KEVZARA is approved for active polyarticular juvenile idiopathic arthritis (pJIA) in pediatric patients who weigh 63 kg or greater. Use of KEVZARA in this patient population is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA, and a pharmacokinetic, pharmacodynamic, dose-finding, and safety study in pediatric patients with pJIA 2 years of age and older. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form

[see

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Rheumatoid Arthritis

All patients in the safety data described below had moderately to severely active rheumatoid arthritis.

The safety of KEVZARA in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received KEVZARA for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks.

The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to KEVZARA. In this population, 582 patients, 579 patients, and 579 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs.

The 52-week placebo-controlled population includes patients from one Phase 2 study of 12-week duration and two Phase 3 efficacy studies (one of 24-week duration and the other of 52-week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs.

Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used.

The most common serious adverse reactions were infections

The most frequent adverse reactions (occurring in at least 3% of patients treated with KEVZARA in combination with DMARDs) observed with KEVZARA in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.

In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with KEVZARA 200 mg, KEVZARA 150 mg, and placebo, respectively.

The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with KEVZARA was neutropenia.

The use of KEVZARA as monotherapy was assessed in 132 patients, of which 67 received KEVZARA 200 mg and 65 patients received KEVZARA 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs.

Overall Infections

In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg KEVZARA + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis.

In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with KEVZARA 200 mg + DMARD, 0.6% (4 patients) treated with KEVZARA 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster

[seeWarnings and Precautions (5.1)]

The overall rate of infections with KEVZARA + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies.

Serious Infections

In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group. In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group.

In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported

[seeWarnings and Precautions (5.1)]

Gastrointestinal Perforation

In the 52-week placebo-controlled population, one patient on KEVZARA therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years).

In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to KEVZARA in the development of GI perforations is not known

[seeWarnings and Precautions (5.3)]

Hypersensitivity Reactions

In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with KEVZARA (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period.

Injection Site Reactions

In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving KEVZARA 200 mg, 6% receiving KEVZARA 150 mg, and 1% receiving placebo. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving KEVZARA.

Laboratory Abnormalities

Decreased neutrophil count

In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm³occurred in 6% and 4% of patients in the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD group, respectively, compared to no patients in the placebo + DMARD groups. Decreases in neutrophil counts less than 500 per mm³occurred in 0.7% of patients in both the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD groups. Decrease in ANC was not associated with the occurrence of infections, including seriou

infections.

In the long-term safety population, the observations on neutrophil counts were consistent with what was seen in the placebo-controlled clinical studies

[seeWarnings and Precautions (5.2)]

Decreased platelet count

In the pre-rescue placebo-controlled population, decreases in platelet counts less than 100,000 per mm³occurred in 1% and 0.7% of patients on 200 mg and 150 mg KEVZARA + DMARD, respectively, compared to no patients on placebo + DMARD, without associated bleeding events.

In the long-term safety population, the observations on platelet counts were consistent with what was seen in the placebo-controlled clinical studies

[seeWarnings and Precautions (5.2)]

Elevated liver enzymes

Liver enzyme elevations in the pre-rescue placebo-controlled population (KEVZARA + DMARD or placebo + DMARD) are summarized in Table 2. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of KEVZARA or reduction in dose, resulted in decrease or normalization of liver enzymes

[seeDosage and Administration (2.6)]

. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment

[seeWarnings and Precautions (5.2)]

Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely Active Rheumatoid ArthritisPhase 3 placebo-controlled safety population through the pre-rescue period
	Placebo + DMARD N=579	KEVZARA 150 mg + DMARD N=579	KEVZARA 200 mg + DMARD N=582
ULN = Upper Limit of Normal
AST
Greater than ULN to 3 times ULN or less	15%	27%	30%
Greater than 3 times ULN to 5 times ULN	0%	1%	1%
Greater than 5 times ULN	0%	0.7%	0.2%
ALT
Greater than ULN to 3 times ULN or less	25%	38%	43%
Greater than 3 times ULN to 5 times ULN	1%	4%	3%
Greater than 5 times ULN	0%	1%	0.7%

Lipid Abnormalities

Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of KEVZARA + DMARDs in the placebo-controlled population. Increases were observed at this time point with no additional increases observed thereafter. Changes in lipid parameters from baseline to Week 4 are summarized below:

Mean LDL increased by 12 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 16 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group.
Mean triglycerides increased by 20 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 27 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group.
Mean HDL increased by 3 mg/dL in both the KEVZARA 150 mg every two weeks + DMARD and KEVZARA 200 mg every two weeks + DMARD groups.

In the long-term safety population, the observations in lipid parameters were consistent with what was observed in the placebo-controlled clinical studies.

Malignancies

In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 1.0 event per 100 patient-years) were diagnosed in patients receiving KEVZARA + DMARD compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 1.0 event per 100 patient-years).

In the long-term safety population, the rate of malignancies was consistent with the rate observed in the placebo-controlled period

[seeWarnings and Precautions (5.4)]

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on KEVZARA + DMARD and greater than those observed in patients on placebo + DMARD are summarized in Table 3.

Table 3: Common Adverse ReactionsAdverse reactions occurring in 2% or more in the 150 mg KEVZARA + DMARD or 200 mg KEVZARA + DMARD groups and greater than observed in Placebo + DMARDin Adults with Moderately to Severely Active Rheumatoid ArthritisPre-rescue, placebo-controlled population
Adverse Reactions	Placebo + DMARD (N=579)	KEVZARA 150 mg + DMARD (N=579)	KEVZARA 200 mg + DMARD (N=582)
Neutropenia	0.2%	7%	10%
Alanine aminotransferase increased	2%	5%	5%
Injection site erythema	0.9%	5%	4%
Injection site pruritus	0.2%	2%	2%
Upper respiratory tract infection	2%	4%	3%
Urinary tract infection	2%	3%	3%
Hypertriglyceridemia	0.5%	3%	1%
Leukopenia	0%	0.9%	2%

Medically relevant adverse reactions occurring at an incidence less than 2% in patients with rheumatoid arthritis treated with KEVZARA in controlled studies was oral herpes.

Polymyalgia Rheumatica

Safety has been studied in one Phase 3 study (Study 3) in 117 PMR patients of whom 59 received subcutaneous KEVZARA 200 mg

[seeClinical Studies (14.2)]

. Of these, 45 patients received KEVZARA for at least 24 weeks, 44 patients for at least 40 weeks, and 10 patients for at least 52 weeks. The total patient years duration in the KEVZARA PMR population was 47.37 patient years during the 12-month double blind, placebo-controlled study.

The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia (15.3%), leukopenia (6.8%), constipation (6.8%), rash pruritic (5.1%), myalgia (6.8%), fatigue (5.1%), and injection site pruritus (5.1%).

Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. In both cases of neutropenia, the participants had a neutrophil count less than 500 per mm³without any infections and resolved following permanent discontinuation of study drug.

The most common adverse reactions that resulted in permanent discontinuation of therapy with KEVZARA were neutropenia in 3 patients (5.1%) and infection in 3 separate patients (5.1%), including COVID-19 (n=1), intervertebral discitis (n=1), and pneumonia (n=1).

Overall Infections

In Study 3, the proportion of patients with infections was lower in the KEVZARA group (37.3%) compared to the placebo group (50.0%). Two patients (3.2%) in the KEVZARA group and 1 patient (1.7%) in the placebo group had an event of herpes zoster.

Serious infections

In Study 3, the proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%).

Injection Site Reactions

In Study 3, three patients (5.1%) in the KEVZARA group experienced injection site reactions of pruritus which were mild in severity. No patient in the placebo group experienced injection site reactions.

Laboratory Abnormalities

Decreased neutrophil count

In Study 3, decreases in neutrophil counts less than 1,000 per mm³occurred in 12% of the KEVZARA treated group and no patient in the placebo treated group. Decreases in neutrophil counts less than 500 per mm³occurred in 3.4% of patients in KEVZARA treated group compared to no patient in the placebo treated group.

Decreased platelet count

In Study 3, decreases in platelet counts between 75,000 to 100,000 per mm³occurred in two patients (3.4%) in the KEVZARA group, compared to no patient in the placebo treated group. These platelet count decreases were transient and not associated with bleeding events.

Elevated liver enzymes

In Study 3, no KEVZARA treated patients had an ALT or AST greater than 3 times the upper limit of normal (ULN). In the placebo treated group, 2 patients had ALT elevations greater than 3 times the ULN.

Lipid Abnormalities

In Study 3, cholesterol levels ≥299.27 mg/dL were observed in 8/58 (13.8%) patients in the KEVZARA group compared to 4/58 (6.9%) patients in the placebo group. Triglycerides ≥407.4 mg/dL were observed in 3/58 (5.2%) patients in the KEVZARA group compared to 1/58 (1.7%) in the placebo group.

No significant differences in mean HDL between KEVZARA group and placebo group were observed. At Week 52, mean increase from baseline for LDL and triglycerides levels were observed in the KEVZARA group though both remained within the normal range.

Polyarticular Juvenile Idiopathic Arthritis (pJIA)

The safety of KEVZARA was studied in patients 2 to 17 years of age with pJIA who have had an inadequate response to current therapy (Study 4)

[seeClinical Studies (14.3)]

. A total of 93 patients received at least one administration of the recommended dose: 79 (84.9%) patients received the recommended dose for 52 weeks, 53 (57%) patients received it for 96 weeks and 30 (32.2%) patients received it for 156 weeks.

The overall median duration of study treatment for the recommended dose was 672 days. The cumulative exposure to treatment for patients who received the recommended dose at any time during the study was 184.1 patient-years.

The most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.

The most common adverse drug reaction that resulted in permanent discontinuation of therapy with KEVZARA was neutropenia (5.4%).

No new adverse reactions and safety concerns were identified in the pJIA population compared to the RA population.

Infections

In Study 4, the rate of infections was 146.6 events per 100 patient-years. The most common infections observed were nasopharyngitis (36.6%) and upper respiratory tract infections (URTI) (14.0%).

Injection Site Reactions

In Study 4, injection site reactions (ISRs) occurred in 13 (14.0%) patients and the most commonly reported ISR was injection site erythema (9.7%). The majority of these events were mild and none of the ISRs required patient withdrawal from treatment or dose interruption.

Laboratory Abnormalities

Decrease neutrophil count

In Study 4, decreases in neutrophil counts less than 1000 per mm³occurred in 10/52 (19.2%) patients weighing in ≥30 kg and 20/41 (48.8%) patients weighing 10 to <30 kg. The frequency of decreased neutrophil count was higher until Week 12. Decrease in ANC was not associated with an occurrence of infections, including serious infections.

Decrease monocyte count

In Study 4, decrease in monocyte counts occurred in 4 (4.3%) patients and were mild in severity and non-serious.

Elevated liver enzymes

In Study 4, nine (9.7%) patients had ALT increases, including one (1.1%) patient who had ALT >3 times upper limit of normal (ULN) and up to ≤5 times ULN, and two (2.2%) patients who had ALT increases >5 times ULN and up to ≤10 times ULN that resulted in permanent discontinuation. All patients recovered.

Lipid Abnormalities

In Study 4, triglyceride levels of ≥150 mg/dL (1 × ULN) were observed in one (1.1%) patient. Three (3.2%) patients overall had elevation in triglycerides, and all were mild in severity and non-serious. No significant changes in mean LDL, HDL or total cholesterol were observed during the entire 156-week treatment period.

12.3 Pharmacokinetics

Rheumatoid Arthritis

Absorption

The pharmacokinetics of sarilumab were characterized in 1770 adult patients with rheumatoid arthritis (RA) treated with sarilumab which included 631 patients treated with 150 mg and 682 patients treated with 200 mg doses by subcutaneous injection every two weeks for up to 52 weeks. The median t_maxwas observed in 2 to 4 days.

At steady state, exposure over the dosing interval measured by area under curve (AUC) increased 2-fold with an increase in dose from 150 to 200 mg every two weeks. Steady state was reached in 14 to 16 weeks with a 2- to 3-fold accumulation compared to single dose exposure.

For the 150 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, C_minand C_maxof sarilumab were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively.

For the 200 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, C_minand C_maxof sarilumab were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively.

Distribution

In patients with RA, the apparent volume of distribution at steady state was 7.3 L.

Elimination

Sarilumab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear saturable target-mediated elimination predominates. The half-life of sarilumab is concentration-dependent. At 200 mg every 2 weeks, the concentration-dependent half-life is up to 10 days in patients with RA at steady state. At 150 mg every 2 weeks, the concentration-dependent half-life is up to 8 days in patients with RA at steady state.

After the last steady state dose of 150 mg and 200 mg sarilumab, the median times to non-detectable concentration are 28 and 43 days, respectively.

Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of sarilumab in the presence of anti-sarilumab antibodies.

Metabolism

The metabolic pathway of sarilumab has not been characterized. As a monoclonal antibody sarilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Excretion

Monoclonal antibodies, including sarilumab, are not eliminated via renal or hepatic pathways.

Polymyalgia Rheumatica

The pharmacokinetic profile of subcutaneous sarilumab in PMR patients was determined using a population pharmacokinetic analysis on a data set including 58 PMR patients treated with repeated subcutaneous administration of sarilumab 200 mg every two weeks. In general, pharmacokinetic exposures were higher in patients with PMR when compared to patients with RA. For this dose regimen, the estimated mean (± SD) steady-state AUC, C_minand C_maxof sarilumab were 551 ± 321 mg.day/L, 27.0 ± 21.5 mg/L, and 46.5 ± 23.0 mg/L, respectively. The median time to steady state in PMR patients was estimated to be 28 weeks. There was accumulation following subcutaneous administration of sarilumab 200 mg, with an accumulation ratio of approximately 6-fold based on the mean trough concentrations.

Polyarticular juvenile idiopathic arthritis (pJIA)

The pharmacokinetics of sarilumab in pJIA patients was characterized by a population pharmacokinetic analysis which included 101 pediatric patients 2 to 17 years of age who were treated with repeated subcutaneous doses of sarilumab.

For 3 mg/kg sarilumab (patients with a body weight ≥30 kg) given every 2 weeks, the estimated mean (±SD) steady-state AUC, Cmin, and Cmax of sarilumab were 276 ± 121 mg.day/L, 9.57 ± 5.84 mg/L, and 27.1 ± 11.6 mg/L, respectively.

For 4 mg/kg sarilumab (patients with a body weight 10 to <30 kg) given every 2 weeks, the estimated mean (± SD) steady-state AUC, Cmin, and Cmax of sarilumab were 395 ± 101 mg.day/L, 14.4 ± 9.81 mg/L, and 40.4 ± 7.77 mg/L, respectively.

Steady state was reached in 12 to 28 weeks with a 2- to 4-fold accumulation compared to single dose exposure for 3 and 4 mg/kg q2w. Steady state concentrations were within the range of exposures in adult RA patients following 150 mg/200 mg every 2 weeks.

Specific Populations

Population pharmacokinetic analyses in adult patients showed that age, gender and race did not meaningfully influence the pharmacokinetics of sarilumab. Although body weight influenced the pharmacokinetics of sarilumab, no dose adjustments are recommended for any of these demographics in adult patients.

Hepatic Impairment

No formal study of the effect of hepatic impairment on the pharmacokinetics of sarilumab was conducted.

Renal Impairment

No formal study of the effect of renal impairment on the pharmacokinetics of sarilumab was conducted. Based on population pharmacokinetic analysis of data from 1770 patients with RA, including patients with mild (creatinine clearance (CL_cr): 60 to 90 mL/min; N=471 at baseline) or moderate (CL_cr: 30 to 60 mL/min; N=74 at baseline) renal impairment, CL_crwas correlated with sarilumab exposure. However, the effect of CL_cron exposure is not sufficient to warrant a dose adjustment

[seeUse in Specific Populations (8.7)]

. Patients with severe renal impairment were not studied.

Drug-Drug Interactions

CYP450 Substrates

Simvastatin is a CYP3A4 and OATP1B1 substrate. In 17 patients with RA, one week following a single 200-mg subcutaneous administration of sarilumab, exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively

[seeDrug Interactions (7.2)]

, and

14.1 Rheumatoid Arthritis

Design of Clinical Studies in Adults with Moderately to Severely Active RA

The efficacy and safety of KEVZARA in RA were assessed in two randomized, double-blind, placebo-controlled multicenter studies (Study 1 and Study 2) in patients older than 18 years with moderately to severely active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline.

Study 1 (NCT01061736) evaluated 1197 patients with moderately to severely active rheumatoid arthritis who had inadequate clinical response to methotrexate (MTX). Patients received subcutaneous KEVZARA 200 mg, KEVZARA 150 mg, or placebo every two weeks with concomitant MTX. After Week 16 in Study 1, patients with an inadequate response could have been rescued with KEVZARA 200 mg every two weeks.

Study 2 (NCT01146652) evaluated 546 patients with moderately to severely active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF-α antagonists. Patients received subcutaneous KEVZARA 200 mg, KEVZARA 150 mg, or placebo every two weeks with concomitant conventional DMARDs (MTX, sulfasalazine, leflunomide, and/or hydroxychloroquine). After Week 12 in Study 2, patients with an inadequate response could have been rescued with KEVZARA 200 mg every two weeks.

In Studies 1 and 2, the primary endpoint was the proportion of patients who achieved an ACR20 response at Week 24. Other key endpoints evaluated included change from baseline in HAQ-DI at Week 16 in Study 1 and at Week 12 in Study 2, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Week 52 in Study 1.

Clinical Response

The percentages of KEVZARA every two weeks + MTX/DMARD-treated patients achieving ACR20, ACR50 and ACR70 responses in Studies 1 and 2 are shown Table 4. In both studies, patients treated with either 200 mg or 150 mg of KEVZARA every two weeks + MTX/DMARD had higher ACR20, ACR50, and ACR70 response rates versus placebo + MTX/DMARD-treated patients at Week 24.

In Studies 1 and 2, a greater proportion of patients treated with KEVZARA 200 mg or 150 mg every two weeks plus MTX/DMARD achieved a low level of disease activity as measured by a Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) <2.6 compared with placebo + MTX/DMARD at the end of the studies (Table 4). In Study 1, the proportion of patients achieving DAS28-CRP <2.6 who had at least 3 or more active joints at the end of Week 24 was 33.1%, 37.8% and 20%, in the KEVZARA 200 mg + MTX/DMARD arm, KEVZARA 150 mg + MTX/DMARD arm, and placebo arm respectively.

Table 4: Clinical Response in Placebo-Controlled Studies 1 and 2 in Adults with Moderately to Severely Active RAPatients who were rescued or discontinued were considered non-responders for the analyses included in this table. In Study 1, at week 52, 196, 270, and 270 patients remained on placebo, KEVZARA 150 mg, and KEVZARA 200 mg respectively.
Percentage of Patients
	Study 1			Study 2
	Placebo + MTX N=398	KEVZARA 150 mg + MTX N=400	KEVZARA 200 mg + MTX N=399	Placebo + DMARD(s)DMARDs in Study 2 included MTX, sulfasalazine, leflunomide, and/or hydroxychloroquine. N=181	KEVZARA 150 mg + DMARD(s) N=181	KEVZARA 200 mg + DMARD(s) N=184
ACR20
Week 12	34.7%	54.0%	64.9%	37.6%	54.1%	62.5%
Difference from placebo (95% CI)Weighted estimate of the rate difference; CI=confidence interval		19.4% (12.6%, 26.1%)	30.2% (23.6%, 36.8%)		16.6% (6.7%, 26.5%)	25.3% (15.7%, 34.8%)
Week 24 Primary end point	33.4%	58.0%	66.4%	33.7%	55.8%	60.9%
Difference from placebo (95% CI)		24.6% (18.0%, 31.3%)	33.0% (26.5%, 39.5%)		22.1% (12.6%, 31.6%)	27.4% (17.7%, 37.0%)
Week 52	31.7%	53.5%	58.6%
Difference from placebo (95% CI)		21.9% (15.2%, 28.5%)	27.0% (20.5%, 33.6%)	NANA=Not Applicable as Study 2 was a 24-week study.	NA	NA
ACR50
Week 12	12.3%	26.5%	36.3%	13.3%	30.4%	33.2%
Difference from placebo (95% CI)		14.2% (8.9%, 19.6%)	24.1% (18.4%, 29.8%)		17.1% (9.2%, 25.1%)	20.1% (12.0%, 28.3%)
Week 24	16.6%	37.0%	45.6%	18.2%	37.0%	40.8%
Difference from placebo (95% CI)		20.4% (14.5%, 26.3%)	29.1% (23.0%, 35.1%)		18.8% (10.2%, 27.4%)	22.8% (14.0%, 31.6%)
Week 52	18.1%	40.0%	42.9%
Difference from placebo (95% CI)		21.9% (15.8%, 28.0%)	24.8% (18.7%, 30.9%)	NA	NA	NA
ACR70
Week 12	4.0%	11.0%	17.5%	2.2%	13.8%	14.7%
Difference from placebo (95% CI)		7.0% (3.4%, 10.6%)	13.5% (9.4%, 17.7%)		11.6% (6.2%, 17.0%)	12.5% (7.1%, 17.9%)
Week 24	7.3%	19.8%	24.8%	7.2%	19.9%	16.3%
Difference from placebo (95% CI)		12.5% (7.8%, 17.1%)	17.5% (12.6%, 22.5%)		12.7% (6.1%, 19.3%)	9.2% (2.8%, 15.7%)
Week 52	9.0%	24.8%	26.8%
Difference from placebo (95% CI)		15.7% (10.6%, 20.8%)	17.8% (12.6%, 23.0%)	NA	NA	NA
Major clinical responseMajor clinical response = ACR70 for at least 24 consecutive weeks during the 52-week period.
Responders	3.0%	12.8%	14.8%	NA	NA	NA
Difference from placebo (95% CI)		9.7% (6.1%, 13.4%)	11.8% (7.9%, 15.6%)
DAS28-CRP < 2.6 Patients with DAS28-CRP <2.6 may have active joints.
Week 12
Percentage of patients	4.8%	18.0%	23.1%	3.9%	17.1%	17.9%
Difference from placebo (95% CI)		13.3% (9.0%, 17.5%)	18.3% (13.7%, 23.0%)		13.3% (7.3%, 19.3%)	14.1% (8.0%, 20.3%)
Week 24
Percentage of patients	10.1%	27.8%	34.1%	7.2%	24.9%	28.8%
Difference from placebo (95% CI)		17.7% (12.5%, 23.0%)	24.0% (18.5%, 29.5%)		17.7% (10.5%, 24.9%)	21.7% (14.3%, 29.1%)

The percent ACR20 response by visit in Study 1 is shown in Figure 1. A similar response curve was observed in Study 2.

Figure 1: Percent of ACR20 Response by Visit for Study 1 (Adults with Moderately to Severely Active RA)

The results of the components of the ACR response criteria at Week 12 for Studies 1 and 2 are shown in Table 5.

Table 5: Mean Change from Baseline in Components of ACR Score at Week 12 (Prior to Rescue) in Adults with Moderately to Severely Active RA
	Study 1			Study 2
Component means (range/units)	Placebo + MTX (N=398)	KEVZARA 150 mg + MTX (N=400)	KEVZARA 200 mg + MTX (N=399)	Placebo + DMARD(s) (N=181)	KEVZARA 150 mg + DMARD(s) (N=181)	KEVZARA 200 mg + DMARD(s) (N=184)
Tender Joints (0–68)
Baseline	26.80	27.21	26.50	29.42	27.66	29.55
Week 12	16.25	12.88	11.78	19.18	13.38	13.10
Change from baseline	-10.51	-14.42	-14.94	-9.79	-14.11	-15.92
Swollen Joints (0–66)
Baseline	16.68	16.60	16.77	20.21	19.60	19.97
Week 12	9.66	7.50	6.79	12.50	8.82	8.28
Change from baseline	-7.02	-9.03	-10.12	-7.25	-10.77	-10.89
Pain VASVAS=visual analog scale(0–100 mm)
Baseline	63.71	65.48	66.71	71.57	71.02	74.86
Week 12	49.25	41.47	36.93	54.77	43.45	41.66
Change from baseline	-14.45	-23.73	-29.77	-16.12	-27.95	-32.77
Physician global VAS (0–100 mm)
Baseline	62.86	63.43	63.59	68.39	68.10	67.76
Week 12	39.25	31.32	28.47	43.73	33.65	30.18
Change from baseline	-23.63	-31.85	-34.84	-24.60	-34.92	-36.92
Patient global VAS (0–100 mm)
Baseline	63.70	64.43	66.49	68.77	67.71	70.89
Week 12	49.37	41.52	38.05	53.67	41.99	41.74
Change from baseline	-13.92	-22.88	-28.39	-15.05	-26.05	-28.83
HAQ-DI (0–3)
Baseline	1.61	1.63	1.69	1.80	1.72	1.82
Week 12	1.34	1.15	1.13	1.49	1.23	1.33
Change from baseline	-0.27	-0.47	-0.57	-0.29	-0.50	-0.49
CRP (mg/L)
Baseline	20.46	22.57	22.23	26.02	23.60	30.77
Week 12	19.61	9.24	3.30	21.72	9.21	4.58
Change from baseline	-0.58	-13.59	-18.31	-3.39	-14.24	-25.91

Figure 1

Radiographic Response

In Study 1, structural joint damage was assessed radiographically and expressed as the van der Heijde-modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score. Radiographs of hands and feet were obtained at baseline, 24 weeks, and 52 weeks and scored independently by at least two well-trained readers who were blinded to treatment group and visit number.

Both doses of KEVZARA + MTX were superior to placebo + MTX in the change from baseline in mTSS over 52 weeks (seeTable 6). Less progression of both erosion and joint space narrowing scores over 52 weeks was reported in the KEVZARA + MTX treatment groups compared to the placebo + MTX group.

Treatment with KEVZARA + MTX was associated with significantly less radiographic progression of structural damage as compared with placebo + MTX. At Week 52, 55.6% of patients receiving KEVZARA 200 mg + MTX and 47.8% of patients receiving KEVZARA 150 mg + MTX had no progression of structural damage (as defined by a change in the Total Sharp Score of zero or less) compared with 38.7% of patients receiving placebo.

Table 6: Mean Radiographic Change from Baseline at Week 52 in Study 1 in Adults with Moderately to Severely Active RAWeek 52 analysis employs linear extrapolation method to impute missing or post-rescue data
	Study 1
	Placebo + MTX (N=398)	KEVZARA 150 mg + MTX (N=400)	KEVZARA 200 mg + MTX (N=399)
Modified Total Sharp Score (mTSS)
Mean change	2.78	0.90	0.25
LSLS=least squaresmean difference (95% CICI=confidence interval)		-1.88 (-2.74, -1.01)	-2.52 (-3.38, -1.66)
Erosion score
Mean change	1.46	0.42	0.05
LS mean difference (95% CI )		-1.03 (-1.53, -0.53)	-1.40 (-1.90, -0.90)
Joint space narrowing score
Mean change	1.32	0.47	0.20
LS mean difference (95% CI )		-0.85 (-1.34, -0.35)	-1.12 (-1.61, -0.63)

Physical Function Response

In Studies 1 and 2, physical function and disability were assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients receiving KEVZARA 200 mg every two weeks + MTX/DMARD and KEVZARA 150 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline in physical function compared to placebo + MTX/DMARD at Week 16 and Week 12 in Studies 1 and 2, respectively (Table 7).

Table 7: Physical Function in Studies 1 and 2 in Adults with Moderately to Severely Active RA
	Study 1			Study 2
	Week 16			Week 12
	Placebo + MTX (N=398)	KEVZARA 150 mg + MTX (N=400)	KEVZARA 200 mg + MTX (N=399)	Placebo + DMARD(s) (N=181)	KEVZARA 150 mg + DMARD(s) (N=181)	KEVZARA 200 mg + DMARD(s) (N=184)
HAQ-DI
Change from baseline	-0.30	-0.54	-0.58	-0.29	-0.50	-0.49
Difference from placebo (95% CI)Difference in adjusted mean change from baseline compared with placebo + DMARD at Week 16 (Study 1) or Week 12 (Study 2) and 95% confidence interval for that difference.		-0.24 (-0.31, -0.16)	-0.26 (-0.34, -0.18)		-0.20 (-0.32, -0.09)	-0.21 (-0.33, -0.10)
% of patients with clinically meaningful improvement Change from baseline greater than 0.3 units	42.5%	53.8%	57.4%	35.9%	47%	51.1%

Other Health Related Outcomes

General health status was assessed by the Short Form health survey (SF-36) in Studies 1 and 2. Patients receiving KEVZARA 200 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline compared to placebo + MTX/DMARD in the physical component summary (PCS) at Week 24, but there was no evidence of a difference between the treatment groups in the mental component summary (MCS) at Week 24. Patients receiving KEVZARA 200 mg + MTX/DMARD reported greater improvement relative to placebo in the domains of

Physical Functioning, Role Physical, Bodily Pain, General Health Perception, Vitality, Social Functioning and Mental Health,

but not in the

Role Emotional

domain

14.3 Polyarticular Juvenile Idiopathic Arthritis (pJIA)

Supportive efficacy and safety data were provided from Study 4, which was a multicenter, open-label, two-phase study in patients aged 2 to 17 years of age with polyarticular juvenile idiopathic arthritis (pJIA) diagnosed according to American College Rheumatology (ACR) classification criteria who had an inadequate response to current therapy. This study was divided into a dose range finding portion and a confirmatory portion. Three doses were investigated in the 12-week core treatment phase of the dose range finding portion. Following the dose selection, patients were enrolled to receive the recommended dose [3 mg/kg every 2 weeks (q2w) in 42 patients weighing ≥30 kg (Group A) and 4 mg/kg q2w in 31 patients weighing ≥10 kg and <30 kg (Group B)]. A total of 101 patients were treated, including 73 patients who received the recommended dose regimen from baseline and 20 patients who had their dose switched to the recommended dose during the study. Of the 73 patients who received the recommended dose throughout treatment, baseline mean disease duration was 2.48 years and a JADAS-27 score of 22.73. At baseline, 84.9% of patients had received at least one conventional DMARD (mainly methotrexate), 13.7% received systemic glucocorticoids, and 19.2% had prior treatment with biological DMARDs (mainly TNF antagonists). The patients treated had subtypes of JIA that, at disease onset, included rheumatoid factor positive (17.8%), negative polyarticular JIA (65.8%), or extended oligoarticular JIA (16.4%).

Use of KEVZARA in pediatric patients with pJIA is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA, and pharmacokinetic (PK) comparability from Study 4

[seeClinical Pharmacology (12.3)]

]

The safety and effectiveness of KEVZARA have not been established in pediatric patients with pJIA below the age of 2 years.

Coverage for Kevzara