Olumiant (baricitinib 1 mg) Dailymed

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of baricitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received baricitinib for 91 to 94 weeks at oral doses up to 8 or 25 mg/kg/day, respectively (approximately 7 and 30 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in Tg.rasH2 mice that received baricitinib for 26 weeks at oral doses up to 300 and 150 mg/kg/day in male and female mice, respectively.

Baricitinib tested negative in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay.

Fertility (achievement of pregnancy) was reduced in male and female rats that received baricitinib at oral doses of 50 and 100 mg/kg/day respectively (approximately 62 and 93 times the MRHD in males and females, respectively, on an AUC basis) based upon findings that 7 of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 1 of 19 (5.3%) control females. It could not be determined from the study design if these findings were attributable to toxicities in one sex or both. Fertility was unaffected in male and female rats at oral doses of 15 mg/kg and 25 mg/kg, respectively (approximately 13 and 26 times the MRHD on an AUC basis). However, maintenance of pregnancy was adversely affected at these doses based upon findings of increased post-implantation losses (early resorptions) and decreased numbers of mean viable embryos per litter. The number of viable embryos was unaffected in female rats that received baricitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 6 times the MRHD on an AUC basis). Reproductive performance was unaffected in male and female rats that received baricitinib at oral doses up to 50 and 100 mg/kg/day respectively (approximately 62 and 93 times the MRHD in males and females, respectively, on an AUC basis).

14 Clinical Studies

14.1 Rheumatoid Arthritis

The OLUMIANT clinical development program included two dose-ranging trials and four confirmatory phase 3 trials in patients with rheumatoid arthritis (RA). Although other doses have been studied, the recommended dosage of OLUMIANT is 2 mg once daily.

Dose-Ranging Studies

The dose-ranging studies RA-1 (NCT01185353) and RA-2 (NCT01469013) included a 12-week randomized comparison of baricitinib 1, 2, 4, and 8 mg orally once daily versus placebo in 301 and 145 patients, respectively.

The results from the dose-ranging studies are shown in Table 11. In dose-ranging Study RA-1, the observed ACR response was similar for baricitinib 1 and 2 mg daily and for baricitinib 4 and 8 mg daily, with the highest response for baricitinib 8 mg daily. In dose-ranging Study RA-2, there was not a clear trend of dose response, with similar response rates for 1 mg and 4 mg and 2 mg and 8 mg.

Table 11: Proportion of Patients with ACR20 Response at Week 12 in Dose-Ranging RA Studies

	% ACR20 Responders
Dose-Ranging Study	Placebo	Baricitinib 1 mg daily	Baricitinib 2 mg daily	Baricitinib 4 mg daily	Baricitinib 8 mg daily
RA-1 (N=301)	41	57	54	75	78
RA-2 (N=145)	31	67	83	67	88

Confirmatory Studies

The efficacy and safety of OLUMIANT 2 mg once daily was assessed in two confirmatory phase 3 trials. These trials were randomized, double-blind, multicenter studies in patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism 2010 criteria. Patients over 18 years of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. The two studies (Studies RA-3 and RA-4) evaluated OLUMIANT 2 mg and baricitinib 4 mg.

Study RA-3 (NCT01721057) was a 24-week trial in 684 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to conventional DMARDs (cDMARDs). Patients received OLUMIANT 2 mg or 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. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Study RA-4 (NCT01721044) was a 24-week trial in 527 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to 1 or more TNF inhibitor therapies with or without other biologic DMARDs (TNFi-IR). Patients received OLUMIANT 2 mg or baricitinib 4 mg once daily or placebo added to background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Clinical Response

The percentages of OLUMIANT-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease Activity Score (DAS28-CRP) <2.6 in Studies RA-3 and RA-4 are shown in Table 8.

Patients treated with OLUMIANT had higher rates of ACR response and DAS28-CRP <2.6 versus placebo-treated patients at Week 12 (Studies RA-3 and RA-4) (Table 12).

In Study RA-4, higher ACR20 response rates (Figure 4) were observed as early as 1 week with OLUMIANT 2 mg versus placebo.

In Study RA-4, the proportions of patients achieving DAS28-CRP <2.6 who had at least 3 active joints at the end of Week 24 were 18.2% and 10.5%, in the placebo and OLUMIANT 2 mg arms, respectively.

Table 12: Clinical Response in RA Studies RA-3 and RA-4^a

a Patients who were rescued or discontinued treatment were considered as non-responders in the analyses.
b 95% confidence interval for the difference (∆) in response rate between OLUMIANT treatment and placebo (Study RA-3, Study RA-4).
	Percent of Patients
	cDMARD-IR		TNFi-IR
	Study RA-3		Study RA-4
	Placebo + cDMARDs	OLUMIANT2 mg/day + cDMARDs ∆ (95% CI) b	Placebo + cDMARDs	OLUMIANT2 mg/day + cDMARDs ∆ (95% CI) b
N	228	229	176	174
ACR 20
Week 12%	39	6627 (18, 35)	27	4922 (12, 32)
Week 24%	42	6119 (10, 28)	27	4518 (8, 27)
ACR 50
Week 12%	13	3421 (13, 28)	8	2012 (5, 19)
Week 24%	21	4120 (12, 28)	13	2310 (2, 18)
ACR 70
Week 12%	3	1815 (9, 20)	2	1311 (5, 16)
Week 24%	8	2517 (11, 24)	3	1310 (4, 16)
DAS28-CRP<2.6
Week 12%	9	26(10, 24)	4	11(2, 12)
Week 24%	11	31(13, 27)	6	11(-1, 11)

The effects of OLUMIANT treatment on the components of the ACR response criteria for Studies RA-3 and RA-4 are shown in Table 13.

Table 13: Components of ACR Response at Week 12 in RA Studies RA-3 and RA-4^a

a Data shown are mean (standard deviation).
b Visual analog scale: 0=best, 100=worst.
c Health Assessment Questionnaire–Disability Index: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
	cDMARD-IR		TNFi-IR
	Study RA-3		Study RA-4
	Placebo+ cDMARDs	OLUMIANT2 mg/day+ cDMARDs	Placebo+ cDMARDs	OLUMIANT2 mg/day+ cDMARDs
N	228	229	176	174
Number of Tender Joints (0-68)
Baseline	24 (15)	24 (14)	28 (16)	31 (16)
Week 12	15 (14)	11 (13)	20 (16)	19 (18)
Number of Swollen Joints (0-66)
Baseline	13 (7)	14 (9)	17 (11)	19 (12)
Week 12	8 (8)	5 (6)	12 (10)	10 (12)
Pain b
Baseline	57 (23)	60 (21)	65 (19)	62 (22)
Week 12	43 (24)	34 (25)	55 (25)	46 (28)
Patient Global Assessment b
Baseline	60 (21)	62 (20)	66 (19)	67 (19)
Week 12	44 (23)	36 (25)	56 (25)	46 (26)
Physician Global Assessment b
Baseline	62 (17)	64 (17)	67 (19)	67 (17)
Week 12	41 (24)	33 (22)	50 (26)	36 (24)
Disability Index (HAQ-DI) c
Baseline	1.50 (0.60)	1.51 (0.62)	1.78 (0.57)	1.71 (0.55)
Week 12	1.17 (0.62)	0.96 (0.69)	1.59 (0.68)	1.31 (0.72)
hsCRP (mg/L)
Baseline	17.7 (20.4)	18.2 (21.5)	20.6 (25.3)	19.9 (22.5)
Week 12	17.2 (19.3)	8.6 (14.6)	19.9 (23.0)	13.5 (20.1)

Figure 4: Percent of RA Patients Achieving ACR20 in Study RA-4

Physical Function Response

Improvement in physical function was measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patients receiving OLUMIANT 2 mg demonstrated greater improvement from baseline in physical functioning compared to placebo at Week 24. The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.24 (-0.35, -0.14) in Study RA-3 and -0.23 (-0.35, -0.12) in Study RA-4.

Other Health Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies RA-3 and RA-4, compared to placebo, patients treated with OLUMIANT 2 mg demonstrated greater improvement from baseline in the physical component summary (PCS) score and the physical function, role physical, bodily pain, vitality, and general health domains at Week 12, with no consistent improvements in the mental component summary (MCS) scores or the role emotional, mental health, and social functioning domains.

14.2 COVID-19

The efficacy and safety of baricitinib were assessed in 2 Phase 3, randomized, double-blind, placebo-controlled clinical trials:

• COVID I (NCT04401579), which evaluated the combination of baricitinib 4 mg + remdesivir compared to placebo + remdesivir.
• COVID II (NCT04421027), which evaluated baricitinib 4 mg compared to placebo. Patients could remain on background therapy, as defined per local guidelines. An additional exploratory sub-study in patients requiring invasive mechanical ventilation or ECMO at baseline was also conducted under this protocol and analyzed separately.

COVID I

A randomized, double-blind, placebo-controlled clinical trial (NCT04401579) of hospitalized adults with confirmed SARS-CoV-2 infection compared treatment with baricitinib plus remdesivir (n = 515) with placebo plus remdesivir (n = 518). Patients had to have laboratory-confirmed SARS-CoV-2 infection as well as at least one of the following to be enrolled in the trial: radiographic infiltrates by imaging, SpO₂ ≤94% on room air, a requirement for supplemental oxygen, or a requirement for mechanical ventilation or ECMO. Patients treated with the combination received the following regimen:

• Baricitinib 4 mg once daily (orally) for up to 14 days or until hospital discharge, whichever came first
• Remdesivir 200 mg on Day 1 and 100 mg once daily (via intravenous infusion) on subsequent days for a total treatment duration of 10 days or until hospital discharge

In this study prophylaxis for venous thromboembolic event (VTEs) was recommended for all patients unless a major contraindication was noted.

For the overall population (N = 1033 patients) at randomization, mean age was 55 years (with 30% of patients aged 65 or older); 63% of patients were male, 51% were Hispanic or Latino, 48% were White, 15% were Black or African American, and 10% were Asian; 14% did not require supplemental oxygen, 55% required supplemental oxygen, 21% required non-invasive ventilation or high-flow oxygen, and 11% required invasive mechanical ventilation or ECMO. The most common comorbidities were obesity (56%), hypertension (52%), and type 2 diabetes (37%). Demographics and disease characteristics were balanced across the combination group and the placebo group.

The primary endpoint, for the intent to treat population, was time to recovery within 29 days after randomization. Recovery was defined as being discharged from the hospital without limitations on activities, being discharged from the hospital with limitations on activities and/or requiring home oxygen or hospitalized but not requiring supplemental oxygen and no longer requiring medical care. The key secondary endpoint was clinical status on Day 15 assessed on an 8-point ordinal scale (OS) consisting of the following categories:

• Not hospitalized, no limitations on activities [OS-1];
• Not hospitalized, limitation on activities and/or requiring home oxygen [OS-2];
• Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care [OS-3];
• Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) [OS 4];
• Hospitalized, requiring supplemental oxygen [OS 5];
• Hospitalized, on non-invasive ventilation or high-flow oxygen devices [OS 6];
• Hospitalized, on invasive mechanical ventilation or ECMO [OS 7]; and
• Death [OS 8]

For the overall population, the median time to recovery (defined as discharged from hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care) was 7 days for baricitinib + remdesivir compared to 8 days for placebo + remdesivir [hazard ratio: 1.16 (95% CI 1.01, 1.33); p = 0.035].

Patients assigned to baricitinib + remdesivir were more likely to have a better clinical status (according to an 8-point ordinal scale) at Day 15 compared to patients assigned to placebo + remdesivir [odds ratio: 1.26 (95% CI 1.01, 1.57); p = 0.044].

The proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation by Day 29 was lower in baricitinib + remdesivir (23%) compared to placebo + remdesivir (28%) [odds ratio: 0.74 (95% CI 0.56, 0.99); p = 0.039]. Patients who required non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation (including ECMO) at baseline needed to worsen by at least 1 point on an 8-point ordinal scale to progress.

The proportion of patients who died by Day 29 was 4.7% (24/515) for baricitinib + remdesivir compared to 7.1% (37/518) for placebo + remdesivir [Kaplan Meier estimated difference in Day 29 probability of mortality: -2.6% (95% CI: -5.8%, 0.5%); hazard ratio = 0.65 (95% CI: 0.39, 1.09)].

COVID II

A randomized, double-blind, placebo-controlled clinical trial (NCT04421027) of hospitalized adults with confirmed SARS-CoV-2 infection compared treatment with baricitinib 4mg once daily (n = 764) with placebo (n = 761) for 14 days or hospital discharge, whichever came first. Patients could remain on background standard of care, as defined per local guidelines, including antimalarials, antivirals, corticosteroids, and/or azithromycin. In this study prophylaxis for venous thromboembolic event (VTE) was required for all patients unless contraindicated.

The most frequently used therapies at baseline were:

• corticosteroids (79% of patients, mostly dexamethasone)
• remdesivir (19% of patients)

Patients had to have laboratory-confirmed SARS-CoV-2 infection, at least one instance of elevation in at least one inflammatory marker above the upper limit of normal according to local laboratory ranges (CRP, D-dimer, LDH, ferritin), and at least one of the following to be enrolled in the trial: radiographic infiltrates by imaging, SpO₂ <94% on room air, evidence of active COVID infection (with clinical symptoms including any of the following: fever, vomiting, diarrhea, dry cough, tachypnea defined as respiratory rate >24 breaths/min) or requirement for supplemental oxygen.

For the overall population (N = 1525 patients) at randomization, mean age was 58 years (with 33% of patients aged 65 or older); 63% of patients were male, 60% were White, 5% were Black or African American, 11% were Asian; 12% did not require supplemental oxygen (OS 4), 63% required supplemental oxygen (OS 5), 24% required non-invasive ventilation or high-flow oxygen (OS 6). The most common comorbidities were hypertension (48%), obesity (33%), and type 2 diabetes (29%). Demographics and disease characteristics were balanced across the baricitinib and placebo groups.

The primary endpoint was the proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation within the first 28-days of the study. Patients who required non-invasive ventilation/high-flow oxygen at baseline needed to worsen by at least 1 point on an 8-point OS to progress (refer to the description of COVID I for the definition of the 8-point OS). A key secondary endpoint was all-cause mortality by Day 28.

The estimated proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation was lower in patients treated with baricitinib (27.8%) compared to placebo (30.5%), but this effect was not statistically significant [odds ratio: 0.85 (95% CI 0.67, 1.08); p = 0.180].

The proportion of patients who died by Day 28 was 8.1% (62/764) for baricitinib compared to 13.3% (101/761) for placebo [estimated difference in Day 28 probability of mortality = -4.9% (95% CI: -8.0%, -1.9%); hazard ratio = 0.56 (95% CI: 0.41, 0.77)].

COVID II Exploratory Sub-Study

In a separate group of patients requiring invasive mechanical ventilation or ECMO at baseline and enrolled in an addendum to COVID II, a pre-specified exploratory analysis showed that the proportion who died by Day 28 was 39.2% (20/51) for baricitinib compared to 58.0% (29/50) for placebo [estimated difference in Day 28 risk of mortality = -18.8% (95% CI: -36.3%, 0.6%); hazard ratio = 0.54 (95% CI: 0.31, 0.96)].

14.3 Alopecia Areata

Two randomized, double-blind, placebo-controlled trials [Trials AA-1 (NCT03570749) and AA-2 (NCT03899259)] enrolled a total of 1200 patients, with alopecia areata (AA), who had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool (SALT) for more than 6 months. The trials enrolled males 18 to 60 years of age and females 18 to 70 years of age. Among the patients enrolled, 61% were female, 2% were 65 years of age or older, and 52% were White, 36% were Asian, and 8% were Black. At baseline, 53% of patients had at least 95% scalp hair loss, 34% had their current episode lasting at least 4 years, 69% had significant gaps in eyebrow hair or no notable eyebrow hair, and 58% had significant gaps in eyelashes or no notable eyelashes.

In the Phase 3 portion of Trial AA-1 and in Trial AA-2, patients received OLUMIANT 2 mg, OLUMIANT 4 mg, or placebo once daily.

Both trials assessed the proportion of patients who achieved at least 80% scalp hair coverage (SALT score of ≤20) at Week 36 as the primary endpoint. Other outcomes at Week 36 included the proportion of patients who achieved at least 90% scalp hair coverage (SALT score of ≤10), patients with Scalp Hair Assessment PRO™ score of 0 or 1 with at least 2-point reduction on the 5-point scale, and assessments of eyebrow and eyelash hair loss.

Clinical Response

The results of the OLUMIANT trials (AA-1 and AA-2) are provided in Table 14 and Figure 5.

Table 14: Clinical Response at Week 36 in Patients with Severe AA

a Not statistically significant under the multiplicity control plan
b Patients evaluated scalp hair coverage on a 5-point scale where 0 = No missing hair (0% of scalp hair missing; full head of hair), 1 = A limited area of scalp hair loss (1% to 20%), 2 = moderate scalp hair loss (21% to 49%), 3 = a large area of scalp hair loss (50% to 94%), and 4 = nearly all or all scalp hair loss (95% to 100%).
	Trial AA-1			Trial AA-2
	Placebo	OLUMIANT2 mg/day	OLUMIANT4 mg/day	Placebo	OLUMIANT2 mg/day	OLUMIANT4 mg/day
Number of subjects with at least 50% scalp hair loss at baseline
N	189	184	281	156	156	234
SALT ≤ 20     Difference from Placebo      (95% CI)	5%	22%16%(10, 23)	35%30%(23, 36)	3%	17%15%(8, 22)	32%30%(23, 36)
SALT ≤ 10     Difference from Placebo      (95% CI)	4%	13%9%(3, 15)	26%22%(16, 28)	1%	11%10%(5, 16)a	24%23%(17, 29)
Number of subjects reporting Scalp Hair Assessment PRO™ score ≥3 at baseline
N	181	175	275	151	149	215
Scalp Hair Assessment PRO score of 0 or 1b      Difference from Placebo      (95% CI)	5%	16%11%(5, 18)	33%28%(21, 34)	4%	16%12%(5, 19)	34%30%(23, 37)

Among patients with substantial eyebrow and eyelash hair loss at baseline, an improvement in eyebrow and eyelash coverage was observed on OLUMIANT 4 mg once daily dosage at Week 36.
Figure 5: Percent of Patients Achieving SALT ≤20

Analyses by age, gender, race, and body weight did not identify differences in response to 36-weeks of treatment with OLUMIANT among these subgroups. SALT ≤20 response rates were higher in all dose groups in patients with baseline SALT 50 to 94 versus SALT 95 to 100. See Table 15.

Table 15: SALT ≤20 at Week 36 by Baseline SALT Severity in AA

	Trials AA-1 and AA-2
	Placebo	OLUMIANT 2 mg/day	OLUMIANT 4 mg/day
50 % to 94% Scalp Hair Loss     N     SALT ≤20	1668%	14733%	24848%
95 % to 100% Scalp Hair Loss     N     SALT ≤20	1781%	19310%	26721%

In AA-2, patients who achieved adequate response (SALT ≤20) to OLUMIANT 4 mg once daily at 52 weeks of treatment entered a randomized down-titration period and received OLUMIANT 2 mg once daily or remained on OLUMIANT 4 mg once daily. After an additional 24 weeks of treatment (76 weeks total), 75% (30/40) of patients randomized to OLUMIANT 2 mg once daily maintained response and 98% (41/42) of patients who remained on OLUMIANT 4 mg once daily maintained response.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Infections

Inform patients that they may be more likely to develop infections when taking OLUMIANT. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection [see Warnings and Precautions (5.1)].

Advise patients that the risk of herpes zoster is increased in patients treated with OLUMIANT and some cases can be serious [see Warnings and Precautions (5.1)].

Malignancies and Lymphoproliferative Disorders

Inform patients that OLUMIANT may increase their risk of developing lymphomas and other malignancies, including of the skin and that periodic skin examinations should be performed while using OLUMIANT. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.3)].

Major Adverse Cardiovascular Events

Inform patients that OLUMIANT may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.4)].

Thrombosis

Advise patients that events of DVT and PE have been reported in clinical studies with OLUMIANT. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions (5.5)].

Hypersensitivity Reactions

Advise patients to discontinue OLUMIANT and seek immediate medical attention if they develop any signs and symptoms of serious allergic reactions [see Warnings and Precautions (5.6)].

Gastrointestinal Perforations

Inform patients that gastrointestinal perforations have been reported in clinical trials with OLUMIANT. Instruct patients to seek medical care immediately if they experience new onset of abdominal pain, fever, chills, nausea, or vomiting [see Warnings and Precautions (5.7)].

Laboratory Abnormalities

Inform patients that OLUMIANT may affect certain lab tests, and that blood tests are required before and during OLUMIANT treatment [see Warnings and Precautions (5.8)].

Live Vaccines

Instruct patients to inform the healthcare practitioner that they are taking OLUMIANT prior to a potential vaccination since the use of live vaccine is not recommended [see Warnings and Precautions (5.9)].

Pregnancy

Advise pregnant females and females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with OLUMIANT. Inform patients to report their pregnancy to Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) [see Use in Specific Populations (8.1, 8.3)].

Lactation

Advise a woman not to breastfeed during treatment with OLUMIANT and for four days after the last dose [see Use in Specific Populations (8.2)].

Literature revised: 06/2022

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

www.olumiant.com

Copyright © 2018, 2022, Eli Lilly and Company. All rights reserved.

OLM-0007-USPI-20220613