Olumiant® ▼ (baricitinib): Ändring av antal trombocyter

Platelet Changes in the Rheumatoid Arthritis Clinical Development Program

Mean Platelet Changes Over Time

In controlled studies, for up to 16 weeks, increases in platelet counts above 600 x 10⁹ cells/L occurred in 2.0 % of patients treated with baricitinib 4 mg and 1.1 % of patients treated with placebo. No association was observed between increased platelet counts and adverse events of a thrombotic nature. The pattern and incidence of increases in platelet counts remained stable at a higher value than baseline over time including in the long term extension study. ¹

5-Study Pooled Dataset

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

Based on the 5-study pooled dataset, mean platelet counts 

• increased early with a peak at week 2

• returned towards baseline at week 4, and

• stabilized after week 8 at levels higher than baseline with extended BARI exposure (Figure 1).^2-4

Figure 1. 5-Study Pooled Dataset Mean (SE) Platelet Levels Over Time²

Abbreviations: BARI = baricitinib; PBO = placebo; SE = standard error  Notes: BARI 2-mg, placebo censored at rescue or dose change, and BARI 4-mg censored at any dose change (including step-down) or rescue in long-term extension study. Lilly-defined large clinical trial population based reference ranges were used.

6-Study Placebo-Controlled Dataset

The 6-study placebo-controlled dataset compared BARI 4 mg vs placebo and included patients with RA who were randomized to BARI 4 mg (N=997) or placebo (N=1070) from 3 phase 2 and 3 phase 3 studies. In the majority of the studies, patients were on background therapy either with MTX or another csDMARD. The BARI 2-mg data is derived from 4 studies in which both BARI 2 mg (N=479) and BARI 4 mg were options during randomization.⁵

Reversibility was evaluated in a subgroup of patients from the 6-Study placebo-controlled dataset who discontinued treatment by Week 24. Reversibility of increased platelet count was observed with the return of mean values to baseline after treatment discontinuation (Figure 2).³

Figure 2. Platelet Count Reversibility in a Patient Subgroup from the 6-Study Placebo-Controlled Dataset³

Notes: Platelet counts were pooled from 6 placebo-controlled phase 2 and 3 studies, including the long-term extension study period, with data through January 1, 2016. Reversibility was evaluated in patients who discontinued study treatment by week 24.

Changes in Mean Platelet Volume

Mean Platelet Changes Over Time

The relationship of platelet count to MPV was assessed, over 16 weeks, in study RA-BEAM, a 52-week, randomized, placebo- and active-controlled study of patients with moderate to severe active rheumatoid arthritis.⁶

The objective of this analysis was to determine if the observed platelet changes were consistent with altered

• platelet synthesis

• platelet release, or

• platelet clearance.⁶

In RA-BEAM, after initiation of BARI treatment

• platelet count increased at week 2, then returned toward baseline at week 4

• MPV decreased at week 2, then returned toward baseline at week 4, and

• both platelet count and MPV remained stable after week 4 through the 16-week observation period (Figure 3).⁶

According to the authors, the pattern of mirrored changes for platelet count and MPV suggests decreased platelet clearance rather than increased platelet production. As a potential explanation, the increase in platelet count at week 2 may represent a transient increase in smaller and older circulating platelets, which might account for the observed MPV decline.⁶

Figure 3. Change in Platelet Count and Mean Platelet Volume Over Time in Patients from Study RA-BEAM⁶

Abbreviations: BARI = baricitinib; CI = confidence interval.
Note: * Within-group p≤.05.

Patients With Abnormal High Platelet Values

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.⁷

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).⁷

4-Study Extended Dataset

The extended dataset included patients with RA randomized to BARI 2 mg (N=479, PYE=675.6, median exposure duration=257 days, maximum exposure duration=1805 days) or BARI 4 mg (N=479, PYE=698.6, median exposure duration=342 days, maximum exposure duration=2520 days ) 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 13 February 2018 unless otherwise specified. Data were censored at rescue or dose change.⁷

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

• 10,127 PYE,

• median exposure of 3.1 yrs,

• maximum exposure of 6.9 yrs, and

• data through 13 February 2018.⁷

Treatment Emergent Abnormally High Platelet Value Analyses

Analyses of treatment emergent high platelet counts (>ULN) across integrated safety datasets are presented in  . ²

Normal limits were defined according to

• lab methodology

• age

• gender, and

• ethnicity.²

Table 1. Treatment Emergent Abnormal High Platelet Values²

	7-Study Placebo-Controlled Dataset, Week 24 PBO (N=1215) (NAR=1033)	7-Study Placebo-Controlled Dataset, Week 24 BARI 2 mg (N=479) (NAR=420)	7-Study Placebo-Controlled Dataset, Week 24 BARI 4 mg (N=1142) (NAR=974)	4-Study Extended Dataset BARI 2 mg (N=479) (NAR=421)	4-Study Extended Dataset BARI 4 mg (N=479) (NAR=426)	All BARI RA Dataset (N=3770) (NAR=3296)
Abnormal High, n (%)	98 (9.5%)	71 (16.9)a	237 (24.3)a	82 (19.5)	129 (30.3)b	1025 (31.1)

Abbreviations: BARI = baricitinib; N = number of patients in the analysis population; n = number of patients with the specified abnormality; NAR = number of patients at risk for the abnormality in each treatment group; PBO = placebo; RA = rheumatoid arthritis

Note: For the 7-Study Placebo-ControlledDataset, the OR is versus placebo. For the 4-Study Extended Dataset, the OR is versus BARI 2 mg. 

^a P-value ≤ 0.05 and OR > 1 (missing ORs are considered >1).

^b BARI incidence ≥10% before rounding and OR >1 (missing ORs are considered >1).

The proportions of patients experiencing a change from ≤ 600 billion cells/L to > 600 billion cells/L are presented in  . ²

Table 2. Proportion of Patients with Platelet Value Changes from ≤ 600 billion cells/L to > 600 billion cells/L²

	7-Study Placebo-Controlled Dataset, Week 24 PBO (N=1215) (NAR=1198)	7-Study Placebo-Controlled Dataset, Week 24 BARI 2 mg (N=479) (NAR=472)	7-Study Placebo-Controlled Dataset, Week 24 BARI 4 mg (N=1142) (NAR=1127)	4-Study Extended Dataset BARI 2 mg (N=479) (NAR=473)	4-Study Extended Dataset BARI 4 mg (N=479) (NAR=473)	All BARI RA Dataset (N=3770) (NAR=3716)
≤ 600 billion cells/L to > 600 billion cells/L	17 (1.4)	5 (1.1)a	27 (2.4)	8 (1.7)	19 (4.0)	127 (3.4)

Abbreviations: BARI = baricitinib; N = number of patients in the analysis population; n = number of patients with the specified abnormality; NAR = number of patients at risk for the abnormality in each treatment group; PBO = placebo; RA = rheumatoid arthritis

^a Through Week 16

Relationship of Increased Platelets to Thrombotic Events

Thrombocytosis and Thromboembolic Adverse Events

In controlled studies, for up to 16 weeks, thrombocytosis (>600 x 10⁹ cells/L) was commonly reported (≥ 1/100 to <1/10). ¹

DVT and PE are listed as uncommon in the table of adverse reactions in the summary of product characteristics. ¹

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib. Baricitinib should be used with caution in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery and immobilisation. If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.¹

The association between thrombocytosis and adverse events of a thrombotic nature were evaluated in patients from the All BARI RA 12-month safety update analysis set.³

Among the 31 patients in the All BARI RA dataset with a reported adverse event of VTE through September 1, 2016, the proportion of patients with high platelet levels was comparable between patients with VTE vs those without VTE (Figure 4). No association was observed between increased platelet counts and VTE events.^3,8

Figure 4. Proportions of BARI-Treated Patients With and Without a DVT/PE Adverse Event According to Thrombocytosis Criteria Applied at Baseline and Post Baseline³

Abbreviations: BARI = baricitinib; DVT/PE = deep venous thromboembolism/pulmonary embolism.
Note: Data from the All BARI RA analysis set with data through September 1, 2016.

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. Kremer J, Huizinga TWJ, Chen L, et al. Analysis of neutrophils, lymphocytes, and platelets in pooled phase 2 and phase 3 studies of baricitinib for rheumatoid arthritis. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 14-17, 2017; Madrid, Spain.

4. Eli Lilly and Company. Lilly FDA Advisory Committee Meeting NDA 207924 Briefing Document. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf. Accessed May 2, 2018a. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf

5. Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol. 2019;46(1):7-18. http://dx.doi.org/10.3899/jrheum.171361

6. Giles JT, Nurmohamed MT, Rinder HM, et al. Mean platelet volume changes with baricitinib indicate reduced new platelet production in baricitinib-treated rheumatoid arthritis patients. Presented at American College of Rheumatology (ACR/ARHP) Annual Meeting; November 19-24, 2018. Chicago, IL.

7. Genovese MC, Smolen JS, Tsutomu 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

8. Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment [published online September 15, 2018]. J Rheumatol. https://dx.doi.org/10.3899/jrheum.171361

Glossary

AD = atopic dermatitis

BARI = baricitinib

DVT = deep vein thrombosis

PBO = placebo

PE = pulmonary embolism

RA = rheumatoid arthritis

TE = treatment-emergent

▼ 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.