KEVZARA EFFICACY

Clinical Remission Data

Relevant Trials: MOBILITY, TARGET, Combination Therapy Open-Label Extension (OLE)

PIVOTAL TRIAL STUDY DESIGNS

CLINICAL REMISSION DATA (DAS28-CRP <2.6) WITH KEVZARA

Significantly more patients achieved DAS28-CRP <2.6 with KEVZARA 200 mg + MTX in MOBILITY and KEVZARA 200 mg + DMARD(s) in TARGET

MOBILITY
(MTX-IR)
target
(TNF-IR)

REMISSION Data (DAS28-CRP <2.6) at week 24: Mobility^1,2

Disease activity response at week 24 in MOBILITY (MTX-IR) as a result of KEVZARA® (sarilumab) treatment

REMISSION DATA (DAS28-CRP <2.6) at week 24: Target^2,3

Disease activity response at week 24 in TARGET (TNF-IR) as a result of KEVZARA® (sarilumab) treatment

Measures of remission do not imply drug-free remission or complete absence of disease.

DAS28-CRP=disease activity score 28-C-reactive protein; MTX=methotrexate; MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; q2w=once every 2 weeks; DMARDs=disease-modifying antirheumatic drugs.

CLINICAL REMISSION DATA (SDAI ≤3.3/CDAI ≤2.8) WITH KEVZARA

KEVZARA 200 mg + MTX showed improvement in CDAI remission compared to placebo + MTX in MOBILITY (MTX-IR)

MOBILITY
(MTX-IR)
target
(TNF-IR)

Remission DATA at week 24: Mobility^1,4

Remission rate at week 24 in MOBILITY (MTX-IR) as a result of KEVZARA® (sarilumab) treatment

Remission at week 24: Target^4,5

Remission rate at week 24 in TARGET (TNF-IR) as a result of KEVZARA® (sarilumab) treatment

Measures of remission do not imply drug-free remission or complete absence of disease.

SDAI=Simple Disease Activity Index; CDAI=Clinical Disease Activity Index; MTX=methotrexate; MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; q2w=once every 2 weeks; DMARDs=disease-modifying antirheumatic drugs.

LONG-TERM COMBINATION THERAPY

ADDITIONAL STUDY DESIGNS

OPEN-LABEL EXTENSION
Combination Therapy

COMBINATION OPEN-LABEL
EXTENSION (OLE) STUDY DESIGN

KEVZARA + MTX/DMARD(s) SAFETY AND EFFICACY EVALUATED OVER TIME¹

KEVZARA® (sarilumab) and MTX/DMARD(s) safety and efficacy evaluated over time

INCIDENCE OF ADVERSE EVENTS (PRIMARY ENDPOINT)

Long-term efficacy was evaluated in adult patients who completed MOBILITY or TARGET and subsequently enrolled in EXTEND OLE¹
Long-term safety was evaluated in all 2887 adult patients who received ≥1 dose of KEVZARA in combination with DMARD(s)¹

*These 2 studies were discontinued due to low enrollment.^2,3
^†Patients participating in the EXTEND OLE trial received KEVZARA 200 mg regardless of prior treatment in the placebo-controlled trials, except for patients who were previously dose-reduced to KEVZARA 150 mg due to safety issues, who continued on KEVZARA 150 mg.¹
^‡Patients in the EASY OLE study received KEVZARA 150 mg regardless of their prior treatment.⁴

References: 1.

Rheumatology (Oxford).

MTX=methotrexate; DMARDs=disease-modifying antirheumatic drugs; MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; q2w=once every 2 weeks; TNF=tumor necrosis factor.

Study context and limitations

OPEN-LABEL EXTENSION (OLE) STUDY LIMITATIONS AND ADDITIONAL STUDY CONTEXT

These data are not included in the KEVZARA US full Prescribing Information. Data presented are truthful and not misleading
Open-label extension studies tend to include patients who respond to treatment and exclude those who discontinue treatment for any reason. As such, evaluating long-term efficacy using continuous variables can be influenced by progressively smaller numbers of patients remaining in the study
Data presented are descriptive in nature, and no statistical comparisons are made
Clinical data were analyzed based on all available data as observed

LONG-TERM SAFETY ANALYSIS

This was a comprehensive safety analysis from pooled studies of patients who received at least 1 dose of sarilumab in combination with DMARD(s)

LONG-TERM EFFICACY ANALYSIS

Efficacy assessments in this analysis did not include all of the primary endpoints from the placebo-controlled period of the pivotal trials analyzed
For analysis of no radiographic progression, linear extrapolation was used to impute missing data. Patients with missing data after the imputation were considered progressors

DMARDs=disease-modifying antirheumatic drugs.

Given the limitations and context described above, caution should be used in interpreting open-label extension (OLE) data. There are limitations associated with open-label study design, including decreasing sample size and potential continued involvement of responders and attrition of non-responders. Data presented are descriptive in nature and no statistical comparisons are made.

OPEN-LABEL EXTENSION DATA: INTERPRET WITH CAUTION

CLINICAL REMISSION DATA (SDAI ≤3.3/CDAI ≤2.8) OVER 4 YEARS

MOBILITY (MTX-IR)
extend
target (TNF-IR)
extend

REMISSION DATA: SDAI ≤3.3/CDAI ≤2.8^4,6

Remission rates in DAS28-CRP observed KEVZARA® (sarilumab) in the open-label extension at 216 weeks and at 244 weeks

REMISSION DATA: SDAI ≤3.3/CDAI ≤2.8^4,6

Disease activities in DAS28-CRP observed KEVZARA® (sarilumab) in the open-label extension at week 216 and week 244

Measures of remission do not imply drug-free remission or complete absence of disease.

SDAI=Simple Disease Activity Index; CDAI=Clinical Disease Activity Index; MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; MTX=methotrexate; q2w=once every 2 weeks; DMARDs=disease-modifying antirheumatic drugs.

OPEN-LABEL EXTENSION DATA: INTERPRET WITH CAUTION

CLINICAL REMISSION DATA (DAS28-CRP <2.6) OVER 4 YEARS

MOBILITY (MTX-IR)
extend
TARGET (TNF-IR)
EXTEND

REMISSION DATA: DAS28-CRP <2.6⁷

Disease activity in DAS28-CRP observed KEVZARA® (sarilumab) in the open-label extension at 244 weeks

REMISSION DATA: DAS28-CRP <2.6⁶

Disease activity in DAS28-CRP observed KEVZARA® (sarilumab) in the open-label extension at week 144

Measures of remission do not imply drug-free remission or complete absence of disease.

DAS28-CRP=disease activity score 28-C-reactive protein; MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; 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

ANC=absolute neutrophil count; GI=gastrointestinal.

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

LONG-TERM COMBINATION
THERAPY SAFETY DATA

Studied in ≈3000 MTX-IR and TNF-IR patients with over 8100 patient-years of exposure^1-3

Mean duration of treatment in the safety population (N=2887) was 2.8 years (max 7.3 years), representing 8188 cumulative PY of exposure

773 patients (27%) were treated for ≥240 weeks (4.6 years)
36 patients (1.2%) were treated for >360 weeks (7 years)

Incidence rate of AEs was generally stable over time, with no indication of increased incidence rate in serious AEs and serious infections.^2,3

MOBILITY (MTX-IR), TARGET (TNF-IR), LONG-TERM SAFETY POPULATIONS^2,3

In the long-term safety population, the rate of thromboembolic events (MedDRA high-level group term “embolism and thrombosis”) were 0.8 per 100 PY (as reported and evaluated post hoc; not a prespecified AESI)²

Rate of DVT was 0.2 per 100 PY; rate of PE was 0.2 per 100 PY

Safety observations in the open-label extension population were consistent with those in the placebo-controlled trials.^2,3

*Incidence rate per 100 PY at risk of first event.
^†TEAE period from day of first treatment dose to 60 days after the last treatment dose.²
^‡Injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 3 (<0.5%) patients receiving KEVZARA.³

MTX-IR=methotrexate inadequate response; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant; PY=patient-years; IR=incidence rate; MTX=methotrexate; DMARDs=disease-modifying antirheumatic drugs; q2w=every 2 weeks; TEAE=treatment-emergent adverse event; ALT=alanine aminotransferase; AESI=adverse event of special interest; DVT=deep vein thrombosis; PE=pulmonary embolism.

References: 1. KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc. 2. 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]. 3. Data on file, Sanofi/Regeneron. Integrated summary. October 25, 2019.

VIEW SAFETY DATA

NEXT: HEAD-TO-HEAD MONOTHERAPY
AND OLE

References:

Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424-1437.
KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc.
Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2017;69(2):277-290.
Data on file, Sanofi/Regeneron. Integrated summary. October 25, 2019.
Data on file, Sanofi/Regeneron. TARGET CSR data. August 2019.
Data on file, Sanofi/Regeneron. EULAR poster SAT0172. June 2018.
Genovese MC, van der Heijde D, Lin Y, et al. Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD Open. 2019;5(2):e000887. doi:10.1136/rmdopen-2018-000887.

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

Clinical Remission Data

PIVOTAL TRIAL STUDY DESIGNS

CLINICAL REMISSION DATA (DAS28-CRP <2.6) WITH KEVZARA

CLINICAL REMISSION DATA (SDAI ≤3.3/CDAI ≤2.8) WITH KEVZARA

LONG-TERM COMBINATION THERAPY

ADDITIONAL STUDY DESIGNS

Study context and limitations

OPEN-LABEL EXTENSION DATA: INTERPRET WITH CAUTION

CLINICAL REMISSION DATA (SDAI ≤3.3/CDAI ≤2.8) OVER 4 YEARS

OPEN-LABEL EXTENSION DATA: INTERPRET WITH CAUTION

CLINICAL REMISSION DATA (DAS28-CRP <2.6) OVER 4 YEARS

COMBINATION THERAPY SAFETY DATA

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

LONG-TERM COMBINATION THERAPY SAFETY DATA

MOBILITY (MTX-IR), TARGET (TNF-IR), LONG-TERM SAFETY POPULATIONS2,3

COMBINATION THERAPY
SAFETY DATA

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

LONG-TERM COMBINATION
THERAPY SAFETY DATA

MOBILITY (MTX-IR), TARGET (TNF-IR), LONG-TERM SAFETY POPULATIONS^2,3