivalent), non- geographical region (ie, eastern Europe, western Europe, South steroidal anti-infl ammatory drugs and one intra-articular injec- America, Asia Pacifi c). For continuous endpoints effi cacy was tion of corticosteroid (80 mg methylprednisolone or equivalent) analysed using analysis of covariance, adjusting for RF status, in a single joint were permitted. Key exclusion criteria com- geographical region and baseline value. For categorical end- prised previous exposure to any biological and B-cell-depleting points, patients who took disallowed medication or withdrew Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:43 PM

from the study were imputed as non-responders. For continuous RF status, the ACR20 response in ofatumumab and placebo endpoints, data were imputed by carrying forward the last value groups, respectively, was 50% (54/108) versus 26% (29/111) recorded before taking disallowed medication or withdrawal for seropositive patients and 48% (10/21) versus 30% (6/20) (last observation carried forward). The intent-to-treat (ITT) pop- for seronegative patients. When examined by anti-CCP status, ulation comprised all randomly assigned patients who received at least one infusion of the study drug. The safety population was identical to the ITT population except that patients were Table 1 Demographics and baseline disease characteristics
analysed according to their actual treatment in case this differed Characteristic
Ofatumumab 700 mg (n=129)
Placebo (n=131)
from their randomised treatment. Mean (SD) age, years Mean (SD) disease Disposition of patients and baseline characteristics
A total of 344 patients was screened and 265 were enrolled and Median (min, max) randomly assigned; the reasons for screening failure are shown methotrexate dose, mg/week in fi gure 1 . Of the 265 randomly assigned patients, 260 (98%) Previous DMARD, n (%) were exposed to investigational product and were included in the safety and ITT populations ( fi gure 1 ). One patient was ran- domly assigned to placebo but received ofatumumab and was Patients receiving oral included in the placebo group for the ITT population (based on corticosteroid, n (%) randomised treatment) and in the ofatumumab group for the Median (min, max) oral safety population (based on actual treatment received). corticosteroid dose, mg/day * Demographics and baseline RA characteristics were balanced RF positive, n (%) between the two groups ( table 1 ). Most patients were women Median (min, max) CRP, mg/l Mean (SD) ESR, mm/h (82%) and RF positive (84%), with a mean age of 53 years. At Mean (SD) total RF, IU/ml † baseline, mean RA duration was 8.5 years, mean DAS28–CRP Mean (SD) SJC (66 joints) was 5.7 and mean DAS28–ESR was 6.5 ( table 1 ). Mean (SD) TJC (68 joints) Mean (SD) DAS28–CRP Clinical response
Mean (SD) DAS28–ESR Mean (SD) HAQ–DI At week 24, a greater proportion of patients administered Mean (SD) FACIT–F ofatumumab 700 mg achieved the primary endpoint of ACR20 compared with placebo (50% and 27%, respectively, * Prednisolone equivalent dose. † At screening. p<0.001). In addition, signifi cantly greater improvements in CRP, C-reactive protein; DAS28, disease activity score based on 28 joints; DMARD, ACR50 and ACR70 were observed with ofatumumab ver- disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; FACIT–F, functional assessment of chronic illness therapy–fatigue; HAQ–DI, health assessment sus placebo (ACR50 27% and 11%, p<0.001; ACR70 13% questionnaire disability index; RF, rheumatoid factor; SJC, swollen joint count; and 2%, p=0.001) ( table 2 and fi gure 2 ). When examined by TJC, tender joint count. Figure 1 Disposition of patients up to week 24. *Patients could have more than one reason for screening failure. †One patient was randomly
assigned to placebo but received ofatumumab. This patient is included in the placebo group for the intent-to-treat population, but in the ofatumumab
group for the safety population.
Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:43 PM Table 2 Summary of disease-activity and quality-of-life clinical endpoints at week 24 for patients receiving ofatumumab or placebo
Ofatumumab 700 mg (n=129)
Placebo (n=131)
OR (95% CI)
2.86 (1.67 to 4.91) 3.29 (1.63 to 6.62) 6.63 (1.87 to 23.51) EULAR response * 3.07 (1.82 to 5.18) Clinical remission † 2.09 (0.76 to 5.77) HAQ–DI response ‡ 1.65 (1.01 to 2.70) Ofatumumab 700 mg (n=129)
Placebo (n=131)
Adjusted mean difference (95% CI)
DAS28–CRP § Baseline, mean (SD) Week 24, mean (SD) Adjusted mean (SE) change −1.00 (−1.29 to −0.72) DAS28–ESR § Baseline, mean (SD) Week 24, mean (SD) Adjusted mean (SE) change −0.99 (−1.29 to −0.69) HAQ–DI § Baseline, mean (SD) Week 24, mean (SD) Adjusted mean (SE) change −0.22 (−0.37 to −0.07) FACIT–F ¶ Baseline, mean (SD) Week 24, mean (SD) Adjusted mean (SE) change 3.75 (1.11 to 6.39) SF-36 physical component summary score * * Baseline, mean (SD) Week 24, mean (SD) Adjusted mean (SE) change 2.48 (0.51 to 4.45) SF-36 mental component summary score * * Baseline, mean (SD) Week 24, mean (SD) Adjusted mean (SE) change 3.03 (0.61 to 5.46) ACR20/50/70, 20%/50%/70% improvement as per American College of Rheumatology (ACR) criteria. * EULAR response of moderate or good, based on DAS28–CRP. † DAS28–CRP score less than 2.6. ‡ Change from baseline HAQ–DI score of 0.22 or greater. § Negative change represents an improvement. Patient numbers assessed: placebo (n=130); ofatumumab (n=126). * * Patient numbers assessed: placebo (n=117); ofatumumab (n=116). ¶ Patient numbers assessed: placebo (n=111); ofatumumab (n=114). Results are reported in accordance with EULAR/ACR collaborative recommendations. 33 CRP, C-reactive protein; DAS28, disease activity score based on 28 joints; EULAR, European League Against Rheumatism; ESR, erythrocyte sedimentation rate; FACIT–F, functional assessment of chronic illness therapy–fatigue; HAQ–DI, health assessment questionnaire disability index; SF-36, short-form health survey. the ACR20 response in ofatumumab and placebo groups, group, CD19 cells increased by 3% at week 24. In the ofatu- respectively, was 50% (56/111) versus 26% (29/113) for sero- mumab group one patient (1%) had a CD19 B-cell count equal positive patients and 44% (7/16) versus 31% (5/16) for sero- to or greater than the lower limit of normal (0.11 GI/l) or the negative patients. baseline value at week 24. No trend for a change in periph- All other secondary effi cacy endpoints, including EULAR eral CD3, CD4 or CD8 T-cell counts was observed in either response and mean change from baseline in DAS28–CRP and DAS28–ESR were signifi cantly improved in the ofatumumab group compared with placebo, except for clinical remission Biomarkers and assessment of immunogenicity
(DAS28–CRP <2.6) ( table 2 and supplementary table S1, avail- At week 24, the median change from baseline in absolute bio- able online only). The mean change from baseline in DAS28–CRP marker levels for ofatumumab and placebo, respectively, were: scores over the 24-week period showed sustained improvement −4.0 versus −0.4 ng/l for IL-6; −53.5 versus −10.9 mg/ml for compared with placebo from week 8 to week 24 ( fi gure 3 ). serum amyloid A; −138 versus 0 units for anti-CCP; −6.3 versus Ofatumumab also provided improvements in patient-reported 0.0 units for RF–IgM; −4.8 versus 0.0 units for RF–IgG and −3.0 outcomes as shown by signifi cantly greater changes from base- versus 0.0 units for RF–IgA. At week 24, the median change line in HAQ–DI, FACIT–F and SF36v2 scores compared with from baseline in immunoglobulin levels for ofatumumab and placebo ( table 2 ). placebo, respectively, were: −1.30 versus −0.60 g/l for IgG; −0.30 versus −0.02 g/l for IgM and −0.23 versus −0.09 g/l for Laboratory fi ndings
IgA. A small number of patients on ofatumumab or placebo had Peripheral B lymphocytes (CD19) were greatly reduced at each immunoglobulins equal to or less than the lower limit of nor- visit relative to baseline in the ofatumumab group: median mal during the study (IgM 6 vs 4; IgG 3 vs 1; IgA, no patients, reductions at weeks 2 (before the second infusion), 4, 12 and respectively). No patients treated with ofatumumab developed 24 were 95%, 96%, 96% and 94%, respectively. In the placebo detectable anti-ofatumumab antibodies at week 24. Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:44 PM

Table 3 Safety of placebo and ofatumumab over 24 weeks (safety
population)
Patients with AE, n (%)
Ofatumumab 700 mg
Placebo (n=130)
Total patient-years of exposure Any SAE (fatal or non-fatal) * AE leading to discontinuation of IP or withdrawal from studyMost common AE (≥5% in either group) Rash Urinary tract infection Figure 2 ACR 20/50/70 responses at week 24 in patients receiving
Throat irritation ofatumumab 700 mg or placebo. ACR20/50/70, 20%/50%/70% Hypersensitivity improvement as per American College of Rheumatology (ACR) criteria. Infusion reactions Any AE on day of fi rst infusion Infusion-related The overall incidence of AE was 89% and 55% in ofatumumab Any AE on day of second infusion and placebo groups, respectively ( table 3 ). Within the ofatu- Infusion-related mumab group the most commonly reported AE were rash Patients with an infection (21%) and urticaria (12%); these events mostly occurred on the No of infections Infections/100 patient-years (95% CI) 105.26 (81.86 to day of fi rst infusion (19% and 12%, respectively). The propor- (58.07 to 103.82) tion of patients experiencing an infusion-related AE on the day Patients with a serious infection of fi rst infusion was 68% for ofatumumab and 6% for placebo; No of infections infusion-related AE on the day of second infusion markedly Infections/100 patient-years (95% CI) 1.75 (0.42 to 9.77) declined (<1% and 0%, respectively). Most AE were of mild or moderate intensity. Severe AE were reported for 8% of patients Cardiac disorders on ofatumumab and 2% on placebo, with 5% and less than 1% occurring on the day of fi rst infusion. AE leading to withdrawal Vascular disorders were 9% for ofatumumab and less than 1% for placebo. Four SAE (bacterial gastroenteritis, pneumonia, myocardial infarc- tion, ischaemic stroke) were reported for four patients (3%) in Neoplasms (benign or malignant) the placebo group and seven SAE (angioedema, interstitial lung disease (fatal), synovitis, pulmonary embolism, diarrhoea and pneumonia, pericardial effusion) were reported for six patients * SAE were bacterial gastroenteritis, pneumonia, myocardial infarction, ischaemic (5%) in the ofatumumab group. Two of these SAE (angioedema, stroke in the placebo group and angioedema, interstitial lung disease (fatal, unrelated pneumonia), both in the ofatumumab group, were considered to ofatumumab), synovitis, pulmonary embolism, diarrhoea and pneumonia, pericardial effusion in the ofatumumab group. by the investigator to be related to the investigational product. † Infusion-related reactions (events likely to represent clinical signs and symptoms There was one fatal SAE of interstitial lung disease in the ofatu- characteristic of ofatumumab infusion reactions in patients with RA) were identifi ed by a safety review team before unblinding. mumab group, which was not considered by the investigator to AE, adverse event; IP, investigational product; RA, rheumatoid arthritis; SAE, serious be related to the investigational product but to RA worsening. AE within the system organ class of infections and infesta- tions were reported for 26% and 32% of patients on placebo and ofatumumab, respectively. None of the events was of severe of ofatumumab in a well-defi ned RA patient population with intensity and none led to discontinuation of the investigational long-standing disease not controlled by standard methotrexate product or withdrawal from the study. One SAE of pneumonia therapy and not previously treated with other available bio- was reported in each group and one SAE of bacterial gastroen- logical DMARD therapies. Ofatumumab, at a dose of 700 mg teritis was reported on placebo ( table 3 ). No serious opportunistic administered twice, added to a background stable dose of meth- infections and no cases of progressive multifocal leukoencephal- otrexate therapy, demonstrated a signifi cantly greater ACR20 opathy were reported. Two neoplasms, both prostatic adenoma response at week 24 (primary endpoint) compared with placebo. and both in the placebo group, were reported. Signifi cantly greater improvements were observed in key sec-ondary endpoints such as ACR50, ACR70, change from baseline in both DAS28–CRP and DAS28–ESR, EULAR response, physi- DISCUSSION
cal function (HAQ–DI) and fatigue (FACIT–F). The results from the 24-week, placebo-controlled, double-blind Effi cacy data from seronegative RA patients, for either RF or phase of this trial confi rm the previously reported effi cacy of anti-CCP, as observed in the study, should be interpreted with one course of intravenous ofatumumab in active RA. 11 In addi- caution because of the small sample size. Data from a number of tion, this study provides further information on the effi cacy clinical trials with rituximab in a range of RA populations seem Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:44 PM

Figure 3 Mean change from baseline for DAS28 using CRP over time. CRP, C-reactive protein; DAS28, disease activity score based on 28 joints.
to suggest that seropositive patients (RF and/or anti-CCP) have time after receiving rituximab. 26 There was no reported correla- a higher likelihood of response to B-cell-depleting therapy com- tion between the development of these human antichimeric anti- pared with seronegative patients, in particular for improving bodies and safety or effi cacy; nevertheless, the possibility of loss signs and symptoms; 18 – 22 however, the statistical signifi cance or reduction of effi cacy, local reactions, serum sickness/immune of these fi ndings remains to be determined. Radiographic end- complex-mediated disease and major allergic reactions (eg, urti- points were not assessed in this ofatumumab trial and data are caria, bronchospasm, bronchoconstrictions) is well recognised. 30 not currently available for the persistence of response beyond In addition to its effi cacy in RA demonstrated in this trial, ofatu- mumab is approved for the treatment of refractory chronic lym- The safety information gathered in this study is consistent phocytic leukaemia. 31 The mechanism of B-cell tumour lysis is with that observed in short-term studies of rituximab in active probably through the activation of both complement-dependent RA. 18 23 24 Although a greater proportion of patients receiving cytotoxicity and antibody-dependent cell-mediated cytotoxicity. ofatumumab experienced mild to moderate infusion-related Compared with rituximab, ofatumumab demonstrates increased reactions on the day of fi rst infusion, despite steroid premedi- binding of C1q and more potent complement-dependent cyto- cation, less than 1% of ofatumumab patients experienced an toxicity, even in chronic lymphocytic leukaemia cells with low infusion-related reaction on the day of second infusion. This CD20 expression levels. 32 It is unknown at this time, however, fi nding may be explained by the sudden cytokine release that whether these mechanistic differences can translate to improved follows the pronounced B-cell lysis occurring after CD20 liga- safety, tolerability, effi cacy, or potency over rituximab. tion, as previously reported in non-Hodgkin's lymphoma In summary, ofatumumab is a fully human mAb binding an patients treated with rituximab. 25 The rate of serious infections epitope of CD20 distinct to that recognised by rituximab. A sin- in patients treated with ofatumumab was low and comparable gle course of two infusions of 700 mg was effi cacious and safe to placebo. Although progressive multifocal leukoencephalop- in biological-naive, active RA patients on background metho- athy has been reported with rituximab, 26 no such cases were trexate up to 24 weeks after treatment. As expected for a fully identifi ed with ofatumumab in the current small study of lim- human mAb, ofatumumab did not induce immunogenicity. ited duration, which excluded patients who screened positive for JC virus DNA at baseline (one patient excluded). Similarly, Acknowledgments The authors would like to thank all participating investiga-
serious opportunistic infections were reported in ocrelizumab tors and their staff who provided and cared for patients and collected data for the study: Argentina: E Lucero, O Rillo, D Siri, I Strusberg, J Velasco; Australia: S Hall, trials, but were not observed in this study. 27 28 P Nash, P Youssef; Chile: M Aliste, R Jimenez, P Miranda, F Radrigan, N Stevensen; Ofatumumab is a fully human mAb, thereby offering a low Czech Republic: L Bortlik, J Vencovsky, P Vitek; Hungary: B Rojkovich, F Szanyó, immunogenicity potential. Although all patients in the study E Vereckei; Peru: E Cabello, O Castañeda; Poland: S Jeka, A Racewicz, Z Ruzga, were on methotrexate, which may suppress the development of A Sawicki; Romania: C Zainea; Russian Federation: O Ershova, O Lesnyak, E Nasonov, T Polikarpova, A Rebrov; Spain: RA Blanco, VR Valverde, MI Oyarzabal, FN Sarabia; antidrug antibodies, 29 and patients only received one course of UK: A Hammond, T Sheeran. treatment over 24 weeks, no anti-ofatumumab antibodies were detectable in any of the treated patients. In contrast, 7.9% and Funding This study was sponsored and funded by Genmab and GlaxoSmithKline
under a collaborative agreement.
5.4% of RA patients who received the chimeric mAb rituximab 500 mg administered twice and 1000 mg administered twice, Competing interests Genmab and GlaxoSmithKline provided fi nancial support
to the institutions that participated in this study. PCT has received research
respectively, in a study of a similar patient population, developed grants from Merck, UCB, AstraZeneca, GlaxoSmithKline and Roche and has human antichimeric antibodies at 24 weeks. 19 Overall, 11% of been an invited speaker and advisor for Abbott, Bristol-Myers Squibb, Centocor, patients with RA have tested positive for auto-antibodies at any Roche, Schering-Plough, Wyeth (acquired by Pfi zer in October 2009), Genmab, Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:45 PM GlaxoSmithKline and UCB. EQ, SM, RK and DJC are employees of GlaxoSmithKline longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum and own stock in GlaxoSmithKline. JP was formerly employed at Genmab and 1995 ; 38 : 44 – 8 .
owned Genmab stocks. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology
preliminary core set of disease activity measures for rheumatoid arthritis clinical
Patient consent Obtained.
trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Contributors Helle Kastberg and Soren Tamer (Genmab) provided advice on
Arthritis Rheum 1993 ; 36 : 729 – 40 .
study design. Peter Critchley, Shilpa Vadher and Janet Perkins (GlaxoSmithKline) Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of
provided clinical operations, data management and programming support. EQ Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients (GlaxoSmithKline), clinical investigation leader and medical monitor of this trial, with rheumatoid arthritis. J Rheumatol 2005 ; 32 : 811 – 19 .
authored the manuscript. Editorial support (writing assistance, assembling tables Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association
and fi gures, collating author comments, grammatical editing, and referencing) was 1987 revised criteria for the classifi cation of rheumatoid arthritis. Arthritis Rheum provided by Julie Taylor of Peak Biomedical Ltd, Macclesfi eld, UK and was funded by 1988 ; 31 : 315 – 24 .
GlaxoSmithKline. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis
refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized,
Ethics approval All participating sites received approval from national, regional,
double-blind, placebo-controlled, phase III trial evaluating primary effi cacy and safety or investigational centre ethics committee or institutional review boards, as at twenty-four weeks. Arthritis Rheum 2006 ; 54 : 2793 – 806 .
Emery P, Deodhar A, Rigby WF, et al. Effi cacy and safety of different doses and
Provenance and peer review Not commissioned; externally peer reviewed.
retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Effi cacy in MTX iNadequate rEsponders REFERENCES
(SERENE)). Ann Rheum Dis 2010 ; 69 : 1629 – 35 .
Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human
Rubbert-Roth A, Tak PP, Zerbini C, et al. Effi cacy and safety of various repeat
CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol treatment dosing regimens of rituximab in patients with active rheumatoid 2006 ; 177 : 362 – 71 .
arthritis: results of a phase III randomized study (MIRROR). Rheumatology (Oxford) Genovese MC, Kaine JL, Lowenstein MB, et al. Ocrelizumab, a humanized
2010 ; 49 : 1683 – 93 .
anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid Tak PP, Rigby WF, Rubbert-Roth A, et al. Inhibition of joint damage and improved
arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. clinical outcomes with rituximab plus methotrexate in early active rheumatoid Arthritis Rheum 2008 ; 58 : 2652 – 61 .
arthritis: the IMAGE trial. Ann Rheum Dis 2011 ; 70 : 39 – 46 .
Goldenberg DM, Rossi EA, Stein R, et al. Properties and structure–function
Isaacs JD, Olech E, Tak PP, et al. Autoantibody-positive rheumatoid arthritis (RA)
relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. patients (pts) have enhanced clinical response to rituximab (RTX) when compared Blood 2009 ; 113 : 1062 – 70 .
with seronegative patients [abstract] . Ann Rheum Dis 2009 ; 68 ( Suppl3 ): 442 .
Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20
Edwards JC, Szczepanski L, Szechinski J, et al. Effi cacy of B-cell-targeted
monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med Blood 2004 ; 104 : 1793 – 800 .
2004 ; 350 : 2572 – 81 .
Cragg MS, Walshe CA, Ivanov AO, et al. The biology of CD20 and its potential as a
Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The effi cacy and safety
target for mAb therapy. Curr Dir Autoimmun 2005 ; 8 : 140 – 74 .
of rituximab in patients with active rheumatoid arthritis despite methotrexate Glennie MJ, French RR, Cragg MS, et al. Mechanisms of killing by anti-CD20
treatment: results of a phase IIB randomized, double-blind, placebo-controlled, monoclonal antibodies. Mol Immunol 2007 ; 44 : 3823 – 37 .
dose-ranging trial. Arthritis Rheum 2006 ; 54 : 1390 – 400 .
Bleeker WK, Munk ME, Mackus WJ, et al. Estimation of dose requirements for
van der Kolk LE, Grillo-López AJ, Baars JW, et al. Complement activation
sustained in vivo activity of a therapeutic human anti-CD20 antibody. Br J Haematol plays a key role in the side-effects of rituximab treatment. Br J Haematol 2008 ; 140 : 303 – 12 .
2001 ; 115 : 807 – 11 .
Beum PV, Lindorfer MA, Beurskens F, et al. Complement activation
Genentech . Rituxan (rituximab) Prescribing Information, 2011 . http://www.gene.com/ on B lymphocytes opsonized with rituximab or ofatumumab produces gene/products/information/pdf/rituxan-prescribing.pdf ( accessed 26 January 2011 ). substantial changes in membrane structure preceding cell lysis. J Immunol Emery P, Rigby WFC, Tak PP, et al. Serious infections with ocrelizumab in rheumatoid
2008 ; 181 : 822 – 32 .
arthritis: pooled results from double-blind periods of the ocrelizumab phase III RA Pawluczkowycz AW, Beurskens FJ, Beum PV, et al. Binding of submaximal C1q
program [abstract] . Arthritis Rheum 2010 ; 62 ( Suppl 10 ): 414 .
promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with Rigby WFC, Tony HPT, Oelke KR, et al. Effi cacy and safety of ocrelizumab in
anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of patients with active rheumatoid arthritis who had an inadequate response to CDC are induced by OFA than by RTX. J Immunol 2009 ; 183 : 749 – 58 .
methotrexate: results from the phase III STAGE trial [abstract] . Arthritis Rheum Saphire EO, Stanfi eld RL, Crispin MD, et al. Contrasting IgG structures reveal
2010 ; 62 ( Suppl 10 ): 383 .
extreme asymmetry and fl exibility. J Mol Biol 2002 ; 319 : 9 – 18 .
Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic effi cacy of multiple
Østergaard M, Baslund B, Rigby W, et al. Ofatumumab, a human anti-CD20
intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate combined with low-dose weekly methotrexate in rheumatoid arthritis. response to one or more disease-modifying antirheumatic drugs: results of a Arthritis Rheum 1998 ; 41 : 1552 – 63 .
randomized, double-blind, placebo-controlled, phase I/II study. Arthritis Rheum European Medicines Agency . Draft Guideline on Immunogenicity Assessment 2010 ; 62 : 2227 – 38 .
of Monoclonal Antibodies Intended for In Vivo Clinical Use. EMA/CHMP/ Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology.
BMWP/86289/2010 , 2010 . http://www.ema.europa.eu/docs/en_GB/document_ Preliminary defi nition of improvement in rheumatoid arthritis. Arthritis Rheum library/Scientifi c_guideline/2010/11/WC500099362.pdf ( accessed 26 January 2011 ). 1995 ; 38 : 727 – 35 .
GlaxoSmithKline . Arzerra (ofatumumab) Prescribing Information, 2010 . http://us.gsk.
van Gestel AM, Prevoo ML, van ‘t Hof MA, et al. Development and validation
com/products/assets/us_arzerra.pdf ( accessed 26 January 2011 ). of the European League Against Rheumatism response criteria for rheumatoid Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20
arthritis. Comparison with the preliminary American College of Rheumatology and immunotherapy in fl udarabine-refractory chronic lymphocytic leukemia. J Clin Oncol the World Health Organization/International League Against Rheumatism Criteria. 2010 ; 28 : 1749 – 55 .
Arthritis Rheum 1996 ; 39 : 34 – 40 .
Aletaha D, Landewe R, Karonitsch T, et al. Reporting disease activity in clinical trials
Prevoo ML, van ‘t Hof MA, Kuper HH, et al. Modifi ed disease activity scores that
of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. include twenty-eight-joint counts. Development and validation in a prospective Ann Rheum Dis 2008 ; 67 : 1360 – 4 .
Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522
10/28/2011 8:01:45 PM Ofatumumab, a fully human anti-CD20
monoclonal antibody, in biological-naive,
rheumatoid arthritis patients with an
inadequate response to methotrexate: a
randomised, double-blind,
placebo-controlled clinical trial
Peter C Taylor, Emilia Quattrocchi, Stephen Mallett, et al.
Ann Rheum Dis 2011 70: 2119-2125 originally published online August22, 2011doi: 10.1136/ard.2011.151522 Updated information and services can be found at: These include: "Web Only Data" This article cites 30 articles, 12 of which can be accessed free at: Open Access
This paper is freely available online under the BMJ Journals unlockedscheme, see http://ard.bmj.com/info/unlocked.dtl Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
To request permissions go to: To order reprints go to: To subscribe to BMJ go to:

Source: http://www.protocolosreumatologia.cl/sitio/descargas/OFATUMUMAB.pdf