Marianne Sweetser

LONGTERM SAFETY OF PATIENTS RECEIVING RITUXIMAB IN RHEUMATOID ARTHRITIS CLINICAL TRIALS

Objective. To evaluate the longterm safety of rituximab in clinical trials in patients with rheumatoid arthritis (RA). Methods. Pooled analysis of safety data, including adverse events (AE) and infections, from patients treated with rituximab in combination with methotrexate in a global clinical trial program. Results. A total of 2578 patients with RA received at least 1 course of rituximab. Safety analyses were based on 5013 patient-years of rituximab exposure. The most frequent AE was infusion-related reactions (25% of patients during the first infusion of Course 1). Less than 1% of infusion-related reactions were considered serious. Rates of AE and serious AE (SAE; 17.85 events/100 patient-yrs, 95% CI 16.72, 19.06) were stable following each course. The overall serious infection rate was 4.31/100 patient-years (95% CI 3.77, 4.92). Infections and serious infections over time remained stable across 5 courses at 4–6 events/100 patient-years. Compared with other patients with RA and with the general US population, there was no increased risk of malignancy. Conclusion. In this longterm safety update in RA clinical trial patients, rituximab remained well tolerated over multiple courses. SAE and infections remained stable over time and by treatment course.

Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis

BACKGROUND Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders. METHODS We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate. RESULTS The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%). CONCLUSIONS Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).

Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients

Objective: To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab. Methods: RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected. Results: Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred. Conclusions: In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial

BACKGROUND In the SELECT trial, disease activity was reduced in patients with multiple sclerosis who received daclizumab high-yield process (HYP) for 52 weeks. The primary aim of the SELECTION extension study was to assess the safety and immunogenicity of extended treatment with daclizumab HYP. METHODS A multicentre, randomised, double-blind, 52-week extension trial was done in 74 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, and the UK between Feb 13, 2009, and Oct 3, 2012. Eligible patients were aged 18-55 years, had relapsing-remitting multiple sclerosis, and had completed the SELECT study. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 mg or 300 mg subcutaneous daclizumab HYP every 4 weeks for 52 weeks (treatment initiation group); those who had received daclizumab HYP were randomly assigned (1:1) to continue their present dose with (washout and re-initiation group) or without (continuous treatment group) a washout period of 20 weeks. All randomisation was done with a centralised, interactive voice-response system. Patients and personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug but had no interaction with patients. The primary endpoints were the safety and immunogenicity of daclizumab HYP. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00870740. FINDINGS 517 (91%) of 567 patients who completed the SELECT trial entered SELECTION, of whom 170 were in the treatment initiation group, 173 in the continuous treatment group, and 174 in the washout and re-initiation group. 11 patients in the treatment initiation group (6%), 13 in the continuous treatment group (8%), and ten in the washout and re-initiation group (6%) had any serious adverse event other than relapse of multiple sclerosis. One patient in the washout and re-initiation group (300 mg daclizumab HYP) died because of autoimmune hepatitis; a contributory role of daclizumab HYP could not be excluded. Seven patients tested positive for neutralising antidrug antibodies: one (1%) of 128 for whom data were available in the continuous treatment group (this patient also tested positive at SELECTION baseline), four (2%) in the treatment initiation group, and two (2%) of 129 in the washout and re-initiation group. INTERPRETATION Adverse events and immunogenicity were not increased in the second year of continuous treatment with daclizumab HYP or during treatment washout and re-initiation. These results support further assessment of daclizumab HYP for relapsing-remitting multiple sclerosis. FUNDING Biogen Idec and AbbVie Biotherapeutics.

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: Results from a randomized controlled trial

OBJECTIVE To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24. RESULTS Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98-49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. CONCLUSION The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience

IntroductionDelayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting.MethodsPreclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy.ResultsAnimal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12–22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up.ConclusionAlthough data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed.FundingBiogen, Inc.

Oral BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis: a review of DEFINE and CONFIRM

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide. Areas covered: This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing–remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups. Expert opinion: The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.

Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis.

Natalizumab is an immunomodulatory drug approved for the treatment of multiple sclerosis. This randomized, multicenter, open-label study evaluated natalizumabs effects on immunization responses to a recall antigen (tetanus toxoid [TT]) and a neoantigen (keyhole limpet hemocyanin [KLH]) in patients with relapsing forms of multiple sclerosis (MS). Natalizumab-naive relapsing MS patients were randomized (1:1; n=30 per group) to receive TT and KLH immunizations either without natalizumab treatment (control) or after 6 months of natalizumab treatment (natalizumab group). An adequate response to immunization was defined as an increase to at least twofold in specific serum immunoglobulin G (IgG) 28 days after the first immunization. All evaluable patients achieved protective levels of anti-TT IgG antibodies, and the proportion of responders to this recall antigen, as well as to primary immunization with KLH, was similar in the presence and absence of natalizumab. This indicates that natalizumab treatment does not appear to affect responses to primary or secondary immunization in a clinically meaningful way.