Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis A phase 2 study
Per S. Sorensen, MD Steen Lisby, MD Richard Grove, MSc Frederick Derosier, DO Steve Shackelford, DVM Eva Havrdova, MD Jelena Drulovic, MD Massimo Filippi, MD
Correspondence to Prof. Sorensen: [email protected]
ABSTRACT
Objectives: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS).
Methods: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed. Results: Thirty-eight patients were randomized (ofatumumab/placebo, n 5 26; placebo/ofatumumab, n 5 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD191 expression. New brain MRI lesion activity was suppressed (.99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p , 0.001) favoring ofatumumab found in new T1 gadoliniumenhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. Conclusions: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS. Classification of evidence: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions. Neurology® 2014;82:573–581 GLOSSARY AE 5 adverse event; EDSS 5 Expanded Disability Status Scale; GdE 5 gadolinium-enhancing; HACA 5 human anti-chimeric antibody; HAHA 5 human anti-human antibody; IDMC 5 independent data monitoring committee; Ig 5 immunoglobulin; IRR 5 infusion-related reaction; mAb 5 monoclonal antibody; MSFC 5 Multiple Sclerosis Functional Composite; RRMS 5 relapsing-remitting multiple sclerosis; SAE 5 serious adverse event.
Multiple sclerosis (MS) is a disease of the CNS characterized by demyelination and axonal damage.1–3 In addition to T cells, B cells and humoral immunity have also been implicated as pathogenic drivers in MS,1,2,4,5 and B-cell depletion appears to be an efficacious therapy.6,7 Current first-line therapies—interferon b preparations and glatiramer acetate—are clinically effective in subsets of patients,8 and second-line therapies natalizumab and fingolimod are associated with side effects.9–11 Teriflunomide and dimethyl fumarate are newly approved oral therapies with similar or larger efficacy vs current first-line therapies.11,12 Rituximab and ocrelizumab (in clinical development) phase 2 trials in relapsing-remitting MS (RRMS) have shown 91% and 96% reduction, respectively, in the total number of gadoliniumenhancing (GdE) T1 lesions vs placebo.6,10 Supplemental data at www.neurology.org From the Danish Multiple Sclerosis Center (P.S.S.), Rigshospitalet, Copenhagen; Genmab (S.L.), Copenhagen, Denmark; GlaxoSmithKline (R.G.), Uxbridge, Middlesex, UK; GlaxoSmithKline (F.D.), Research Triangle Park; GlaxoSmithKline (S.S.), Raleigh, NC; Charles University (E.H.), Prague, Czech Republic; School of Medicine University of Belgrade (J.D.), Serbia; and San Raffaele Scientific Institute and Vita-Salute San Raffaele University (M.F.), Milan, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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Ofatumumab is a next-generation immunoglobulin (Ig) G subclass 1 monoclonal antibody (mAb) that binds to CD20 on B lymphocytes and induces B-cell depletion via complementdependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, causing their rapid death.13 Ofatumumab binds to a novel membrane-proximal epitope, with a dissociation rate slower than rituximab, therefore leading to improved complement-dependent cytotoxicity.14 Unlike rituximab, ofatumumab has a very low immunogenic risk profile because it is a human antibody. Ofatumumab has demonstrated efficacy in hematologic malignancies14–22 and in active rheumatoid arthritis.23 METHODS Patient eligibility. Eligible patients were those who had RRMS meeting McDonald (2005 revision) criteria,24 were 18 to 55 years of age, had an Expanded Disability Status Scale (EDSS)25 score of 0 to 5.0, were neurologically stable with no evidence of relapse for $30 days, and had one of the following: $2 confirmed relapses #24 months before screening; $1 confirmed relapse #12 months before screening; or 1 confirmed relapse 12 to 24 months before screening and $1 documented T1 GdE lesion on MRI performed #12 months before screening. Patients with secondary progressive MS and primary progressive MS were excluded. Patients were ineligible if they had received treatment with lymphocyte-depleting therapies, mitoxantrone, cyclophosphamide, or anti-CD201 agents at any time; glatiramer acetate or interferon b #3 months before randomization; other immunosuppressive or immunomodulatory agents #6 months before randomization; plasmapheresis for treatment of relapses #2 months before randomization; or glucocorticoids or adrenocorticotropic hormone or a live vaccine #1 month before screening.
Standard protocol approvals, registrations, and patient consents. All patients provided written informed consent, and the protocol was approved by regional ethics committees or institutional review boards for each study site. The study was overseen by an independent data monitoring committee (IDMC). This study, funded by GlaxoSmithKline and Genmab, is registered with ClinicalTrials.gov (NCT00640328). The study was designed jointly by sponsors and investigators. Data were collected by the investigators and held and analyzed by the sponsor. All authors had full access to the data and approved their completeness and analysis. The corresponding author had final responsibility for the decision to submit for publication.
Study design: Randomization and treatment allocation. The study was a randomized, double-blind, placebo-controlled trial assessing safety and preliminary efficacy of ofatumumab in patients with MS. After a screening period scheduled to last #5 weeks, eligible patients completed two 24-week treatment periods (weeks 0–24 and weeks 24–48), with an individualized follow-up period for B-cell repletion and safety monitoring purposes (figure e-1 on the Neurology® Web site at www. neurology.org). The 0- to 24-week treatment period was of primary importance. Because of the long-lasting effect of ofatumumab, no treatment comparisons were made after week 24. At week 24, patients randomized to placebo were treated with 574
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ofatumumab and vice versa. This was specified in the protocol to ensure that all subjects received a potentially active therapy during the study. Randomization was performed using a computer-generated schedule created by ClinPhone (Nottingham, UK) in a 2:1 ratio (ofatumumab to placebo) within each cohort without stratification. An interactive voice response system was used for patient randomization. Patients were allocated to receive 2 IV infusions of either ofatumumab (100, 300, or 700 mg) or placebo 2 weeks apart. Recruitment into the 300-mg cohort was permitted only after IDMC review of weeks 1 to 4 data from the 100-mg cohort; a similar review of the data from the 300-mg cohort was required before recruitment into the 700-mg cohort (figure e-1, yellow and gray arrows). Ofatumumab was prepared as a clear, colorless liquid dissolved with 0.9% NaCl. Placebo infusions were 0.9% NaCl. All patients received premedications with acetaminophen, an antihistamine, and a corticosteroid before each infusion to address the potential for cell-lysis reaction in ofatumumab-treated patients. Doses were selected based on B-cell depletion data with ofatumumab in non-Hodgkin follicular lymphoma, efficacy data with rituximab in rheumatoid arthritis, and data from preclinical studies.10,13
Study conduct. Patients attended scheduled visits every 4 weeks during the treatment periods plus visits at weeks 2 and 26. At each visit, physical and neurologic examinations, including EDSS and MS Functional Composite (MSFC) assessments, were performed by a blinded evaluating physician different from the treating physician. Routine laboratory tests (biochemistry, hematology, and IgG, IgA, and IgM), JC virus (PCR), levels of peripheral CD191 B cells, and human anti-human antibodies (HAHA) were measured in blood samples, and urinalysis, ECGs, and MRI were performed. The CD19 B-cell marker was used as a surrogate measure for CD201 cells because ofatumumab interferes with the flow-cytometric analysis of CD20. Adverse events (AEs) were recorded and graded by the investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0,26 including suspected causality of the AEs regarding study medication. MRI was conducted according to a strict study imaging protocol and scans were assessed at the MRI analysis center of the Neuroimaging Research Unit at the Scientific Institute and University Ospedale San Raffaele. MRI scans included postcontrast (0.1 mmol/kg gd-DTPA [diethylenetriaminepentaacetate]) sequences. The MRI protocol is more fully described in e-Methods. After completing or withdrawing from the study, patient monitoring in individualized follow-up occurred every 3 months until B-cell normalization. Endpoints and data analysis. The primary objective was to evaluate ofatumumab safety in patients with RRMS through AE assessments, MRI, and clinical laboratory tests. No hypothesis testing of safety data was planned and, as such, no formal samplesize calculations were performed. The safety population included all patients who had been exposed to ofatumumab, irrespective of compliance; the intention-to-treat population included all patients who had been randomized, which in this study was identical with the safety population. Data analyses reported herein refer to this population. The key efficacy endpoints (prospectively assessed) were the cumulative number of new GdE lesions, T2 lesions, and T1 hypointense lesions measured on monthly MRI. The predefined assessment window was the cumulative number of new lesions from week 8 to week 24. Clinical endpoints included the proportion of relapse-free patients, relapse rate, and change
in EDSS and MSFC scores from baseline to week 24 and from week 24 to week 48. Relapse was defined as an appearance of a new neurologic abnormality or a reappearance of a previously observed neurologic abnormality that occurred in the absence of fever or known infections and persisted for at least 48 hours. No objective change on EDSS or MSFC score was required to diagnose a relapse. The main immunologic endpoint was peripheral CD191 counts.
Statistical methods. Assuming a withdrawal rate of approximately 15%, the number of patients planned to be enrolled and randomized was 36. Twelve subjects in each cohort were considered sufficient to clinically assess initial safety/tolerability of ofatumumab in this population, the primary objective of this study, so no formal sample-size calculations were required. Safety and efficacy data were summarized primarily using descriptive statistics. MRI efficacy endpoints were analyzed by nonparametric analyses using the Wilcoxon rank-sum test, and estimates of treatment differences and confidence intervals were generated using Hodges-Lehmann methodology. All statistical tests were 2-sided (a 5 0.05).
Classification of evidence. Is ofatumumab safe in patients with RRMS at doses of 100, 300, and 700 mg? What is the effect of ofatumumab on MRI outcome measures of monthly MRI scans compared with placebo? This study provides Class II
Figure 1
evidence that ofatumumab is well-tolerated and effective in RRMS at doses of 100, 300, and 700 mg. Significant relative reductions were observed for ofatumumab relative to placebo in the number of new T1 GdE lesions (p , 0.001), total number of T1 GdE lesions (p , 0.001), and new and/or enlarging T2 lesions (p , 0.001).
RESULTS Patients. Thirty-eight of 54 screened patients across 13 European sites were eligible and randomized to receive either ofatumumab/placebo (n 5 26) or placebo/ofatumumab (n 5 12; figure 1). Thirty-six of 38 patients completed both treatment periods and received all planned infusions; 2 patients prematurely withdrew because of AEs during their first ofatumumab infusion. Demographics and baseline clinical and MRI characteristics were similar between treatment groups and dose cohorts (table 1). Patients were recruited from May 2008 until April 2009 and followed up until October 2011.
Safety data. Safety data are shown in table 2. During
both periods, the percentage of patients with any AE, any drug-related AE, or any drug-related AE on the
Patient disposition
All patients allocated to treatment received the designated intervention. AE 5 adverse event. Neurology 82
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0.3 (0.7) [0.0 (0.0–2.0)] 1.5 (3.1) [0.0 (0.0–13.0)] 0.5 (1.0) [0.0 (0.0–2.0)] 2.7 (4.6) [1.0 (0.0–13.0)]
2.5 (2.6) [1.8 (0.4–8.7)]
8.1 (4.7) [8.2 (2.2–13.9)]
2.4 (0.9) [2.0 (1.5–4.0)]
0.5 (0.9) [0.0 (0.0–2.0)]
0.6 (1.2) [0.0 (0.0–3.0)]
Time since diagnosis, y
Time since first symptoms, y
EDSS score
No. of new T1 GdE lesions at baseline
No. of new and/or enlarging T2 lesions at baseline
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Abbreviations: EDSS 5 Expanded Disability Status Scale; GdE 5 gadolinium-enhancing. Data are mean (SD) [median (range)] unless otherwise indicated.
1.4 (2.8) [0.0 (0.0–9.0)] 0.0 (0.0) [0.0 (0.0–0.0)]
0.5 (0.6) [0.5 (0.0–1.0)]
0.2 (0.4) [0.0 (0.0–1.0)] 2.2 (5.0) [0.5 (0.0–25.0)] 0.3 (0.5) [0.0 (0.0–1.0)] 5.1 (9.2) [1.0 (0.0–25.0)] 1.6 (1.6) [1.0 (0.0–4.0)] 0.0 (0.0) [0.0 (0.0–0.0)]
0.3 (0.5) [0.0 (0.0–1.0)]
2.5 (1.0) [2.3 (1.0–4.5)] 2.8 (1.3) [2.5 (0.0–5.0)] 2.5 (0.7) [2.3 (2.0–3.5)] 2.6 (1.6) [2.5 (0.0–4.5)] 3.1 (1.3) [3.5 (1.0–5.0)] 3.1 (1.3) [3.0 (2.0–4.5)]
2.0 (0.9) [2.0 (1.0–3.0)]
6.5 (7.8) [2.6 (0.8–25.8)] 8.5 (5.7) [6.6 (1.7–24.6)] 8.7 (11.6) [4.0 (0.8–25.8)] 11.5 (7.5) [6.8 (4.9–24.6)] 6.8 (4.9) [5.5 (1.7–19.6)] 8.6 (7.4) [7.6 (1.8–17.2)]
2.3 (0.4) [2.3 (1.9–2.7)]
1.7 (2.1) [0.9 (0.1–6.7)] 3.8 (3.7) [26 (0.4–13.9)] 0.4 (0.3) [0.3 (0.1–0.8)] 5.0 (4.6) [4.4 (0.4–13.7)] 4.1 (3.8) [3.6 (0.7–13.9)] 3.5 (2.9) [3.3 (0.5–6.7)]
1.2 (0.8) [1.4 (0.1–2.1)]
100
50.0 61.5
100 100
0.0 57.1 75.0 54.5
100 100 100
75.0
100 100
75.0
White race, %
Female, %
36.0 (9.1) [35.0 (24.0–51.0)] 36.3 (7.9) [33.5 (26.0–52.0)] 44.0 (8.1) [44.0 (37.0–51.0)] 33.7 (8.4) [29.0 (26.0–46.0)] 27.0 (2.2) [27.5 (24.0–29.0)] 36.6 (7.0) [35.0 (28.0–48.0)] 37.0 (6.5) [37.0 (30.0–43.0)] 38.0 (9.0) [35.5 (26.0–52.0)] Age, y
Placebo/ofatumumab (n 5 12) Ofatumumab/ placebo (n 5 26) Ofatumumab/placebo Placebo/ofatumumab (n 5 11) (n 5 4) Ofatumumab/placebo Placebo/ofatumumab (n 5 8) (n 5 4)
Ofatumumab/placebo Placebo/ofatumumab (n 5 7) (n 5 4)
Total 700 mg 300 mg 100 mg
Demographics and baseline clinical characteristics Table 1 576
first infusion day of each period was higher with ofatumumab than with placebo across dosing cohorts. The most common AE was the infusionrelated reaction (IRR) of rash, most often reported on the first infusion day. Most AEs were grade 1 or 2, and no grade 4 or 5 AEs were reported. The percentage of patients with $1 infection was not higher with ofatumumab. Serious AEs (SAEs) were reported in 2 patients during the first period: one case of influenza (placebo) and one case of headache leading to hospitalization (ofatumumab 300 mg; considered unrelated to ofatumumab). One SAE in a patient with anemia caused by prolonged menstrual bleeding was reported during the second period. All SAEs resolved and the patients remained in the study. During the first period, one patient receiving ofatumumab 300 mg discontinued treatment during the first infusion because of the grade-3 AEs pruritic rash, bronchospasm, and cough, which were considered study drug–related by the investigator. During the second period, one patient receiving ofatumumab 300 mg discontinued treatment during the first infusion because of the grade-2 AEs pharyngeal edema, erythema, nasal congestion, and pruritus, which were considered study drug–related by the investigator. The AEs resolved in both patients. No patient tested positive for HAHA by week 48, indicating there was no immunogenicity induced by ofatumumab. Only marginal changes in IgG, IgA, and IgM were observed. Results of clinical laboratory tests (hematology, biochemistry, and urinalysis), physical examinations, and ECGs were unremarkable during both periods. There were no cases of opportunistic infections, including progressive multifocal leukoencephalopathy. Efficacy data. MRI endpoints. Tables 3 and 4 and figure e-2 summarize MRI results. For weeks 8–24, profound and significant relative reductions were observed for ofatumumab relative to placebo in the number of new T1 GdE lesions (p , 0.001), total number of T1 GdE lesions (p , 0.001), and new and/or enlarging T2 lesions (p , 0.001). The percentage reduction in the total number of T1 GdE lesions from weeks 8 to 24 was .99% (table 3). In the first 24-week period, similar reductions were estimated for all doses of ofatumumab, although none of the patients in the 700-mg group had any MRI lesions. For weeks 8–24, only one patient (100 mg ofatumumab) had a single new T1 GdE lesion, whereas 8 of 12 placebo-treated patients (67%) had $1 new T1-weighted GdE lesion. Ofatumumab did not provide significant benefit regarding T1 hypointense lesions. For weeks 32–48, new GdE lesion activity continued to be minimal for patients who received ofatumumab
Table 2
Adverse events summary Weeks 0–24 100 mg
300 mg
700 mg
Total
Treatment at weeks 0–24
Ofatumumab Placebo Ofatumumab Placebo Ofatumumab Placebo Ofatumumab Placebo (n 5 8) (n 5 4) (n 5 11) (n 5 4) (n 5 7) (n 5 4) (n 5 26) (n 5 12)
Any adverse event
8 (100)
3 (75.0) 10 (90.9)
2 (50.0) 7 (100)
2 (50.0) 25 (96.2)
7 (58.3)
Any drug-related adverse event
7 (87.5)
2 (50.0) 10 (90.9)
0 (0)
7 (100)
1 (25.0) 24 (92.3)
3 (25.0)
Any serious adverse event
0 (0)
1 (25.0)
1 (9.1)
0 (0)
0 (0)
0 (0)
1 (3.8)
1 (8.3)
1 (9.1)
0 (0)
1 (14.3)
0 (0)
2 (7.7)
1 (8.3)
10 (90.9)
0 (0)
7 (100.0)
1 (25.0) 23 (88.5)
1 (8.3)
Adverse events ‡grade 3
0 (0)
1 (25.0)
Drug-related adverse event on first infusion of treatment period
6 (75.0)
0 (0)
Infections
5 (62.5)
3 (75.0)
4 (36.4)
2 (50.0) 1 (14.3)
1 (25.0) 10 (38.5)
6 (50.0)
Rash
2 (25.0)
0 (0)
3 (27.3)
0 (0)
4 (57.1)
0 (0)
9 (34.6)
0 (0)
Erythema
2 (25.0)
0 (0)
1 (9.1)
0 (0)
1 (14.3)
0 (0)
4 (15.4)
0 (0)
Upper respiratory tract infection
1 (12.5)
2 (50.0)
2 (18.2)
0 (0)
1 (14.3)
0 (0)
4 (15.4)
2 (16.7)
Viral infection
1 (12.5)
0 (0)
2 (18.2)
0 (0)
0 (0)
0 (0)
3 (11.5)
0 (0)
Throat irritation
3 (37.5)
0 (0)
4 (36.4)
0 (0)
2 (28.6)
0 (0)
9 (34.6)
0 (0)
Adverse events in ‡3 patients
Headache
1 (12.5)
1 (25.0)
1 (9.1)
0 (0)
0 (0)
0 (0)
2 (7.7)
1 (8.3)
Fatigue
2 (25.0)
1 (25.0)
2 (18.2)
0 (0)
0 (0)
0 (0)
4 (15.4)
1 (8.3)
Back pain
1 (12.5)
1 (25.0)
1 (9.1)
0 (0)
0 (0)
0 (0)
2 (7.7)
1 (8.3)
Flushing
0 (0)
0 (0)
2 (18.2)
0 (0)
1 (14.3)
1 (25.0)
3 (11.5)
1 (8.3)
Weeks 24–48 100 mg
300 mg
700 mg
Total
Treatment at weeks 24–48
Placebo Ofatumumab Placebo Ofatumumab Placebo Ofatumumab Placebo Ofatumumab (n 5 26) (n 5 12) (n 5 8) (n 5 4) (n 5 11) (n 5 4) (n 5 7) (n 5 4)
Any adverse event
4 (50.0) 3 (75.0)
5 (45.0) 4 (100)
4 (57.0) 4 (100)
Any drug-related adverse event
0 (0)
2 (50.0)
0 (0)
4 (100)
1 (14.0) 4 (100) 0 (0)
13 (50)
11 (92)
1 (4)
10 (83)
1 (4)
0 (0)
Any serious adverse event
0 (0)
0 (0)
1 (9.0)
0 (0)
0 (0)
Adverse events ‡grade 3
0 (0)
1 (25.0)
1 (9.0)
0 (0)
2 (29.0) 1 (25.0)
3 (12)
2 (17)
Drug-related adverse event on first infusion of treatment period
0 (0)
2 (50.0)
0 (0)
3 (75.0)
1 (14.0) 3 (75.0)
1 (4)
8 (67)
Infections
2 (25.0) 0 (0)
2 (18.0) 1 (25.0)
2 (29.0) 1 (25.0)
6 (23)
2 (17)
Nasopharyngitis
2 (25)
0 (0)
0 (0)
0 (0)
1 (14)
0 (0)
3 (12)
0 (0)
Rash
0 (0)
2 (50)
0 (0)
0 (0)
0 (0)
2 (50)
0 (0)
4 (33)
Adverse events in ‡3 patients
Data are n (%).
during the first period: one patient had a single new GdE lesion and one patient had 2 new T1 GdE lesions. Among patients receiving ofatumumab during the second period, suppression of new GdE lesions between weeks 32 and 48 was observed in all but one patient, who had one GdE lesion. Clinical endpoints. During weeks 0–24, relapses were documented in 5 patients (19%) who received ofatumumab, of whom one experienced a relapse 2 weeks after infusion, and 3 (25%) who received placebo. During weeks 24–48, relapse was
documented in one additional patient who initially received ofatumumab. None of the 12 patients receiving ofatumumab in the second period experienced a relapse. All patients who relapsed were treated with IV corticosteroids; 5 were hospitalized for relapse (3 of whom received ofatumumab during the first period). All relapses resolved. None of the patients treated with ofatumumab 700 mg experienced relapses. It should be noted that there were no clinically significant changes observed in EDSS or MSFC scores (from baseline or between treatment groups). Neurology 82
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Table 3
MRI endpoints summary Weeks 8–24 100 mg
300 mg
Treatment at weeks 0–24
Ofatumumab Placebo (n 5 8) (n 5 4)
Ofatumumab (n 5 11)
Placebo (n 5 4)
Ofatumumab (n 5 7)
Placebo (n 5 4)
Ofatumumab (n 5 26)
Placebo (n 5 12)
No. of new T1 GdE lesions
0.13a (0.35)
3.06 (4.66)
0.0b (0.0)
23.50 (43.03)
0.0a (0.0)
2.50 (3.32)
0.04b,c (0.20)
9.69 (24.86)
No. of total T1 GdE lesions
0.13a (0.35)
3.63 (5.02)
0.09a (0.30)
25.75 (46.23)
0.0a (0.0)
4.50 (7.14)
0.08b,c (0.27)
11.29 (26.79)
a
700 mg
a
a
Total
b,c
No. of new and/or enlarging T2 lesions
0.25 (0.71)
4.00 (6.52)
0.09 (0.30)
25.00 (46.03)
0.0 (0.0)
3.00 (4.24)
0.12
(0.43)
10.67 (26.58)
No. of new T1 hypointense lesions
0.0 (0.0)
1.50 (3.00)
0.27 (0.47)
5.00 (9.35)
0.29 (0.49)
0.25 (0.50)
0.19 (0.40)
2.25 (5.55)
Percentage change (SD) in volume of T2 lesionsd
24.7 (9.6)
7.6 (4.5)
23.1 (6.3)
24.9 (13.4)
20.9 (4.1)
21.0 (2.0)
23.0 (7.0)
11.0 (14.0)
Weeks 32–48 100 mg
300 mg
700 mg
Total
Treatment at weeks 24–48
Placebo (n 5 8)
Ofatumumab (n 5 4)
Placebo (n 5 11)
Ofatumumab (n 5 4)
Placebo (n 5 7)
Ofatumumab (n 5 4)
Placebo (n 5 26)
Ofatumumab (n 5 26)
No. of new T1 GdE lesions
0.13 (0.35)
0.0 (0.0)
0.0 (0.0)
0.33 (0.58)
0.29 (0.76)
0.0 (0.0)
0.12 (0.44)
0.09 (0.30)
No. of total T1 GdE lesions
0.13 (0.35)
0.0 (0.0)
0.0 (0.0)
3.00 (5.20)
0.43 (1.13)
0.0 (0.0)
0.16 (0.62)
0.82 (2.71)
No. of new and/or enlarging T2 lesions
0.13 (0.35)
0.0 (0.0)
0.0 (0.0)
0.33 (0.58)
0.29 (0.76)
0.0 (0.0)
0.12 (0.44)
0.09 (0.30)
No. of new T1 hypointense lesions
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
3.00 (4.36)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.82 (2.40)
Abbreviation: GdE 5 gadolinium-enhancing. Data are mean (SD). The p values are from the Wilcoxon test (for pooled placebo vs an active group or vs pooled active data) or Kruskal-Wallis test (all 4 groups). a p , 0.05 vs placebo. b p # 0.001 vs placebo. c p , 0.001 for overall test for dose effect. d Change from baseline to week 24. Percentage change in volume of T2 lesions from week 24 to week 48 is not reported because subjects initially randomized to ofatumumab were excluded from further analysis because of carryover effect.
Peripheral CD191 B-cell counts.
Ofatumumab treatment was associated with profound reductions in CD191 cells in peripheral blood at all 3 dose levels in both periods (figure e-3). The median value of CD191 cells decreased to zero within 1 week of ofatumumab treatment. During both periods, recovery started after approximately 12 to 16 weeks in the ofatumumab 100-mg group, after 20 weeks in a few Table 4
Nonparametric analysis of MRI endpoints Difference in counts (ofatumumab vs placebo) a
a
b
Treatment at weeks 0–24
Estimate
95% CI
p Value
Cumulative no. of new T1 GdE lesions
21.3
24.0, 21.0
,0.001
Cumulative no. of total T1 GdE lesions
22.0
26.0, 0.0
,0.001
Cumulative no. of new and/or enlarging T2 lesions
21.3
24.0, 0.0
,0.001
0.0
0.0, 0.0
0.256
Cumulative no. of new T1 hypointense lesions
Abbreviations: CI 5 confidence interval; GdE 5 gadolinium-enhancing. a Hodges-Lehmann method. b Wilcoxon rank-sum test. 578
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patients in the ofatumumab 300-mg group, whereas all patients in the ofatumumab 700-mg group experienced persistent and complete CD191 suppression at week 24. In the ofatumumab/placebo groups, CD191 cell counts continued to increase, and repletion, defined as recovery to or above the lower limit of normal of 100 CD191 cells/mm3, was observed in a few patients in each dose group by week 48, but CD191 cell repletion was observed in all patients during the follow-up period. DISCUSSION The current study showed that administration of ofatumumab up to 700 mg twice at a 2-week interval produced no unexpected safety signals or dose-related safety concerns and was well tolerated. IRRs, most often mild, were common on the first day of ofatumumab dosing, even with premedication, but were not observed on the second infusion day. Based on the small number of patients in each cohort, neither incidence nor severity of IRRs appeared to be dose-related. The IRRs observed in this
study are consistent with the known safety profile of ofatumumab, which has been studied in more than 500 patients for other indications.14,15,23 The IRRs are most likely attributable to cytokine release after pronounced B-cell depletion at first infusion.27 Because ofatumumab is a human mAb, low immunogenicity was expected. In fact, none of the patients in this study tested HAHA positive. In a phase 2 study of ocrelizumab, the number of patients with HAHA was similar between the ocrelizumab group and the placebo group (2%–3%).10 In contrast, human anti-chimeric antibodies (HACA) were detected in 24.6% of patients treated with rituximab 11.1 months after randomization.6 No association between HACA and AEs or efficacy responses was noted in that phase 2 rituximab trial, but because HACA occurred in the last part of the study (after 24 weeks) in all HACA-positive patients and the primary and secondary endpoints were measured only up to 24 weeks, it would have been unlikely to observe any negative effects of HACA.6 The percentage of patients with $1 infection was similar between the ofatumumab and placebo treatment groups. Most infections were categorized as grade 1 and none were grade 3 or higher. Regarding efficacy endpoints, we observed minimal new GdE T1 MRI lesions after ofatumumab administration across all doses during both the first period (weeks 8–24) and the second period (weeks 32–48). The effects on CD201 reduction and suppression of MRI activity observed in this study were very similar to those reported in the phase 2 trial of ocrelizumab at doses of 600 and 2,000 mg (89% and 96% T1 GdE lesion reduction, respectively) administered twice with a 2-week interval.10 Similar results were observed for other MRI endpoints, although statistical separation was not observed for new T1 hypointense lesions. The magnitude of suppression, however, should be interpreted cautiously because of the small sample size. One patient in the group treated with placebo during the first period had 88 new GdE lesions, but, interestingly, this patient had no GdE lesions in the second period after crossing over to receive active therapy with ofatumumab 300 mg. We observed a prolonged effect of ofatumumab, resulting in very low MRI activity in the 25 patients treated with placebo in the second period (weeks 32–48), consistent with the longlasting suppression of B cells observed in patients treated with ofatumumab in the first period. The relatively higher relapse rate observed in the first period in the study are explained, at least partly, by a less restrictive relapse definition than the definitions used in the majority of recent phase 2 and 3 RRMS clinical trials. From studies that have reported both qualifying relapses and all relapses (qualifying and nonqualifying relapses), it appears that the less restrictive definition used in
daily clinical practice and adopted in this trial yields approximately 50% to 100% more relapses than the more rigorous definition of a qualifying relapse.28,29 In the phase 2 trial of rituximab that used the same relapse definition as the present study, the annualized relapse rate in the rituximab group was 0.4 at both 24 weeks and 48 weeks, which was similar to or higher than that in the present study.6 The annualized relapse rate in the ocrelizumab study that used the more rigorous relapse definition was, as expected, lower: 0.13 in the 600-mg and 0.17 in the 2,000-mg treatment group.10 Ofatumumab treatment was associated with a profound, selective reduction in B cells as measured by CD191 expression, similar to that observed with ocrelizumab.10 This effect was observed across all ofatumumab doses examined; it would be interesting to study lower doses to elucidate when such profound depletion is no longer observed and to assess the ofatumumab dose effect on efficacy. B-cell repletion to the lower limit of normal was observed in all patients during the individualized follow-up period. Consistent with the lack of expression of CD201 on stem cells or plasma cells,30 Ig levels remained within normal range during the study. The human mAb ofatumumab administered to patients with RRMS as a single agent in 2 IV infusions in doses up to 700 mg, 2 weeks apart, was not associated with any unexpected safety concerns, was well-tolerated, and showed a profound reduction in MRI activity. Notably, this small 48-week study was not designed to assess clinical efficacy or longterm safety or to detect less-common AEs. The results warrant further exploration of the efficacy and safety of ofatumumab in RRMS in a larger phase 2b study. It would be important to study a wider range of doses of ofatumumab to identify the most optimal dosing regimen. AUTHOR CONTRIBUTIONS P.S.S., R.G., and M.F. designed the study. P.S.S., E.H., and J.D. acquired the data. W.H. Clausen analyzed the data. M.F. designed the MRI protocol, and analyzed and interpreted the MRI data. P.S.S., R.G., and M.F. prepared the manuscript. P.S.S., M.F., S.L., R.G., F.D., S.S., E.H., and J.D. reviewed the manuscript.
ACKNOWLEDGMENT The sponsors and authors thank the patients who volunteered to participate in this study. The sponsors and authors also thank the IDMC members: Professor Ludwig Kappos (Chair), Dr. Michel Clanet, Dr. Gary Cutter, and Professor Ralf Gold; the progressive multifocal leukoencephalopathy adjudication committee members: Dr. Joseph Berger (Chair), Dr. Lars Nielsen, and Dr. Eugene Major; and the MRI Analysis Center, Neuroimaging Research Unit: Massimo Filippi (Chair), Maria A. Rocca, Martina Absinta, Paola Valsasina, Alessandro Meani, and Mauro Sibilia. Dr. Wan Hui Ong Clausen at Larix (Ballerup, Denmark) conducted all statistical analyses. Contributors: Jane Saiers, PhD (The Write Medicine, Inc., performed substantive editing of the manuscript), Francesca Balordi, PhD (Medicus International New York, performed substantive editing of the manuscript), Jennifer Granit, PhD (Medicus International New York, performed substantive editing of the manuscript), Ken Wiesen, PhD Neurology 82
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(Medicus International New York, performed substantive editing of the manuscript), Cara Hunsberger, MS, CMPP (Medicus International New York, edited the manuscript for nonintellectual content), Gail Huggins (Medicus International New York, edited the manuscript for nonintellectual content), and Michele Springer (Medicus International New York, edited the manuscript for nonintellectual content).
4.
5.
6. STUDY FUNDING GlaxoSmithKline and Genmab (Copenhagen, Denmark) sponsored the study described in this manuscript.
7.
DISCLOSURE
8.
P. Sorensen has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Genmab, Teva Pharmaceutical Industries Ltd., Elan, and GlaxoSmithKline; has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Genmab, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, and Bayer Schering, and has received funding of travel for these activities; has served as Editor-in-Chief of the European Journal of Neurology and is currently an editorial board member for Multiple Sclerosis Journal, European Journal of Neurology, and Therapeutic Advances in Neurological Disorders; and has received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Bayer Schering, sanofi-aventis, Genzyme, and Novartis. His department has received research support from Biogen Idec, Bayer Schering, Merck Serono, Teva Pharmaceutical Industries Ltd., Baxter, sanofi-aventis, BioMS, Novartis, Bayer, RoFAR, Roche, and Genzyme, and from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life Sciences, Genomics and Biotechnology for Health. S. Lisby is an employee of Genmab A/S. R. Grove is an employee of GlaxoSmithKline and holds shares in the company. F. Derosier is a former employee of GlaxoSmithKline and holds shares in the company. S. Shackelford is a former employee of GlaxoSmithKline and holds shares in the company. E. Havrdova has received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme, and Teva, as well as support for research activities from Biogen Idec and Merck Serono. She has been supported by the Czech Ministry of Education, Research Projects MSM0021620849, PRVOUK-P26/LF1/4. J. Drulovic serves on scientific advisory boards for Bayer Schering Pharma and Biogen Idec, has received speaker honoraria from Novartis and travel grants from Bayer Schering Pharma, and has received research grant support from the Ministry of Education and Science, Republic of Serbia (project no. 175031). M. Filippi serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Genmab A/S; has received funding for travel from Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves on speakers bureaus for Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; receives research support from Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, and CurePSP. Go to Neurology.org for full disclosures.
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19. Received June 26, 2013. Accepted in final form November 4, 2013. REFERENCES 1. Meier UC, Giovannoni G, Tzartos JS, Khan G. Translational mini-review series on B cell subsets in disease: B cells in multiple sclerosis: drivers of disease pathogenesis and Trojan horse for Epstein-Barr virus entry to the central nervous system? Clin Exp Immunol 2012;167:1–6. 2. Ontaneda D, Hyland M, Cohen JA. Multiple sclerosis: new insights in pathogenesis and novel therapeutics. Annu Rev Med 2012;63:389–404. 3. Rizvi SA, Agius MA. Current approved options for treating patients with multiple sclerosis. Neurology 2004;63:S8–S14. 580
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with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 2011;118:5126–5129. Ostergaard M, Baslund B, Rigby W, et al. Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study. Arthritis Rheum 2010;62:2227–2238. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840–846. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444–1452. National Cancer Institute common terminology criteria for adverse events v3.0 [online]. 2006. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/docs/ctcaev3.pdf. Accessed August 15, 2013.
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This Week’s Neurology® Podcast Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis (See p. 556) This podcast begins and closes with Dr. Robert Gross, Editor-inChief, briefly discussing highlighted articles from the February 18, 2014, issue of Neurology. In the second segment, Dr. Alex Menze talks with Dr. Jerome Honnorat about his paper on the clinical specificities of patients with NMDA receptor antibodies encephalitis. Dr. James Addington reads our e-Pearl of the week about posterior interosseous nerve syndrome. In the next part of the podcast, Dr. Mark McAllister focuses his interview with Dr. Seemant Chaturvedi on a brief review of a new oral anticoagulant (Apixaban), reference clinical trial, indication, and dosing. Disclosures can be found at www.neurology.org. At www.neurology.org, click on “RSS” in the Neurology Podcast box to listen to the most recent podcast and subscribe to the RSS feed. CME Opportunity: Listen to this week’s Neurology Podcast and earn 0.5 AMA PRA Category 1 CME Credits™ by answering the multiple-choice questions in the online Podcast quiz.
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Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study Per S. Sorensen, Steen Lisby, Richard Grove, et al. Neurology 2014;82;573-581 Published Online before print January 22, 2014 DOI 10.1212/WNL.0000000000000125 This information is current as of January 22, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/7/573.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/01/22/WNL.0000000000 000125.DC1.html http://www.neurology.org/content/suppl/2014/04/09/WNL.0000000000 000125.DC2.html
References
This article cites 26 articles, 8 of which you can access for free at: http://www.neurology.org/content/82/7/573.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Clinical trials Randomized controlled (CONSORT agreement) http://www.neurology.org//cgi/collection/clinical_trials_randomized_c ontrolled_consort_agreement MRI http://www.neurology.org//cgi/collection/mri Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Per S. Sorensen, MD Steen Lisby, MD Richard Grove, MSc Frederick Derosier, DO Steve Shackelford, DVM Eva Havrdova, MD Jelena Drulovic, MD Massimo Filippi, MD
Correspondence to Prof. Sorensen: [email protected]
ABSTRACT
Objectives: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS).
Methods: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed. Results: Thirty-eight patients were randomized (ofatumumab/placebo, n 5 26; placebo/ofatumumab, n 5 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD191 expression. New brain MRI lesion activity was suppressed (.99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p , 0.001) favoring ofatumumab found in new T1 gadoliniumenhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. Conclusions: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS. Classification of evidence: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions. Neurology® 2014;82:573–581 GLOSSARY AE 5 adverse event; EDSS 5 Expanded Disability Status Scale; GdE 5 gadolinium-enhancing; HACA 5 human anti-chimeric antibody; HAHA 5 human anti-human antibody; IDMC 5 independent data monitoring committee; Ig 5 immunoglobulin; IRR 5 infusion-related reaction; mAb 5 monoclonal antibody; MSFC 5 Multiple Sclerosis Functional Composite; RRMS 5 relapsing-remitting multiple sclerosis; SAE 5 serious adverse event.
Multiple sclerosis (MS) is a disease of the CNS characterized by demyelination and axonal damage.1–3 In addition to T cells, B cells and humoral immunity have also been implicated as pathogenic drivers in MS,1,2,4,5 and B-cell depletion appears to be an efficacious therapy.6,7 Current first-line therapies—interferon b preparations and glatiramer acetate—are clinically effective in subsets of patients,8 and second-line therapies natalizumab and fingolimod are associated with side effects.9–11 Teriflunomide and dimethyl fumarate are newly approved oral therapies with similar or larger efficacy vs current first-line therapies.11,12 Rituximab and ocrelizumab (in clinical development) phase 2 trials in relapsing-remitting MS (RRMS) have shown 91% and 96% reduction, respectively, in the total number of gadoliniumenhancing (GdE) T1 lesions vs placebo.6,10 Supplemental data at www.neurology.org From the Danish Multiple Sclerosis Center (P.S.S.), Rigshospitalet, Copenhagen; Genmab (S.L.), Copenhagen, Denmark; GlaxoSmithKline (R.G.), Uxbridge, Middlesex, UK; GlaxoSmithKline (F.D.), Research Triangle Park; GlaxoSmithKline (S.S.), Raleigh, NC; Charles University (E.H.), Prague, Czech Republic; School of Medicine University of Belgrade (J.D.), Serbia; and San Raffaele Scientific Institute and Vita-Salute San Raffaele University (M.F.), Milan, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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Ofatumumab is a next-generation immunoglobulin (Ig) G subclass 1 monoclonal antibody (mAb) that binds to CD20 on B lymphocytes and induces B-cell depletion via complementdependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, causing their rapid death.13 Ofatumumab binds to a novel membrane-proximal epitope, with a dissociation rate slower than rituximab, therefore leading to improved complement-dependent cytotoxicity.14 Unlike rituximab, ofatumumab has a very low immunogenic risk profile because it is a human antibody. Ofatumumab has demonstrated efficacy in hematologic malignancies14–22 and in active rheumatoid arthritis.23 METHODS Patient eligibility. Eligible patients were those who had RRMS meeting McDonald (2005 revision) criteria,24 were 18 to 55 years of age, had an Expanded Disability Status Scale (EDSS)25 score of 0 to 5.0, were neurologically stable with no evidence of relapse for $30 days, and had one of the following: $2 confirmed relapses #24 months before screening; $1 confirmed relapse #12 months before screening; or 1 confirmed relapse 12 to 24 months before screening and $1 documented T1 GdE lesion on MRI performed #12 months before screening. Patients with secondary progressive MS and primary progressive MS were excluded. Patients were ineligible if they had received treatment with lymphocyte-depleting therapies, mitoxantrone, cyclophosphamide, or anti-CD201 agents at any time; glatiramer acetate or interferon b #3 months before randomization; other immunosuppressive or immunomodulatory agents #6 months before randomization; plasmapheresis for treatment of relapses #2 months before randomization; or glucocorticoids or adrenocorticotropic hormone or a live vaccine #1 month before screening.
Standard protocol approvals, registrations, and patient consents. All patients provided written informed consent, and the protocol was approved by regional ethics committees or institutional review boards for each study site. The study was overseen by an independent data monitoring committee (IDMC). This study, funded by GlaxoSmithKline and Genmab, is registered with ClinicalTrials.gov (NCT00640328). The study was designed jointly by sponsors and investigators. Data were collected by the investigators and held and analyzed by the sponsor. All authors had full access to the data and approved their completeness and analysis. The corresponding author had final responsibility for the decision to submit for publication.
Study design: Randomization and treatment allocation. The study was a randomized, double-blind, placebo-controlled trial assessing safety and preliminary efficacy of ofatumumab in patients with MS. After a screening period scheduled to last #5 weeks, eligible patients completed two 24-week treatment periods (weeks 0–24 and weeks 24–48), with an individualized follow-up period for B-cell repletion and safety monitoring purposes (figure e-1 on the Neurology® Web site at www. neurology.org). The 0- to 24-week treatment period was of primary importance. Because of the long-lasting effect of ofatumumab, no treatment comparisons were made after week 24. At week 24, patients randomized to placebo were treated with 574
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ofatumumab and vice versa. This was specified in the protocol to ensure that all subjects received a potentially active therapy during the study. Randomization was performed using a computer-generated schedule created by ClinPhone (Nottingham, UK) in a 2:1 ratio (ofatumumab to placebo) within each cohort without stratification. An interactive voice response system was used for patient randomization. Patients were allocated to receive 2 IV infusions of either ofatumumab (100, 300, or 700 mg) or placebo 2 weeks apart. Recruitment into the 300-mg cohort was permitted only after IDMC review of weeks 1 to 4 data from the 100-mg cohort; a similar review of the data from the 300-mg cohort was required before recruitment into the 700-mg cohort (figure e-1, yellow and gray arrows). Ofatumumab was prepared as a clear, colorless liquid dissolved with 0.9% NaCl. Placebo infusions were 0.9% NaCl. All patients received premedications with acetaminophen, an antihistamine, and a corticosteroid before each infusion to address the potential for cell-lysis reaction in ofatumumab-treated patients. Doses were selected based on B-cell depletion data with ofatumumab in non-Hodgkin follicular lymphoma, efficacy data with rituximab in rheumatoid arthritis, and data from preclinical studies.10,13
Study conduct. Patients attended scheduled visits every 4 weeks during the treatment periods plus visits at weeks 2 and 26. At each visit, physical and neurologic examinations, including EDSS and MS Functional Composite (MSFC) assessments, were performed by a blinded evaluating physician different from the treating physician. Routine laboratory tests (biochemistry, hematology, and IgG, IgA, and IgM), JC virus (PCR), levels of peripheral CD191 B cells, and human anti-human antibodies (HAHA) were measured in blood samples, and urinalysis, ECGs, and MRI were performed. The CD19 B-cell marker was used as a surrogate measure for CD201 cells because ofatumumab interferes with the flow-cytometric analysis of CD20. Adverse events (AEs) were recorded and graded by the investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0,26 including suspected causality of the AEs regarding study medication. MRI was conducted according to a strict study imaging protocol and scans were assessed at the MRI analysis center of the Neuroimaging Research Unit at the Scientific Institute and University Ospedale San Raffaele. MRI scans included postcontrast (0.1 mmol/kg gd-DTPA [diethylenetriaminepentaacetate]) sequences. The MRI protocol is more fully described in e-Methods. After completing or withdrawing from the study, patient monitoring in individualized follow-up occurred every 3 months until B-cell normalization. Endpoints and data analysis. The primary objective was to evaluate ofatumumab safety in patients with RRMS through AE assessments, MRI, and clinical laboratory tests. No hypothesis testing of safety data was planned and, as such, no formal samplesize calculations were performed. The safety population included all patients who had been exposed to ofatumumab, irrespective of compliance; the intention-to-treat population included all patients who had been randomized, which in this study was identical with the safety population. Data analyses reported herein refer to this population. The key efficacy endpoints (prospectively assessed) were the cumulative number of new GdE lesions, T2 lesions, and T1 hypointense lesions measured on monthly MRI. The predefined assessment window was the cumulative number of new lesions from week 8 to week 24. Clinical endpoints included the proportion of relapse-free patients, relapse rate, and change
in EDSS and MSFC scores from baseline to week 24 and from week 24 to week 48. Relapse was defined as an appearance of a new neurologic abnormality or a reappearance of a previously observed neurologic abnormality that occurred in the absence of fever or known infections and persisted for at least 48 hours. No objective change on EDSS or MSFC score was required to diagnose a relapse. The main immunologic endpoint was peripheral CD191 counts.
Statistical methods. Assuming a withdrawal rate of approximately 15%, the number of patients planned to be enrolled and randomized was 36. Twelve subjects in each cohort were considered sufficient to clinically assess initial safety/tolerability of ofatumumab in this population, the primary objective of this study, so no formal sample-size calculations were required. Safety and efficacy data were summarized primarily using descriptive statistics. MRI efficacy endpoints were analyzed by nonparametric analyses using the Wilcoxon rank-sum test, and estimates of treatment differences and confidence intervals were generated using Hodges-Lehmann methodology. All statistical tests were 2-sided (a 5 0.05).
Classification of evidence. Is ofatumumab safe in patients with RRMS at doses of 100, 300, and 700 mg? What is the effect of ofatumumab on MRI outcome measures of monthly MRI scans compared with placebo? This study provides Class II
Figure 1
evidence that ofatumumab is well-tolerated and effective in RRMS at doses of 100, 300, and 700 mg. Significant relative reductions were observed for ofatumumab relative to placebo in the number of new T1 GdE lesions (p , 0.001), total number of T1 GdE lesions (p , 0.001), and new and/or enlarging T2 lesions (p , 0.001).
RESULTS Patients. Thirty-eight of 54 screened patients across 13 European sites were eligible and randomized to receive either ofatumumab/placebo (n 5 26) or placebo/ofatumumab (n 5 12; figure 1). Thirty-six of 38 patients completed both treatment periods and received all planned infusions; 2 patients prematurely withdrew because of AEs during their first ofatumumab infusion. Demographics and baseline clinical and MRI characteristics were similar between treatment groups and dose cohorts (table 1). Patients were recruited from May 2008 until April 2009 and followed up until October 2011.
Safety data. Safety data are shown in table 2. During
both periods, the percentage of patients with any AE, any drug-related AE, or any drug-related AE on the
Patient disposition
All patients allocated to treatment received the designated intervention. AE 5 adverse event. Neurology 82
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0.3 (0.7) [0.0 (0.0–2.0)] 1.5 (3.1) [0.0 (0.0–13.0)] 0.5 (1.0) [0.0 (0.0–2.0)] 2.7 (4.6) [1.0 (0.0–13.0)]
2.5 (2.6) [1.8 (0.4–8.7)]
8.1 (4.7) [8.2 (2.2–13.9)]
2.4 (0.9) [2.0 (1.5–4.0)]
0.5 (0.9) [0.0 (0.0–2.0)]
0.6 (1.2) [0.0 (0.0–3.0)]
Time since diagnosis, y
Time since first symptoms, y
EDSS score
No. of new T1 GdE lesions at baseline
No. of new and/or enlarging T2 lesions at baseline
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Abbreviations: EDSS 5 Expanded Disability Status Scale; GdE 5 gadolinium-enhancing. Data are mean (SD) [median (range)] unless otherwise indicated.
1.4 (2.8) [0.0 (0.0–9.0)] 0.0 (0.0) [0.0 (0.0–0.0)]
0.5 (0.6) [0.5 (0.0–1.0)]
0.2 (0.4) [0.0 (0.0–1.0)] 2.2 (5.0) [0.5 (0.0–25.0)] 0.3 (0.5) [0.0 (0.0–1.0)] 5.1 (9.2) [1.0 (0.0–25.0)] 1.6 (1.6) [1.0 (0.0–4.0)] 0.0 (0.0) [0.0 (0.0–0.0)]
0.3 (0.5) [0.0 (0.0–1.0)]
2.5 (1.0) [2.3 (1.0–4.5)] 2.8 (1.3) [2.5 (0.0–5.0)] 2.5 (0.7) [2.3 (2.0–3.5)] 2.6 (1.6) [2.5 (0.0–4.5)] 3.1 (1.3) [3.5 (1.0–5.0)] 3.1 (1.3) [3.0 (2.0–4.5)]
2.0 (0.9) [2.0 (1.0–3.0)]
6.5 (7.8) [2.6 (0.8–25.8)] 8.5 (5.7) [6.6 (1.7–24.6)] 8.7 (11.6) [4.0 (0.8–25.8)] 11.5 (7.5) [6.8 (4.9–24.6)] 6.8 (4.9) [5.5 (1.7–19.6)] 8.6 (7.4) [7.6 (1.8–17.2)]
2.3 (0.4) [2.3 (1.9–2.7)]
1.7 (2.1) [0.9 (0.1–6.7)] 3.8 (3.7) [26 (0.4–13.9)] 0.4 (0.3) [0.3 (0.1–0.8)] 5.0 (4.6) [4.4 (0.4–13.7)] 4.1 (3.8) [3.6 (0.7–13.9)] 3.5 (2.9) [3.3 (0.5–6.7)]
1.2 (0.8) [1.4 (0.1–2.1)]
100
50.0 61.5
100 100
0.0 57.1 75.0 54.5
100 100 100
75.0
100 100
75.0
White race, %
Female, %
36.0 (9.1) [35.0 (24.0–51.0)] 36.3 (7.9) [33.5 (26.0–52.0)] 44.0 (8.1) [44.0 (37.0–51.0)] 33.7 (8.4) [29.0 (26.0–46.0)] 27.0 (2.2) [27.5 (24.0–29.0)] 36.6 (7.0) [35.0 (28.0–48.0)] 37.0 (6.5) [37.0 (30.0–43.0)] 38.0 (9.0) [35.5 (26.0–52.0)] Age, y
Placebo/ofatumumab (n 5 12) Ofatumumab/ placebo (n 5 26) Ofatumumab/placebo Placebo/ofatumumab (n 5 11) (n 5 4) Ofatumumab/placebo Placebo/ofatumumab (n 5 8) (n 5 4)
Ofatumumab/placebo Placebo/ofatumumab (n 5 7) (n 5 4)
Total 700 mg 300 mg 100 mg
Demographics and baseline clinical characteristics Table 1 576
first infusion day of each period was higher with ofatumumab than with placebo across dosing cohorts. The most common AE was the infusionrelated reaction (IRR) of rash, most often reported on the first infusion day. Most AEs were grade 1 or 2, and no grade 4 or 5 AEs were reported. The percentage of patients with $1 infection was not higher with ofatumumab. Serious AEs (SAEs) were reported in 2 patients during the first period: one case of influenza (placebo) and one case of headache leading to hospitalization (ofatumumab 300 mg; considered unrelated to ofatumumab). One SAE in a patient with anemia caused by prolonged menstrual bleeding was reported during the second period. All SAEs resolved and the patients remained in the study. During the first period, one patient receiving ofatumumab 300 mg discontinued treatment during the first infusion because of the grade-3 AEs pruritic rash, bronchospasm, and cough, which were considered study drug–related by the investigator. During the second period, one patient receiving ofatumumab 300 mg discontinued treatment during the first infusion because of the grade-2 AEs pharyngeal edema, erythema, nasal congestion, and pruritus, which were considered study drug–related by the investigator. The AEs resolved in both patients. No patient tested positive for HAHA by week 48, indicating there was no immunogenicity induced by ofatumumab. Only marginal changes in IgG, IgA, and IgM were observed. Results of clinical laboratory tests (hematology, biochemistry, and urinalysis), physical examinations, and ECGs were unremarkable during both periods. There were no cases of opportunistic infections, including progressive multifocal leukoencephalopathy. Efficacy data. MRI endpoints. Tables 3 and 4 and figure e-2 summarize MRI results. For weeks 8–24, profound and significant relative reductions were observed for ofatumumab relative to placebo in the number of new T1 GdE lesions (p , 0.001), total number of T1 GdE lesions (p , 0.001), and new and/or enlarging T2 lesions (p , 0.001). The percentage reduction in the total number of T1 GdE lesions from weeks 8 to 24 was .99% (table 3). In the first 24-week period, similar reductions were estimated for all doses of ofatumumab, although none of the patients in the 700-mg group had any MRI lesions. For weeks 8–24, only one patient (100 mg ofatumumab) had a single new T1 GdE lesion, whereas 8 of 12 placebo-treated patients (67%) had $1 new T1-weighted GdE lesion. Ofatumumab did not provide significant benefit regarding T1 hypointense lesions. For weeks 32–48, new GdE lesion activity continued to be minimal for patients who received ofatumumab
Table 2
Adverse events summary Weeks 0–24 100 mg
300 mg
700 mg
Total
Treatment at weeks 0–24
Ofatumumab Placebo Ofatumumab Placebo Ofatumumab Placebo Ofatumumab Placebo (n 5 8) (n 5 4) (n 5 11) (n 5 4) (n 5 7) (n 5 4) (n 5 26) (n 5 12)
Any adverse event
8 (100)
3 (75.0) 10 (90.9)
2 (50.0) 7 (100)
2 (50.0) 25 (96.2)
7 (58.3)
Any drug-related adverse event
7 (87.5)
2 (50.0) 10 (90.9)
0 (0)
7 (100)
1 (25.0) 24 (92.3)
3 (25.0)
Any serious adverse event
0 (0)
1 (25.0)
1 (9.1)
0 (0)
0 (0)
0 (0)
1 (3.8)
1 (8.3)
1 (9.1)
0 (0)
1 (14.3)
0 (0)
2 (7.7)
1 (8.3)
10 (90.9)
0 (0)
7 (100.0)
1 (25.0) 23 (88.5)
1 (8.3)
Adverse events ‡grade 3
0 (0)
1 (25.0)
Drug-related adverse event on first infusion of treatment period
6 (75.0)
0 (0)
Infections
5 (62.5)
3 (75.0)
4 (36.4)
2 (50.0) 1 (14.3)
1 (25.0) 10 (38.5)
6 (50.0)
Rash
2 (25.0)
0 (0)
3 (27.3)
0 (0)
4 (57.1)
0 (0)
9 (34.6)
0 (0)
Erythema
2 (25.0)
0 (0)
1 (9.1)
0 (0)
1 (14.3)
0 (0)
4 (15.4)
0 (0)
Upper respiratory tract infection
1 (12.5)
2 (50.0)
2 (18.2)
0 (0)
1 (14.3)
0 (0)
4 (15.4)
2 (16.7)
Viral infection
1 (12.5)
0 (0)
2 (18.2)
0 (0)
0 (0)
0 (0)
3 (11.5)
0 (0)
Throat irritation
3 (37.5)
0 (0)
4 (36.4)
0 (0)
2 (28.6)
0 (0)
9 (34.6)
0 (0)
Adverse events in ‡3 patients
Headache
1 (12.5)
1 (25.0)
1 (9.1)
0 (0)
0 (0)
0 (0)
2 (7.7)
1 (8.3)
Fatigue
2 (25.0)
1 (25.0)
2 (18.2)
0 (0)
0 (0)
0 (0)
4 (15.4)
1 (8.3)
Back pain
1 (12.5)
1 (25.0)
1 (9.1)
0 (0)
0 (0)
0 (0)
2 (7.7)
1 (8.3)
Flushing
0 (0)
0 (0)
2 (18.2)
0 (0)
1 (14.3)
1 (25.0)
3 (11.5)
1 (8.3)
Weeks 24–48 100 mg
300 mg
700 mg
Total
Treatment at weeks 24–48
Placebo Ofatumumab Placebo Ofatumumab Placebo Ofatumumab Placebo Ofatumumab (n 5 26) (n 5 12) (n 5 8) (n 5 4) (n 5 11) (n 5 4) (n 5 7) (n 5 4)
Any adverse event
4 (50.0) 3 (75.0)
5 (45.0) 4 (100)
4 (57.0) 4 (100)
Any drug-related adverse event
0 (0)
2 (50.0)
0 (0)
4 (100)
1 (14.0) 4 (100) 0 (0)
13 (50)
11 (92)
1 (4)
10 (83)
1 (4)
0 (0)
Any serious adverse event
0 (0)
0 (0)
1 (9.0)
0 (0)
0 (0)
Adverse events ‡grade 3
0 (0)
1 (25.0)
1 (9.0)
0 (0)
2 (29.0) 1 (25.0)
3 (12)
2 (17)
Drug-related adverse event on first infusion of treatment period
0 (0)
2 (50.0)
0 (0)
3 (75.0)
1 (14.0) 3 (75.0)
1 (4)
8 (67)
Infections
2 (25.0) 0 (0)
2 (18.0) 1 (25.0)
2 (29.0) 1 (25.0)
6 (23)
2 (17)
Nasopharyngitis
2 (25)
0 (0)
0 (0)
0 (0)
1 (14)
0 (0)
3 (12)
0 (0)
Rash
0 (0)
2 (50)
0 (0)
0 (0)
0 (0)
2 (50)
0 (0)
4 (33)
Adverse events in ‡3 patients
Data are n (%).
during the first period: one patient had a single new GdE lesion and one patient had 2 new T1 GdE lesions. Among patients receiving ofatumumab during the second period, suppression of new GdE lesions between weeks 32 and 48 was observed in all but one patient, who had one GdE lesion. Clinical endpoints. During weeks 0–24, relapses were documented in 5 patients (19%) who received ofatumumab, of whom one experienced a relapse 2 weeks after infusion, and 3 (25%) who received placebo. During weeks 24–48, relapse was
documented in one additional patient who initially received ofatumumab. None of the 12 patients receiving ofatumumab in the second period experienced a relapse. All patients who relapsed were treated with IV corticosteroids; 5 were hospitalized for relapse (3 of whom received ofatumumab during the first period). All relapses resolved. None of the patients treated with ofatumumab 700 mg experienced relapses. It should be noted that there were no clinically significant changes observed in EDSS or MSFC scores (from baseline or between treatment groups). Neurology 82
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Table 3
MRI endpoints summary Weeks 8–24 100 mg
300 mg
Treatment at weeks 0–24
Ofatumumab Placebo (n 5 8) (n 5 4)
Ofatumumab (n 5 11)
Placebo (n 5 4)
Ofatumumab (n 5 7)
Placebo (n 5 4)
Ofatumumab (n 5 26)
Placebo (n 5 12)
No. of new T1 GdE lesions
0.13a (0.35)
3.06 (4.66)
0.0b (0.0)
23.50 (43.03)
0.0a (0.0)
2.50 (3.32)
0.04b,c (0.20)
9.69 (24.86)
No. of total T1 GdE lesions
0.13a (0.35)
3.63 (5.02)
0.09a (0.30)
25.75 (46.23)
0.0a (0.0)
4.50 (7.14)
0.08b,c (0.27)
11.29 (26.79)
a
700 mg
a
a
Total
b,c
No. of new and/or enlarging T2 lesions
0.25 (0.71)
4.00 (6.52)
0.09 (0.30)
25.00 (46.03)
0.0 (0.0)
3.00 (4.24)
0.12
(0.43)
10.67 (26.58)
No. of new T1 hypointense lesions
0.0 (0.0)
1.50 (3.00)
0.27 (0.47)
5.00 (9.35)
0.29 (0.49)
0.25 (0.50)
0.19 (0.40)
2.25 (5.55)
Percentage change (SD) in volume of T2 lesionsd
24.7 (9.6)
7.6 (4.5)
23.1 (6.3)
24.9 (13.4)
20.9 (4.1)
21.0 (2.0)
23.0 (7.0)
11.0 (14.0)
Weeks 32–48 100 mg
300 mg
700 mg
Total
Treatment at weeks 24–48
Placebo (n 5 8)
Ofatumumab (n 5 4)
Placebo (n 5 11)
Ofatumumab (n 5 4)
Placebo (n 5 7)
Ofatumumab (n 5 4)
Placebo (n 5 26)
Ofatumumab (n 5 26)
No. of new T1 GdE lesions
0.13 (0.35)
0.0 (0.0)
0.0 (0.0)
0.33 (0.58)
0.29 (0.76)
0.0 (0.0)
0.12 (0.44)
0.09 (0.30)
No. of total T1 GdE lesions
0.13 (0.35)
0.0 (0.0)
0.0 (0.0)
3.00 (5.20)
0.43 (1.13)
0.0 (0.0)
0.16 (0.62)
0.82 (2.71)
No. of new and/or enlarging T2 lesions
0.13 (0.35)
0.0 (0.0)
0.0 (0.0)
0.33 (0.58)
0.29 (0.76)
0.0 (0.0)
0.12 (0.44)
0.09 (0.30)
No. of new T1 hypointense lesions
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
3.00 (4.36)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.82 (2.40)
Abbreviation: GdE 5 gadolinium-enhancing. Data are mean (SD). The p values are from the Wilcoxon test (for pooled placebo vs an active group or vs pooled active data) or Kruskal-Wallis test (all 4 groups). a p , 0.05 vs placebo. b p # 0.001 vs placebo. c p , 0.001 for overall test for dose effect. d Change from baseline to week 24. Percentage change in volume of T2 lesions from week 24 to week 48 is not reported because subjects initially randomized to ofatumumab were excluded from further analysis because of carryover effect.
Peripheral CD191 B-cell counts.
Ofatumumab treatment was associated with profound reductions in CD191 cells in peripheral blood at all 3 dose levels in both periods (figure e-3). The median value of CD191 cells decreased to zero within 1 week of ofatumumab treatment. During both periods, recovery started after approximately 12 to 16 weeks in the ofatumumab 100-mg group, after 20 weeks in a few Table 4
Nonparametric analysis of MRI endpoints Difference in counts (ofatumumab vs placebo) a
a
b
Treatment at weeks 0–24
Estimate
95% CI
p Value
Cumulative no. of new T1 GdE lesions
21.3
24.0, 21.0
,0.001
Cumulative no. of total T1 GdE lesions
22.0
26.0, 0.0
,0.001
Cumulative no. of new and/or enlarging T2 lesions
21.3
24.0, 0.0
,0.001
0.0
0.0, 0.0
0.256
Cumulative no. of new T1 hypointense lesions
Abbreviations: CI 5 confidence interval; GdE 5 gadolinium-enhancing. a Hodges-Lehmann method. b Wilcoxon rank-sum test. 578
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patients in the ofatumumab 300-mg group, whereas all patients in the ofatumumab 700-mg group experienced persistent and complete CD191 suppression at week 24. In the ofatumumab/placebo groups, CD191 cell counts continued to increase, and repletion, defined as recovery to or above the lower limit of normal of 100 CD191 cells/mm3, was observed in a few patients in each dose group by week 48, but CD191 cell repletion was observed in all patients during the follow-up period. DISCUSSION The current study showed that administration of ofatumumab up to 700 mg twice at a 2-week interval produced no unexpected safety signals or dose-related safety concerns and was well tolerated. IRRs, most often mild, were common on the first day of ofatumumab dosing, even with premedication, but were not observed on the second infusion day. Based on the small number of patients in each cohort, neither incidence nor severity of IRRs appeared to be dose-related. The IRRs observed in this
study are consistent with the known safety profile of ofatumumab, which has been studied in more than 500 patients for other indications.14,15,23 The IRRs are most likely attributable to cytokine release after pronounced B-cell depletion at first infusion.27 Because ofatumumab is a human mAb, low immunogenicity was expected. In fact, none of the patients in this study tested HAHA positive. In a phase 2 study of ocrelizumab, the number of patients with HAHA was similar between the ocrelizumab group and the placebo group (2%–3%).10 In contrast, human anti-chimeric antibodies (HACA) were detected in 24.6% of patients treated with rituximab 11.1 months after randomization.6 No association between HACA and AEs or efficacy responses was noted in that phase 2 rituximab trial, but because HACA occurred in the last part of the study (after 24 weeks) in all HACA-positive patients and the primary and secondary endpoints were measured only up to 24 weeks, it would have been unlikely to observe any negative effects of HACA.6 The percentage of patients with $1 infection was similar between the ofatumumab and placebo treatment groups. Most infections were categorized as grade 1 and none were grade 3 or higher. Regarding efficacy endpoints, we observed minimal new GdE T1 MRI lesions after ofatumumab administration across all doses during both the first period (weeks 8–24) and the second period (weeks 32–48). The effects on CD201 reduction and suppression of MRI activity observed in this study were very similar to those reported in the phase 2 trial of ocrelizumab at doses of 600 and 2,000 mg (89% and 96% T1 GdE lesion reduction, respectively) administered twice with a 2-week interval.10 Similar results were observed for other MRI endpoints, although statistical separation was not observed for new T1 hypointense lesions. The magnitude of suppression, however, should be interpreted cautiously because of the small sample size. One patient in the group treated with placebo during the first period had 88 new GdE lesions, but, interestingly, this patient had no GdE lesions in the second period after crossing over to receive active therapy with ofatumumab 300 mg. We observed a prolonged effect of ofatumumab, resulting in very low MRI activity in the 25 patients treated with placebo in the second period (weeks 32–48), consistent with the longlasting suppression of B cells observed in patients treated with ofatumumab in the first period. The relatively higher relapse rate observed in the first period in the study are explained, at least partly, by a less restrictive relapse definition than the definitions used in the majority of recent phase 2 and 3 RRMS clinical trials. From studies that have reported both qualifying relapses and all relapses (qualifying and nonqualifying relapses), it appears that the less restrictive definition used in
daily clinical practice and adopted in this trial yields approximately 50% to 100% more relapses than the more rigorous definition of a qualifying relapse.28,29 In the phase 2 trial of rituximab that used the same relapse definition as the present study, the annualized relapse rate in the rituximab group was 0.4 at both 24 weeks and 48 weeks, which was similar to or higher than that in the present study.6 The annualized relapse rate in the ocrelizumab study that used the more rigorous relapse definition was, as expected, lower: 0.13 in the 600-mg and 0.17 in the 2,000-mg treatment group.10 Ofatumumab treatment was associated with a profound, selective reduction in B cells as measured by CD191 expression, similar to that observed with ocrelizumab.10 This effect was observed across all ofatumumab doses examined; it would be interesting to study lower doses to elucidate when such profound depletion is no longer observed and to assess the ofatumumab dose effect on efficacy. B-cell repletion to the lower limit of normal was observed in all patients during the individualized follow-up period. Consistent with the lack of expression of CD201 on stem cells or plasma cells,30 Ig levels remained within normal range during the study. The human mAb ofatumumab administered to patients with RRMS as a single agent in 2 IV infusions in doses up to 700 mg, 2 weeks apart, was not associated with any unexpected safety concerns, was well-tolerated, and showed a profound reduction in MRI activity. Notably, this small 48-week study was not designed to assess clinical efficacy or longterm safety or to detect less-common AEs. The results warrant further exploration of the efficacy and safety of ofatumumab in RRMS in a larger phase 2b study. It would be important to study a wider range of doses of ofatumumab to identify the most optimal dosing regimen. AUTHOR CONTRIBUTIONS P.S.S., R.G., and M.F. designed the study. P.S.S., E.H., and J.D. acquired the data. W.H. Clausen analyzed the data. M.F. designed the MRI protocol, and analyzed and interpreted the MRI data. P.S.S., R.G., and M.F. prepared the manuscript. P.S.S., M.F., S.L., R.G., F.D., S.S., E.H., and J.D. reviewed the manuscript.
ACKNOWLEDGMENT The sponsors and authors thank the patients who volunteered to participate in this study. The sponsors and authors also thank the IDMC members: Professor Ludwig Kappos (Chair), Dr. Michel Clanet, Dr. Gary Cutter, and Professor Ralf Gold; the progressive multifocal leukoencephalopathy adjudication committee members: Dr. Joseph Berger (Chair), Dr. Lars Nielsen, and Dr. Eugene Major; and the MRI Analysis Center, Neuroimaging Research Unit: Massimo Filippi (Chair), Maria A. Rocca, Martina Absinta, Paola Valsasina, Alessandro Meani, and Mauro Sibilia. Dr. Wan Hui Ong Clausen at Larix (Ballerup, Denmark) conducted all statistical analyses. Contributors: Jane Saiers, PhD (The Write Medicine, Inc., performed substantive editing of the manuscript), Francesca Balordi, PhD (Medicus International New York, performed substantive editing of the manuscript), Jennifer Granit, PhD (Medicus International New York, performed substantive editing of the manuscript), Ken Wiesen, PhD Neurology 82
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(Medicus International New York, performed substantive editing of the manuscript), Cara Hunsberger, MS, CMPP (Medicus International New York, edited the manuscript for nonintellectual content), Gail Huggins (Medicus International New York, edited the manuscript for nonintellectual content), and Michele Springer (Medicus International New York, edited the manuscript for nonintellectual content).
4.
5.
6. STUDY FUNDING GlaxoSmithKline and Genmab (Copenhagen, Denmark) sponsored the study described in this manuscript.
7.
DISCLOSURE
8.
P. Sorensen has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Genmab, Teva Pharmaceutical Industries Ltd., Elan, and GlaxoSmithKline; has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Genmab, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, and Bayer Schering, and has received funding of travel for these activities; has served as Editor-in-Chief of the European Journal of Neurology and is currently an editorial board member for Multiple Sclerosis Journal, European Journal of Neurology, and Therapeutic Advances in Neurological Disorders; and has received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Bayer Schering, sanofi-aventis, Genzyme, and Novartis. His department has received research support from Biogen Idec, Bayer Schering, Merck Serono, Teva Pharmaceutical Industries Ltd., Baxter, sanofi-aventis, BioMS, Novartis, Bayer, RoFAR, Roche, and Genzyme, and from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life Sciences, Genomics and Biotechnology for Health. S. Lisby is an employee of Genmab A/S. R. Grove is an employee of GlaxoSmithKline and holds shares in the company. F. Derosier is a former employee of GlaxoSmithKline and holds shares in the company. S. Shackelford is a former employee of GlaxoSmithKline and holds shares in the company. E. Havrdova has received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme, and Teva, as well as support for research activities from Biogen Idec and Merck Serono. She has been supported by the Czech Ministry of Education, Research Projects MSM0021620849, PRVOUK-P26/LF1/4. J. Drulovic serves on scientific advisory boards for Bayer Schering Pharma and Biogen Idec, has received speaker honoraria from Novartis and travel grants from Bayer Schering Pharma, and has received research grant support from the Ministry of Education and Science, Republic of Serbia (project no. 175031). M. Filippi serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Genmab A/S; has received funding for travel from Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves on speakers bureaus for Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; receives research support from Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, and CurePSP. Go to Neurology.org for full disclosures.
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10.
11.
12.
13.
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18.
19. Received June 26, 2013. Accepted in final form November 4, 2013. REFERENCES 1. Meier UC, Giovannoni G, Tzartos JS, Khan G. Translational mini-review series on B cell subsets in disease: B cells in multiple sclerosis: drivers of disease pathogenesis and Trojan horse for Epstein-Barr virus entry to the central nervous system? Clin Exp Immunol 2012;167:1–6. 2. Ontaneda D, Hyland M, Cohen JA. Multiple sclerosis: new insights in pathogenesis and novel therapeutics. Annu Rev Med 2012;63:389–404. 3. Rizvi SA, Agius MA. Current approved options for treating patients with multiple sclerosis. Neurology 2004;63:S8–S14. 580
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This Week’s Neurology® Podcast Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis (See p. 556) This podcast begins and closes with Dr. Robert Gross, Editor-inChief, briefly discussing highlighted articles from the February 18, 2014, issue of Neurology. In the second segment, Dr. Alex Menze talks with Dr. Jerome Honnorat about his paper on the clinical specificities of patients with NMDA receptor antibodies encephalitis. Dr. James Addington reads our e-Pearl of the week about posterior interosseous nerve syndrome. In the next part of the podcast, Dr. Mark McAllister focuses his interview with Dr. Seemant Chaturvedi on a brief review of a new oral anticoagulant (Apixaban), reference clinical trial, indication, and dosing. Disclosures can be found at www.neurology.org. At www.neurology.org, click on “RSS” in the Neurology Podcast box to listen to the most recent podcast and subscribe to the RSS feed. CME Opportunity: Listen to this week’s Neurology Podcast and earn 0.5 AMA PRA Category 1 CME Credits™ by answering the multiple-choice questions in the online Podcast quiz.
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Neurology 82
February 18, 2014
581
Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study Per S. Sorensen, Steen Lisby, Richard Grove, et al. Neurology 2014;82;573-581 Published Online before print January 22, 2014 DOI 10.1212/WNL.0000000000000125 This information is current as of January 22, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/7/573.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/01/22/WNL.0000000000 000125.DC1.html http://www.neurology.org/content/suppl/2014/04/09/WNL.0000000000 000125.DC2.html
References
This article cites 26 articles, 8 of which you can access for free at: http://www.neurology.org/content/82/7/573.full.html##ref-list-1
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