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Inebilizumab for treatment of neuromyelitis optica spectrum disorder in patients with prior rituximab use from the N-MOmentum Study

Open AccessPublished:October 26, 2021DOI:https://doi.org/10.1016/j.msard.2021.103352
      • The anti-CD19 B-cell−depleting antibody inebilizumab demonstrated efficacy in preventing attacks in participants with neuromyelitis optica spectrum disorder regardless of prior rituximab use
      • Inebilizumab had a comparable safety profile in participants with or without prior rituximab use, with similar rates of treatment-emergent adverse events and infusion-related reactions
      • Prior rituximab use did not appear to be associated with an increased rate of serious or grade ≥3 infections
      • Findings from this analysis of the N-MOmentum study suggest that inebilizumab may be a suitable treatment choice for individuals with neuromyelitis optica spectrum disorder who were previously treated with rituximab and warrant further investigation in a larger cohort

      Abstract

      Background: The B-cell–depleting agent rituximab (anti-CD20) was historically used to prevent attacks in neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab, which targets and depletes CD19-expressing B cells, plasmablasts, and some plasma cells, received approval from the US Food and Drug Administration for treatment of NMOSD based on results from the randomized, placebo-controlled, phase 2/3 N-MOmentum trial. Because of their closely related mechanisms of action, consideration as to whether inebilizumab may be a suitable treatment option for patients with prior rituximab experience is important. This post hoc analysis of data from N-MOmentum assessed inebilizumab efficacy and tolerability in participants previously treated with rituximab.
      Methods: Adjudicated attacks, secondary efficacy outcomes, and treatment-emergent adverse events were assessed by prior rituximab use during a 6-month randomized control period and open-label period.
      Results: Seventeen participants in N-MOmentum had prior rituximab use, of whom 13 were randomly assigned to the inebilizumab treatment group. Seven of these participants had breakthrough attacks prior to enrollment (annualized attack rate, 0.78 attacks/person-year) despite rituximab use. While they were receiving inebilizumab in the randomized control period, 1 of 13 participants with prior rituximab use had an attack (hazard ratio vs all placebo, 0.16; 95% confidence interval: 0.02 1.20; p = 0.07). Two additional participants with prior rituximab use experienced attacks on inebilizumab during the open-label period, with an overall annualized attack rate of 0.08 (95% confidence interval: 0.02 0.34) attacks/person-year. This annualized attack rate was similar to that of participants without prior rituximab use (0.10 [95% confidence interval: 0.07 0.15]). None of the 7 participants who experienced attacks while taking rituximab experienced an attack while receiving inebilizumab. Two (12%) participants with prior rituximab use experienced serious treatment-emergent adverse events related to inebilizumab, with serious or grade ≥3 infections occurring in 3 (18%) participants each. No deaths or opportunistic infections were reported in this cohort.
      Conclusions: These findings support the efficacy of inebilizumab in participants with NMOSD who had previously been treated with rituximab. Infections occurred in nearly all study participants with prior rituximab exposure, highlighting a need for clinical vigilance in such individuals. Further studies are necessary to determine potential safety concerns of inebilizumab, including risk of infection, in rituximab-experienced patients.
      ClinicalTrials.gov identifier: NCT02200770

      Keywords

      1. Introduction

      Neuromyelitis optica spectrum disorder (NMOSD) is a rare, chronic, autoimmune inflammatory disorder of the central nervous system characterized by recurrent attacks of optic neuritis and transverse myelitis and, less commonly, by brain involvement. (
      • Pandit L
      • Asgari N
      • Apiwattanakul M
      • et al.
      Demographic and clinical features of neuromyelitis optica: a review.
      ;
      • Wingerchuk DM
      • Banwell B
      • Bennett JL
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ) Aquaporin-4 (AQP4)–immunoglobulin (Ig)G antibodies are a sensitive (>75% by cell-based assay) and highly specific (>99% by cell-based assay) diagnostic biomarker of NMOSD that appear to be pathogenic. (
      • Wingerchuk DM
      • Banwell B
      • Bennett JL
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ;
      • Jasiak-Zatonska M
      • Kalinowska-Lyszczarz A
      • Michalak S
      • Kozubski W.
      The immunology of neuromyelitis optica-current knowledge, clinical implications, controversies and future perspectives.
      ;
      • Lennon VA
      • Kryzer TJ
      • Pittock SJ
      • Verkman AS
      • Hinson SR.
      IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
      ;
      • Lennon VA
      • Wingerchuk DM
      • Kryzer TJ
      • et al.
      A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
      ;
      • Waters PJ
      • Pittock SJ
      • Bennett JL
      • Jarius S
      • Weinshenker BG
      • Wingerchuk DM.
      Evaluation of aquaporin-4 antibody assays.
      ) The role of pathogenic antibodies in NMOSD provided rationale for use of the B-cell–depleting antibody rituximab, which targets the B-cell antigen CD20, to prevent NMOSD attacks. (
      • Cree BA
      • Lamb S
      • Morgan K
      • Chen A
      • Waubant E
      • Genain C.
      An open label study of the effects of rituximab in neuromyelitis optica.
      ;
      • Damato V
      • Evoli A
      • Iorio R.
      Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis.
      ;
      • Trebst C
      • Jarius S
      • Berthele A
      • et al.
      Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).
      ) Although evidence for use of rituximab in NMOSD largely comes from retrospective studies, (
      • Cree BA
      • Lamb S
      • Morgan K
      • Chen A
      • Waubant E
      • Genain C.
      An open label study of the effects of rituximab in neuromyelitis optica.
      ;
      • Damato V
      • Evoli A
      • Iorio R.
      Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis.
      ;
      • Trebst C
      • Jarius S
      • Berthele A
      • et al.
      Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).
      ) its efficacy was supported by recent results from the randomized, placebo-controlled RIN-1 study conducted in Japan. (
      • Tahara M
      • Oeda T
      • Okada K
      • et al.
      Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.
      )
      Inebilizumab is an afucosylated humanized immunoglobulin (Ig) G1κ monoclonal antibody that binds to the B-cell surface antigen CD19 and depletes a wide range of B cells, including plasmablasts and plasma cells. (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ;
      • Forsthuber TG
      • Cimbora DM
      • Ratchford JN
      • Katz E
      • Stuve O.
      B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.
      ) The efficacy and safety of inebilizumab in individuals with NMOSD were demonstrated in the randomized, double-blind, phase 2/3 placebo-controlled N-MOmentum study (ClinicalTrials.gov identifier: NCT02200770). (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) Because of their closely related mechanisms of action, it is possible that inebilizumab may not be a suitable treatment option for patients previously treated with rituximab who experienced ongoing disease activity or adverse events with rituximab treatment. Inebilizumab targets a broader range of B cells, including antibody-producing cells unrecognized by anti-CD20 agents (
      • Forsthuber TG
      • Cimbora DM
      • Ratchford JN
      • Katz E
      • Stuve O.
      B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.
      ); therefore, it is also possible that inebilizumab may have a greater therapeutic impact than rituximab. This post hoc analysis assessed efficacy and safety outcomes in participants with prior rituximab use who received inebilizumab in N-MOmentum to evaluate whether prior rituximab exposure was associated with attack activity or unexpected safety signals during inebilizumab treatment. Both of these concerns are of pragmatic interest to neurologists who may be considering the merits of initiating inebilizumab in patients with NMOSD previously treated with rituximab.

      2. Materials and methods

      Detailed methods of N-MOmentum were previously published. (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) Briefly, adults with NMOSD were randomized 3:1 to receive intravenous inebilizumab or placebo during a 6-month randomized control period. At the end of that period, participants could choose to receive inebilizumab during an open-label period. Patients who were previously treated with rituximab were permitted to enroll in the study, provided that their most recent rituximab treatment was >6 months before the baseline visit or that their B-cell counts had reconstituted above the lower level of normal (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) due to the similarity of mechanisms of action between rituximab and inebilizumab and also to characterize the B-cell depletion following inebilizumab treatment. Exclusion criteria, including a list of concomitant medications that precluded study enrollment, have been previously published. (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) No patients received intravenous Ig or subcutaneous Ig during the study.
      Post hoc analysis of efficacy and safety outcomes were performed in the subgroups of participants with and without prior rituximab use. Attacks during the randomized control period were analyzed using a Cox proportional hazards regression, (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) with all participants who received placebo (regardless of rituximab use) as the reference group. Annualized attack rates (AARs) after the first dose of inebilizumab (randomized control period and open-label period) were calculated using total exposure in person-years. Secondary endpoints assessed included change from baseline in Expanded Disability Status Scale scores, number of active lesions on magnetic resonance imaging (MRI), and number of NMOSD-related hospital stays. (
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) Safety outcomes included the number of treatment-emergent adverse events (TEAEs) and laboratory parameters (B-cell count, IgG level, and lymphocyte and neutrophil counts). Secondary endpoints and safety outcomes were summarized with descriptive statistics.

      3. Results

      Of 230 participants who were randomized and received ≥1 dose of inebilizumab or placebo, 17 were treated with rituximab before entering the study; of these, 13 received inebilizumab and 4 received placebo (Table 1). Reported reasons for discontinuation of rituximab were available for 10 of 17 participants and included ongoing disease activity during rituximab treatment (n = 4), changes in insurance coverage (n = 4), change in health care professional (n = 1), and participation in the N-MOmentum trial (n = 1). Most participants with prior rituximab use were women (94%) and seropositive for AQP4-IgG (94%), with a median age of 46 (interquartile range, 31 49) years. Prior to the first dose of inebilizumab, the AAR of this cohort was 0.78 attacks/person-year. Seven participants in this cohort experienced attacks within 6 months of after a rituximab infusion. Baseline characteristics of participants with prior use of rituximab were similar to those without prior experience with rituximab (n = 208), including prior use of azathioprine and mycophenolate mofetil (Supplemental Table 1).
      Table 1Demographics and Baseline Characteristics of Participants in N-MOmentum With Prior Rituximab Use
      ParameterRandomized control group
      Inebilizumab

      (n=13)
      Placebo

      (n=4)
      Overall

      (N=17)
      Age, median (IQR), y47 (32-50)38 (29-46)46 (31-49)
      Women, n (%)13 (100)3 (75)16 (94)
      White or Asian, n (%)4 (31)1 (25)5 (29)
      AQP4-IgG seropositive12 (92)4 (100)16 (94)
      B-cell count, median (IQR), cells/µL

      CD19+

      CD20+


      239.8 (181.2-319.3)

      235.7 (181.2-300.9)


      150.3 (67.8-330.1)

      150.7 (66.4-333.1)


      239.7 (171.8-319.3)

      219.5 (173.1-300.9)
      Time between last rituximab dose and first dose of inebilizumab, median (range), y1.5 (0.8-4.4)1.3 (0.9-3.1)1.5 (0.8-4.4)
      Rituximab doses, median (range), n1 (1-11)1 (1-2)1 (1-11)
      Attack while on rituximab, n (%)5 (38)2 (50)7 (41)
      AAR before first dose of inebilizumab (range)0.73 (0.34-1.89)0.92 (0.40-1.88)0.78 (0.34-1.89)
      AQP4, aquaporin-4; AAR, annualized attack rate; IgG, immunoglobulin; IQR, interquartile range. Statistical comparisons between the two groups were not performed because the sample size of the prior rituximab group was too small for meaningful analysis.
      The individual attack timelines of the 17 participants with prior rituximab use are presented in Fig. 1A. During the randomized control period, 1 of 13 (8%) participants with prior rituximab use who received inebilizumab experienced an attack compared with 22 of 56 (39%) participants assigned to placebo (regardless of rituximab use; hazard ratio [HR] 0.16; 95% confidence interval [CI]: 0.02 1.20; p = 0.07). Two additional participants with prior rituximab use experienced attacks while receiving inebilizumab during the open-label period, both of whom were originally randomized to placebo. The 3 rituximab-experienced participants who had attacks while taking inebilizumab had 1 attack each during their time in the study (1.54 years for the participant randomized to inebilizumab; 0.51 and 2.74 years for the participants randomized to placebo). All 3 attacks were myelitis, one of which was graded as mild by the opticospinal impairment scale. (
      • Wingerchuk DM
      • Hogancamp WF
      • O'Brien PC
      • Weinshenker BG.
      The clinical course of neuromyelitis optica (Devic's syndrome).
      ) After the first inebilizumab administration, the AAR of rituximab-experienced participants was similar to those without prior rituximab use (0.08 and 0.10 attacks/person-year, respectively; Fig. 1B).
      Fig. 1
      Fig. 1Summary of attack data in participants with prior rituximab use. (A) Timeline of treatment history and adjudicated attacks by treatment assignment in the randomized control period. (B) Kaplan–Meier plot of attack-free probability after the first dose of inebilizumab by prior rituximab use. AAR, annualized attack rate; CI, confidence interval; NMOSD, neuromyelitis optica spectrum disorder; OLE, open-label period; P-Y, participant year; RCP, randomized control period.
      Secondary endpoints assessed during the randomized control period are summarized in Supplemental Table 2. Among 13 participants with prior use of rituximab who received inebilizumab during the randomized control period, 2 (15%) experienced worsening of Expanded Disability Status Scale scores, 6 (46%) had active lesions on MRI, and 1 (8%) had a hospital stay related to NMOSD. One of the 2 cases of Expanded Disability Status Scale score worsening and hospitalization were related to the attack that occurred during the randomized controlled period. Secondary outcomes in the inebilizumab groups were generally similar regardless of prior rituximab use.
      Nine of 17 (53%) participants with prior rituximab use and 79 of 208 (38%) without prior rituximab use experienced a TEAE associated with inebilizumab (Table 2). Low rates were observed of serious TEAEs related to inebilizumab in both groups. Serious TEAEs related to inebilizumab were reported in 2 (12%) participants with prior rituximab use and included urinary tract infection and cellulitis. The proportions of participants who experienced infusion-related reactions while receiving inebilizumab were similar regardless of prior rituximab use. Most participants, with or without prior rituximab experience (94% and 70%, respectively), had ≥1 infection while receiving inebilizumab. Serious and grade ≥3 infections each occurred in 3 (18%) participants with prior rituximab experience and 20 (10%) and 22 (11%) participants, respectively, without prior rituximab experience. In participants with prior rituximab use, serious and/or grade ≥3 infections included nasopharyngitis (grade 3), urinary tract infection (serious and grade 3), cellulitis (serious and grade 3), and perforated appendicitis (serious and grade 4), all occurring in 1 participant each. No deaths, opportunistic infections, or cases of progressive multifocal leukoencephalopathy, a recognized complication of B–cell-depleting therapies, (
      • Focosi D
      • Tuccori M
      • Maggi F.
      Progressive multifocal leukoencephalopathy and anti-CD20 monoclonal antibodies: What do we know after 20 years of rituximab.
      ) were reported among the 17 rituximab-experienced participants. The most common AEs in participants with prior rituximab use were urinary tract infection and influenza (Supplemental Table 3).
      Table 2TEAEs, Serious TEAEs, and TEAEs of Special Interest After Receiving Inebilizumab by Prior Rituximab Use
      Event, n (%)Prior rituximab use

      (n=17)
      No prior use of rituximab

      (n=208)
      TEAE
      Any17 (100)190 (91)
      Related to inebilizumab9 (53)79 (38)
      Leading to treatment discontinuation1 (6)6 (3)
      Grade ≥35 (29)46 (22)
      Serious6 (35)38 (18)
      Serious and related to inebilizumab2 (12)9 (4)
      Death02 (1)
      TEAE of special interest
      Any16 (94)157 (76)
      Infusion-related reaction2 (12)25 (12)
      Anaphylactic reaction00
      Hypersensitivity1 (6)2 (1)
      Infections16 (94)146 (70)
      Serious3 (18)20 (10)
      Grade
      19 (53)115 (55)
      212 (71)75 (36)
      32 (12)17 (8)
      41 (6)4 (2)
      501 (<1)
      Hepatic function abnormality1 (6)14 (7)
      Cytopenia1 (6)12 (6)
      Opportunistic infections02 (1)
      Unconfirmed PML01 (1)a
      PML, progressive multifocal leukoencephalopathy; TEAE, treatment-emergent adverse event. aMagnetic resonance imaging and JCV results were inconclusive.11 Statistical comparisons between the two groups were not performed because the sample size of the prior rituximab group was too small for meaningful analysis.
      CD20+ B-cell counts decreased with inebilizumab treatment in all participants with prior rituximab use (Fig. 2). After inebilizumab treatment, participants with and without prior rituximab use experienced annual reductions from baseline in IgG levels of 42.3 mg/dL/year and 49.5 mg/dL/year, respectively (p = 0.67). While they were receiving inebilizumab, 6 (35%) participants with prior rituximab use and 30 (15%) participants without prior rituximab use experienced IgG levels <500 mg/dL (Fig. 3). No correlation between IgG level and infections was observed in a previous analysis of the N-MOmentum study. (
      • Greenburg B
      • She D
      • Ratchford J
      • et al.
      ) IgM levels were similarly reduced following inebilizumab treatment regardless of prior rituximab use (Supplemental Fig. 1). Generally similar lymphocyte and neutrophil counts by toxicity grade were observed with the inebilizumab treatment group regardless of prior rituximab experience, with most reported as grade 0/1 in both groups (Supplemental Table 4).
      Fig. 2
      Fig. 2Absolute CD20+ B-cell counts of individual participants with prior rituximab use during the randomized control period (weeks 0-28) and open-label period (>week 28). All participants received inebilizumab during the open-label period.
      Fig. 3
      Fig. 3IgG concentrations at baseline and with inebilizumab treatment in participants with and without prior use of rituximab. IgG, immunoglobulin G.

      4. Discussion

      This post hoc analysis of N-MOmentum assessed the efficacy and safety of inebilizumab in participants with NMOSD who were previously treated with rituximab. Because inebilizumab and rituximab target and deplete B cells, (
      • Damato V
      • Evoli A
      • Iorio R.
      Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis.
      ;
      • Cree BAC
      • Bennett JL
      • Kim HJ
      • et al.
      Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.
      ) this analysis aimed to provide insight as to whether prior experience with rituximab may predict the efficacy of inebilizumab in this cohort. Overall, efficacy of inebilizumab was comparable for participants with or without prior rituximab exposure. The AAR of the cohort of participants with prior rituximab use decreased from 0.78 at baseline to 0.08 with inebilizumab treatment and was similar to the AAR of participants without prior rituximab use (0.10). Furthermore, none of the 7 participants in the study who experienced breakthrough attacks while previously being treated with rituximab went on to experience an attack while taking inebilizumab, suggesting that inebilizumab might be effective in participants who experience treatment failure with rituximab.
      A similar analysis was performed to assess eculizumab, (
      • Pittock SJ
      • Berthele A
      • Fujihara K
      • et al.
      Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder.
      ) a terminal complement inhibitor, in 46 participants with prior rituximab experience in the PREVENT study. (
      • Levy M
      • et al.
      Efficacy and safety of eculizumab in patients with neuromyelitis optica spectrum disorder previously treated with rituximab: findings from the phase 3 PREVENT study.
      ) This study found a significantly lower risk of adjudicated relapse with eculizumab compared with placebo (HR 0.09; 95% CI: 0.01 0.77; p<0.01) in the rituximab-experienced cohort. Eculizumab targets the terminal complement pathway (a critical component of the innate immune system); therefore, the potential risks of eculizumab might be different than the risks of inebilizumab, which targets B cells involved in adaptive immune responses, in patients with prior rituximab use. Rituximab is commonly used for treatment of NMOSD; therefore, continuing to investigate the efficacy and safety of newer therapies in the NMOSD treatment landscape will be crucial in patients previously treated with rituximab.
      Findings of the current analysis provide important insight into whether previous experience with a B-cell–depleting agent may introduce unique safety concerns for inebilizumab in patients with NMOSD. Inebilizumab had a generally similar safety profile in participants with and without prior rituximab use, with similar rates of TEAEs and infusion-related reactions. Sixteen (94%) participants with prior use of rituximab experienced infections, resulting in an infection rate numerically higher than the group with no prior use of rituximab (70%); however, most of these infections were grade 1/2. Furthermore, the low number of participants greatly limits the assessment of infection risk in this cohort. The same is true of the numerically greater proportion of participants with prior rituximab use who experienced IgG levels <500 mg/dL than those with no prior use of rituximab. Additional data from more patients being converted from rituximab to inebilizumab are needed to better characterize the infection risk and correlation to IgG level in this group.
      A key limitation of the current analysis is the limited number of participants with prior rituximab experience relative to the number of study participants in N-MOmentum. The low enrollment of rituximab-experienced participants is likely attributable to the related mechanisms of the two agents and the exclusion of patients with rituximab use in the 6 months before screening. Another limitation to this study is the inclusion criteria that required patients with prior rituximab exposure to either reconstitute B cells to the lower limit of normal or to not have been treated with rituximab for ≥6 months. These inclusion requirements were employed to limit the potentially confounding effects of prior rituximab use during the relatively short duration of the randomized control period (limited to a maximum of 6.5 months of potential placebo). These concerns are not relevant to clinical practice in which efficacy is evaluated on an individual basis. Patients could potentially be switched from rituximab to inebilizumab without evidence of B cell reconstitution, or sooner than 6 months after the last rituximab infusion, and the inebilizumab prescribing information does not include such limitations.

      5. Conclusions

      Overall, the findings of this analysis may support the efficacy of inebilizumab in preventing attacks in participants with NMOSD regardless of prior rituximab experience. Further studies are necessary to determine potential safety concerns of inebilizumab, including risk of infection and hypogammaglobulinemia, in patients with prior rituximab use.

      Competing Interests

      Eoin P. Flanagan is a site principal investigator of a trial funded by MedImmune/Horizon Therapeutics (formerly Viela Bio) and received funding to support the trial. Michael Levy has received research support from Genentech, Horizon Therapeutics (formerly Viela Bio), and Alexion and has received consulting fees from Genentech, Horizon Therapeutics, Alexion, Mitsubishi Pharma, and UCB Pharmaceuticals. Bruce A.C. Cree has received consulting fees from Alexion, Atara, Autobahn, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini and has received research support from Genentech. Daniel Cimbora, Jorn Drappa, Eliezer Katz, Maureen A. Mealy, and Dewei She are employees of and own stock in Horizon Therapeutics (formerly Viela Bio).

      Acknowledgments

      This study was supported by Horizon Therapeutics (formerly Viela Bio). Medical writing and editorial assistance were provided under the direction of the authors by Sara Gibson, PhD, of MedThink SciCom and Sherri Damlo, ELS, with support from Horizon Therapeutics.

      Source of funding

      The sponsor, Horizon Therapeutics (formerly Viela Bio), played a role in the design and conduct of the study, as well as the analysis and interpretation of the data, in collaboration with the study's investigators.

      Data statement

      Data that are nonproprietary in nature can be shared on request.

      Author statement

      All listed authors meet the criteria for authorship set forth by the International Committee of Medical Journal Editors.

      Appendix. Supplementary materials

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