Summary
Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based ...on long‐term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient‐years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy‐six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit‐risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.
Background
The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high‐disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major ...adverse vascular events (MAVEs; including thrombotic events TEs); anemia; and/or physician‐reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated.
Methods
Registry patients were stratified by baseline HDA and eculizumab‐treatment status. Longitudinal changes in laboratory and clinical PNH‐related endpoints were evaluated using linear mixed models (continuous variables) or Poisson regression (incidence rates).
Results
As of May 1, 2017, 3009 patients (HDA/eculizumab‐treated, n = 913; HDA/never‐treated, n = 651; no‐HDA/eculizumab‐treated, n = 173; no‐HDA/never‐treated, n = 1272) were analyzed. Higher proportions of eculizumab‐treated patients had HDA and history of MAVEs. In patients with and without HDA, respectively, eculizumab treatment resulted in reductions from baseline for (1) LDH ratio (mean SD: −5.3 4.0 and −2.3 3.8); (2) incidence rate ratio (IRR) for MAVEs (−80% and −70%); (3) IRR for TEs (−80% for both); and (4) units of red blood cell transfusions per year (from 6.8 to 2.8 and 3.6 to 2.5 units).
Conclusions
Eculizumab treatment in a real‐world setting improved outcomes, including substantial decreases in hemolysis, MAVE rates, TEs, and transfusions in PNH patients regardless of HDA.
In Phase III studies (DEFINE Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS/CONFIRM Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), ...delayed-release dimethyl fumarate (DMF) demonstrated significant efficacy and a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS). Post hoc analyses of integrated data from DEFINE/CONFIRM were conducted to evaluate the effect of DMF in patients previously treated with interferon (IFN) beta.
Patients (age 18–55 years; Expanded Disability Status Scale score, 0–5.0) were randomized to receive DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only) for up to 2 years. Previous IFN users received at least 1 IFN treatment >3 months before randomization. Data for DMF 240 mg BID (approved dosing regimen) are reported.
In the integrated intention-to-treat population, 172 and 169 patients receiving DMF or placebo, respectively, had received ≥1 prior IFN. In this subgroup, significant reductions with DMF versus placebo were observed for the annualized relapse rate (rate ratio, 0.55 95% CI, 0.40–0.77), new/newly enlarging T2-hyperintense lesions (lesion mean ratio, 0.16 95% CI, 0.09–0.29), odds of having more gadolinium-enhancing lesions (odds ratio, 0.17 95% CI, 0.07–0.44), and new T1-hypointense lesions (lesion mean ratio, 0.25 95% CI, 0.14–0.45). Median Expanded Disability Status Scale scores remained stable during the study period. Adverse events associated with DMF included flushing and gastrointestinal events.
In this post hoc analysis in patients with previous IFN treatment, DMF demonstrated significant efficacy over 2 years versus placebo and an adverse event profile consistent with the overall population of DEFINE/CONFIRM. ClinicalTrials.gov identifiers: DEFINE, NCT00420212; and CONFIRM, NCT00451451.
Objective: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and fingolimod are approved oral disease-modifying treatments for relapsing-remitting multiple sclerosis. In ...phase 3 trials, DMF (DEFINE/CONFIRM) and fingolimod (FREEDOMS/FREEDOMS II) resulted in significant reductions in clinical and magnetic resonance imaging activity, with acceptable safety profiles. Direct comparisons of these treatments are not possible due to a lack of head-to-head trials. We compared 2 year efficacy of DMF versus fingolimod at the approved dosage using a matching-adjusted indirect approach.
Research design and methods: Individual patient data from DEFINE and CONFIRM, and aggregate data from FREEDOMS and FREEDOMS II, were pooled and compared using the matching-adjusted in-direct method. To account for cross-trial differences, data from trials with available individual patient data were adjusted to match aggregate data (i.e. average patient characteristics) from trials without patient-level data. Data from DMF-treated patients were weighted such that average baseline characteristics matched those of fingolimod-treated patients. After matching, weighted treatment outcomes for DMF-treated patients (240 mg twice daily) were compared with summary outcomes for fingolimod-treated patients (0.5 mg once daily). All comparison results of DMF versus fingolimod used fingolimod as the reference.
Results: After matching, baseline characteristics were balanced between DMF and fingolimod. At year 2, the efficacy of DMF was similar to that of fingolimod for annualized relapse rate (rate ratio 95% confidence interval (CI): 1.11 0.88, 1.40), 12 week confirmed disability progression (hazard ratio 95% CI: 0.90 0.63, 1.29), and Multiple Sclerosis Functional Composite (mean difference 95% CI: 0.04 −0.05, 0.13). For patient-reported outcomes (EuroQoL 5-Dimensions questionnaire), the mean differences (95% CI) were 0.05 (0.01, 0.08) for utility score and 3.22 (0.58, 5.86) for visual analog scale score, significantly favoring DMF. There was no significant difference in the percentage of patients with no evidence of disease activity (NEDA) for DMF versus fingolimod among matching-adjusted patients with complete NEDA data: rate ratio (95% CI): 0.92 (0.51, 1.64).
Conclusions: Using the matching-adjusted indirect comparison approach, the efficacy of DMF and fingolimod were similar on all clinical outcomes, while patient-reported outcomes showed greater benefit with DMF. Study limitations include possible confounding from unobserved/unknown differences between trials, and trial length may have been insufficient to detect significant differences on disability progression.
Clinical trial registration: NCT00420212 (DEFINE); NCT00451451 (CONFIRM); NCT00289978 (FREEDOMS); NCT00355134 (FREEDOMS II).
Introduction: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement ...activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. Methods: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). Results: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, −3.4; Ecu + c-IST, −3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. Discussion/conclusion: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence.
Introduction
Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated clinical and neuroradiologic efficacy and safety in the Phase 3 DEFINE and CONFIRM trials, and in ...the extension study (ENDORSE), in patients with relapsing–remitting multiple sclerosis (RRMS). This post hoc analysis assessed DMF efficacy in newly diagnosed patients with RRMS with 6-year minimum follow-up.
Methods
Patients randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on same dosage in ENDORSE. Patients randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re-randomized to DMF BID or TID. Results for DMF BID (approved dosage) are reported. Newly diagnosed patients were diagnosed within 1 year prior to DEFINE/CONFIRM entry and either treatment-naive or previously treated with corticosteroids alone.
Results
The newly diagnosed population included 144 patients continuously treated with DMF BID in DEFINE/CONFIRM and ENDORSE (DMF/DMF) and 85 treated with PBO for 2 years in DEFINE/CONFIRM followed by 4 years of DMF BID in ENDORSE (PBO/DMF). At 6 years (ENDORSE Year 4), the annualized relapse rates ARR; 95% confidence interval (CI) were 0.137 (0.101, 0.186) and 0.168 (0.113, 0.252) for DMF/DMF and PBO/DMF, respectively; representing 19% risk reduction (
P
= 0.3988
)
. PBO/DMF patients demonstrated improvements in ARR after switching to DMF in ENDORSE: 0.260 (0.182, 0.372) for Years 0–2 (DEFINE/CONFIRM) and 0.102 (0.064, 0.163) for Years 3–6 (ENDORSE), representing 61% risk reduction for Years 3–6 versus Years 1–2 (
P
< 0.0001). The proportion of patients with 24-week confirmed disability progression (95% CI) at 6 years was 15.7% (10.3%, 23.7%) in DMF/DMF and 24.3% (15.9%, 36.2%) in PBO/DMF, representing 49% risk reduction versus PBO/DMF (
P
= 0.0397).
Conclusion
Long-term DMF treatment demonstrated strong and sustained efficacy in newly diagnosed patients. Results suggest greater clinical benefits with earlier initiation of treatment in this patient population.
Funding
Biogen.
Trial registration
ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).
Introduction
Clinical course and treatment response may vary according to race/ethnicity in multiple sclerosis (MS) patients. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant ...DMF) demonstrated significant efficacy and a favorable benefit–risk profile in relapsing-remitting MS (RRMS) patients in the 2-year phase III DEFINE/CONFIRM studies.
Methods
In this post hoc analysis of integrated data from DEFINE/CONFIRM, we assessed clinical efficacy and safety/tolerability in black, Hispanic, and Asian patients treated with DMF 240 mg twice daily (approved dosage) or placebo. Eligible patients were 18–55 years of age with an Expanded Disability Status Scale score of 0–5.0. In the integrated intention-to-treat population, 769 and 771 patients were treated with DMF or placebo, respectively, of whom 10 and 19 were black, 31 and 23 were Hispanic, and 66 and 70 were Asian.
Results
In the black, Hispanic, and Asian subgroups, DMF was associated with lower annualized relapse rates at 2 years compared with placebo rate ratio (95% confidence interval (CI)), 0.05 (0.00–1.07); 0.31 (0.10–0.95); and 0.64 (0.30–1.34), respectively. The percentage of black, Hispanic, and Asian patients with 12-week confirmed disability progression was lower with DMF (43%, 8%, and 20%, respectively) compared with placebo 57%, 30%, and 25%, respectively; hazard ratio (95% CI), 0.53 (0.02–1.39); 0.17 (0.00–0.60); and 0.71 (0.32–1.58), respectively. The safety/tolerability profile of DMF was generally consistent with that in the overall population of DEFINE/CONFIRM. The incidence of adverse events leading to treatment discontinuation in black, Hispanic, and Asian patients was 2/10, 2/31, and 3/66, respectively, with DMF, and 2/19, 1/23, and 8/70, respectively, with placebo.
Conclusion
DMF may be an efficacious treatment with a favorable benefit–risk profile in black, Hispanic, and Asian patients with RRMS. Further clinical studies are needed to characterize differences in MS presentation and treatment outcomes across ethnic and racial groups.
Funding
Biogen.
Trial Registration
DEFINE: ClinicalTrials.gov identifier NCT00420212; CONFIRM ClinicalTrials.gov identifier NCT00451451.
The effect of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on the Multiple Sclerosis Functional Composite (MSFC) was assessed using integrated Phase 3 DEFINE and ...CONFIRM data. Patients treated with DMF (n = 769) demonstrated significant superiority on the MSFC, and each component, compared with placebo (n = 771) over two years: mean change for DMF vs placebo was 0.054 vs −0.053 on MSFC; −0.088 vs −0.286 on Timed 25-Foot Walk, 0.047 vs 0.003 on 9-Hole Peg Test and 0.178 vs 0.123 on Paced Auditory Serial Addition Test. DMF was an efficacious treatment for patients with MS.
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