Baricitinib: Reproductive Risks in Males

Combined Male and Female Animal Fertility Study

Male rats were dosed with 0, 5, 15, or 50 mg/kg of BARI daily for 6 weeks including 4 weeks prior to cohabitation with female rats treated with 0, 5, 25, or 100 mg/kg.¹

The NOAEL for male fertility was 15 mg/kg based on rat studies.¹

Effects on Reproductive Organs and Sperm

Histologic studies found no change in male reproductive organs, and no effects on sperm motility, concentration, and morphology at any BARI dose level.¹

Effects on Fertility and Early Embryonic Development

Results by Doses

At doses of 50 and 100 mg/kg/day (approximately 113 and 169 times a baricitinib dose of 2 mg in male and females, respectively), reproductive performance was unaffected in both genders.¹  

At doses of 15 mg/kg and 25 mg/kg (approximately 25 and 48 times a baricitinib dose of 2 mg), fertility was unaffected in male and female rats.¹

Potential Cause of Decreased Fertility

Based on the study design, it could not be determined if fertility results were attributable to toxicities in one sex or both. However, since there were no effects on spermatogenesis or semen/sperm endpoints in male rats, the decreased overall mating performance was likely the result of fertility effects in female rats including

• decreased corpora lutea and implantation sites,

• increased pre-implantation loss, and

• adverse effects on intrauterine survival.¹

The NOAEL was 5 mg/kg for female fertility and early embryonic development based on rat studies.¹

Treatment-Emergent Adverse Events

A TEAE is an adverse event that either occurred or worsened in severity after the first dose of study treatment and did not necessarily have a causal relationship to study treatment.¹

Rheumatoid Arthritis

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 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.²

Data from BARI 2 mg (N=479, PYE=185.8) were 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).²

In this safety analysis, through 24 weeks of treatment, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported in any of the study arms (BARI 4 mg, BARI 2 mg, and placebo).¹

All BARI RA Analysis Set

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, and 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 September 1, 2019.^3,4

In this safety analysis, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported.¹

Sperm analysis was not routinely conducted throughout the studies and male participants were required to use birth control throughout the duration of the study as described above.¹

Atopic Dermatitis

Placebo-Controlled Analysis

The largest placebo-controlled dataset included patients with AD from 1 phase 2 and 5 phase 3 studies (BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, and BREEZE-AD7). These patients were randomized to BARI (n=721, PYE=210.6) and placebo (n=889, PYE=252.7); treatment period was 0 to 16 weeks.¹

In this safety analysis, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported.¹

All BARI AD Analysis Set

The All BARI AD analysis set includes 2531 patients (PYE=2274.4) with AD who received at least 1 dose of BARI at different strengths from 1 phase 2, 5 phase 3 (BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, and BREEZE-AD7), and 2 phase 3 extension studies (BREEZE-AD3 and BREEZE-AD6).¹

In this safety analysis, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported.¹

Postmarketing Spontaneous Reports

The following information is valid for data received up through June 22, 2020. The data do not represent the number of AEs in a treated population. They merely represent the number of a particular AE reported to the company. The following MedDRA preferred terms have not been reported to the Eli Lilly and Company spontaneous AE database

• spermatogenesis abnormal, and

• paternal exposure during pregnancy.¹

Spontaneous reporting of AEs can be highly variable and is not controlled clinical information on which to assess causality of a drug to an AE. Spontaneous reporting has limitations due to bias in reporting including incomplete information concerning the patient. When verification of product manufactured by Lilly is not obtainable, these cases are included in the spontaneous database.

Use in Individuals of Reproductive Potential

Based on the mechanism of action and findings in animals, BARI may cause fetal harm.¹

If the patient becomes pregnant while taking BARI, inform the patient of the potential for hazard to the fetus. BARI should only be continued during pregnancy if the potential benefit justifies the potential risk to the fetus.¹

Women of reproductive potential should take appropriate precautions to avoid becoming pregnant during treatment with BARI and for at least 1 week after the final BARI treatment.¹

Reference

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

2. 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

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.

Glossary

AD = atopic dermatitis

AE = adverse event

BARI = baricitinib

DMARD = disease-modifying antirheumatic drug

Lilly = Eli Lilly and Company

MedDRA = Medical Dictionary for Regulatory Activities

MRHD = maximum recommended human dose

MTX = methotrexate

NOAEL = no observed adverse effect level

PYE = patient-years of exposure

RA = rheumatoid arthritis

TEAE = treatment-emergent adverse event