Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by Original research Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis Xavier Montalban,1 Daniel Wallace,2 Mark C Genovese,3 Davorka Tomic,4 Dana Parsons-­Rich,5,6 Claire Le Bolay,7 Amy H Kao,8 Hans Guehring9 ► Additional supplemental ABSTRACT material is published online Objective Analyse the integrated safety profile WHAT IS ALREADY KNOWN ON THIS TOPIC only. To view, please visit ⇒ Evobrutinib is an orally administered, central the journal online (http://​dx.​ of evobrutinib, a Bruton’s tyrosine kinase inhibitor doi.​org/​10.​1136/​jnnp-​2022-​ (BTKi), using pooled data from multiple sclerosis nervous system-­penetrating, highly selective, 328799). (MS), rheumatoid arthritis (RA) and systemic lupus covalent Bruton’s tyrosine kinase (BTK) erythematosus (SLE) trials. inhibitor, currently in phase III for multiple For numbered affiliations see sclerosis (MS) and has also been investigated Methods Phase II, randomised, double-­blind, placebo-­ end of article. controlled trial data were analysed (N=1083; MS: in patients with rheumatoid arthritis (RA) and n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, systemic lupus erythematosus (SLE) up to Correspondence to Dr Xavier Montalban, Vall 52W). The analysis included all patients who received phase II. In the three phase II trials (one for d’Hebron University Hospital, ≥1 dose of evobrutinib (25 mg or 75 mg once daily, each indication), evobrutinib was well tolerated Passeig de la Vall d’Hebron, or 50 mg or 75 mgtwice daily) or placebo. Descriptive with no dose effect on the incidence of adverse 119-­129, 08035 Barcelona, events. statistics and exposure-­adjusted incidence rates (EAIR) Spain; x​ avier.​montalban@​cem-​ cat.o​ rg were used to report treatment-­emergent adverse events WHAT THIS STUDY ADDS (TEAEs). ⇒ The results from this integrated phase II copyright. Received 5 January 2022 Results Data from 1083 patients were pooled: Accepted 11 August 2022 safety analysis demonstrate that evobrutinib evobrutinib, n=861; placebo, n=271 (sum >1083 due to treatment (all doses) was generally well MS trial design: n=49 received both placebo (W0–24) tolerated across indications. This analysis was and evobrutinib 25 mg (W25–48)); median follow-­up based on the extensive evobrutinib safety time (pt-­years): evobrutinib, 0.501; placebo, 0.463. database of over 1000 patients enrolled in Across indications, the proportion of patients with the phase II trials and represents the only TEAEs and the EAIR were similar for evobrutinib and integrated safety analysis of a BTK inhibitor placebo (66.2% (247.6 events/100 pt-­years) vs 62.4% that includes patients with MS. (261.4 events/100 pt-­years)). By indication, the EAIR (events/100 pt-­years) of TEAEs for evobrutinib versus HOW THIS STUDY MIGHT AFFECT RESEARCH, placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; PRACTICE AND/OR POLICY SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). ⇒ This integrated safety analysis adds confidence The serious infections EAIR was 2.7 and 2.1 events/100 in the safety profile of evobrutinib—being pt-­years for evobrutinib and placebo. For previously generally well tolerated in patients with MS, reported BTKi-­class effects, the EAIR of transient elevated RA and SLE—and supports the continued alanine aminotransferase/aspartate aminotransferase development of evobrutinib for MS in the TEAEs (events/100 pt-­years) with evobrutinib versus ongoing phase III trial. placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-­treated patients. modulation of signal responsiveness in these Conclusions This is the first BTKi-­integrated safety cells.1–3 Overexpression of BTK has been shown to analysis that includes patients with MS. Overall, © Author(s) (or their be associated with certain autoimmune diseases due evobrutinib treatment (all doses) was generally well employer(s)) 2022. Re-­use to an increase in autoreactive B cells and autoan- tolerated across indications. permitted under CC BY-­NC. No tibodies.3 This is exemplified in the multiple scle- commercial re-­use. See rights Trial registration numbers NCT02975349, rosis (MS) setting where elevated BTK levels have and permissions. Published NCT03233230, NCT02975336. by BMJ. been detected in B cells of relapsing-­remitting MS and secondary-­progressive MS patients as well as in To cite: Montalban X, microglia within progressive MS lesions.4 5 There- Wallace D, Genovese MC, et al. J Neurol Neurosurg INTRODUCTION fore, BTK represents a rational therapeutic target in Psychiatry Epub ahead of Bruton’s tyrosine kinase (BTK), a member of the autoimmune diseases and, as a result, several BTK print: [please include Day Tec family of non-­ receptor tyrosine kinases, is inhibitors are being investigated in autoimmune Month Year]. doi:10.1136/ expressed in B cells, macrophages and microglia, conditions including MS, rheumatoid arthritis (RA) jnnp-2022-328799 and is involved in signal propagation and and/or systemic lupus erythematosus (SLE).6 7 BTK Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 1 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by Table 1 Overview of trials included in the integrated evobrutinib safety analyses Patients randomised, Duration, Trial identifier Phase Indication n Treatment weeks Eligibility Reference NCT02975349 II MS 267 Placebo (Week 0–24) + evobrutinib 25 mg QD 48 ► Adults 18–65 years Montalban et al23 (Week 25–48) (n=54) ► Relapsing–remitting or secondary progressive MS with Evobrutinib 25 mg QD (n=52) superimposed relapses Evobrutinib 75 mg QD (n=53) ► EDSS score ≤6 Evobrutinib 75 mg BID (n=54) Dimethyl fumarate (n=54, open-­label reference arm; patients in this treatment arm were not included in the integrated safety analysis) NCT03233230 IIb RA 390 Placebo (n=97) 12 ► Adults 18–75 years Peterfy et al25 Evobrutinib 25 mg QD (n=98) ► Confirmed diagnosis of RA ≥6 months duration prior to Evobrutinib 75 mg QD (n=96) screening Evobrutinib 50 mg BID (n=99) ► Active moderate to severe RA at screening and randomisation (≥6 swollen joints and ≥6 tender joints) ► An hsCRP ≥5.0 mg/L (≥0.50 mg/dL) from two samples collected during screening ► Patients had received methotrexate treatment 7.5–25 mg/ week for ≥16 weeks at stable dose for ≥8 weeks NCT02975336 II SLE 469* Placebo (n=117) 52 ► Adults 18–75 years Wallace et al26 Evobrutinib 25 mg QD (n=118) ► Diagnosed with SLE by either the SLICC criteria, or at least Evobrutinib 75 mg QD (n=117) four of the ACR criteria ≥6 months prior to screening Evobrutinib 50 mg BID (n=117) ► At screening, patients must have a SLEDAI-­2K score ≥6, including a SLEDAI-­2K clinical score ≥4, and be auto-­antibody positive (a positive test result for anti-­double-­stranded DNA antibody and/or antinuclear antibody (human epithelial cell-­2 antinuclear antibody ≥1:80) and/or anti-­Smith antibody) ► Vaccination against Streptococcus pneumoniae and influenza was required, as per local guidelines *The primary analysis from the SLE trial was conducted before all patients had completed the trial. Therefore, the integrated analysis reports the safety analysis set that included all patients (n=480). ACR, American College of Rheumatology; BID, twice daily; EDSS, Expanded Disability Status Scale; hsCRP, high-­sensitivity C-­reactive protein; MS, multiple sclerosis; QD, once daily; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI-­2K, Systemic Lupus Erythematosus Disease Activity Index-­2000; SLICC, Systemic Lupus International Collaborating Clinics. inhibitors impact B cell function via inhibition of BTK signalling endogenous BTK protein, this inhibition is reversable following rather than depleting the B cell population as per the effect of drug withdrawal.19 20 In preclinical studies, evobrutinib has anti-­CD20 therapies currently used for the treatment of MS, RA been demonstrated to decrease the activation, proliferation and and SLE, which have been associated with hypogammaglobulin- cytokine release of B cells, as well as inhibit proinflammatory emia and increased risks of infections.3 8–11 Additionally, BTK macrophage differentiation.21 22 In the clinical setting, evobru- copyright. inhibitors target innate immune cells involved in the pathogen- tinib has been investigated in patients with MS, RA and SLE esis of MS, including macrophages, microglia and astrocytes.7 in three phase II trials.23–26 In the double-­ blind, randomised Published evidence suggests that as central nervous system (CNS) controlled trial in patients with relapsing MS, evobrutinib met resident cells, microglia and astrocytes may play a critical role in its efficacy endpoints and no clinically relevant changes in immu- neurodegeneration and disease progression.12–15 noglobulin (Ig) or immune cell levels were observed.23 24 The Evobrutinib is an orally administered, CNS-­ penetrating, RA and SLE trials did not meet their primary endpoints.25 26 In highly selective, covalent BTK inhibitor, with a low potential all three phase II trials, evobrutinib was well tolerated with no for off-­target-­related adverse effects.16–18 The covalent binding dose effect on the incidence of adverse events. The open-­label of evobrutinib to BTK results in continued target inhibition extension (OLE) period from the MS trial is currently ongoing, even after it has been cleared from the circulation (geometric but initial data have demonstrated that the safety of evobrutinib mean half-­life ~2 hours), but due to the continuous turnover of was maintained for over 2 years.27 28 The clinical development of Table 2 Patient disposition and baseline characteristics MS RA SLE Placebo Evobrutinib Placebo Evobrutinib Placebo Evobrutinib (n=54) (n=208) (n=97) (n=293) (n=120) (n=360) Age (years) 41.5 (±10.7) 42.2 (±10.5) 52.9 (±12.1) 52.6 (±12.3) 40.2 (±12.4) 40.7 (±12.3) Age group, n (%)  ≤55 years 48 (88.9) 183 (88.0) 54 (55.7) 160 (54.6) 108 (90.0) 315 (87.5)  ≥55 years 6 (11.1) 25 (12.0) 43 (44.3) 133 (45.4) 12 (10.0) 45 (12.5) Gender, n (%)  Female 40 (74.1) 144 (69.2) 77 (79.4) 235 (80.2) 112 (93.3) 339 (94.2)  Male 14 (25.9) 64 (30.8) 20 (20.6) 58 (19.8) 8 (6.7) 21 (5.8) Race, n (%)  White 54 (100.0) 208 (100.0) 92 (94.8) 282 (96.2) 66 (55.0) 224 (62.2)  Black 0 (0.0) 0 (0.0) 1 (1.0) 2 (0.7) 10 (8.3) 35 (9.7)  Asian 0 (0.0) 0 (0.0) 1 (1.0) 2 (0.7) 26 (21.7) 59 (16.4)  Other 0 (0.0) 0 (0.0) 3 (3.1) 7 (2.4) 18 (15.0) 42 (11.7) Duration of disease (years) 7.0 (±6.4) 7.6 (±6.3) 6.1 (±6.4) 7.0 (±6.6) 6.3 (±6.2) 6.6 (±6.2) Weight (kg) 69.5 (±13.6) 70.6 (±15.1) 74.5 (±19.7) 75.0 (±16.7) 67.5 (±18.4) 69.3 (±18.9) Data are mean (±SD), unless stated otherwise. MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus. 2 Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by evobrutinib in relapsing MS is ongoing, with two phase III trials 247.6 EAIR 14.5 20.9 that have recently completed enrollment (evolutionRMS 1 and 0.4 9.5 0.6 1.3 9.1 2; NCT04338022 and NCT04338061).29 *Both patients were in the high disease activity subpopulation. One patient was in the evobrutinib 25 mg QD group. Fatal TEAEs of acute kidney injury, hepatitis and pancreatitis were reported, none of which were considered to be related to evobrutinib. The other Evobrutinib We analysed the integrated safety profile of evobrutinib using 102 (11.8) 570 (66.2) patient was in the evobrutinib 75 mg QD group and died from infection-­related complications due to bone marrow failure with a history of and concomitant leflunomide treatment. This fatal event was considered to be treatment related by the Investigator. (n=861) pooled data from the three phase II trials in MS, RA and SLE, to 2 (0.2)* 75 (8.7) 48 (5.6) 46 (5.3) 3 (0.3) 7 (0.8) n (%) further characterise the overall safety profile of evobrutinib in auto- Total immune indications. This is the first BTK inhibitor integrated safety analysis that includes patients with MS. 261.4 EAIR 18.0 23.5 9.8 1.4 9.1 – – METHODS Trials included in the analysis 169 (62.4) 32 (11.8) Placebo (n=271) 26 (9.6) 14 (5.2) 13 (4.8) 0 (0.0) 0 (0.0) 2 (0.7) Data from three phase II, randomised, double-­blind, placebo-­ n (%) controlled trials of evobrutinib in MS, RA or SLE were anal- ysed. All three trials have been described previously and are summarised in table 1.23 25 26 The trials are registered with​ 343.0 EAIR 15.7 12.1 11.4 28.6 0.7 1.0 1.7 ClinicalTrials.​gov and were conducted in accordance with the Declaration of Helsinki and the International Conference on Evobrutinib 309 (85.8) Harmonisation Good Clinical Practice Guidelines. 47 (13.1) 78 (21.7) (n=360) 2 (0.6)* 35 (9.7) 33 (9.2) 3 (0.8) 5 (1.4) n (%) SLE Endpoints Safety endpoints for all trials included the assessment of the EAIR, exposure-­adjusted incidence rates; MS, multiple sclerosis; QD, once daily; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TEAEs, treatment-­emergent adverse events. 302.1 EAIR 15.1 10.1 10.2 27.3 nature, severity and occurrence of treatment-­emergent adverse 1.0 – – events (TEAEs) as well as vital signs, electrocardiograms and clinical laboratory safety parameters. Ig and CD19+ B cell levels 15 (12.5) 25 (20.8) 99 (82.5) Placebo (n=120) 10 (8.3) 10 (8.3) 0 (0.0) 0 (0.0) 1 (0.8) were assessed in each trial. n (%) Statistical analyses 331.8 EAIR The analysis included all patients who received ≥1 dose of 16.8 12.3 7.7 1.5 4.6 – – evobrutinib or placebo. TEAEs were summarised by treatment group, severity (using NCI-­CTCAE V.4.03 criteria) and rela- Evobrutinib copyright. 146 (49.8) tionship to evobrutinib. Descriptive statistics and exposure-­ (n=293) 11 (3.8) 0 (0.0) 5 (1.7) 0 (0.0) 1 (0.3) 3 (1.0) 8 (2.7) n (%) adjusted incidence rates (EAIR) were used to report TEAEs. RA EAIR in each treatment arm was defined as the ratio of the number of patients with an event to the sum of the duration 306.8 EAIR 28.9 of exposure to treatment of the patients up to the time of the 9.7 4.9 9.7 – – – first event or the end of observation (whichever occurred first) and was expressed as the rate per 100 patient-­years (pt-­years). 44 (45.4) Placebo (n=97) Overall, results are reported (as appropriate) as evobrutinib 0 (0.0) 6 (6.2) 2 (2.1) 0 (0.0) 0 (0.0) 1 (1.0) 2 (2.1) n (%) (pooled doses) versus placebo across indications (integrated analysis) and by individual indication. The data cut-­offs for each trial were: MS, 13 July 2018; RA, 25 October 2019; SLE, 119.7 EAIR 11.1 10.6 5.3 0.7 6.6 21 August 2020. – – Changes in IgG, A and M levels and CD19+ B cell levels were Evobrutinib 115 (55.3) (n=208) summarised across each treatment group by individual indica- 17 (8.2) 10 (4.8) 16 (7.7) 0 (0.0) 8 (3.8) 0 (0.0) 1 (0.5) n (%) tion from baseline to Week 48 (MS), Week 12 (RA) and Week 52 MS (SLE) after randomisation. In the MS trial, the placebo group switched to evobrutinib 148.3 25 mg once daily (QD) at 24 weeks. Therefore, data from Weeks EAIR 20.8 20.9 8.4 4.2 8.3 – 0–24 are included for the placebo analysis group (n=54) and – data from Weeks 25–48 for the evobrutinib analysis group 26 (48.1) Placebo (n=54) (n=49). 0 (0.0) 5 (9.3) 2 (3.7) 0 (0.0) 1 (1.9) 2 (3.7) 5 (9.3) n (%) RESULTS EAIR presented as events/100 patient-­years.  Any treatment-­related Grade ≥4 TEAE  Any treatment-­related Grade ≥3 TEAE TEAEs leading to treatment withdrawal Patient disposition and demographics Overall, data from the three trials (MS: n=213; RA: n=390; Overall TEAEs SLE: n=480) were pooled and included 1083 patients. Of these, 861 patients were treated with evobrutinib and 271 patients Any TEAE leading to death with placebo (note: the sum of the groups is >1083 due to the  Any Grade ≥4 TEAE  Any Grade ≥3 TEAE MS trial design, whereby 49 patients in the MS trial are included Any serious TEAE in the placebo group for Weeks 0–24 and the evobrutinib group Table 3 for Weeks 25–48; see Methods section for additional details). Any TEAE Treatment exposure was 145.1, 185.5, 168.3, 120.2 and 44.9 pt-­years for placebo, evobrutinib 25 mg QD, 75 mg QD, 50 mg Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 3 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by Figure 1 EAIRs of TEAEs, serious TEAEs and infections among evobrutinib-­treated and placebo-­treated patients in MS, RA, SLE and across indications. EAIR, exposure-­adjusted incidence rates; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TEAEs, treatment-­emergent copyright. adverse events. twice daily (BID) and 75 mg BID, respectively (median follow-­up evobrutinib treatment group from the SLE trial were fatal. One time (pt-­years): evobrutinib, 0.501; placebo, 0.463). of these events was considered to be treatment related by the The demographics and baseline characteristics were investigator (additional details in table 3). By indication, the balanced between evobrutinib and placebo within the EAIR of TEAEs for evobrutinib versus placebo were: MS: 119.7 same indication (table 2). Per RA and SLE trial designs, vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1 events/100 concomitant immunosuppressants/immunomodulators (RA: pt-­years. The majority of these TEAEs occurred in patients with methotrexate; SLE: azathioprine, 6-­ mercaptopurine, myco- SLE. phenolate, methotrexate, sulfasalazine and leflunomide), The most common TEAEs reported by evobrutinib-­treated non-­steroidal anti-­ inflammatory drugs and corticosteroids patients were urinary tract infections (9.5% vs 8.5% placebo), were permitted. Given the different background therapies headache (9.2% vs 10.3% placebo), nasopharyngitis (7.3% vs for these three disease areas, anticipated differences between 5.5% placebo), diarrhoea (6.2% vs 4.8% placebo) and alanine indications were observed for immunosuppressants/immuno-­ aminotransferase (ALT) increase (5.0% vs 3.0% placebo). modulators and corticosteroids at baseline (online supple- Serious TEAEs were reported by 48 patients (5.6%; EAIR mental eTable 1). As expected, a greater proportion of patients 9.5 events/100 pt-­ years) treated with evobrutinib and 14 in the SLE trial used analgesics, immunosuppressants/immuno-­ patients (5.2%; EAIR 9.8 events/100 pt-­years) treated with modulators and corticosteroids at baseline compared with placebo (table 3 and figure 1). The most frequent serious the MS and RA trials. Within each trial, the proportions of TEAEs in the evobrutinib treatment group were related to patients using analgesics, immunosuppressants/immuno-­ infections and infestations, primarily occurring in patients modulators and corticosteroids were similar for those patients with SLE (table 4 and online supplemental eTable 2). treated with placebo and those treated with evobrutinib. Serious infections Overall TEAEs Across trials, there was no imbalance in the EAIR of serious infec- Overall, the proportion of patients with TEAEs and the rate tions between evobrutinib doses (25 mg QD: 4.4; 75 mg QD: of events were similar for evobrutinib and placebo by indica- 2.4; 50 mg BID: 1.7; 75 mg BID: 0.0 events/100 pt-­years) and tion and across trials (table 3 and figure 1). A total of 570/861 no notable differences compared with placebo (2.1 events/100 (66.2%) and 169/271 (62.4%) patients treated with evobru- pt-­years). In the MS trial, no serious infections in any of the tinib or placebo had a TEAE, respectively. The EAIR of TEAEs evobrutinib treatment arms were observed. By indication, there was 247.6 events/100 pt-­ years for evobrutinib versus 261.4 were no serious infections reported with the highest evobrutinib events/100 pt-­years for placebo. The majority of these TEAEs dose in the MS and RA trials, while the EAIR for the highest were mild or moderate. In the MS and RA trials, there were evobrutinib dose in the SLE trial was similar to placebo (50 mg no fatal TEAEs in either treatment group. Two TEAEs in the BID: 2.1 vs 2.0 events/100 pt-­years). 4 Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by Table 4 EAIRs of BTK inhibitor or concomitant drug class-­associated TEAEs by preferred term Total Total Placebo Evobrutinib Placebo Evobrutinib (n=271) (n=861) (n=271) (n=861) n (%) EAIR n (%) EAIR Cont’d n (%) EAIR n (%) EAIR Cardiac disorders Infections  Tachycardia 0 (0.0) – 1 (0.1) 0.2  Serious infections and infestations 3 (1.1) 2.1 14 (1.6) 2.7  Ventricular arrhythmia 0 (0.0) – 1 (0.1) 0.2  Herpes zoster 3 (1.1) 2.1 9 (1.0) 1.8  Coronary artery disease 0 (0.0) – 1 (0.1) 0.2 Immune system disorders Haemorrhage-­related TEAEs  Hypersensitivity 1 (0.4) 0.7 3 (0.3) 0.6  Bleeding* 7 (2.6) 2.4 13 (1.5) 0.6 Musculoskeletal and connective tissue disorders  Bruising† 1 (0.4) 0.7 5 (0.6) 0.5  Osteonecrosis 1 (0.4) 0.7 3 (0.3) 0.6 Vascular disorders Liver-­related TEAEs  Hypertension 1 (0.4) 0.7 19 (2.2) 3.7  ALT increase‡ 4 (1.5) 2.8 25 (2.9) 4.8 Neoplasms  AST increase‡ 1 (0.4) 0.7 18 (2.1) 3.5  Neoplasms benign, malignant and 5 (1.8) 3.5 7 (0.8) 1.4 Pancreas-­related TEAEs unspecified (SOC)   Anogenital warts 1 (0.4) 0.7 2 (0.2) 0.4  Amylase increase 10 (3.7) 7.0 26 (3.0) 5.1 Fibrous histiocytoma    1 (0.4) 0.7 0 (0.0) –  Lipase increase‡ 4 (1.5) 2.8 17 (2.0) 4.0    Lipoma 1 (0.4) 0.7 0 (0.0) – Leucopenia-­related TEAEs Lung neoplasm    1 (0.4) 0.7 0 (0.0) –  Lymphopenia‡ 10 (3.7) 7.2 16 (1.9) 3.1 Oral papilloma    0 (0.0) – 1 (0.1) 0.2  Neutropenia‡ 6 (2.2) 4.2 10 (1.2) 1.9   Papillary thyroid cancer 1 (0.4) 0.7 0 (0.0) – Thrombocytopenia-­related TEAEs Skin papilloma    0 (0.0) – 1 (0.1) 0.2  Thrombocytopenia‡ 0 (0.0) – 2 (0.2) 0.4   Thyroid adenoma 0 (0.0) – 1 (0.1) 0.2   Uterine leiomyoma    0 (0.0) – 2 (0.2) 0.4 *Defined by medical concept as epistaxis, haematoma, haematoma muscle, haemorrhagic diathesis. †Defined by medical concept as ecchymosis and petechiae. ‡The event with the highest severity for a patient during the treatment period and meeting the AESI definition was included in the summary. AESI, adverse event of special interest; EAIR, exposure-­adjusted incidence rates; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SOC, system organ class; TEAEs, treatment-­emergent adverse events. copyright. Liver-related TEAEs higher EAIR observed in the SLE trial (4.4 vs 0.0 events/100 A higher EAIR of ALT and aspartate aminotransferase (AST) pt-­years). elevations was observed with evobrutinib compared with placebo across trials (table 4). These events occurred at a higher EAIR in Ig levels the MS and RA trials compared with the SLE trial (online supple- For all trials, IgG and subtype levels were maintained, and no mental eTable 2). However, these elevations in ALT and AST relevant changes were observed at the end of each trial (MS: levels were typically asymptomatic and reversible on withdrawal Week 48; RA: Week 12; SLE: Week 52) relative to baseline for of evobrutinib. evobrutinib and placebo (figure 2). In the MS and SLE trials, IgA levels increased in both the placebo and evobrutinib treat- Other potential BTK inhibitor or concomitant drug class- ment arms; however, in the RA trial, IgA levels were maintained. associated TEAEs Across all three trials, IgM levels decreased in the evobrutinib Cardiovascular disorders were similar between evobrutinib treatment arms but remained comparable with baseline levels in and placebo (1.9 vs 2.1 events/100 pt-­years) across trials with the placebo treatment arm except in the MS trial; after Week 24, a slightly higher frequency occurring in the SLE trial compared IgM levels decreased to similar levels as the evobrutinib treat- with the MS and RA trials (table 4 and online supplemental ment arms due to patients switching from placebo to evobrutinib eTable 2). An increased EAIR of bleeding-­associated or bruising-­ 25 mg QD. Overall, IgA and IgM levels remained within normal associated events was not observed with evobrutinib across trials ranges for both treatment groups across the three trials. or within each indication compared with placebo. Across trials, increase in amylase levels occurred at a similar EAIR with evobru- Immune cell levels tinib and placebo, which was also reflected in the individual Total CD19+ B cells decreased in the MS and SLE trials and trials. The EAIR of increase in lipase levels was higher in the increased in the RA trial in the evobrutinib treatment groups evobrutinib treatment arm versus placebo (4.0 vs 2.8 events/100 compared with baseline; however, overall, these levels remained pt-­years), due to a higher EAIR observed in the SLE trial (3.4 vs within the normal range (107–698 cells/µL; figure 3). For the 2.0 events/100 pt-­years). Neoplasms occurred at a lower EAIR SLE trial, an increase in B cells was initially observed with with evobrutinib compared with placebo across trials and within evobrutinib at week 4 (percent change from baseline at Week 4: the MS and SLE trials (no events were observed in the RA trial). 40–59%) before decreasing. The EAIR of other TEAEs known to be associated with concomitant medications typically used by patients with RA and SLE, such as hypersensitivity, herpes zoster infection, osteone- DISCUSSION crosis and diarrhoea, were similar between placebo and evobru- This is the first integrated analysis of evobrutinib safety data tinib across trials (table 4 and online supplemental eTable 2). The derived from phase II trials across MS, RA and SLE indications. EAIR of hypertension was higher in the evobrutinib treatment Data from over 1000 patients treated with either evobrutinib or arm versus placebo (3.7 vs 0.7 events/100 pt-­years), due to a placebo contributed to this analysis. The majority of TEAEs were Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 5 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by copyright. Figure 2 Ig levels change from baseline over time. Normal ranges (g/L): IgG: 7–16; IgA: 0.7–4.0; IgM: 0.4–2.3. BID, twice daily; CFB, change from baseline; Ig, immunoglobulin; MS, multiple sclerosis; QD, once daily; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus. mild or moderate. An enhanced risk of serious infections (despite The results from our analysis demonstrate that treatment with background immunosuppressant therapy) was not observed with evobrutinib for up to a year is not associated with an increased evobrutinib treatment. A higher rate of elevations in ALT and risk of adverse events common to current therapies used in the AST were observed with evobrutinib compared with placebo. treatment of MS, RA and SLE, except for an association with These ALT and AST elevations were typically asymptomatic elevated levels of ALT and AST, which was in line with the and reversible following drug discontinuation. Other drug class-­ observations from the individual MS, RA and SLE trials.23 25 26 associated TEAEs, such as bleeding/bruising events or neoplasms, However, as was observed in the MS and SLE trials, these eleva- were not observed to be differential between evobrutinib and tions were typically transient and resolved following withdrawal placebo with the exception of hypertension and increased lipase. of evobrutinib.23 26 In addition, in the MS trial, these elevations Overall, the evobrutinib safety profile was comparable with that were observed only in the first 24 weeks of the trial.23 Further- of placebo across indications, with no apparent relationship to more, results from the MS trial OLE have demonstrated that the evobrutinib dose. evobrutinib safety profile in the double-­blind period was main- Current treatment options for MS, RA and SLE are associated tained at 2 years with no new safety signals identified.27 28 These with a positive–benefit risk ratio in terms of adverse outcomes. results are substantiated further by the latest data from over 2.5 However, targeted therapies that have a safety profile condu- years of OLE treatment, whereby 59/213 patients (27.7%) had a cive to long-­term use as necessitated by the chronic nature of treatment-­related TEAE; six serious TEAEs were deemed treat- these diseases may be beneficial for patients. In the RA and ment related.40 Severe/opportunistic infections (Grade ≥3) were SLE settings, long-­ term use of corticosteroids and immuno- reported by 9/213 patients (4.2%) of which three were fatal and suppressants/immunomodulators is associated with infections, not considered treatment related (COVID-­19 pneumonia (n=2) cardiovascular events, malignancies, renal disorders and damage and E. coli sepsis (n=1)). At OLE Week 120, most patients had to multiple organ systems.30–34 In MS, several, currently avail- IgG (91%), IgA (88%) and IgM (82%) levels within normal able B cell-­targeting treatments are highly effective at reducing ranges. Overall mean CD19+ B cell levels were 0.218×106 cells/ inflammation but are associated with some tolerability and safety mL (OLE baseline) and 0.122×106 cells/mL (OLE Week 96). concerns, notably an increased risk of infections and malignan- ALT and AST elevations were observed only in patients previ- cies.35–39 In addition to the above, treatments used in MS, RA ously receiving dimethyl fumarate or evobrutinib 25 mg QD and SLE are also associated with liver-­related adverse events. in the double-­blind period and occurred within 12 weeks of 6 Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by with evobrutinib that inhibits 2/221 off-­target kinases to the same degree.41 Interaction with the off-­target kinases Tec and members of the epidermal growth factor receptor family has been implicated in the adverse events associated with ibrutinib.6 The ibrutinib-­associated adverse events were not identified as common events with evobrutinib suggesting that the improved selectivity of evobrutinib (a second-­generation BTK inhibitor) has overcome these class-­associated TEAEs. Overall, mean Ig levels remained within normal ranges with evobrutinib treatment, and across trials, there was no imbalance in the rate of serious infections between evobru- tinib doses. Unlike BTK inhibitors, use of anti-­CD20 therapies results in a near-­complete depletion of B cells, which carries a risk of hypogammaglobulinaemia. Hypogammaglobulinaemia is associated with an increased susceptibility to infections.8–11 While mild hypogammaglobulinaemia may be asymptomatic, more severe cases of hypogammaglobulinaemia usually result in recurrent infections. In MS, there are currently no data on Ig levels from other BTK inhibitors; however, treatment with fenebrutinib in RA and SLE reduced IgG levels from baseline by approximately 1 g/L and 2.25 g/L, respectively, but levels remained within the normal range.43 Similarly, IgG levels in the evobrutinib RA and SLE trials also remained within the normal range (RA: −0.24 g/L; SLE: 0.11 g/L). However, it should be noted that studies have observed that the incidence of hypogam- maglobulinaemia increases with longer treatment durations, with infrequent events observed in the first years of treatment with anti-­CD20s.44–46 Therefore, continued monitoring of the ongoing extension phases from BTK inhibitor trials will provide further insights into the longer term effects of BTK inhibitors on Ig levels and the associated risk of infections. copyright. A similar integrated safety analysis from another BTK inhib- itor, fenebrutinib, has been conducted in RA, SLE and chronic spontaneous urticaria patients.43 In terms of overall TEAEs, serious TEAEs, serious infections and aminotransferase eleva- tions, similar proportions of patients experienced these events with fenebrutinib as was observed in the evobrutinib trials. This analysis has some limitations. The different trial designs, trial durations and patient populations may have restricted the extent of the comparisons that could be made between trials. In addition, the short duration of the RA trial limited the number of TEAEs and malignancies reported by this patient group. Further- more, the baseline concomitant medications were different for Figure 3 CD19+ B cells levels over time. Normal range: 107–698 cells/ these trials, in particular, for MS versus the RA and SLE trials. µL. *B cell levels for the SLE trial are total B cell levels; the other trials are The greater level of concomitant medications, including use of CD19+ B cell levels. BID, twice daily; MS, multiple sclerosis; QD, once daily; corticosteroids and immunosuppressants, required by RA and RA, rheumatoid arthritis; SLE, systemic lupus erythematosus. SLE patients may explain the higher EAIR of infections in these trials compared with the MS trial. Finally, the stopping rules for evobrutinib varied across the trials; however, the variation OLE initiation (ie, evobrutinib 75 mg QD). Amylase and lipase was relatively minimal and is not expected to have impacted increases occurred in 6 (2.8%) and 24 (11.3%) patients, respec- the results considerably. However, this analysis benefits from tively, but without clinical signs and symptoms.40 The above having the largest BTK inhibitor patient data set across MS, RA indication of the acceptable tolerability of evobrutinib with no and SLE indications to date with a long cumulative treatment new safety signals is likely due to both the BTK specificity of exposure across indications. Furthermore, the patients with SLE evobrutinib with minimal off-­target kinase interactions as well were using a greater level of concomitant medications, including as its mode of action that modulates B cell function by inhibiting immunosuppressants, which may have subsequently contributed BTK signalling rather than depleting the B cell population by to the higher EAIR of infections. cell lysis.3 17 41 As a class, earlier forms of BTK inhibitors, namely, ibrutinib used in oncology, have been associated with an increased risk CONCLUSION of bleeding, cardiovascular events, skin reactions, diarrhoea These results represent the only integrated safety analysis of and infections.6 42 Evidence suggests that these events are a BTK inhibitor that includes patients with MS. The analysis likely due to the low selectivity of ibrutinib. Ibrutinib has been was based on the extensive evobrutinib safety database of over shown to inhibit 22/221 off-­target kinases by ≥80% compared 1000 patients with a long cumulative treatment exposure from Montalban X, et al. J Neurol Neurosurg Psychiatry 2022;0:1–9. doi:10.1136/jnnp-2022-328799 7 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2022-328799 on 23 November 2022. Downloaded from http://jnnp.bmj.com/ on November 24, 2022 by guest. Protected by three phase II trials across autoimmune indications. Overall, Data availability statement Data are available upon reasonable request. Any this analysis adds to our understanding of the safety profile of requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck’s Data Sharing Policy. All requests should evobrutinib, confirms evobrutinib treatment was well tolerated be submitted in writing to Merck’s data sharing portal https://www.merckgroup.​ in MS, RA and SLE, and supports the continued development of com/en/research/our-approach-to-research-and-development/healthcare/clinical-​ evobrutinib for MS and the ongoing phase III programme. trials/commitment-responsible-data-sharing.html. When Merck has a co-­research, co-­development, or co-­marketing or co-­promotion agreement, or when the product Author affiliations has been out-­licensed, the responsibility for disclosure might be dependent on the 1 Department of Neurology-­Neuroimmunology, Centre d’Esclerosi Múltiple de agreement between parties. Under these circumstances, Merck will endeavour to Catalunya (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain gain agreement to share data in response to requests. 2 Cedars-­Sinai Medical Center, David Geffen School of Medicine, University of Supplemental material This content has been supplied by the author(s). California, Los Angeles, California, USA It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not 3 Division of Immunology and Rheumatology, Stanford University, Palo Alto, have been peer-­reviewed. Any opinions or recommendations discussed are California, USA solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all 4 Global Clinical Development, Ares Trading SA, Eysins, Switzerland, an affiliate of liability and responsibility arising from any reliance placed on the content. Merck KGaA Where the content includes any translated material, BMJ does not warrant the 5 Global Clinical Development, EMD Serono Research & Development Institute, Inc, accuracy and reliability of the translations (including but not limited to local Billerica, Massachusetts, USA, an affiliate of Merck KGaA (affiliation at the time the regulations, clinical guidelines, terminology, drug names and drug dosages), and research was conducted) is not responsible for any error and/or omissions arising from translation and 6 ECD-­Early Clinical Development, Pfizer, Cambridge, Massachusetts, USA adaptation or otherwise. 7 Biostatistics, Merck Healthcare KGaA, Darmstadt, Germany 8 Open access This is an open access article distributed in accordance with the Translational Innovation Platform in Immunology & Neuroscience, EMD Serono Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Research & Development Institute, Inc, Billerica, Massachusetts, USA, an affiliate of permits others to distribute, remix, adapt, build upon this work non-­commercially, Merck KGaA 9 and license their derivative works on different terms, provided the original work is Global Patient Safety, Merck Healthcare KGaA, Darmstadt, Germany properly cited, appropriate credit is given, any changes made indicated, and the use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. Acknowledgements The authors would like to thank the patients, investigators, co-­investigators and the trial teams at each of the participating centres; Emily Martin (EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA) and Daniela Sera and Karin Broeder (Merck Healthcare KGaA, REFERENCES Darmstadt, Germany) for providing assistance with the statistical analyses; and 1 López-H­ errera G, Vargas-­Hernández A, González-­Serrano ME, et al. Bruton’s tyrosine Francesca Hemingway of Bioscript Group Ltd., Macclesfield, UK for providing medical kinase--an integral protein of B cell development that also has an essential role in the writing and editorial support (funded by Merck). innate immune system. J Leukoc Biol 2014;95:243–50. 2 Bender AT, Gardberg A, Pereira A, et al. 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