KEVZARA EFFICACY

SIGNS AND SYMPTOMS

CONTROL OF IL-6–RELATED SIGNS AND SYMPTOMS

RELEVANT TRIALS: MOBILITY, TARGET, MONARCH

Pivotal Trial Study Designs

MONARCH STUDY DESIGN

Head-to-Head Superiority Trial
(Monotherapy)

MONARCH STUDY DESIGN: A 24-week, randomized, double-blind, double-dummy, phase 3 superiority study to evaluate the efficacy and safety of KEVZARA 200 mg q2w monotherapy (n=184) vs adalimumab 40 mg q2w monotherapy (n=185) in patients who should not continue treatment with MTX due to intolerance or inadequate response.^*†‡ The primary endpoint was ΔDAS28-ESR; secondary endpoints included ΔDAS28-ESR <2.6, ACR20/50/70, ΔDAS28-CRP, ΔHAQ-DI.¹

PRIMARY ENDPOINT DATA¹

Change from baseline DAS28-ESR at 24 weeks: -3.28^§ with KEVZARA 200 mg q2w monotherapy compared to -2.20 with adalimumab 40 mg q2w monotherapy
The safety profiles of KEVZARA and adalimumab were generally comparable except for neutropenia and injection site erythema for KEVZARA and headache and RA for adalimumab

*Efficacy analyses were conducted in the ITT population, which included all randomized patients, including those who increased the dose frequency of adalimumab or matching placebo. Data collected after permanent treatment discontinuation period were excluded; ^†After week 16, dose escalation to adalimumab qw was permitted for patients who did not achieve ≥20% improvement in TJC and SJC; ^‡The recommended dose of adalimumab SC is 40 mg q2w. Some patients not taking concomitant MTX may derive additional benefit from increasing the SC dosing frequency to 40 mg qw; see adalimumab full Prescribing Information.^1,2; ^§P<0.0001; difference: -1.08 (95% CI: -1.36 to -0.79).¹

q2w=once every 2 weeks; MTX=methotrexate; DAS28-ESR=Disease Activity Score-28 Erythrocyte Sedimentation Rate; ACR20=American College of Rheumatology 20% improvement criteria; DAS28-CRP=disease activity score 28-C-reactive protein; HAQ-DI=Health Assessment Questionnaire-Disability Index; ITT=intent to treat; TJC=tender joint count; SJC=swollen joint count; SC=subcutaneous; qw=once daily.

References: 1. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847. 2. Humira [package insert]. North Chicago, IL: AbbVie Inc; 2019.

Study context and limitations

MONARCH ADDITIONAL STUDY CONTEXT

MONARCH data are not included in the KEVZARA US full Prescribing Information
DAS28-ESR and FACIT-Fatigue were endpoints in MONARCH; however, there are no DAS28-ESR or FACIT-Fatigue data in the KEVZARA US full Prescribing Information

USE OF ADALIMUMAB

Adalimumab and KEVZARA have different indications and can be used differently in clinical practice
Dose escalation from adalimumab 40 mg q2w to 40 mg qw was permitted after week 16 in patients who had not achieved at least 20% improvement in TJC and SJC. By week 24, dosing for 8.6% of patients on adalimumab was adjusted

STUDY LIMITATIONS (MONARCH)

KEVZARA and adalimumab can be used as monotherapy or in combination with nonbiologic DMARD(s). In MONARCH, both agents were only used as monotherapy
The efficacy of KEVZARA monotherapy has not been compared to that of KEVZARA + MTX or adalimumab + MTX
MONARCH did not evaluate radiographic outcomes in either treatment group

Given the limitations and context described above, caution should be used in interpreting these data.

DAS28-ESR=Disease Activity Score-28 Erythrocyte Sedimentation Rate; FACIT-Fatigue=Functional Assessment of Chronic Illness Therapy-Fatigue; q2w=once every 2 weeks; qw=once daily; TJC=tender joint count; SJC=swollen joint count; DMARDs=disease-modifying antirheumatic drugs; MTX=methotrexate.

MONARCH data are not included in the KEVZARA US full Prescribing Information. Please see Study Context and Limitations for details.

RAPIDLY NORMALIZED CRP LEVELS^1,2

CRP levels returned to normal (<10 mg/L) as early as 2 weeks after the first dose of KEVZARA.^3,4*

mobility (mtx-ir)

target (tnf-ir)

monarch (mtx-ir)

Changes in CRP levels over a 24 week period with KEVZARA® (sarilumab)

*CRP levels were not a prespecified endpoint. Studied as part of the ACR20/50/70 response endpoints in MOBILITY, TARGET, MONARCH.^3,5

CRP=C-reactive protein; MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; LS=least squares; MTX=methotrexate; q2w=once every 2 weeks; DMARDs=disease-modifying antirheumatic drugs; ACR20=American College of Rheumatology 20% improvement criteria.

REDUCTIONS IN MORNING STIFFNESS^5,6

target (tnf-ir)

monarch (mtx-ir)

Reductions in morning stiffness with KEVZARA® (sarilumab)

Morning stiffness was not assessed in MOBILITY.

TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; MTX-IR=methotrexate inadequate response; LS=least squares; VAS=visual analogue scale; DMARDs=disease-modifying antirheumatic drugs; q2w=once every 2 weeks.

REDUCTIONS IN PAIN^2,5,7

mobility (mtx-ir)

target (tnf-ir)

monarch (mtx-ir)

Reductions in pain with KEVZARA® (sarilumab)

MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; LS=least squares; VAS=visual analogue scale; MTX=methotrexate; q2w=once every 2 weeks; DMARDs=disease-modifying antirheumatic drugs.

COMBINATION THERAPY
SAFETY DATA

Common adverse reactions in pre-rescue, placebo-controlled trials^1*

*Adverse reactions occurring in ≥2% of patients administered KEVZARA 200 mg or KEVZARA 150 mg + DMARD(s) and greater than observed in patients on placebo + DMARD(s).

Medically relevant AE occurring at an incidence of less than 2% in patients with RA treated with KEVZARA in controlled studies was oral herpes¹
Decrease in ANC was not associated with higher incidence of infections, including serious infections¹
In the long-term safety population, the overall rates of serious infections, GI perforations, neutrophil counts, platelet counts, and lipid parameters were consistent with what was observed in the placebo-controlled trials¹

DMARDs=disease-modifying antirheumatic drugs; ALT=alanine aminotransferase; ANC=absolute neutrophil count; GI=gastrointestinal.

Reference: 1. KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc.

MonoTherapy Safety Data

KEVZARA SAFETY PROFILE AS MONOTHERAPY^1,2

In MONARCH, the safety profiles of KEVZARA and adalimumab were generally comparable, except for neutropenia and injection site erythema for KEVZARA and headache and RA for adalimumab³

*One patient was randomized, but not treated, in the adalimumab group and was not included in the safety population; ^†Patient years per group are as follows: 80.5 (adalimumab 40 mg) and 80.1 (KEVZARA 200 mg). ^‡In the randomized trial, 1 patient in the KEVZARA group died of acute cardiac failure secondary to aortic dissection and papillary muscle rupture on day 36; ^§In the randomized trial, 1 patient receiving KEVZARA was diagnosed with infective bursitis and another patient was diagnosed with mastitis, and 1 patient receiving adalimumab was diagnosed with bacterial arthritis and another patient was diagnosed with a respiratory tract infection; ^||Protocol defined as ≥2 doses within 11 calendar days or within 6 days for adalimumab-treated patients who switched to weekly dosing; ^¶Dyslipidemia was defined by standardized MedDRA query.^2,3

q2w=once every 2 weeks; PY=patient-years; TEAE=treatment emergent adverse event; ALT=alanine aminotransferase.

References: 1. Fleischmann R, Genovese M, Lin Y, et al. Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years’ follow-up. Rheumatology (Oxford). 2019. doi:10.1093/rheumatology/kez265. [Epub ahead of print]. 2. Data on file, Sanofi/Regeneron. Integrated summary. October 25, 2019. 3. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.

VIEW SAFETY DATA

NEXT: KEVZARA SAFETY DATA

References:

Data on file, Sanofi/Regeneron. Integrated summary. October 25, 2019.
Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.
KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc.
Center for Devices and Radiological Health. Guidance for industry and FDA staff: review criteria for assessment of C-reactive protein (CRP), high sensitivity C-reactive protein (hsCRP) and cardiac C-reactive protein (cCRP) assays. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/review-criteria-assessment-c-reactive-protein-crp-high-sensitivity-c-reactive-protein-hscrp-and-0. Accessed September 3, 2020.
Strand V, Reaney M, Chen CI, et al. Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors. RMD Open. 2017;3(1):e000416. doi:10.1136/rmdopen-2016-000416.
Strand V, Gossec L, Proudfoot CWJ, et al. Patient-reported outcomes from a randomized phase III trial of sarilumab monotherapy versus adalimumab monotherapy in patients with rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):129. doi:10.1186/s13075-018-1614-z.
Strand V, Kosinski M, Chen CI, et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18:198. doi:10.1186/s13075-016-1096-9.

INDICATION

KEVZARA is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Avoid use of KEVZARA in patients with an active infection.

Reported infections include:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before KEVZARA use and during therapy. Treatment for latent infection should be initiated prior to KEVZARA use.
Invasive fungal infections, such as candidiasis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral and other infections due to opportunistic pathogens.

Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled.

Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection.

CONTRAINDICATION

Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.

WARNINGS AND PRECAUTIONS

Infections. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents for rheumatoid arthritis (RA). The most frequently observed serious infections with KEVZARA included pneumonia and cellulitis. Among opportunistic infections, TB, candidiasis, and pneumocystis were reported with KEVZARA.
- Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.
- Patients with latent TB should be treated with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection.
- Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have: chronic or recurrent infection, a history of serious or opportunistic infections, underlying conditions in addition to RA that may predispose them to infection, been exposed to TB, or lived in or traveled to areas of endemic TB or endemic mycoses.
- Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA.
Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals.
Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms.
Immunosuppression. Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with KEVZARA on the development of malignancies is not known but malignancies have been reported in clinical studies.
Hypersensitivity Reactions. Hypersensitivity reactions have been reported in association with KEVZARA. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of KEVZARA immediately. Do not administer KEVZARA to patients with known hypersensitivity to sarilumab.
Active Hepatic Disease and Hepatic Impairment. Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations.
Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA.

ADVERSE REACTIONS

The most common serious adverse reactions were infections. The most frequently observed serious infections included pneumonia and cellulitis. The most common adverse reactions (occurred in at least 3% of patients treated with KEVZARA + DMARDs) are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.

DRUG INTERACTIONS

Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate.
Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations.

USE IN SPECIFIC POPULATIONS

KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KEVZARA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
Use caution when treating the elderly.

Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Please click here to see full Prescribing Information, including Boxed WARNING.

KEVZARA EFFICACY

CONTROL OF IL-6–RELATED SIGNS AND SYMPTOMS

Pivotal Trial Study Designs

MONARCH STUDY DESIGN

Study context and limitations

RAPIDLY NORMALIZED CRP LEVELS1,2

REDUCTIONS IN MORNING STIFFNESS5,6

REDUCTIONS IN PAIN2,5,7

COMBINATION THERAPY SAFETY DATA

Common adverse reactions in pre-rescue, placebo-controlled trials1*

MonoTherapy Safety Data

KEVZARA SAFETY PROFILE AS MONOTHERAPY1,2

RAPIDLY NORMALIZED CRP LEVELS^1,2

REDUCTIONS IN MORNING STIFFNESS^5,6

REDUCTIONS IN PAIN^2,5,7

COMBINATION THERAPY
SAFETY DATA

Common adverse reactions in pre-rescue, placebo-controlled trials^1*

KEVZARA SAFETY PROFILE AS MONOTHERAPY^1,2