Olumiant® ▼ (baricitinib): Lipid Effekter

Treatment-Emergent Adverse Events Related to Hyperlipidemia in the Rheumatoid Arthritis Clinical Development Program

Safety Dataset Descriptions

7-Study Placebo-Controlled Dataset

The 7-study pooled dataset included patients with RA randomized to BARI 4 mg (N=1142, PYE=471.8) or placebo (N=1215, PYE=450.8) from 3 phase 2 studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Patients in the placebo group could have been taking background MTX or other conventional DMARDs. Evaluation time periods included through

• the 12-week placebo-controlled period in phase 2 studies

• 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and

• 24 weeks of assigned treatment or until rescue in phase 3 studies.¹

Data from BARI 2 mg (N=479, PYE=185.8) is derived from 4 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (2 phase 2 studies as well as RA-BUILD and RA-BEACON).¹

4-Study Extended Dataset

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) from 2 phase 2 and 2 phase 3 studies (RA-BUILD, RA-BEACON) and 1 long term extension study (RA-BEYOND). The evaluation time periods included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified. Data were censored at rescue or dose change.²

All BARI RA Dataset

The All BARI RA analysis set included 3770 patients with RA who received BARI at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with

• 13,148 PYE,

• median exposure of 4.2 years,

• maximum exposure of 8.4 years, and

• data through 01 September 2019.^3,4

Results From the 7-Study Placebo-Controlled Dataset

The proportion of patients who reported hyperlipidemia was

• 3.2% in the BARI 4-mg group (p=.003 vs placebo)

• 1.3% in the BARI 2-mg group, and 

• 1.3% in the placebo group.²

Furthermore, the proportion of patients who reported hypercholesterolaemia was

• 3.4% in the BARI 4-mg group (p=.002 vs placebo)

• 1.9% in the BARI 2-mg group, and

• 1.5% in the placebo group.²

There were no serious hyperlipidemia events or temporary or permanent discontinuations from study drug due to hyperlipidemia events up to week 24.²

Results From the 4-Study Extended Dataset

In the combined 4-study extended dataset

• hyperlipidaemia was reported by

  • 17 (3.5%; EAIR=2.2) patients in the BARI 4-mg group, and

  • 15 (3.1%; EAIR=1.9) patients in the BARI 2-mg group (p=.718 vs BARI 4 mg), and

• hypercholesterolaemia was reported by

  • 33 (6.9%; EAIR=4.2) patients in the BARI 4-mg group, and

  • 14 (2.9%; EAIR=1.8) patients in the BARI 2-mg group (p=.005 vs BARI 4 mg).²

Results From the All BARI RA Dataset

In the All BARI RA dataset consisting of 3770 patients treated with BARI with maximum exposure of 8.4 yrs (PYE=13,148), the MedDRA preferred terms of

• hyperlipidaemia was reported in 218 patients (5.8%; 1.7 EAIR), and

• hypercholesterolaemia was reported in 250 patients (6.6%; 1.9 EAIR).²

None of these events were considered serious; 1 hyperlipidaemia event led to permanent discontinuation of study drug.²

Changes in Lipid Analytes and Lipid Particle Size

Mean Changes in Lipid Analytes From Baseline

The 5-study pooled dataset included patients with RA randomized to BARI 4 mg or placebo from 1 phase 2 study and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with data through 13 February 2018.²

BARI 2 mg data is pooled from 3 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (1 phase 2 study as well as RA-BUILD and RA-BEACON).²

Compared to placebo, treatment with BARI 2 mg and BARI 4 mg was associated with statistically significant percent increases from baseline through week 24 in

• LDL-C

• HDL-C, and

• total cholesterol (p≤.001 for all).²

Compared to placebo, treatment with BARI 4 mg was also associated with statistically significant percent increases from baseline through week 24 in triglycerides (p≤.001).^2,5

The lipid elevations plateaued after week 12.^2,5

Changes in Lipid Particle Size

In RA-BEAM, the NMR lipoprotein profile revealed similar changes for BARI and ADA treatment groups relative to the placebo group. Compared to placebo, BARI had statistically significant

• increases in

  • total LDL (p≤.05) and large LDL (p≤.001) mean particle number

  • total HDL (p≤.001) and all subfractions of HDL (p≤.05) mean particle number, and

• decreases in small, medium small, and very small LDL (p≤.01 for all) mean particle numbers.⁵

Compared to placebo, BARI had statistically significant

• increases in LDL (p≤.001) and VLDL (p≤.01) mean particle size, and

• modest decrease in HDL (p≤.05) mean particle size.⁵

Effect of Statins in Combination With Baricitinib on Lipid Analytes

The long-term BARI cohort included patients randomized to receive

• BARI 4 mg in RA-BEAM, RA-BUILD, and RA-BEACON, and

• BARI 2 mg in RA-BUILD and RA-BEACON.⁵

The dataset also included data from RA-BEYOND which was censored at dose change or rescue.⁵

In the long-term BARI cohort, 25 patients receiving BARI 2 mg and 58 patients receiving BARI 4 mg initiated statin therapy after starting BARI. The effects of statin therapy were comparable between the BARI groups and placebo group (n=20) for

• LDL-C

• total cholesterol, and

• triglycerides.⁵

Monitoring and Management

Dose dependent increases in blood lipid parameters were reported in patients treated with baricitinib compared to placebo.⁶

• Elevations in LDL cholesterol decreased to pre- treatment levels in response to statin therapy.⁶

• Lipid parameters should be assessed approximately 12 weeks following initiation of baricitinib therapy and thereafter patients should be managed according to international clinical guidelines for hyperlipidaemia.⁶

• The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.⁶

Information From the Label

In controlled studies, for up to 16 weeks hypercholesterolaemia was very commonly reported (≥ 1/10) and hypertriglyceridaemia was uncommonly reported (≥ 1/1,000 to < 1/100 ).⁶

Lipid Elevations

In rheumatoid arthritis clinical studies, baricitinib treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 12 weeks and remained stable thereafter at a higher value than baseline including in the long-term extension study.⁶

In studies which included both doses, a dose-relationship was observed with increased total cholesterol ≥ 5.17 mmol/L reported in 48.8 %, 34.7 % and 17.8 % of patients up to 16 weeks in the 4 mg, 2 mg and placebo groups, respectively.⁶

Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy.⁶

In controlled studies, for up to 16 weeks, the following frequencies were observed for baricitinib 4 mg vs. placebo:

• Increased total cholesterol ≥ 5.17 mmol/L:

  • Rheumatoid Arthritis: 49.1 % vs.15.8 %, respectively

• Increased LDL cholesterol ≥ 3.36 mmol/L:

  • Rheumatoid Arthritis: 33.6 % vs. 10.3 %, respectively

• Increased HDL cholesterol ≥ 1.55 mmol/L:

  • Rheumatoid Arthritis: 42.7 % vs. 13.8 %, respectively

• Increased triglycerides ≥ 5.65 mmol/L:

  • Rheumatoid Arthritis: 0.4 % vs. 0.5 %, respectively.⁶

References

1. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):E347-E357. https://doi.org/10.1016/S2665-9913(20)30032-1

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

3. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. https://ard.bmj.com/content/79/Suppl_1/642.1

4. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

5. Taylor PC, Kremer JM, Emery P, et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann Rheum Dis. 2018;77(7):988-995. http://dx.doi.org/10.1136/annrheumdis-2017-212461

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

Glossary

ADA = adalimumab

BARI = baricitinib

DMARD = disease-modifying antirheumatic drug

EAIR = exposure-adjusted incidence rate

HDL = high-density lipoprotein

HDL-C = high-density lipoprotein cholesterol

LDL = low-density lipoprotein

LDL-C = low-density lipoprotein cholesterol

MedDRA = Medical Dictionary for Regulatory Activities

MTX = methotrexate

NMR = nuclear magnetic resonance

PYE = patient-years of exposure

RA = rheumatoid arthritis

VLDL = very low-density lipoprotein

▼ 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.