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Olumiant ® (baricitinib) tabletter

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Olumiant® (baricitinib): Lipid Effekter

Baricitinib var associerat med ökade lipidparametrar i fas 3 klinisk utvecklingsprogram för reumatoid artrit (RA).

SE_cFAQ_BAR130A_X1_LIPID_EFFECTS_RA
SE_cFAQ_BAR130A_X1_LIPID_EFFECTS_RA
en-GB

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

    1Genovese 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

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

    3Genovese 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. Ann Rheum Dis. 2020;79(suppl 1):638. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

    4Genovese 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.

    5Taylor 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

    6Olumiant [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

    Datum fӧr senaste ӧversyn May 27, 2020

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