Safety and efficacy of switching from adalimumab to sarilumab in patients with rheumatoid arthritis in the ongoing MONARCH open-label extension =============================================================================================================================================== * Gerd R Burmester * Vibeke Strand * Andrea Rubbert-Roth * Howard Amital * Tatiana Raskina * Antonio Gómez-Centeno * Claudia Pena-Rossi * Leon Gervitz * Karthinathan Thangavelu * Gregory St John * Susan Boklage * Mark C Genovese ## Abstract **Objective** Evaluate open-label sarilumab monotherapy in patients with rheumatoid arthritis switching from adalimumab monotherapy in MONARCH ([NCT02332590](http://rmdopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02332590&atom=%2Frmdopen%2F5%2F2%2Fe001017.atom)); assess long-term safety and efficacy in patients continuing sarilumab during open-label extension (OLE). **Methods** During the 48-week OLE, patients received sarilumab 200 mg subcutaneously once every 2 weeks. Safety (March 2017 cut-off) and efficacy, including patient-reported outcomes, were evaluated. **Results** In the double-blind phase, patients receiving sarilumab or adalimumab monotherapy showed meaningful improvements in disease activity; sarilumab was superior to adalimumab for improving signs, symptoms and physical function. Overall, 320/369 patients completing the 24-week double-blind phase entered OLE (155 switched from adalimumab; 165 continued sarilumab). Sarilumab safety profile was consistent with previous reports. Treatment-emergent adverse events were similar between groups; no unexpected safety signals emerged in the first 10 weeks postswitch. Among switch patients, improvement in disease activity was evident at OLE week 12: 47.1%/34.8% had changes ≥1.2 in Disease Activity Score (28 joints) (DAS28)-erythrocyte sedimentation rate/DAS28-C-reactive protein. In switch patients achieving low disease activity (LDA: Clinical Disease Activity Index (CDAI) ≤10; Simplified Disease Activity Index (SDAI) ≤11) by OLE week 24, 70.7%/69.5% sustained CDAI/SDAI LDA at both OLE weeks 36 and 48. Proportions of switch patients achieving CDAI ≤2.8 and SDAI ≤3.3 by OLE week 24 increased through OLE week 48. Improvements postswitch approached continuation-group values, including scores ≥normative values. **Conclusions** During this OLE, there were no unexpected safety issues in patients switching from adalimumab to sarilumab monotherapy, and disease activity improved in many patients. Patients continuing sarilumab reported safety consistent with prolonged use and had sustained benefit. * DMARDs (biologic) * rheumatoid arthritis * DAS28 * disease activity * treatment ### Key messages #### What is already known about this subject? * In the 24-week phase III MONARCH study ([NCT02332590](http://rmdopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02332590&atom=%2Frmdopen%2F5%2F2%2Fe001017.atom)), both sarilumab 200 mg every 2 weeks and adalimumab 40 mg every 2 weeks were associated with a meaningful improvement in disease activity in adult patients with rheumatoid arthritis (RA) who were intolerant of, or inadequate responders to, methotrexate (MTX) or who were deemed inappropriate for MTX treatment. Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy for improving RA signs and symptoms and physical function. #### What does this study add? * Findings from this open-label extension (OLE) study support the long-term safety and efficacy of sarilumab in patients who continued sarilumab from double-blind through OLE for a total of 72 weeks. Safety profile and incidence of treatment-emergent adverse events were similar for patients who switched from adalimumab to sarilumab on entry into the OLE versus patients who continued on sarilumab. * Patients switching from adalimumab to sarilumab achieved additional clinically meaningful improvements in disease activity and in patient-reported outcomes in the OLE, primarily within 12 weeks of switching. These improvements approached levels of improvement observed in patients who continued sarilumab after completing the double-blind phase. ### Key messages #### How might this impact on clinical practice or future developments? * Treatment guidelines endorse a ‘treat-to-target’ approach to RA management, aiming for sustained remission or low disease activity. Sustained clinical improvement following the switch from adalimumab to sarilumab provides support for therapy switching as a management option for select patients. * These data may help optimise treatment approaches in RA requiring not only proactive, early identification of suboptimal disease control but also a collaborative goal-setting approach between rheumatologists and patients in deciding when potential changes in therapy, including the use of biological disease-modifying antirheumatic drug monotherapy, may be warranted. ## Introduction Rheumatoid arthritis (RA) is a debilitating, chronic condition requiring early treatment with disease-modifying antirheumatic drugs (DMARDs) to provide symptom relief, reduce disease activity and slow progression, as well as improve health-related quality of life (HRQoL).1 2 Although treatment guidelines recommend the addition of biological or targeted synthetic DMARDs (b/tsDMARD) following inadequate responses to initial conventional synthetic DMARDs (csDMARDs), registry data suggest that at least one third of patients use bDMARDs as monotherapy.3–6 Driving factors for b/tsDMARD monotherapy include poor adherence and intolerance/contraindications to methotrexate (MTX) or other csDMARDs.7 8 Expansion of therapeutic options in RA has increased the need to better understand comparative safety and efficacy among bDMARDs, particularly in head-to-head randomised controlled trials (RCTs). Such trials present opportunities to evaluate patient-reported outcomes (PROs) for safety and efficacy during open-label extension (OLE) periods, during which patients previously randomised to an active comparator are switched to the bDMARD being investigated. Switching to a bDMARD with a different mechanism of action offers an option for patients who do not achieve target responses with first-line treatment, as well as for patients unsuited to csDMARD therapy.1 2 The efficacy and tolerability of sarilumab administered subcutaneously as monotherapy and in combination with csDMARDs have been demonstrated in phase III trials in adults with RA.9–14 In the 24-week RCT, MONARCH ([NCT02332590](http://rmdopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02332590&atom=%2Frmdopen%2F5%2F2%2Fe001017.atom)), monotherapy with sarilumab was superior to adalimumab at reducing disease activity and improving signs and symptoms of RA, as well as improving physical function and several PROs: Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study Short-Form (36-item) Health Survey (SF-36) physical component summary (PCS) and four of eight domains, patient global assessment of disease activity (PtGA) by visual analogue scale (VAS) and pain VAS.9 12 The objective of this paper is to understand and report the safety and efficacy of monotherapy with open-label sarilumab for up to 48 weeks in the ongoing MONARCH OLE among patients who switched to sarilumab from adalimumab, and in those who continued sarilumab, at the completion of the double-blind phase (DBP). ## Materials and methods ### Study design and patient population The methodology and results of the 24-week, phase III superiority RCT have been published previously.9 12 Briefly, adult patients (aged ≥18 years) with active RA who were intolerant of, or inadequate responders to, MTX or who were deemed inappropriate for MTX treatment, were eligible for inclusion. Patients were randomised to sarilumab 200 mg plus placebo every 2 weeks or adalimumab 40 mg plus placebo every 2 weeks, administered subcutaneously for 24 weeks. After 16 weeks, dose escalation to weekly administration of adalimumab or matching placebo was permitted for patients who failed to achieve ≥20% improvement in tender or swollen joint counts. Patients who completed the 24-week DBP in the head-to-head trial were eligible to enter the OLE phase, during which patients who had been randomised to adalimumab were switched to open-label sarilumab 200 mg (switch group), and patients who had been randomised to sarilumab 200 mg every 2 weeks continued treatment at this dosage (continuation group). The last visit of the DBP was the first visit (baseline) of the OLE. Per protocol, patients could reduce their dosage to sarilumab 150 mg every 2 weeks to manage laboratory abnormalities or per investigator’s discretion, or could withdraw from the OLE at any time, for any reason, or per investigator’s discretion. All patients who withdrew from treatment were asked to complete an early discontinuation visit 6 weeks afterwards. Each patient gave written informed consent before study participation. The study was conducted in compliance with institutional review board regulations, the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. ### Patient and public involvement The clinical trial was recorded on public registry websites prior to the enrolment of the first patient. This research was done without patient consultation. At the time this study was conducted, there were no funds or time allocated for patient/public involvement in study design or result-dissemination planning. ### Safety Safety data were reported for all patients in the OLE as of March 2017. Safety assessments included incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and laboratory measures. Adverse events (AEs) were described by the Medical Dictionary for Regulatory Activities (V.18.1) preferred term; AEs of special interest (AESIs) were identified using prespecified search criteria. Sarilumab was to be temporarily or permanently discontinued in cases of opportunistic infections (eg, tuberculosis), symptoms of hypersensitivity, severe neurological disease, acute renal failure, pregnancy or significant laboratory abnormalities (eg, neutropenia, thrombocytopenia or increased alanine aminotransferase (ALT) levels), as previously described.9 ### Efficacy endpoints Efficacy data were reported complete through OLE week 48. Efficacy endpoints included the proportion of switch patients achieving the following through week 48 in the OLE: Disease Activity Score (28 joints; DAS28) ≥minimally important difference (MID) for DAS28-erythrocyte sedimentation rate (ESR) ≥1.2 change from OLE entry and DAS28-C-reactive protein (CRP) ≥1.2 change from OLE entry; Clinical Disease Activity Index (CDAI) ≤2.8 (remission) and ≤10 (low disease activity (LDA)); Simplified Disease Activity Index (SDAI) ≤3.3 (remission) and ≤11 (LDA); American College of Rheumatology 20%/50%/70% (ACR20/50/70) response and improvement of HAQ-DI ≥0.22 units from baseline. Change from OLE at baseline to OLE at week 48 in DAS28-ESR, DAS28-CRP, CDAI, SDAI and HAQ-DI was also evaluated. PROs included PtGA VAS; pain VAS; Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); SF-36 PCS and mental component summary (MCS) and domain scores; EuroQol 5-Dimensions questionnaire (EQ-5D) VAS and EQ-5D single-index utility; Rheumatoid Arthritis Impact of Disease (RAID) and morning stiffness VAS. Details of each PRO assessed in the DBP, including minimally clinically important differences (MCIDs) and scores ≥normative values, have been reported previously.12 PROs were assessed at OLE baseline and OLE week 24; PtGA and pain VAS were also assessed at week 48. Patients reporting scores ≥normative values for the US general population in HAQ-DI (≤0.25),15 FACIT-F (≥40.1),16 SF-36 PCS and MCS (≥50) and for each of the SF-36 domains were also assessed. ### Statistical analysis Safety data were reported for the OLE period, the baseline of which coincided with week 24 of the DBP. Efficacy results were reported for the OLE period and, for select endpoints, for both DBP and OLE periods. Responder rates were reported using frequency and percentages for the full intent-to-treat (ITT) population, counting patients with missing data as nonresponders. Continuous efficacy outcomes were reported as observed cases (without imputation of missing data) using means (±SE) at each visit or as least-squares mean changes from mixed models for repeated measures. Data collected after discontinuation from treatment were excluded from analyses of continuous data. ## Results ### Patient population and exposure Of 369 patients who enrolled in the RCT, 321 completed the DBP and 320 (87%) entered the OLE. Patients either switched from adalimumab 40 mg every 2 weeks to sarilumab 200 mg every 2 weeks (switch group, n=155) or continued sarilumab (continuation group, n=165; figure 1). ![Figure 1](http://rmdopen.bmj.com/https://rmdopen.bmj.com/content/rmdopen/5/2/e001017/F1.medium.gif) [Figure 1](http://rmdopen.bmj.com/content/5/2/e001017/F1) Figure 1 Consolidated Standards of Reporting Trials flow diagram of the DBP and OLE stages of MONARCH. *Primary reasons for patient ineligibility were meeting the exclusion criteria related to tuberculosis (12.0%) or failure to meet the inclusion criterion for severity of disease (8.1%). †One patient was randomised but not treated in the adalimumab group. ‡The actual numbers of patients who received a dose-escalation kit on the basis of meeting protocol criteria were six (3.2%) in the adalimumab group and five (2.7%) in the sarilumab group. ALT, alanine aminotransferase; DBP, double-blind phase; OLE, open-label extension; q2w, every 2 weeks. Characteristics of the OLE patient population at entry to the DBP, including age, weight and disease severity, were similar between switch and continuation groups; overall mean age was 51.6 years, and the majority (>80%) were female (table 1). Mean time since RA diagnosis was 6.7 years in the switch group and 8.2 years in the continuation group; both groups had moderate-to-high baseline disease activity. View this table: [Table 1](http://rmdopen.bmj.com/content/5/2/e001017/T1) Table 1 Patient demographics and disease characteristics of the OLE patient population at entry to the DBP and disease characteristics of the OLE population at entry to the OLE (ITT population) At the time of data cut-off, 46/320 (14%) patients had discontinued the OLE before week 48 (72 weeks since DBP randomisation). Proportions of discontinued patients were similar in the switch (24/155, 15%) and continuation (22/165, 13%) groups; the most common reason for discontinuation (20/46, 43%) being AEs (figure 1). ### Safety Safety findings reported for the OLE period were based on 165.7 and 182.4 patient-years (PY) of exposure in switch and continuation groups, respectively. AEs, SAEs, AESIs and laboratory abnormalities reported in the OLE were consistent with those previously reported in the DBP.9 AEs, SAEs and AESIs that occurred within 70 days (≈5.5 drug half-lives) postswitch were also reported. ### AEs (serious and non-serious) and AESIs The overall incidence and exposure-adjusted rates of TEAEs were 76.1%, and 267.4 events/100 PY, respectively, in the switch group and 70.9% and 230.2 events/100 PY, respectively, in the continuation group (table 2). The proportion of patients with TEAEs occurring within 70 days postswitch was 42.6% and 420.5 events/100 PY in the switch group and 38.2% and 386.4 events/100 PY in the continuation group (online supplementary table 1). During the OLE, the most common AESIs were infection (switch: 41.9%, 66.4/100 PY; continuation: 35.8%, 53.2/100 PY), neutropenia (switch: 13.5%, 27.8/100 PY; continuation: 12.7%, 28.5/100 PY) and injection-site reactions (switch: 9.0%, 39.8/100 PY; continuation: 10.3%, 55.4/100 PY), including erythema (table 2). There were no reports of gastrointestinal (GI) ulcerations or perforations in either group. ### Supplementary data [[rmdopen-2019-001017supp001.pdf]](pending:yes) View this table: [Table 2](http://rmdopen.bmj.com/content/5/2/e001017/T2) Table 2 TEAEs reported during the OLE TEAEs leading to treatment discontinuation during the OLE were similar between the switch (n=10, 6.5%) and continuation (n=12; 7.3%) groups (table 2). The most common reasons for discontinuation were infection (n=2 in both groups; 1.3% and 1.2% in switch versus continuation groups, respectively), neoplasms (switch group, n=2; 1.3%) and blood and lymphatic system disorders (switch group, n=1; 0.6%, continuation group, n=2; 1.2%). As of March 2017, three deaths had been reported: two in the switch (1.2/100 PY) group and one in the continuation (0.5/100 PY) group. In the switch group, one death was due to malignancy and the other due to a cerebrovascular accident. The death in the continuation group was due to a subarachnoid haemorrhage. None of the deaths were considered treatment related. A greater incidence of treatment-emergent SAEs was noted in the switch versus continuation groups (table 2): rates of treatment-emergent SAEs were 11.0%, 15.1 events/100 PY in the switch group and 3.6%, 4.4 events/100 PY in the continuation group. However, there were no unexpected SAEs and no changes in the overall safety profile reported during the OLE. The most common (≥1%) treatment-emergent SAEs that occurred in switch patients were infections and infestations, three patients (1.9%); neoplasms, three (1.9%); cardiac disorders, three (1.9%); nervous system disorders, two (1.3%); vascular disorders, two (1.3%); musculoskeletal disorders, two (1.3%); and product issues, two (1.3%). Three serious infections occurred in the switch group (1.9%; 1.8/100 PY): pharyngotonsillitis (83 days after first dose in OLE), osteomyelitis (142 days after first dose) and pneumonia (94 days after first dose); none occurred in the continuation group. ### Laboratory abnormalities During the OLE, an absolute neutrophil count (ANC) 1.0× and ≤1.5× the upper limit of normal (ULN): switch, 23.4%; continuation, 24.8%. ALT levels >3× to 5× ULN occurred in 5.2% and 3.0% of switch and continuation patients, respectively, and ALT >5× ULN occurred in 1/154 (0.6%) switch patient and 4/165 (2.4%) continuation patients, respectively (online supplementary table 2). Among switch patients, 11/150 (7.3%) had antidrug antibodies (ADAbs) and 11/163 (6.7%) continuation patients had ADAbs. Three of these 22 (13.6%) ADAb-positive patients had hypersensitivity reactions (dermatitis, pruritic rash), compared with 19/291 (6.5%) patients who were ADAb-negative. There were no cases of anaphylaxis. The incidence of injection-site reactions was similar in ADAb-positive and ADAb-negative patients, and no ADAb-positive patients permanently discontinued treatment because of a lack of efficacy. ### Efficacy In the DBP, the mean change from baseline in DAS28-ESR, DAS28-CRP and HAQ-DI and the proportion of patients achieving LDA (CDAI ≤10) were greater with sarilumab monotherapy versus adalimumab monotherapy (figure 2).9 ![Figure 2](http://rmdopen.bmj.com/https://rmdopen.bmj.com/content/rmdopen/5/2/e001017/F2.medium.gif) [Figure 2](http://rmdopen.bmj.com/content/5/2/e001017/F2) Figure 2 Mean (±SE) change from DBP baseline in (A) DAS28-ESR, (B) DAS28-CRP, (C) HAQ-DI and (D) the proportion of patients achieving LDA (CDAI≤10) in the DBP and OLE. Mean change from baseline (panels A, B and C) is reported for observed cases, with no imputation for missing patients. Proportion of patients achieving LDA (panel D) is reported for the full ITT population, counting missing patients as nonresponders. Note: point of switch/continuation is indicated with a dotted vertical line; week number followed by an E refers to the number of weeks since entry into the OLE. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score (28 joints); DBP, double-blind phase; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; ITT, intent-to-treat; LDA, low disease activity; OLE, open-label extension. At DBP week 24/OLE baseline, the mean (SD) change from DBP baseline in DAS28-ESR was −2.28 (1.31) in the switch group and −3.36 (1.36) in the continuation group, and the change in DAS28-CRP was −2.08 (1.22) and −2.93 (1.25), respectively. Following the switch from adalimumab to sarilumab, rapid improvement was observed in the mean DAS28-ESR and DAS28-CRP, trending towards values observed in the sarilumab continuation group (figure 2A,B). The mean change (SD) from DBP baseline to OLE week 48 (total treatment: 72 weeks) in DAS28-ESR was −4.06 (1.25) in the switch group and −4.18 (1.35) in the continuation group, while the mean change in DAS28-CRP was −3.61 (1.23) and −3.63 (1.32), respectively. In the OLE ITT population, within 12 weeks of switching from adalimumab to sarilumab, 47.1% (95% CI 39.2% to 55.0%) of patients in the switch group showed improvement in disease activity ≥MID for DAS28-ESR (≥1.2 change from OLE baseline) and 34.8% (95% CI 27.3% to 42.3%) exceeded MID for DAS28-CRP (≥1.2 change from OLE baseline). This proportion increased to 45.8% (95% CI 38.0% to 53.7%) for DAS28-CRP at week 48 (figure 3A). A similar trend in improvement was observed for DAS28-ESR during OLE (data not shown); by week 48, 52.9% (95% CI 45.0% to 60.8%) of patients exceeded MID for DAS28-ESR. Patients in the continuation group also showed continued improvement during the OLE, with an additional 16.4% (95% CI 10.7% to 22.0%) and 11.5% (95% CI 6.6% to 16.4%) of patients exceeding the MID for DAS28-ESR and DAS28-CRP, respectively, at OLE week 12 and 28.5% (95% CI 21.6% to 35.4%) and 18.8% (95% CI 12.8% to 24.7%), respectively, exceeding MID at OLE week 48 (data not shown). ![Figure 3](http://rmdopen.bmj.com/https://rmdopen.bmj.com/content/rmdopen/5/2/e001017/F3.medium.gif) [Figure 3](http://rmdopen.bmj.com/content/5/2/e001017/F3) Figure 3 Proportions of switch patients (A) achieving MID in DAS28-CRP (≥1.2 change from OLE entry), (B) reporting improvements from OLE entry ≥MID in CDAI* and (C) reporting improvements from OLE entry ≥MCID (≥0.22 units) in HAQ-DI. Proportions of patients meeting or exceeding these levels are reported for the full ITT population, counting missing patients as nonresponders. Note: baseline =week 0E; a week number followed by an E refers to the number of weeks since entry into the OLE. *For CDAI, the definitions of MID were: MID=12 if baseline CDAI >22; MID=6 if baseline CDAI=10–22; MID=1 if baseline CDAI <10. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score (28 joints); HAQ-DI, Health Assessment Questionnaire-Disability Index; ITT, intent-to-treat; MCID, minimally clinically important difference; MID, minimally important difference; OLE, open-label extension. Improvement in CDAI (achievement of LDA or improvement exceeding the MID) was observed in both groups during the OLE (figures 2D and 3B). In switch patients who achieved LDA (CDAI ≤10 or SDAI ≤11) by OLE week 24, the majority sustained LDA at weeks 36 and 48 (70.7% and 69.5%, respectively; online supplementary figure 1). The proportion of switch patients who achieved CDAI (≤2.8) or SDAI (≤3.3) remission through week 48 (online supplementary figure 2) increased rapidly (within 2–4 weeks) from the point of switch and continued to increase to week 48. Among adalimumab patients who achieved CDAI-based or SDAI-based LDA or remission by the end of DBP, the majority maintained or improved their response after switching to sarilumab for OLE. By the end of the DBP/OLE entry, 41 switch patients had achieved CDAI LDA without remission (2.8