KEVZARA EFFICACY
LONG-TERM
COMBINATION THERAPY
References:
- Data on file, Sanofi/Regeneron. Integrated summary. October 25, 2019.
- 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.
- Data on file, Sanofi/Regeneron. Number of records at baseline in analysis. October 12, 2020.
Mobility (MTX-ir) Study Design1
- *P<0.0001.
After week 16 in MOBILITY, patients with an inadequate response could have been treated with open-label KEVZARA 200 mg every 2 weeks.1
CO-PRIMARY ENDPOINTS1-3
ACR20 response at week 24: Patients achieved 66%* with KEVZARA 200 mg + MTX compared to 33% with placebo + MTX
ΔHAQ-DI at week 16: -0.58* with KEVZARA 200 mg + MTX compared to -0.30 with placebo + MTX
ΔmTSS from baseline at week 52: 0.25 with KEVZARA 200 mg vs 2.78 with placebo*: KEVZARA 200 mg + MTX provided an absolute difference of -2.52 units (CI: -3.38, -1.66) in mean ΔmTSS relative to placebo + MTX
TARGET (TNF-IR) Study Design1
- *P<0.0001; †P<0.001.
CO-PRIMARY ENDPOINT DATA (TNF-IR)1-3
ACR20 response at week 24: Patients achieved 61%* with KEVZARA 200 mg + DMARD(s) compared to 34% with placebo + DMARD(s)
ΔHAQ-DI at week 12: -0.49† with KEVZARA 200 mg + DMARD(s) compared to -0.29 with placebo + DMARD(s)
Long-Term Combination Therapy
Relevant Trials: Long-term Combination Therapy
Pivotal Trial Study Designs
Combination Therapy
COMBINATION OPEN-LABEL
EXTENSION (OLE) STUDY DESIGN
KEVZARA + MTX/DMARD(s) SAFETY AND EFFICACY EVALUATED OVER TIME1
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. 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. NIH. Effect of SAR153191 (REGN88) with methotrexate in patients with active rheumatoid arthritis who failed TNF-α blockers. https://clinicaltrials.gov/ct2/show/NCT01217814. Accessed September 3, 2020. 3. National Library of Medicine. An evaluation of sarilumab plus methotrexate compared to etanercept plus methotrexate in RA patients not responding to adalimumab plus methotrexate (RA-COMPARE). https://clinicaltrials.gov/ct2/show/NCT01764997. Accessed September 3, 2020. 4. Data on file, Sanofi/Regeneron. Integrated summary. October 25, 2019.
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.
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 Response Over 5 Years
- ACR20=American College of Rheumatology 20% improvement criteria; DMARDs=disease-modifying antirheumatic drugs.
OPEN-LABEL EXTENSION DATA: INTERPRET WITH CAUTION
HAQ-DI OVER 5 YEARS
Data in patients who received initial treatment with KEVZARA compared with those who initially received placebo.
mobility extend
This analysis has not been performed for the TNF-IR population.
- *Mean HAQ-DI scores were calculated based on observed cases, without imputation of missing data.
- HAQ-DI=Health Assessment Questionnaire-Disability Index; SE=standard error; MTX=methotrexate; q2w=once every 2 weeks; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant.
HAQ-DI was measured in patients who
continued treatment with KEVZARA for up to 5 years1,2
OPEN-LABEL EXTENSION DATA: INTERPRET WITH CAUTION
INHIBITION OF RADIOGRAPHIC PROGRESSION OVER 5 YEARS
MOBILITY EXTEND
- *Radiographic progression was assessed by change from baseline in mTSS, reported using a post hoc integrated analysis of 4 separate reading campaigns. Change from baseline in mTSS was recorded in 1 campaign during the randomized controlled phase and 3 campaigns during the OLE. A post hoc integrated analysis was conducted to analyze radiographic progression based on all available campaign data.2
- mTSS=modified total Sharp score; SE=standard error; MTX=methotrexate.
Inhibition of structural progression was measured in patients who
continued treatment with KEVZARA for up to 5 years2
Common adverse reactions in pre-rescue, placebo-controlled trials1*
- *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.
Studied in ≈3000 MTX-IR and TNF-IR patients with over 8100 patient-years of exposure1-3
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 POPULATIONS2,3
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.