Rheumatoid Arthritis Efficacy

A trial designed for patients still in need^1,2

BEACON (Study RA-4) was one of four phase 3 clinical trials evaluating the efficacy of Olumiant across the RA treatment algorithm^1,2

Olumiant was evaluated in a 24-week, randomized, double-blind, placebo-controlled trial in 527 patients with moderately to severely active RA who had an inadequate response or intolerance to at least 1 TNF inhibitor. Patients received Olumiant 2 mg (n=174) or baricitinib 4 mg (n=177) once daily or placebo (n=176), added to stable background cDMARD treatment.

Olumiant was evaluated in a 24-week randomized, double-blind, phase 3, placebo-controlled trial in 527 patients with moderately to severely active RA who had an inadequate response or intolerance to one or more TNF inhibitors; the patients could have had prior therapy with other biologic DMARDs.^* The patients in this study were on stable background cDMARDs.

From week 16, non-responding patients could be rescued to a higher dose (baricitinib 4 mg/day). Baricitinib 4 mg is not an approved dose for RA.

Primary endpoint

Proportion of patients achieving ACR20 response at week 12 with Olumiant 4mg + cDMARDs which is not an approved dose in RA.

Select inclusion criteria

Inadequate response or intolerance to ≥1 TNFi. The patients in the study could have had prior therapy with other biologic DMARDs
Stable background cDMARDs

Secondary measures included

ACR50 and ACR70
DAS28-CRP
HAQ-DI

^* Biologic DMARDs included TNF inhibitors (etanercept, adalimumab, infliximab, golimumab, certolizumab), non-TNF inhibitors (abatacept, tocilizumab, rituximab, anakinra), and non-approved agents.

RA=rheumatoid arthritis; TNFi=tumor necrosis factor inhibitor; DMARD=disease-modifying antirheumatic drug; cDMARD=conventional disease-modifying antirheumatic drug; ACR20/50/70=American College of Rheumatology 20%/50%/70% improvement criteria; DAS28-CRP=Disease Activity Score 28–C-reactive protein; HAQ-DI=Health Assessment Questionnaire-Disability Index.

Patient characteristics and disease activity in the BEACON trial (Study RA-4) ^2,4,5

	Placebo + cDMARDs (n=176)	Olumiant 2 mg + cDMARDs (n=174)
Mean (SD) age, years	Placebo + cDMARDs (n=176): 56 (11)	Olumiant 2 mg + cDMARDs (n=174): 55 (11)
Female	Placebo + cDMARDs (n=176): 145 (82)	Olumiant 2 mg + cDMARDs (n=174): 137 (79)
Mean (SD) duration of RA, years	Placebo + cDMARDs (n=176): 14 (10)	Olumiant 2 mg + cDMARDs (n=174): 14 (8)
ACPA positive	Placebo + cDMARDs (n=176): 125 (71)	Olumiant 2 mg + cDMARDs (n=174): 124 (71)
RF positive	Placebo + cDMARDs (n=176): 130 (74)	Olumiant 2 mg + cDMARDs (n=174): 128 (74)
No. of prior TNFi: 1	Placebo + cDMARDs (n=176): 104 (59)	Olumiant 2 mg + cDMARDs (n=174): 102 (59)
No. of prior TNFi: 2	Placebo + cDMARDs (n=176): 50 (28)	Olumiant 2 mg + cDMARDs (n=174): 60 (35)
No. of prior TNFi: ≥3	Placebo + cDMARDs (n=176): 19 (11)	Olumiant 2 mg + cDMARDs (n=174): 12 (7)
No. of prior non-TNFi: 1	Placebo + cDMARDs (n=176): 37 (21)	Olumiant 2 mg + cDMARDs (n=174): 45 (26)
No. of prior non-TNFi: 2	Placebo + cDMARDs (n=176): 15 (9)	Olumiant 2 mg + cDMARDs (n=174): 14 (8)
No. of prior non-TNFi: ≥3	Placebo + cDMARDs (n=176): 10 (6)	Olumiant 2 mg + cDMARDs (n=174): 11 (6)
No. of prior bDMARDs: 1	Placebo + cDMARDs (n=176): 81 (46)	Olumiant 2 mg + cDMARDs (n=174): 69 (40)
No. of prior bDMARDs: 2	Placebo + cDMARDs (n=176): 47 (27)	Olumiant 2 mg + cDMARDs (n=174): 55 (32)
No. of prior bDMARDs: ≥3	Placebo + cDMARDs (n=176): 47 (27)	Olumiant 2 mg + cDMARDs (n=174): 50 (29)
No. of concomitant cDMARDS: 1	Placebo + cDMARDs (n=176): 160 (91)	Olumiant 2 mg + cDMARDs (n=174): 156 (90)
No. of concomitant cDMARDS: ≥2	Placebo + cDMARDs (n=176): 16 (9)	Olumiant 2 mg + cDMARDs (n=174): 17 (10)
Concomitant MTX use	Placebo + cDMARDs (n=176): 143 (81)	Olumiant 2 mg + cDMARDs (n=174): 141 (81)
Mean (SD) MTX dose, mg/week	Placebo + cDMARDs (n=176): 16 (5)	Olumiant 2 mg + cDMARDs (n=174): 16 (5)
Concomitant corticosteroid use	Placebo + cDMARDs (n=176): 116 (66)	Olumiant 2 mg + cDMARDs (n=174): 92 (53)

Data displayed are n (%) unless otherwise noted.

959 patients were screened to randomize 527 patients in the following regions: US and Canada (44%), Europe (30%), Central and South America (10%), Asia (6%), and Rest of World (10%).

	Placebo + cDMARDs (n=176)	Olumiant 2 mg + cDMARDs (n=174)
Swollen joint count (SJC), of 66	Placebo + cDMARDs (n=176): 17 (11)	Olumiant 2 mg + cDMARDs (n=174): 19 (12)
Tender joint count (TJC), of 68	Placebo + cDMARDs (n=176): 28 (16)	Olumiant 2 mg + cDMARDs (n=174): 31 (16)
Physician Global Assessment^†	Placebo + cDMARDs (n=176): 67 (19)	Olumiant 2 mg + cDMARDs (n=174): 67 (17)
Patient Global Assessment^†	Placebo + cDMARDs (n=176): 66 (19)	Olumiant 2 mg + cDMARDs (n=174): 67 (19)
Pain^†	Placebo + cDMARDs (n=176): 65 (19)	Olumiant 2 mg + cDMARDs (n=174): 62 (22)
HAQ-DI^‡	Placebo + cDMARDs (n=176): 1.78 (0.57)	Olumiant 2 mg + cDMARDs (n=174): 1.71 (0.55)
hsCRP, mg/L^§	Placebo + cDMARDs (n=176): 21 (25)	Olumiant 2 mg + cDMARDs (n=174): 20 (22)
ESR, mm/hr	Placebo + cDMARDs (n=176): 47 (24)	Olumiant 2 mg + cDMARDs (n=174): 45 (24)
DAS28-CRP	Placebo + cDMARDs (n=176): 5.9 (0.9)	Olumiant 2 mg + cDMARDs (n=174): 6.0 (0.9)

Data displayed are mean (standard deviation).

^†Scores for the physician global assessment, patient global assessment, and pain range from 0 to 100 mm on a visual analog scale (VAS), with higher scores indicating greater levels of reported disease activity or pain.

^‡Scores on the HAQ-DI range from 0 to 3, with higher scores indicating greater disability.

^§The upper limit of normal range (ULN) for the hsCRP level is 3 mg/L.

SD=standard deviation; ACPA=anti-citrullinated peptide/protein antibody; RF=rheumatoid factor; bDMARD=biologic disease-modifying antirheumatic drug; MTX=methotrexate; hsCRP=high-sensitivity C-reactive protein. ESR = erythrocyte sedimentation rate. DAS28 = Disease Activity Score modified to include the 28-joint count. HAQ-DI = Health Assessment Questionnaire-Disability Index. ULN=upper limit of normal. ESR = Erythrocyte sedimentation rate. DAS28-CRP=Disease Activity Score 28–C-reactive protein.

Reach for results

Olumiant reduced the signs and symptoms of RA^1-3

TNFi-IR patients receiving Olumiant demonstrated higher ACR response rates vs placebo at weeks 12 and 24

Statistical significance declared without control for multiple comparisons in the hierarchical testing.

The American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response rates at weeks 12 and 24 are presented as bar graphs.

In the following results, patients taking Olumiant 2 milligrams (mg)/day plus conventional disease-modifying antirheumatic drugs (cDMARDs) (n=174) were compared to patients taking placebo plus cDMARDs (n=176).

At week 12, 49% of patients taking Olumiant 2 mg/day plus cDMARDs achieved an ACR20 response compared to 27% of patients taking placebo plus cDMARDs, with a p-value of ≤0.001. At week 12, 20% of patients taking Olumiant 2 mg/day plus cDMARDs achieved an ACR50 response compared to 8% of patients taking placebo plus cDMARDs, with a p-value of ≤0.01. At week 12, 13% of patients taking Olumiant 2 mg/day plus cDMARDs achieved an ACR70 response compared to 2% of patients taking placebo plus cDMARDs, with a p-value of ≤0.001.

At week 24, 45% of patients taking Olumiant 2 mg/day plus cDMARDs achieved an ACR20 response compared to 27% of patients taking placebo plus cDMARDs, with a p-value of ≤0.001. At week 24, 23% of patients taking Olumiant 2 mg/day plus cDMARDs achieved an ACR50 response compared to 13% of patients taking placebo plus cDMARDs, with a p-value of ≤0.05. At week 24, 13% of patients taking Olumiant 2 mg/day plus cDMARDs achieved an ACR70 response compared to 3% of patients taking placebo plus cDMARDs, with a p-value of ≤0.001.

From week 16, non-responding patients could be rescued to a higher dose which is not approved for RA. Patients who were rescued or discontinued treatment were considered non-responders in the analysis.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12 with Olumiant 4mg which is not approved for RA.

See RA-BEACON trial design

SELECT IMPORTANT SAFETY INFORMATION: WARNING RELATED TO SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS

SERIOUS INFECTIONS: Olumiant-treated patients are at increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with Olumiant if a serious infection occurs until the infection is controlled. Olumiant should not be given to patients with active tuberculosis. Test for latent TB before and during therapy, except for COVID-19; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.

MORTALITY: Higher rate of all-cause mortality, including sudden cardiovascular death was observed with another Janus kinase (JAK) inhibitor vs. tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients.

MALIGNANCIES: Malignancies have also occurred in patients treated with Olumiant. Higher rate of lymphomas and lung cancers was observed with another JAK inhibitor vs. TNF blockers in RA patients.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE): Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) was observed with another JAK inhibitor vs. TNF blockers in RA patients.

THROMBOSIS: Thrombosis has occurred in patients treated with Olumiant. Increased incidence of pulmonary embolism, venous and arterial thrombosis was observed with another JAK inhibitor vs. TNF blockers.

ACR20 Response Rates at Week 12 by Treatment History^1-3

Statistical significance declared without control for multiple comparisons in the hierarchical testing.

The American College of Rheumatology 20% improvement criteria (ACR20) response rates at week 12 by treatment history are presented as bar graphs.

In all patients (N=350), the percentage of patients with ACR20 response rates at week 12 in patients taking Olumiant 2 mg +cDMARDS (n=174) was 49% compared to 27% of patients taking placebo +cDMARDs (n=176). The p-value was ≤0.001.

In patients who had a treatment history of <3 biologic disease-modifying antirheumatic drug (bDMARDs) (n=253), the percentage of patients with ACR20 response rates taking Olumiant 2 mg/day plus cDMARDs was 53% compared to 33% of patients taking placebo plus cDMARDs.

In patients who had a treatment history of ≥3 bDMARDs (n=97), the percentage of patients with ACR20 response rates taking Olumiant 2 mg/day plus cDMARDs was 38% compared to 13% of patients taking placebo plus cDMARDs.

In patients who had a treatment history of one tumor necrosis factor inhibitor (TNFi) (n=206), the percentage of patients with ACR20 response rates taking Olumiant 2 mg/day plus cDMARDs was 53% compared to 30% of patients taking placebo plus cDMARDs.

In patients who had a treatment history of ≥2 TNFis (n=141), the percentage of patients with ACR20 response rates taking Olumiant 2 mg/day plus cDMARDs was 43% compared to 25% of patients taking placebo plus cDMARDs.

Patients who discontinued treatment were considered non-responders in the analysis.

The subgroup data presented were from prespecified (patients by number of prior bDMARDs) or post hoc analysis (patients by number of prior TNFis), but were not type I error controlled. Therefore, treatment differences between Olumiant and placebo for the subgroup analysis cannot be regarded as statistically significant.

Inclusion criteria for the BEACON study (Study RA-4) required inadequate response or intolerance to ≥1 TNFi.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12 with Olumiant 4 mg + cDMARDs which is not an approved dose for RA.

Prior treatment experience in BEACON

40% of the patients taking Olumiant 2 mg + cDMARDs or placebo + cDMARDs in the study had prior treatment experience with ≥2 TNFis
28% of patients taking Olumiant 2 mg + cDMARDs or placebo + cDMARDs in the study had prior treatment experience with ≥3 bDMARDs

See RA-BEACON trial design

Results TNFi-IR patients can feel

Pain improvement at weeks 1, 12, and 24^1,2

Percentage of TNF-IR patients achieving ≥30%, ≥50%, and ≥70% reduction in pain from baseline

Pain Improvement Graphs — The percentages of patients with pain improvement ≥30%, ≥50%, and ≥70% at weeks 1, 12, and 24 are presented as bar graphs.

In the following results, patients taking Olumiant 2 milligrams (mg)/day plus conventional disease-modifying antirheumatic drugs (cDMARDs) (n=174) were compared to patients taking placebo plus cDMARDs (n=176).

At week 1, the percentage of patients with ≥30% pain improvement was 25% for the Olumiant 2 mg/day plus cDMARDs arm compared to 20% in the placebo plus cDMARDs arm. At week 1, the percentage of patients with ≥50% pain improvement was 9% for the Olumiant 2 mg/day plus cDMARDs arm compared to 6% in the placebo plus cDMARDs arm. At week 1, the percentage of patients with ≥70% pain improvement was 3% for the Olumiant 2 mg/day plus cDMARDs arm compared to 2% in the placebo plus cDMARDs arm.

At week 12, the percentage of patients with ≥30% pain improvement was 43% for the Olumiant 2 mg/day plus cDMARDs arm compared to 31% in the placebo plus cDMARDs arm. At week 12, the percentage of patients with ≥50% pain improvement was 31% for the Olumiant 2 mg/day plus cDMARDs arm compared to 17% in the placebo plus cDMARDs arm. At week 12, the percentage of patients with ≥70% pain improvement was 19% for the Olumiant 2 mg/day plus cDMARDs arm compared to 7% in the placebo plus cDMARDs arm.

At week 24, the percentage of patients with ≥30% pain improvement was 44% for the Olumiant 2 mg/day plus cDMARDs arm compared to 34% in the placebo plus cDMARDs arm. At week 24, the percentage of patients with ≥50% pain improvement was 32% for the Olumiant 2 mg/day plus cDMARDs arm compared to 20% in the placebo plus cDMARDs arm. At week 24, the percentage of patients with ≥70% pain improvement was 22% for the Olumiant 2 mg/day plus cDMARDs arm compared to 9% in the placebo plus cDMARDs arm.

From week 16, non-responding patients could be rescued to a higher dose which is not approved for RA.

Missing data for pain analyses, tender and swollen joint counts were reported as mLOCF.

The data presented were from a post hoc analysis of the ACR component pain (VAS, 0-100) and were not type I error controlled. Therefore treatment differences between Olumiant and placebo cannot be regarded as statistically significant.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12.

In BEACON (TNFi-IR) (Olumiant 2 mg/day n=174; placebo n=176), 49% of patients receiving Olumiant + cDMARDs achieved ACR20 response at week 12 vs 27% of patients receiving placebo + cDMARDs. Patients who discontinued treatment were considered non-responders in the analysis.

For number of tender joints (0-68), the mean for placebo + cDMARD patients was 28 at baseline and 20 at week 12 and for Olumiant 2 mg + cDMARD patients the mean was 31 at baseline and 19 at week 12.

For number of swollen joints (0-66), the mean for placebo + cDMARD patients was 17 at baseline and 12 at week 12 and for Olumiant 2 mg + cDMARD patients the mean was 19 at baseline and 10 at week 12.

For pain, the mean score (VAS, 0-100) for placebo + cDMARD patients was 65 at baseline and 55 at week 12 and for Olumiant 2 mg + cDMARD patients the mean score was 62 at baseline and 46 at week 12.

See RA-BEACON trial design

SELECT IMPORTANT SAFETY INFORMATION RELATED TO SERIOUS INFECTIONS

The most common serious infections reported with Olumiant included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with Olumiant. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid Olumiant in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Olumiant. Closely monitor patients for development of infections during and after Olumiant treatment. Interrupt Olumiant if the patient develops a serious infection, an opportunistic infection, or sepsis. Do not resume Olumiant until the infection is controlled.

TNFi-IR=tumor necrosis factor inhibitor-inadequate response; mLOCF=modified last observation carried forward; cDMARD=conventional disease-modifying antirheumatic drug; ACR20=American College of Rheumatology 20% improvement criteria; VAS=visual analog scale;0=best, 100=worst.

Pain improvement at week 12 by treatment history^1,2

The percentages of patients with pain improvement at week 12 by treatment history are presented as bar graphs.

In patients who had a treatment history of 1 tumor necrosis factor inhibitor (TNFi) (n=203), the percentage of patients with ≥30% pain improvement was 45% in the Olumiant 2 mg/day plus conventional disease-modifying antirheumatic drugs (cDMARDs) arm compared to 34% in the placebo plus cDMARDs arm. In patients who had a treatment history of >1 TNFi (n=137), the percentage of patients with ≥30% pain improvement was 41% in the Olumiant 2 mg/day plus cDMARDs arm compared to 29% in the placebo plus cDMARDs arm. In patients who had a treatment history of <3 biologic disease-modifying antirheumatic drugs (bDMARDs) (n=249), the percentage of patients with ≥30% pain improvement was 47% in the Olumiant 2 mg/day plus cDMARDs arm compared to 37% in the placebo plus cDMARDs arm. In patients who had a treatment history of ≥3 bDMARDs (n=94), the percentage of patients with ≥30% pain improvement was 34% in the Olumiant 2 mg/day plus cDMARDs arm compared to 16% in the placebo plus cDMARDs arm.

In patients who had a treatment history of 1 TNFi (n=203), the percentage of patients with ≥50% pain improvement was 32% in the Olumiant 2 mg/day plus cDMARDs arm compared to 21% in the placebo plus cDMARDs arm. In patients who had a treatment history of >1 TNFi (n=137), the percentage of patients with ≥50% pain improvement was 30% in the Olumiant 2 mg/day plus cDMARDs arm compared to 12% in the placebo plus cDMARDs arm. In patients who had a treatment history of <3 bDMARDs (n=249), the percentage of patients with ≥50% pain improvement was 36% in the Olumiant 2 mg/day plus cDMARDs arm compared to 21% in the placebo plus cDMARDs arm. In patients who had a treatment history of ≥3 bDMARDs (n=94), the percentage of patients with ≥50% pain improvement was 20% in the Olumiant 2 mg/day plus cDMARDs arm compared to 7% in the placebo plus cDMARDs arm.

In patients who had a treatment history of 1 TNFi (n=203), the percentage of patients with ≥70% pain improvement was 21% in the Olumiant 2 mg/day plus cDMARDs arm compared to 8% in the placebo plus cDMARDs arm. In patients who had a treatment history of >1 TNFi (n=137), the percentage of patients with ≥70% pain improvement was 16% in the Olumiant 2 mg/day plus cDMARDs arm compared to 6% in the placebo plus cDMARDs arm. In patients who had a treatment history of <3 bDMARDs (n=249), the percentage of patients with ≥70% pain improvement was 22% in the Olumiant 2 mg/day plus cDMARDs arm compared to 8% in the placebo plus cDMARDs arm. In patients who had a treatment history of ≥3 bDMARDs (n=94), the percentage of patients with ≥70% pain improvement was 10% in the Olumiant 2 mg/day plus cDMARDs arm compared to 5% in the placebo plus cDMARDs arm.

Missing data for pain analyses, tender and swollen joint counts were reported as mLOCF.

The data presented were from a post hoc analysis of the ACR component pain (VAS 0-100). The BEACON study was not powered for these subgroups analyses, nor were the analyses type I error controlled. Therefore, treatment differences between Olumiant and placebo, observed in these subgroups, cannot be regarded as statistically significant.

Inclusion criteria for the BEACON study required inadequate response or intolerance to ≥1 TNFi.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12 with Olumiant 4 mg + cDMARDs which is not an approved dose for RA.

For pain, the mean score (VAS, 0-100) for placebo + cDMARD patients was 65 at baseline and 55 at week 12 and for Olumiant 2 mg + cDMARD patients the mean score was 62 at baseline and 46 at week 12.

For number of tender joints (0-68), the mean for placebo + cDMARD patients was 28 at baseline and 20 at week 12 and for Olumiant 2 mg + cDMARD patients the mean was 31 at baseline and 19 at week 12.

For number of swollen joints (0-66), the mean for placebo + cDMARD patients was 17 at baseline and 12 at week 12 and for Olumiant 2 mg + cDMARD patients the mean was 19 at baseline and 10 at week 12.

See RA-BEACON trial design

Improved physical function may be within reach with Olumiant^1,2

Differences in HAQ-DI improvement between Olumiant vs placebo were significant at week 24

Change in HAQ-DI Graph — A line graph representing change in HAQ-DI in the placebo plus cDMARD arm (n=176) and the Olumiant 2 mg/day plus cDMARD arm (n=174) is shown. In the figure, the Y-axis represents the LS mean change from baseline in HAQ-DI score, and the X-axis represents the timepoint in weeks. Data points on the placebo plus cDMARD line include 0 at week 0, -0.09 at week 1, -0.16 at week 2, -0.18 at week 4, -0.21 at week 8, -0.17 at week 12, -0.17 at week 14, -0.17 at week 16, -0.16 at week 20, and -0.15 at week 24. Data points on the Olumiant 2 mg/day plus cDMARD line include 0 at week 0, -0.18 at week 1, -0.21 at week 2, -0.3 at week 4, -0.36 at week 8, -0.37 at week 12, -0.38 at week 14, -0.42 at week 16, -0.4 at week 20, and -0.37 at week 24. Nominal p-values are indicated at weeks 1, 4, 8, 12, 14, 16, and 20. A p-value ≤0.001 is indicated at week 24.

From week 16, non-responding patients could be rescued to a higher dose which is not approved for RA.

Missing data were reported as mLOCF except for week 12, which was reported as mBOCF.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12.

Mean baseline HAQ-DI was 1.71 for Olumiant 2 mg +cDMARDs and 1.78 for placebo +cDMARDs.

See RA-BEACON trial design

SELECT IMPORTANT SAFETY INFORMATION RELATED TO TUBERCULOSIS

Evaluate patients for active infection prior to initiating Olumiant. Olumiant should not be given to patients with active TB. Test patients for latent TB and if positive, treat with standard antimycobacterial therapy before initiating Olumiant. Monitor patients for development of signs and symptoms of TB, including patients who tested negative for latent TB prior to initiating therapy.

HAQ-DI=Health Assessment Questionnaire-Disability Index; cDMARD=conventional disease-modifying antirheumatic drug; LS=least squares; ACR20=American College of Rheumatology 20% improvement criteria; mLOCF=modified last observation carried forward; mBOCF=modified baseline observation carried forward.

Help TNFi-IR patients achieve low disease activity^1,2

Percentage of patients achieving DAS28 <2.6 and ≤3.2 at weeks 12 and 24^1,2

DAS28 results graph — The percentages of patients with a Disease Activity Score-28 (DAS28) of <2.6 and ≤3.2 at weeks 12 and 24 are presented as bar graphs.

In the following results, patients taking Olumiant 2 milligrams (mg)/day plus conventional disease-modifying antirheumatic drugs (cDMARDs) (n=174) were compared to patients taking placebo plus cDMARDs (n=176).

At week 12, 11% of patients taking Olumiant 2 mg/day plus cDMARDs achieved a DAS28 score of <2.6 compared to 4% of patients taking placebo plus cDMARDs, with a p-value of ≤0.05. At week 12, the percentage of patients with a DAS28 score of ≤3.2 was 24% for the Olumiant 2 mg/day plus cDMARDs arm compared to 9% in the placebo plus cDMARDs arm.

At week 24, the percentage of patients with a DAS28 score of <2.6 was 11% for the Olumiant 2mg/day plus cDMARDs arm compared to 6% in the placebo plus cDMARDs arm. At week 24, the percentage of patients with a DAS28 score of ≤3.2 was 20% for the Olumiant 2 mg/day plus cDMARDs arm compared to 11% in the placebo plus cDMARDs arm.

From week 16, non-responding patients could be rescued to a higher dose, which is not approved for RA. Patients who were rescued or discontinued treatment were considered non-responders in the analysis.

DAS28 ≤3.2 presented were from a prespecified analysis, but were not type I error controlled. Therefore treatment differences between Olumiant and placebo cannot be regarded as statistically significant.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12.

See RA-BEACON trial design

SELECT IMPORTANT SAFETY INFORMATION RELATED TO VIRAL REACTIVATION

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical trials with Olumiant. If a patient develops herpes zoster, interrupt Olumiant treatment until the episode resolves. The impact of Olumiant on chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis in accordance with clinical guidelines before starting therapy with Olumiant.

TNFi-IR=tumor necrosis factor inhibitor-inadequate response; DAS28=Disease Activity Score-28; cDMARD=conventional disease-modifying antirheumatic drug; ACR20=American College of Rheumatology 20% improvement criteria. RA=rheumatoid arthritis.

ACR responses for Olumiant and placebo in cDMARD-IR patients¹

BUILD ACR20/50/70 response rates — The American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response rates at weeks 12 and 24 are presented as bar graphs.

In the following results, patients taking Olumiant 2 milligrams (mg)/day plus conventional disease-modifying antirheumatic drugs (cDMARDs) (n=229) were compared to patients taking placebo plus cDMARDs (n=228).

At week 12, the percentage of patients with ACR20 response was 66% in the Olumiant 2 mg/day plus cDMARDs arm compared to 39% in the placebo plus cDMARDs arm. At week 12, percentage of patients with ACR50 response was 34% in the Olumiant 2 mg/day plus cDMARDs arm compared to 13% in the placebo plus cDMARDs arm. At week 12, the percentage of patients with ACR70 response was 18% in the Olumiant 2mg/day plus cDMARDs arm compared to 3% in the placebo plus cDMARDs arm.

At week 24, the percentage of patients with ACR20 response was 61% in the Olumiant 2 mg/day plus cDMARDs arm compared to 42% in the placebo plus cDMARDs arm. At week 24, percentage of patients with ACR50 response was 41% in the Olumiant 2 mg/day plus cDMARDs arm compared to 21% in the placebo plus cDMARDs arm. At week 24, the percentage of patients with ACR70 response was 25% in the Olumiant 2mg/day plus cDMARDs arm compared to 8% in the placebo plus cDMARDs arm.

Olumiant is not indicated for cDMARD-IR patients.

Patients who were rescued or discontinued treatment were considered non-responders in the analysis.

BUILD (Study RA-3) was a 24 -week trial in 684 patients with moderately to severely active RA who had an inadequate response or intolerance to cDMARDs. Patients received Olumiant 2 mg or baricitinib 4 mg once daily or placebo added to existing background cDMARD treatment. From week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. Baricitinib 4 mg is not an approved dose for RA. Primary endpoint was the proportion of patients achieving ACR20 response at week 12.

SELECT IMPORTANT SAFETY INFORMATION RELATED TO MORTALITY

In a large, randomized, postmarketing safety study in RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant.

cDMARD-IR=conventional disease-modifying antirheumatic drug-inadequate response.

Components of ACR Response at week 12¹

BUILD ACR Components at week 12 — The components of the American College of Rheumatology (ACR) response at week 12 in conventional disease-modifying antirheumatic drug-inadequate response (cDMARD-IR) patients are presented as bar graphs.

In the following results, patients taking Olumiant 2 milligrams (mg)/day plus conventional disease-modifying antirheumatic drugs (cDMARDs) (n=229) were compared to patients taking placebo plus cDMARDs (n=228).

For the number of tender joints (0-68), the mean baseline number was 24 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -13 and the mean baseline number was 24 in the placebo plus cDMARDs arm with a change from baseline of -9.

For the number of swollen joints (0-66), the mean baseline number was 14 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -9 and the mean baseline number was 13 in the placebo plus cDMARDs arm with a change from baseline of -5.

For pain, the mean baseline score was 60 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -26 and the mean baseline score was 57 in the placebo plus cDMARDs arm with a change from baseline of -14.

For patient global assessment, the mean baseline score was 62 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -26 and the mean baseline score was 60 in the placebo plus cDMARDs arm with a change from baseline of -16.

For physician global assessment, the mean baseline score was 64 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -31 and the mean baseline score was 62 in the placebo plus cDMARDs arm with a change from baseline of -21.

For Health Assessment Questionnaire-Disability Index (HAQ-DI), the mean baseline score was 1.51 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -0.55 and the mean baseline score was 1.50 in the placebo plus cDMARDs arm with a change from baseline of -0.33.

For high-sensitivity C-reactive protein (hsCRP) (mg/L), the mean baseline number was 18.2 in the Olumiant 2 mg/day plus cDMARDs arm with a change from baseline of -9.6 and the mean baseline number was 17.7 in the placebo plus cDMARDs arm with a change from baseline of -0.5.

Olumiant is not indicated for cDMARD-IR patients.

A modified last observation carried forward (mLOCF) was used for missing data and patients who discontinued treatment.

Data shown are mean.

Primary endpoint was the proportion of patients achieving ACR20 response at week 12 with Olumiant 4 mg which is not approved for RA.

^aVisual analog scale: 0=best, 100=worst.

^bHealth Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

See RA-BUILD trial design

cDMARD-IR=conventional disease-modifying antirheumatic drug-inadequate response.

References

Olumiant. Prescribing Information. Lilly USA, LLC. Eli Lilly and Company; 2022.
Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243-1252.
Genovese MC, Kremer J, Kartman C, et al. Previous biologic disease-modifying antirheumatic drug exposure and efficacy and safety analysis from a phase 3 study of baricitinib in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitors. Poster presented at: ACR Annual; 2015; San Francisco, CA.
Smolen JS, Kremer JM, Gaich CL, et al. Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis. 2017;0:1-7.
Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(suppl):1-30.
Genovese MC, Kremer JM, Kartman CE, et al. Response to baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis. Rheumatology (Oxford). 2018;57:900-908.
Taylor P, Zhu B, Gaich C, et al. SAT0055 Baricitinib showed rapid and greater reduction in pain compared to adalimumab or placebo in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76:788.
Pope JE, Quebe A, Zhu B, et al. Assessment of pain relief with baricitinib by treatment history in patients with refractory rheumatoid arthritis [abstract]. Arthritis Rheumatol. 2018;70(suppl 10).

INDICATIONS

Alopecia Areata

Olumiant is indicated for the treatment of adult patients with severe alopecia areata.

Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants.

Rheumatoid Arthritis

Olumiant is a Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) blockers.

Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants, such as azathioprine and cyclosporine.

COVID-19

Olumiant is a Janus kinase (JAK) inhibitor indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

IMPORTANT SAFETY INFORMATION FOR OLUMIANT (baricitinib) tablets

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS

SERIOUS INFECTIONS
Patients treated with Olumiant are at risk for developing serious infections that may lead to hospitalization or death. Most patients with rheumatoid arthritis (RA) who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt Olumiant until the infection is controlled. Reported infections include:

Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Olumiant should not be given to patients with active tuberculosis. Test patients, except those with COVID-19, for latent TB before initiating Olumiant and during therapy. If positive, start treatment for latent infection prior to Olumiant use.
Invasive fungal infections, including candidiasis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of Olumiant prior to initiating therapy in patients with chronic or recurrent infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Olumiant including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Avoid use of Olumiant in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Olumiant in patients: with chronic or recurrent infection; who have been exposed to TB; with a history of a serious or an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection.

The risks and benefits of treatment with Olumiant in COVID-19 patients with other concurrent infections should be considered.

Consider anti-TB therapy prior to initiation of Olumiant in patients with a 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 who have risk factors for TB infection.

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with Olumiant. If a patient develops herpes zoster, interrupt Olumiant treatment until the episode resolves. The impact of Olumiant on chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis in accordance with clinical guidelines before initiating Olumiant.

MORTALITY
In a large, randomized, postmarketing safety study in RA patients 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase (JAK) inhibitor to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant.

MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with Olumiant. In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers and an additional increased risk of overall malignancies were observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

NMSCs have been reported in patients treated with Olumiant. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

MAJOR ADVERSE CARDIOVASCULAR EVENTS
In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction [MI], and stroke) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue Olumiant in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur.

THROMBOSIS
Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with Olumiant compared to placebo. In addition, there were cases of arterial thrombosis. Many of these adverse events were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid Olumiant in patients at risk. Discontinue Olumiant and promptly evaluate patients with symptoms of thrombosis.

HYPERSENSITIVITY
Reactions such as angioedema, urticaria, and rash that may reflect drug hypersensitivity have been observed in patients receiving Olumiant, including serious reactions. If a serious hypersensitivity reaction occurs, promptly discontinue Olumiant while evaluating the potential causes of the reaction.

GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in Olumiant clinical studies. Monitor Olumiant-treated patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Promptly evaluate patients who present with new onset abdominal symptoms for early identification of gastrointestinal perforation.

LABORATORY ABNORMALITIES
Neutropenia - Olumiant treatment was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm³) compared to placebo. Evaluate at baseline and thereafter according to routine patient management.

In patients with RA or alopecia areata (AA), avoid initiation or interrupt Olumiant treatment in patients with an ANC <1000 cells/mm³. In patients with COVID-19, avoid initiation or interrupt Olumiant treatment in patients with an ANC <500 cells/mm³.

Lymphopenia - Absolute lymphocyte count (ALC) <500 cells/mm³ were reported in Olumiant clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with Olumiant, but not placebo. Evaluate at baseline and thereafter according to routine patient management.

In patients with RA or AA, avoid initiation or interrupt Olumiant treatment in patients with an ALC <500 cells/mm³. In patients with COVID-19, avoid initiation or interrupt Olumiant treatment in patients with an ALC <200 cells/mm³.

Anemia - Decreases in hemoglobin levels to <8 g/dL were reported in Olumiant clinical trials. Evaluate at baseline and thereafter according to routine patient management.

In patients with RA or AA, avoid initiation or interrupt Olumiant treatment in patients with hemoglobin <8 g/dL. In patients with COVID-19, there is limited information regarding use of Olumiant in patients with hemoglobin less than 8 g/dL.

Liver Enzyme Elevations - Olumiant treatment was associated with increased incidence of liver enzyme elevation compared to placebo. Increases of alanine transaminase (ALT) ≥5x upper limit of normal (ULN) and increases of aspartate transaminase (AST) ≥10x ULN were observed in patients in Olumiant clinical trials.

Evaluate at baseline and thereafter according to routine patient management. Promptly investigate the cause of liver enzyme elevation to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt Olumiant until this diagnosis is excluded.

Lipid Elevations - Treatment with Olumiant was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Assess lipid parameters approximately 12 weeks following Olumiant initiation in patients with RA or AA. Manage patients according to clinical guidelines for the management of hyperlipidemia.

VACCINATIONS
Avoid use of live vaccines with Olumiant. Update immunizations in patients with RA or AA prior to initiating Olumiant therapy in agreement with current immunization guidelines.

ADVERSE REACTIONS
In RA trials, the most common adverse reactions (≥1%) reported with Olumiant were: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster.

In COVID-19 trials, the most common adverse reactions (≥1%) reported with Olumiant were: ALT ≥3x ULN, AST ≥3x ULN, thrombocytosis (platelets >600,000 cells/mm³), creatine phosphokinase >5x ULN, neutropenia (ANC <1000 cells/mm³), DVT, PE, and urinary tract infection.

In AA trials, the most common adverse reactions (≥1%) reported with Olumiant were: upper respiratory tract infections, headache, acne, hyperlipidemia, creatine phosphokinase increase, urinary tract infections, liver enzyme elevations, folliculitis, lower respiratory tract infections, nausea, anemia, neutropenia, vulvovaginal candidiasis, abdominal pain, herpes zoster, and weight increase.

PREGNANCY AND LACTATION
Based on animal studies, Olumiant may cause fetal harm when administered during pregnancy. Advise pregnant women and women of reproductive potential of the potential risk to a fetus. Consider pregnancy planning and prevention for women of reproductive potential. Advise women not to breastfeed during treatment with Olumiant and for 4 days after the last dose.

HEPATIC AND RENAL IMPAIRMENT
Olumiant is not recommended in patients with RA or AA and severe hepatic impairment or severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m²).

Olumiant should only be used in patients with COVID-19 and severe hepatic impairment if the potential benefit outweighs the potential risk. Olumiant is not recommended in patients with COVID-19 who are on dialysis, have end-stage renal disease, or with eGFR <15 mL/min/1.73m².

Please click to access full Prescribing Information, including Boxed Warning about Serious Infections, Mortality, Malignancy, Major Adverse Cardiovascular Events, and Thrombosis, and Medication Guide.

BA HCP ISI ALL 13JUN2022

Rheumatoid Arthritis Efficacy

A trial designed for patients still in need^1,2

BEACON (Study RA-4) was one of four phase 3 clinical trials evaluating the efficacy of Olumiant across the RA treatment algorithm^1,2

Patient characteristics and disease activity in the BEACON trial (Study RA-4) ^2,4,5

Olumiant reduced the signs and symptoms of RA^1-3

TNFi-IR patients receiving Olumiant demonstrated higher ACR response rates vs placebo at weeks 12 and 24

ACR20 Response Rates at Week 12 by Treatment History^1-3

Reach for results starting at week 1^1,2

Olumiant demonstrated rapid improvement, with ACR20 responses seen as early as week 1 in TNFi-IR patients

Efficacy across all ACR components^1-3

Pain improvement at weeks 1, 12, and 24^1,2

Percentage of TNF-IR patients achieving ≥30%, ≥50%, and ≥70% reduction in pain from baseline

Pain improvement at week 12 by treatment history^1,2

Improved physical function may be within reach with Olumiant^1,2

Differences in HAQ-DI improvement between Olumiant vs placebo were significant at week 24

Percentage of patients achieving MCID in HAQ-DI at weeks 12 and 24^1-3

Help TNFi-IR patients achieve low disease activity^1,2

Percentage of patients achieving DAS28 <2.6 and ≤3.2 at weeks 12 and 24^1,2

Olumiant reduced disease activity as early as 1 week¹

Olumiant patients experienced changes in disease activity as early as week 1 and through week 24¹

ACR responses for Olumiant and placebo in cDMARD-IR patients¹

Components of ACR Response at week 12¹

Disease activity in cDMARD-IR patients¹

Rheumatoid Arthritis Efficacy

A trial designed for patients still in need1,2

BEACON (Study RA-4) was one of four phase 3 clinical trials evaluating the efficacy of Olumiant across the RA treatment algorithm1,2

Patient characteristics and disease activity in the BEACON trial (Study RA-4) 2,4,5

Olumiant reduced the signs and symptoms of RA1-3

TNFi-IR patients receiving Olumiant demonstrated higher ACR response rates vs placebo at weeks 12 and 24

ACR20 Response Rates at Week 12 by Treatment History1-3

Reach for results starting at week 11,2

Olumiant demonstrated rapid improvement, with ACR20 responses seen as early as week 1 in TNFi-IR patients

Efficacy across all ACR components1-3

Pain improvement at weeks 1, 12, and 241,2

Percentage of TNF-IR patients achieving ≥30%, ≥50%, and ≥70% reduction in pain from baseline

Pain improvement at week 12 by treatment history1,2

Improved physical function may be within reach with Olumiant1,2

Differences in HAQ-DI improvement between Olumiant vs placebo were significant at week 24

Percentage of patients achieving MCID in HAQ-DI at weeks 12 and 241-3

Help TNFi-IR patients achieve low disease activity1,2

Percentage of patients achieving DAS28 <2.6 and ≤3.2 at weeks 12 and 241,2

Olumiant reduced disease activity as early as 1 week1

Olumiant patients experienced changes in disease activity as early as week 1 and through week 241

ACR responses for Olumiant and placebo in cDMARD-IR patients1

Components of ACR Response at week 121

Disease activity in cDMARD-IR patients1

A trial designed for patients still in need^1,2

BEACON (Study RA-4) was one of four phase 3 clinical trials evaluating the efficacy of Olumiant across the RA treatment algorithm^1,2

Patient characteristics and disease activity in the BEACON trial (Study RA-4) ^2,4,5

Olumiant reduced the signs and symptoms of RA^1-3

ACR20 Response Rates at Week 12 by Treatment History^1-3

Reach for results starting at week 1^1,2

Efficacy across all ACR components^1-3

Pain improvement at weeks 1, 12, and 24^1,2

Pain improvement at week 12 by treatment history^1,2

Improved physical function may be within reach with Olumiant^1,2

Percentage of patients achieving MCID in HAQ-DI at weeks 12 and 24^1-3

Help TNFi-IR patients achieve low disease activity^1,2

Percentage of patients achieving DAS28 <2.6 and ≤3.2 at weeks 12 and 24^1,2

Olumiant reduced disease activity as early as 1 week¹

Olumiant patients experienced changes in disease activity as early as week 1 and through week 24¹

ACR responses for Olumiant and placebo in cDMARD-IR patients¹

Components of ACR Response at week 12¹

Disease activity in cDMARD-IR patients¹