In June 2022, the US Food and Drug Administration (FDA) approved Olumiant (baricitinib; Eli Lilly and Company), a Janus kinase (JAK) inhibitor, for the treatment of adults with severe alopecia areata. 

Baricitinib acts by inhibiting the intracellular JAK enzymes, which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, phosphorylation of JAKs promotes the activation of signal transducers and activators of transcription (STATs), which influence intracellular activity, including gene expression. By preventing the phosphorylation of JAKs, baricitinib inhibits the activation of STATs and modulates the signaling pathway.

For patients receiving Olumiant for alopecia areata, coadministration with other JAK inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants is not recommended.

Additional indications of Olumiant include the treatment of adults with moderately to severely active rheumatoid arthritis who have had an  inadequate response to at least 1 tumor necrosis factor (TNF) blocker and the treatment of COVID-19 in hospitalized adults who require supplemental oxygen, either invasive or noninvasive mechanical ventilation, or extracorporeal membrane oxygenation. 

Clinical Trials

The approval of Olumiant for alopecia areata was based on the results obtained from 2 clinical trials, BRAVE-AA1 (ClinicalTrials.gov Identifier: NCT03570749) and BRAVE-AA2 (ClinicalTrials.gov Identifier: NCT03899259), which evaluated the safety and efficacy of the drug in patients with alopecia areata. 

The studies were randomized, double-blind, placebo-controlled phase 3 clinical trials. Patients included in the studies were required to have at least 50% scalp hair loss according to the Severity of Alopecia Tool (SALT) for more than 6 months. Of the total patients enrolled in the studies (N=1200), 61% were female, 52% were White, 36% were Asian, and 8% were Black. The ages of male and female patients enrolled in the study ranged from 18 to 60 years and 18 to 70 years, respectively; 2% of the patients included in the studies were 65 years of age or older. 

At baseline, 53% of study participants had at least 95% scalp hair loss, 34% experienced their current episode for at least 4 years, 69% had either significant eyebrow hair gaps or no eyebrow hair, and 58% had either significant eyelash gaps or no eyelashes. 

In both trials, patients were randomly assigned to receive Olumiant 2 mg, Olumiant 4 mg, or placebo once daily. The primary endpoint for both studies was the proportion of patients who attained at least 80% scalp hair coverage (SALT score of ≤20) at week 36. Additional endpoints assessed at week 36 included the proportion of patients who attained at least 90% scalp hair coverage (SALT score of ≤10), the proportion of patients who achieved a Scalp Hair Assessment PRO™ score of 0 or 1 with a reduction of at least 2 points, and evaluations of eyebrow and eyelash hair loss. 

Efficacy findings revealed Olumiant significantly increased the proportion of patients who achieved at least 80% scalp hair coverage (SALT score of ≤20) and at least 90% scalp hair coverage (SALT score of ≤10) at week 36 compared with placebo (Table 1). A significant increase in the proportion of patients who achieved a Scalp Hair Assessment PRO score of 0 or 1 was also observed among patients who received Olumiant compared with those who received placebo.




At week 36, treatment with Olumiant 4 mg was also found to be associated with an improvement in both eyebrow and eyelash coverage in patients who had substantial eyebrow and eyelash hair loss at baseline. No differences in treatment response were observed in subgroup analyses based on age, gender, race, or body weight. 

Efficacy findings also showed higher SALT ≤20 response rates among patients treated with Olumiant who had less severe scalp hair loss at baseline compared with those with severe hair loss at baseline. In patients with baseline scalp hair loss of 50% to 94%, 33% of patients who received Olumiant 2 mg/d (n=147) and 48% of patients who received Olumiant 4 mg/d (n=248) achieved a SALT score of ≤20 at week 36 of treatment compared with 8% of patients who received placebo (n=166). Similarly, in patients with baseline scalp hair loss of 95% to 100%, 10% of patients who received Olumiant 2 mg/d (n=193) and 21% of patients who received Olumiant 4 mg/d (n=267) achieved a SALT score of ≤20 at week 36 of treatment compared with 1% of patients who received placebo (n=178).

Patients in BRAVE-AA2 who attained an adequate response (SALT ≤20) after 52 weeks of treatment with Olumiant 4 mg/d were entered into a down-titration period. During this period, these patients were randomly assigned to initiate Olumiant 2 mg/d or continue with Olumiant 4 mg/d. After an additional 24 weeks of treatment (76 weeks total), response was maintained in 75% of patients who received Olumiant 2 mg/d (30/40) and 98% of patients who received Olumiant 4 mg/d (41/42).

Dosage and Administration

Olumiant is supplied as 1-mg, 2-mg, and 4-mg tablets. The recommended dosage of Olumiant for the treatment of alopecia areata is 2 mg once daily orally with or without food. If the patient does not adequately respond to treatment, the dosage can be increased to 4 mg once daily. 

Treatment with Olumiant 4 mg once daily can be considered for patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss. 

It is recommended to decrease the dosage of Olumiant to 2 mg once daily once  an adequate response to treatment with 4 mg is achieved. 

Several evaluations are recommended prior to the initiation of Olumiant. Because Olumiant should not be administered to patients with active tuberculosis (TB), active and latent TB infection evaluations should be completed. Treatment for TB should be considered prior to the initiation of Olumiant in patients with latent infection. Viral hepatitis screening is also recommended prior to Olumiant initiation as well as completion of all recommended immunizations in accordance with current immunization guidelines.

Complete blood count should be performed and hepatic function and renal function assessed prior to and during Olumiant treatment. Olumiant should be avoided in patients with alopecia areata who have the following baseline values: absolute lymphocyte count (ALC) <500 cells/μL, absolute neutrophil count (ANC) <1000 cells/μL, or hemoglobin level <8 g/dL. 

The dose of Olumiant should be modified based on changes in complete blood count, hepatic and renal function, and laboratory abnormalities, or during coadministration of Olumiant with a strong organic anion transporter 3 (OAT3) inhibitor (Table 2). 



Olumiant should be avoided in patients with an active, serious, or opportunistic infection. This includes localized infections. In patients who develop serious infections during treatment, withhold Olumiant until the infection is controlled. 

Use of Olumiant is not recommended in patients with severe hepatic impairment. Treatment should be interrupted if a patient’s alanine transaminase (ALT) or aspartate aminotransferase (AST) levels increase and drug-induced liver injury (DILI) is suspected (until the diagnosis of DILI is excluded).

Oral dispersion, gastrostomy tube (G tube), nasogastric tube (NG tube), and orogastric tube (OG tube) may be considered for patients who are not able to swallow tablets whole. 

In order to facilitate dispersion, tablets may be crushed and dispersed in water (Figure 1). Tablets dispersed in water are stable for up to 4 hours. Intact tablets are not hazardous; however, proper control measures and personal protective equipment are recommended when crushing tablets as it is not known whether the powder may constitute a reproductive hazard to the preparer.  



Contraindications, Warnings, Precautions, and Adverse Reactions

Serious Infections
The prescribing information for Olumiant includes a Boxed Warning regarding the risk of serious and sometimes fatal infections caused by bacterial, mycobacterial, invasive fungal, viral, and other opportunistic pathogens. The most common serious infections associated with Olumiant use include pneumonia, herpes zoster, and urinary tract infection. Opportunistic infections, including TB, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus, have also been reported with Olumiant use. Both disseminated as well as localized disease have been observed among patients, who were often taking immunosuppressants concomitantly. 

Olumiant should be avoided in patients with active serious infections, including localized infections. Prior to initiation, the risks and benefits of Olumiant treatment must be considered in patients who have chronic or recurrent infections, a past exposure to TB, a past history of a serious or an opportunistic infection, lived in or traveled to areas of endemic TB or endemic mycoses, and in those who have underlying conditions that predispose them to infection. 

Patients should be closely monitored for signs and symptoms of an infection developing during and after Olumiant treatment. Development of a serious infection, an opportunistic infection, or sepsis requires the interruption of Olumiant. Patients who develop a new infection while being treated with Olumiant should undergo immediate and complete diagnostic testing appropriate for an immunocompromised patient and initiation of antimicrobial treatment while being monitored closely. Olumiant should be interrupted in patients unresponsive to therapy and should only be resumed once the infection is controlled.

Prior to the initiation of Olumiant, patients should be evaluated and tested for both latent as well as active TB infection. Olumiant should be avoided in patients with active TB. Prior to initiating Olumiant, standard antimycobacterial therapy should be used to treat patients with latent TB. It is recommended to consider anti-TB therapy before Olumiant initiation in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed and in patients who have a negative latent TB test but are at risk for infection. It is recommended to consult a physician specializing in TB treatment in order to determine whether anti-TB therapy is appropriate. Patients should be monitored for the signs and symptoms of TB during treatment with Olumiant, including those who received a negative latent TB test prior to treatment initiation. 

During clinical trials, Olumiant was found to cause viral reactivation, including herpes virus reactivation. Olumiant should be temporarily discontinued in patients who develop herpes zoster until the episode resolves. 

Because patients with active hepatitis B or C infection were excluded during clinical trials, the effect of Olumiant on chronic viral hepatitis is not known. Patients who were permitted to enroll in clinical trials included those who were positive for hepatitis C antibody but negative for hepatitis C virus RNA and those with positive hepatitis B surface antibody and hepatitis B core antibody without hepatitis B surface antigen. Close monitoring for the expression of hepatitis B virus (HBV) DNA is recommended and a hepatologist should be consulted if detection of HBV DNA occurs during treatment with Olumiant. Viral hepatitis screenings should be performed according to clinical guidelines before Olumiant is initiated. 

Mortality 
The prescribing information for Olumiant includes a Boxed Warning regarding an increased risk of all-cause mortality. Findings of a postmarketing safety study in patients with rheumatoid arthritis revealed another JAK inhibitor to be associated with a higher rate of all-cause mortality, including sudden cardiovascular death, compared with those receiving TNF blockers. The risks and benefits of Olumiant must be considered before and during treatment. 

Malignancy and Lymphoproliferative Disorders
The prescribing information for Olumiant includes a Boxed Warning regarding the incidence of malignancies, including lymphomas, observed during clinical trials in patients treated with Olumiant. Increased rates of malignancies (excluding nonmelanoma skin cancer [NMSC]) and lymphomas were observed in a postmarketing safety study of patients with rheumatoid arthritis who received treatment with another JAK inhibitor compared with those who received TNF blockers. The rate of lung cancers was also found to be higher among patients who received the other JAK inhibitor and smoked or had a history of smoking compared with those who received TNF blockers. An additional increased risk of overall malignancies in current or past smokers was also observed during this study.  

The risks and benefits of Olumiant treatment should be considered for each individual patient, especially those with a known malignancy (excluding effectively managed NMSC) who develop a malignancy during treatment and patients who smoke or have a history of smoking.

There have been cases of NMSC reported in patients treated with Olumiant. Periodic skin examinations should be performed in patients who are at increased risk for skin cancer.

Major Adverse Cardiovascular Events (MACE)
The prescribing information for Olumiant includes a Boxed Warning regarding the increased risk of MACE, which is defined as cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. A large postmarketing safety study observed an increased risk of MACE associated with the use of another JAK inhibitor in patients with rheumatoid arthritis who were 50 years of age and older with at least 1 cardiovascular risk factor compared with those who received TNF blockers. An additional increased risk was observed in current or past smokers.

The risks and benefits of treatment with Olumiant should be considered for each individual patient, especially those with cardiovascular risk factors and those who currently smoke or who have a history of smoking. Counseling patients on the symptoms and management of serious cardiovascular events is recommended. In patients who have experienced an MI or stroke, Olumiant should be discontinued.

Thrombosis
The prescribing information for Olumiant includes a Boxed Warning regarding the increased risk of thrombosis. During clinical studies, the incidence of thrombosis (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) was increased among patients treated with Olumiant compared with those receiving placebo. In addition, arterial thrombosis events in the extremities were also observed among patients receiving Olumiant during clinical studies. Many of these cases were considered to be serious, with some resulting in death. No association between elevations in platelet count and thrombotic events was observed.

A large postmarketing safety study found an increased rate of overall thrombosis, DVT, and PE associated with the use of another JAK inhibitor in patients with rheumatoid arthritis who were 50 years of age and older with at least 1 cardiovascular risk factor compared with those who received TNF blockers. 

Olumiant is not recommended for use in patients who are at increased risk for thrombosis. Olumiant should be discontinued in a patient who presents with clinical features of DVT, PE, or arterial thrombosis. If thrombosis is suspected, the patient should be evaluated and treated appropriately. 

Hypersensitivity Reactions
Cases of serious hypersensitivity reactions, including angioedema, urticaria, and rash, have occurred in patients receiving Olumiant. Olumiant should be immediately discontinued in patients who experience a serious hypersensitivity reaction, and evaluation of the cause of the reaction should be performed. 

Gastrointestinal Perforations
During clinical studies with Olumiant, cases of gastrointestinal perforations were reported. Patients receiving Olumiant who are at increased risk for gastrointestinal perforation should be closely monitored and promptly evaluated if new-onset abdominal symptoms occur.

Laboratory Abnormalities
Laboratory abnormalities have been observed in patients receiving Olumiant. 

Olumiant use has been associated with an increased incidence of neutropenia (ANC <1000 cells/mm3) compared with placebo. Treatment should not be initiated or should be temporarily interrupted in patients with an ANC <1000 cells/mm3. It is recommended to evaluate ANC at baseline as well as during treatment according to routine patient management. The dose of Olumiant should be adjusted based on ANC.

In clinical trials, cases of lymphopenia (ALC <500 cells/mm3) were observed in patients receiving Olumiant. Patients with lymphocyte counts less than the lower limit of normal receiving Olumiant were found to have an increased risk of infection compared with those receiving placebo. Treatment should not be initiated or should be temporarily interrupted in patients with an ALC <500 cells/mm3. It is recommended to evaluate ALC at baseline as well as during treatment according to routine patient management. The dose of Olumiant should be adjusted based on ALC.

In clinical trials, cases of anemia (hemoglobin <8 g/dL) were observed in patients receiving Olumiant. Treatment should not be initiated or should be temporarily interrupted in patients with a hemoglobin level of <8 g/dL. It is recommended to evaluate hemoglobin levels at baseline as well as during treatment according to routine patient management. The dose of Olumiant should be adjusted based on a patient’s hemoglobin levels.

Elevations in liver enzyme levels have also been found to be associated with  Olumiant use. In clinical trials, treatment with Olumiant was associated with increases in ALT level ≥5 times the upper limit of normal (ULN) and increases in AST level ≥10 times the ULN. It is recommended to evaluate liver enzyme levels at baseline as well as during treatment according to routine patient management. In order to identify possible DILI cases, it is recommended to investigate the cause of elevation of liver enzyme levels immediately. Olumiant should be temporarily interrupted if ALT or AST levels are increased and drug-induced liver injury is suspected.

Increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, have also been observed in patients treated with Olumiant. Lipid parameters should be assessed approximately 12 weeks after the initiation of Olumiant, and management of hyperlipidemia should be in accordance with clinical guidelines. 

Vaccinations
Live vaccines should be avoided during treatment with Olumiant. Prior to Olumiant use, immunizations should be updated based on the current immunization guidelines. 

Adverse Reactions
The safety of Olumiant in patients with alopecia areata was assessed in 2 placebo-controlled studies, BRAVE-AA1 and BRAVE-AA2. The safety population was assessed over the duration of the studies (36 weeks) and included patients who received placebo (n=371), Olumiant 2 mg (n=365), and Olumiant 4 mg (n=540). A total of 845 patients received Olumiant for at least 1 year.

The most common adverse reactions reported in these trials (≥1%) included upper respiratory tract infections, headache, acne, hyperlipidemia, increased creatine phosphokinase level, urinary tract infection, elevated liver enzyme levels, folliculitis, fatigue, lower respiratory tract infections, nausea, genital Candida infections, anemia, neutropenia, abdominal pain, herpes zoster, and increased weight.

Adverse reactions that occurred in <1% of patients treated with any dose of Olumiant include arterial thrombosis, B-cell lymphoma, lymphopenia, and fungal skin infections. Additional adverse reactions that were observed after 52 weeks of treatment with Olumiant include venous thromboembolic events (including DVT and PE) and malignancy (including NMSC).

Drug Interactions

Strong OAT3 Inhibitors
Coadministration of Olumiant with a strong OAT3 inhibitor, such as probenecid, increases drug exposure. Half of the recommended dose of Olumiant should be used in patients receiving Olumiant and a strong OAT3 inhibitor concomitantly. 

Coadministration of Olumiant with other JAK inhibitors or biologic DMARDs has not been studied. 

Considerations for Specific Populations

There are insufficient data on the risk associated with Olumiant use in humans during pregnancy. Based on animal study findings, use of Olumiant has the potential to cause harm to a developing fetus. Pregnancies should be reported to Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979). 
 
No data currently exist on the presence of Olumiant in breast milk, its effect in a breastfed child, or its effect on milk production. Based on animal study data, Olumiant is excreted in milk. Due to its potential for excretion into human milk and its risk of harm to an infant, patients should be advised to avoid breastfeeding during treatment with Olumiant and for 4 days following the last dose.  

Due to its potential to cause fetal harm, pregnancy planning for females of reproductive potential should be considered. 

The efficacy and safety of Olumiant have not been established in pediatric patients. 

There was an insufficient number of patients aged 65 years and older in BRAVE-AA1 and BRAVE-AA2 (29/1200) to determine whether there was a difference in response based on the age of the patient. The risk of adverse reactions may be increased in patients with impaired renal function since Olumiant is substantially excreted by the kidney. It is recommended to carefully select a geriatric patient’s dose and monitor renal function since geriatric patients are more likely to have decreased renal function. 

No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Olumiant use is not recommended in patients with severe hepatic impairment since it has not been studied in this population of patients. 

In patients with moderate renal impairment (eGFR 30-<60 mL/min/1.73 m2), half of the recommended dose of Olumiant should be administered. Olumiant should be avoided in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2).

Key Takeaways

  • Olumiant is approved for the treatment of adult patients with severe alopecia areata. 
  • The recommended dosage of Olumiant is 2 mg once daily, which may be increased to 4 mg once daily if the response to treatment is not adequate.
  • In patients with nearly complete scalp hair loss, a dosage of 4 mg once daily may be considered. 
  • Prior to initiating treatment, evaluate for TB, screen for viral hepatitis, obtain a complete blood count, evaluate baseline hepatic and renal function, and update immunizations.

Reference

Olumiant [prescribing information]. Indianapolis, IN: Lilly USA, LLC.; June 2022. https://pi.lilly.com/us/olumiant-uspi.pdf. Accessed June 27, 2022.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Dermatology Advisor had no role in this content’s preparation.

Reviewed July 2022