Olumiant® ▼ (baricitinib)

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Olumiant® ▼ (baricitinib): Renal-Related Adverse Events and Analyte Changes in Atopic Dermatitis

In the atopic dermatitis clinical trials, small mean changes in serum creatinine and cystatin C with baricitinib treatment were not associated with renal dysfunction adverse events.

Baricitinib Label Information Related to Renal Impairment and Creatinine

Dosing Recommendations in Renal Impairment

Renal function was found to significantly affect baricitinib exposure.1

The recommended dose is 2 mg once daily in patients with creatinine clearance between 30 and 60 mL/min. Baricitinib is not recommended for use in patients with creatinine clearance < 30 mL/min.1

Creatinine

In rheumatoid arthritis, baricitinib induced a mean increase in serum creatinine levels of 3.8 µmol/L after two weeks of treatment, as compared to placebo, which remained stable thereafter during up to 104 weeks of treatment. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules.1

Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse events.1

In atopic dermatitis, baricitinib was associated with a decrease in cystatin C (also used to estimate glomerular filtration rate) of 0.1 mg/L at week 4, with no further decrease noted up to week 16.1

Renal Impairment in Atopic Dermatitis Clinical Trials

Dose Adjustments for Renal Impairment

In the AD phase 3 studies with the highest dose of 4 mg, patients with an eGFR ≥40 and <60 mL/min/1.73 m2

  • received BARI 2 mg once daily if assigned to either the BARI 2 mg or BARI 4 mg treatment arms, and

  • received BARI 1 mg if assigned to the BARI 1 mg treatment arm.2

Patients were excluded from these phase 3 studies if they had an eGFR <40 mL/min/1.73 m2.2

In the AD phase 3 studies with the highest dose of BARI 2 mg (BREEZE-AD5 and BREEZE-AD6), patients with an eGFR <60 mL/min/1.73 m2 were excluded from the studies.2

Estimated GFRs were calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration Creatinine 2009 equation.2,3

Treatment Interruptions Due to Renal Impairment

In the AD phase 3 clinical trials, routine laboratory monitoring of serum creatinine to calculate eGFR was collected. Clinical trial criteria regarding study treatment interruption based on decreased eGFR are provided in Table 1.2

Table 1. Clinical Trial Criteria for Temporary Interruption and Resumption of Study Treatment Based on eGFRa in AD Clinical Trials2

Atopic Dermatitis Clinical Trials

Study treatment was interrupted if

Study treatment was resumed when

BREEZE-AD1, BREEZE-AD2, BREEZE-AD3, BREEZE-AD4, and BREEZE-AD7

eGFR decreased to <40 mL/min/1.73 m2 in patients with a screening eGFR ≥60 mL/min/1.73 m2

eGFR increased to ≥50 mL/min/1.73 m2

eGFR decreased to <30 mL/min/1.73 m2 in patients with a screening eGFR ≥40 to <60 mL/min/1.73 m2

eGFR increased to ≥40 mL/min/1.73 m2

BREEZE-AD5 and BREEZ-AD6

eGFR decreased to <50 mL/min/1.73 m2

eGFR increased to ≥60 mL/min/1.73 m2

Abbreviations: AD = atopic dermatitis; eGFR = estimated glomerular filtration rate.

a Based on serum creatinine.

Integrated Safety Datasets Used to Evaluate Safety

The integrated datasets used to evaluate safety in the AD clinical trials are described in detail in Table 4

Mean Renal-Related Laboratory Changes

Mean Serum Creatinine Changes

In the AD clinical trial program, minor dose-dependent increases in serum creatinine were observed with BARI treatment; however, the changes were not considered clinically meaningful.2

Mean changes in serum creatinine from baseline to each measurement time point are provided in Figure 1 for the placebo-controlled period and Figure 2 for the BARI 2 mg and 4 mg extended dataset.

Figure 1. Mean Change in Serum Creatinine for AD Placebo-Controlled Datasets2

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; Max = maximum; Min = minimum; PBO = placebo; PC = placebo-controlled; StdDev = standard deviation.

Figure 2. Mean Change in Serum Creatinine for AD BARI 2 mg vs 4 mg Extended Dataset2

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; ext = extended; Max = maximum; Min = minimum; StdDev = standard deviation.

Mean Serum Cystatin C Changes

In the AD clinical trial program, there was a mean decrease in serum cystatin C in all treatment groups through week 12, with no further decrease through week 16. The mean changes were not associated with AEs of renal dysfunction.2

Mean changes in serum cystatin C from baseline to each measurement time point are provided in Figure 3 for the placebo-controlled period and Figure 4 for the BARI 2 mg and 4 mg extended dataset.

Figure 3. Mean Change in Serum Cystatin C for AD Placebo-Controlled Dataset2

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib;  Max = maximum; Min = minimum; PBO = placebo; PC = placebo-controlled; StdDev = standard deviation.

Figure 4. Mean Change in Serum Cystatin C for AD BARI 2 mg vs 4 mg Extended Dataset2

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; ext = extended; Max = maximum; Min = minimum; StdDev = standard deviation.

Renal Related Laboratory Adverse Events

CTCAE Grade Shifts in Creatinine

Categorical changes in creatinine values were assessed by determining the proportion of patients with a TE value above the ULN as well as the proportion of patients with a TE increase in CTCAE grades. Normal limits were defined according to

  • laboratory methodology

  • age, and

  • sex.2

CTCAE grade shifts are defined as:

  • Grade 0: (normal): ≤ULN

  • Grade 1: >ULN and ≤1.5 × ULN

  • Grade 2: >1.5 × ULN and ≤3 × ULN

  • Grade 3: >3 × ULN and ≤6 × ULN, and

  • Grade 4: >6 × ULN2

Through 16 weeks, a significantly higher proportion of patients had an increase in any CTCAE grade shift in creatinine in the

  • BARI 2 mg group than placebo group (6.2% vs 3.6%; p≤.01)

  • BARI 4 mg group than placebo group (8.4% vs 3.6%; p≤.001), and

  • BARI 4 mg group than BARI 2 mg group (8.4% vs 5.3%; p≤.05).

The majority of the shifts in all treatment groups were to Grade 1.2 See Table 2 for more details.

Table 2. CTCAE Grade Changes in Creatinine (umol/L)2

 

Any Grade Increase

Increased to Grade ≥1

Increased to Grade ≥2

Increased to Grade ≥3

Increased to Grade ≥4

BARI 2 mg placebo-controlleda, n/NAR (%)

Placebo, n=889

31/871 (3.6)

31/821 (3.8)

1/870 (0.1)

1/871 (0.1)

0/871

BARI 2 mg, n=721

44/709 (6.2)b

42/661 (6.4)b

3/708 (0.4)

0/709

0/709

BARI 4 mg placebo-controlleda, n /NAR (%)

Placebo, n=743

26/729 (3.6)

26/693 (3.8)

1/728 (0.1)

1/729 (0.1)

0/729

BARI 4 mg, n=489

41/488 (8.4)c

40/468 (8.5)c

1/488 (0.2)

0/488

0/488

BARI 2 mg vs 4 mga, n/NAR (%)

BARI 2 mg, n=576

30/570 (5.3)

30/538 (5.6)

1/569 (0.2)

0/570

0/570

BARI 4 mg, n=489

41/488 (8.4)d

40/468 (8.5)

1/488 (0.2)

0/488

0/488

BARI 2 mg vs 4 mg extended, n/NAR (%)

BARI 2 mg, n=576

53/570 (9.3)

53/538 (9.9)

2/569 (0.4)

0/570 

0/570

BARI 4 mg, n=489

56/488 (11.5)

55/468 (11.8)

1/488 (0.2)

0/488

0/488

All BARI AD, n/NAR (%)

All doses, N=2531

246/2497 (9.9)

240/2312 (10.4)

9/2495 (0.4)

1/2497 (0.0)

1/2497 (0.0)

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number at risk.

a Data through 16-week placebo-controlled period.

b p≤.01 vs placebo.

c p≤.001 vs placebo.

d p≤.05 vs BARI 2 mg.

Abnormal High Laboratory Results

High Serum Creatinine

A high serum creatinine was defined as above the defined reference range by age and sex.2

Through 16 weeks, compared to placebo, a significantly higher proportion of patients had a TE high serum creatinine in the

  • BARI 2 mg group (6.4% vs 3.8%; p≤.01), and

  • BARI 4 mg group (8.5% vs 3.8%; p≤.001).2

There was no significant difference in high serum creatinine between BARI 2 mg and BARI 4 mg groups through 16 weeks and extended treatment.2

High Serum Cystatin C

A high serum cystatin C was defined as above the defined reference range by age and sex.2

Through 16 weeks, TE high serum cystatin C was

  • significantly lower in the BARI 2 mg group than placebo (2.9% vs 7.9%; p≤.001), and

  • not different in the BARI 4 mg group and placebo group (4.5% vs 8.3%).2

There was no significant difference in high serum cystatin C between BARI 2 mg and BARI 4 mg groups through 16 weeks and extended treatment.2

Renal-Related Adverse Events

Of the 2531 patients treated with BARI, renal-related TEAEs were reported in 39 (1.5%, IR=1.7) patients. Events of most interest included

  • 4 (IR=0.2) cases of renal impairment

  • 3 (IR=0.1) cases of acute kidney injury, and

  • 1 (IR=0.0) case of renal failure.2

Of these 8 events, most were considered mild or moderate in severity after medical review, and 5 were not considered related to study drug.2

Table 3 provides more details on renal-related TEAEs by safety dataset and treatment arms.

Table 3. Renal-Related Treatment Emergent Adverse Events2

 

 

 

 

 

 

 

 

 

 

 

BARI 2 mg Placebo-Controlleda
n (adj %)
b

BARI 4 mg Placebo-Controlleda
n (adj %)
b

BARI 2 mg vs 4 mga
n (adj %)
b

BARI 2 mg vs 4 mg ext
n (adj %)
b [adj IR]

All BARI AD
n (%) [IR]


Placebo
n=889

BARI 2 mg
n=721

Placebo
n=743

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

All Doses
N=2531

Renal and urinary disorders SOC

4 (0.6)

3 (0.3)

3 (0.5)

9 (1.7)c

2 (0.2)

9 (1.7)d

9 (1.4) [2.1]

12 (2.2) [2.6]

39 (1.5 ) [1.7]

Serious AE

0

0

0

0

0

0


0

0

2 (0.1) [0.1]e

Led to temp int

0

0

0

1 (0.2)

0

1 (0.2)

0

1 (0.2) [0.2]

2 (0.1) [0.1]

Led to perm D/C

0

0

0

1 (0.2)

0

1 (0.2)

0

1 (0.2) [0.2]

1 (0.0) [0.0]

Abbreviations: AD = atopic dermatitis; adj = adjusted; AE = adverse event; BARI = baricitinib; ext = extended; IR = incidence rate; perm D/C = permanent discontinuation; SOC = system organ class; temp int = temporary interruption.

a Data through 16-week placebo-controlled period.

b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

c p≤.05 vs placebo.

d p≤.05 vs BARI 2 mg.

e Includes 1 patient with 2 events (calculus urinary and renal colic) and 1 patient with 1 event (renal failure).

Potential Role of JAK Inhibition in Tubular Secretion of Creatinine

Baricitinib is a selective, and reversible inhibitor of the JAK family of protein tyrosine kinases, specifically JAK1 and JAK2.4

In vitro experiments using cell systems expressing individual or multiple renal transporters indicated that BARI may competitively inhibit tubular secretion of creatinine by inhibiting OCT2-mediated uptake of creatinine as well as MATE1/MATE2-K-mediated efflux of creatinine. The pattern of small increases in creatinine seen rapidly after initiation of BARI is consistent with such a mechanism.2,5

The mechanism of the small, reversible, and dose-dependent increases in serum creatinine observed with BARI treatment has not been fully characterized.2

Integrated Safety Datasets

Table 4. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or

  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or

  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or

  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or

  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=538, PYE=245.9)

  • BARI 2 mg (n=1580, PYE=1129.5), and

  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763564/

4. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

5. Zhang Y, Warren MS, Zhang X, et al. Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110. Drug Metab Dispos. 2015;43(4):485-489. http://dx.doi.org/10.1124/dmd.114.060673

Glossary

AD = atopic dermatitis

AE = adverse event

BARI = baricitinib

CTCAE = Common Terminology Criteria for Adverse Events

eGFR = estimated glomerular filtration rate

IR = incidence rate

JAK = Janus kinase

MATE = multidrug and toxin extrusion protein

OCT = organic cation transporter

TE = treatment-emergent

TEAE = treatment-emergent adverse event

ULN = upper limit of normal

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: August 31, 2020


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