Leqselvi: Package Insert / Prescribing Info

2.1 Recommended Evaluations and Immunizations Prior to and During Treatment

Perform the following prior to treatment with LEQSELVI:

• CYP2C9 genotype determination: Test patients for CYP2C9 variants to determine CYP2C9 genotype. LEQSELVI is contraindicated in patients who are CYP2C9 poor metabolizers (patients with decreased cytochrome P450 (CYP) 2C9 function) [see Contraindications (4)]. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of LEQSELVI is not currently available.
• Evaluation for use of concomitant CYP2C9 inhibitors: LEQSELVI is contraindicated in patients taking moderate or strong CYP2C9 inhibitors [see Warnings and Precautions (5.6)].
• Active and latent tuberculosis (TB) evaluation: LEQSELVI treatment is not recommended in patients with active TB. For patients with latent TB or those with a negative latent TB test who are at high risk of TB, start preventive therapy for TB prior to LEQSELVI treatment [see Warnings and Precautions (5.1)].
• Viral hepatitis screening in accordance with clinical guidelines: LEQSELVI treatment is not recommended in patients with active hepatitis B or hepatitis C.
• Hepatitis B infection screening: If hepatitis B infection is discovered, follow hepatitis B clinical guidelines, or refer to a liver specialist. Monitor patients for reactivation in accordance with clinical guidelines during treatment [see Warnings and Precautions (5.1)].
• Complete blood count (CBC): LEQSELVI treatment is not recommended in patients with an absolute lymphocyte count (ALC) <500 cells/mm3 absolute neutrophil count (ANC) <1,000 cells/mm3, or hemoglobin level <8 g/dl. Monitor complete blood counts periodically during treatment and modify dosage as recommended [see Dosage and Administration (2.3) and Warnings and Precautions (5.8)].
• Complete any necessary immunizations, including herpes zoster vaccinations, according to current immunization guidelines prior to LEQSELVI treatment [see Warnings and Precautions (5.9)].

2.2 Recommended Dosage

The recommended dosage of LEQSELVI for the treatment of severe alopecia areata is 8 mg orally twice daily, with or without food [see Clinical Pharmacology (12.3)].

If a dose is missed, skip the missed dose and resume dosing at the next scheduled dose.

2.3 Treatment Interruption and Resumption

Serious or Opportunistic Infections

If a patient develops a serious or opportunistic infection, interrupt LEQSELVI treatment until the infection is controlled [see Warnings and Precautions (5.1)].

Hematological Abnormalities

Recommendations for LEQSELVI treatment interruption for hematologic abnormalities are described in Table 1 [see Warnings and Precautions (5.8)].

5.1 Serious Infections

Serious infections have been reported in subjects with alopecia areata receiving LEQSELVI [see Adverse Reactions (6.1)].

Avoid use of LEQSELVI in patients with an active, serious infection including localized infections.

Prior to LEQSELVI treatment, consider the risks and benefits in patients:

• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with LEQSELVI. If the patient develops a serious infection, interrupt treatment with LEQSELVI until the infection resolves or is adequately treated. If a patient develops a new infection during treatment with LEQSELVI, initiate complete diagnostic testing appropriate for an immunocompromised patient and appropriate antimicrobial therapy.

Tuberculosis

Evaluate patients for latent and active tuberculosis (TB) infection prior to LEQSELVI treatment. LEQSELVI is not recommended for use in patients with active TB.

Treat patients with latent TB before LEQSELVI treatment. Consider anti-TB therapy prior to LEQSELVI treatment in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

Monitor patients receiving LEQSELVI for signs and symptoms of active TB during treatment, including patients who tested negative for latent TB infection prior to treatment.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were reported in clinical trials with LEQSELVI [see Adverse Reactions (6.1)]. If a patient develops herpes zoster, consider interrupting LEQSELVI treatment until the episode resolves.

The impact of LEQSELVI on chronic viral hepatitis reactivation is unknown. Subjects with positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), or hepatitis C virus (HCV) with detectable HCV RNA at screening were excluded from LEQSELVI clinical trials. Perform screening for viral hepatitis before treatment with LEQSELVI. LEQSELVI is not recommended for use in patients with active hepatitis B or hepatitis C (HCV RNA detected).

If non-active hepatitis B infection is discovered, monitoring for reactivation or prophylactic treatment is recommended. Follow hepatitis B clinical guidelines or refer to a liver specialist. Hepatitis B viral load (HBV-DNA titer) increase, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, has been reported in subjects with chronic HBV infections receiving JAK inhibitors used to treat inflammatory conditions. The effect of LEQSELVI on viral replication in patients with chronic HBV infection is unknown.

5.2 Mortality

In a large, randomized, postmarketing safety trial of another JAK inhibitor in rheumatoid arthritis (RA) subjects 50 years and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in subjects treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to and during treatment with LEQSELVI.

5.3 Malignancy and Lymphoproliferative Disorders

Malignancies were observed in clinical trials of LEQSELVI [see Adverse Reactions 6.1)].

In a large, randomized, postmarketing safety trial of another JAK inhibitor in subjects with RA, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this trial, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to and during treatment with LEQSELVI, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Non-melanoma skin cancers

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with LEQSELVI. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

5.4 Major Adverse Cardiovascular Events (MACE)

In a large, randomized, postmarketing safety trial of another JAK inhibitor in subjects with RA 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to and during treatment with LEQSELVI, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue LEQSELVI in patients that have experienced a myocardial infarction or stroke.

5.5 Thrombosis

Thrombosis, including pulmonary embolism (PE), deep vein thrombosis (DVT) and cerebral venous sinus thrombosis (CVT) have been reported in clinical trials of deuruxolitinib [see Adverse Reactions (6.1)]. There was no clear relationship between platelet count elevations and thrombotic events.

Thrombosis, including DVT, PE, and arterial thrombosis have been reported in subjects receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death.

In a large, randomized, postmarketing safety trial of another JAK inhibitor in subjects with RA 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

Avoid LEQSELVI in patients who may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue LEQSELVI and evaluate and treat patients appropriately.

5.6 Increased Risk of LEQSELVI-Associated Serious Adverse Reactions in CYP2C9 Poor Metabolizers or with Concomitant Use of Moderate or Strong CYP2C9 Inhibitors

Higher plasma concentrations of deuruxolitinib, which may increase the risk of LEQSELVI-associated serious adverse reactions such as thrombosis, may occur when LEQSELVI is used in patients who:

• Are CYP2C9 poor metabolizers [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.5)].
• Are on a concomitant moderate or strong CYP2C9 inhibitor [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Prior to LEQSELVI treatment, test patients for CYP2C9 variants to determine if they are poor metabolizers [see Dosage and Administration (2.1)]. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of LEQSELVI is not currently available.

LEQSELVI is contraindicated in patients who are CYP2C9 poor metabolizers or patients who are on concomitant moderate or strong CYP2C9 inhibitors [see Contraindications (4)].

5.7 Gastrointestinal Perforations

Gastrointestinal perforations have been reported in clinical trials with LEQSELVI.

Monitor patients treated with LEQSELVI who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Evaluate promptly patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

5.8 Lipid Elevations, Anemia, Neutropenia, and Lymphopenia

Perform a CBC prior to and periodically during treatment with LEQSELVI [see Dosage and Administration (2.1)].

Lipid Elevations

Treatment with LEQSELVI was associated with increases in triglycerides and total cholesterol, including HDL-C and LDL-C [see Adverse Reactions 6.1)]. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Perform assessment of lipid parameters at baseline and periodically during treatment with LEQSELVI. Manage patients according to clinical guidelines for hyperlipidemia.

Anemia

Treatment with LEQSELVI was associated with an increased incidence of anemia (hemoglobin less than 8 g/dL) compared to placebo [see Adverse Reactions (6.1)]. Avoid or interrupt LEQSELVI treatment in patients with hemoglobin less than 8 g/dL [see Dosage and Administration (2.3)].

Neutropenia

Treatment with LEQSELVI was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo [see Adverse Reactions (6.1)]. Avoid or interrupt LEQSELVI treatment in patients with an ANC less than 1,000 cells/mm3[see Dosage and Administration (2.3)].

Lymphopenia

Treatment with LEQSELVI was associated with an increased incidence of lymphopenia (ALC less than 500 cells/mm3) compared to placebo [see Adverse Reactions (6.1)]. Avoid or interrupt LEQSELVI treatment in patients with an ALC less than 500 cells/mm3[see Dosage and Administration (2.3)].

5.9 Immunizations

Prior to LEQSELVI treatment, complete all necessary immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in accordance with current immunization guidelines. Avoid use of live vaccines during or immediately prior to LEQSELVI treatment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of LEQSELVI was evaluated in three randomized, placebo-controlled clinical trials (including a dose-ranging trial), two open-label trials, and two long-term extension trials in adult subjects with severe alopecia areata. These subjects had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool (SALT) for more than six months. A total of 1,730 subjects with alopecia areata were treated across all trials, representing 1,962.9 patient-years of exposure. There were 974 subjects who were exposed to either LEQSELVI 8 mg or deuruxolitinib 12 mg for at least 1 year and 104 subjects who were exposed for at least 3 years.

Deuruxolitinib 12 mg is not approved.

Among 1,020 subjects enrolled in the placebo-controlled clinical trials, 640 subjects received LEQSELVI 8 mg twice daily, 380 subjects received deuruxolitinib 12 mg twice daily and 299 subjects received placebo twice daily for up to 24 weeks [see Clinical Studies (14)].

Adverse Reactions occurring at ≥1% in the LEQSELVI 8 mg or deuruxolitinib 12 mg twice daily group and at a higher rate than in the placebo group are presented in Table 2. A total of 20 (3.1%) of subjects treated with LEQSELVI 8 mg were discontinued from the trials due to adverse reactions.

Additional adverse drug reactions occurring in fewer than 1% of subjects: herpes zoster, lipase increased, and candidiasis.

A total of 868 subjects in the long-term extension trials received treatment with LEQSELVI 8 mg twice daily and 991 subjects received treatment with deuruxolitinib 12 mg twice daily for 52 weeks. In two open-label extension trials up to 3 years, 829 subjects received treatment with LEQSELVI 8 mg twice daily, and 1066 subjects received treatment with deuruxolitinib 12 mg twice daily.

Specific Adverse Reactions (0-52 weeks)

All Infections

During the 24-week treatment period, infections were reported in 97 subjects (88.0 per 100 patient-years) treated with placebo, 222 subjects (101.5 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 153 subjects (117.0 per 100 patient years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, infections were reported in 435 subjects (95.5 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 408 subjects (74.1 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Serious Infections

During the 24-week treatment period, serious infections were reported in 1 subject (0.8 per 100 patient-years) treated with placebo, 5 subjects (1.8 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 2 subjects (1.2 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, serious infections were reported in 5 subjects (0.7 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 4 subjects (0.5 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Herpes Zoster

During the 24-week treatment period, opportunistic infections (herpes zoster) were reported in 0 subjects treated with placebo, 3 subjects (1.1 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 3 subjects (1.8 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, herpes zoster was reported in 10 subjects (1.5 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 15 subjects (1.9 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Malignancies

During the 0-52 week period, malignancy excluding NMSC was reported in 3 subjects (0.4 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 4 subjects (0.5 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Thrombosis

During the 0-52 week period, thrombosis was reported in 0 subjects treated with LEQSELVI 8 mg twice daily and 1 subject (0.1 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily who developed bilateral pulmonary embolism.

Laboratory Abnormalities

Anemia

During the 24-week treatment period, anemia was reported in 3 subjects (2.3 per 100 patient- years) treated with placebo, 19 subjects (6.9 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 16 subjects (9.6 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, anemia was reported in 17 subjects (2.6 per 100 patient- years) treated with LEQSELVI 8 mg twice daily and 38 subjects (5.0 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Neutropenia

During the 24-week treatment period, neutropenia was reported in 3 subjects (2.3 per 100 patient-years) treated with placebo, 10 subjects (3.6 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 10 subjects (6.0 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, neutropenia was reported in 11 subjects (1.6 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 15 subjects (1.9 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Lymphopenia

During the 24-week treatment period, lymphopenia was reported in 2 subjects (1.5 per 100 patient-years) treated with placebo, 2 subjects (0.7 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 7 subjects (4.2 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, lymphopenia was reported in 4 subjects (0.6 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 10 subjects (1.3 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Lipid Elevations

During the 24-week treatment period, lipid elevations were reported in 10 subjects (7.7 per 100 patient-years) treated with placebo, 30 subjects (11.0 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 18 subjects (10.9 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, lipid elevations were reported in 47 subjects (7.2 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 66 subjects (8.7 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Creatine Phosphokinase (CPK) Elevations

During the 24-week treatment period, CPK elevations were reported in 7 subjects (5.4 per 100 patient-years) treated with placebo, 35 subjects (12.9 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 27 subjects (16.6 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, CPK elevations were reported in 49 subjects (7.6 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 46 subjects (6.1 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Thrombocytosis

During the 24-week treatment period, an increase in platelet count was reported in 0 subjects treated with placebo, 18 subjects (6.6 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 6 subjects (3.6 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

During the 0-52 week period, an increase in platelet count was reported in 20 subjects (3.0 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 26 subjects (3.4 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Adverse Reactions Observed after 52 weeks

Thrombosis

Venous thromboembolic events were reported in 4 subjects treated with deuruxolitinib 12 mg twice daily between Week 52 and Week 98. These 4 subjects experienced 7 thrombotic events (0.2 per 100 patient-years), including deep vein thrombosis (DVT), bilateral pulmonary embolism (PE), pulmonary embolism, and cerebral venous sinus thrombosis (CVT).

8.1 Pregnancy

Risk Summary

Based on the findings from animal reproduction studies, deuruxolitinib may cause fetal harm during pregnancy. Available data from pregnancies reported in clinical trials with LEQSELVI are not sufficient to evaluate for a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of deuruxolitinib to pregnant rats during the period of organogenesis at a dose 4.8 times the maximum recommended human dose (MRHD) resulted in reduced fetal weight and increased skeletal malformation. Oral administration of deuruxolitinib to pregnant rabbits during the period of organogenesis at a dose 0.3 times the MRHD resulted in maternal toxicity, reduced fetal weight, and increased post-implantation loss. Oral administration of deuruxolitinib to pregnant rats during pregnancy and lactation periods at a dose 5 times the MRHD resulted in maternal toxicity, decreased pup survival, and adverse effects on postnatal development (see Data). Advise pregnant women of the potential risk to a fetus.

The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2 to 4% of the general population and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

Data

Animal Data

In an embryo-fetal development study, deuruxolitinib was administered to pregnant rats during the period of organogenesis at oral doses of 15, 30, and 60 mg/kg/day. Reduced fetal weight and increased fetal skeletal malformation were noted at 60 mg/kg/day (4.8 times the MRHD based on AUC comparison) with no maternal toxicity. No embryo-fetal toxicity was observed at doses up to 30 mg/kg/day (equivalent to MRHD based on AUC comparison). In another embryo-fetal development study, deuruxolitinib was administered to pregnant rabbits during the period of organogenesis at oral doses of 6, 30, and 60 mg/kg/day. Reduced fetal weight and increased post-implantation loss were noted at 60 mg/kg/day (0.3 times the MRHD based on AUC comparison), at which maternal toxicity was observed. No embryo-fetal toxicity was noted at doses up to 30 mg/kg/day (0.05 times the MRHD based on AUC comparison).

In a pre- and postnatal development study in rats, deuruxolitinib was administered to pregnant rats during pregnancy and lactation periods at oral doses of 15, 30, and 75 mg/kg/day. Decreases in liveborn pups and pup survival, decreased pup activity and lower pup body weights, and adverse effects on reproductive outcome in the second generation females (decreased corpora lutea, implantation, and number of live embryos, and increased resorption and post-implantation loss) were noted at 75 mg/kg/day (5 times the MRHD based on AUC comparison), at which maternal toxicity was also observed. No adverse effects on pre- and postnatal development were noted at doses up to 30 mg/kg/day (0.8 times the MRHD based on AUC comparison).

8.2 Lactation

Risk Summary

There are no data on the presence of deuruxolitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Deuruxolitinib was present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment with LEQSELVI and for one day after the last dose (approximately 5 to 6 elimination half-lives).

Data

Animal Data

Following a single oral dose of 10 mg/kg administered to lactating rats on lactation day 14, deuruxolitinib concentrations were up to 20 times higher in milk than in plasma.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Based on animal studies, deuruxolitinib may cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Consider pregnancy planning and prevention for females of reproductive potential.

8.4 Pediatric Use

The safety and effectiveness of LEQSELVI have not been established in pediatric patients.

8.5 Geriatric Use

Of the 600 subjects treated with LEQSELVI 8 mg in phase 3 clinical trials, 2 (0.3%) were 65 years of age or older. Clinical trials of LEQSELVI did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

8.6 Renal Impairment

LEQSELVI is not recommended for use in patients with severe renal impairment or end-stage renal disease (eGFR < 30 ml/min). No adjustment of dosage is required in patients with mild or moderate renal impairment.

The effect of severe renal impairment on deuruxolitinib pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

LEQSELVI is not recommended for use in patients with severe hepatic impairment (Child Pugh C). No adjustment of dosage is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.

The effect of severe hepatic impairment on deuruxolitinib pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].

8.8 CYP2C9 Poor Metabolizers

Based on modeling, higher exposure of deuruxolitinib in patients who are CYP2C9 poor metabolizers is expected with concomitant use of LEQSELVI, which may increase the risk of LEQSELVI-associated serious adverse reactions. Before initiation of treatment with LEQSELVI, test patients to determine CYP2C9 genotype. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of LEQSELVI is not currently available [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.5)].

12.1 Mechanism of Action

Deuruxolitinib is a Janus kinase (JAK) inhibitor. JAKs mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

In an in vitro kinase activity assay, deuruxolitinib had greater inhibitory potency for JAK1, JAK2 and TYK2 relative to JAK3. The relevance of inhibition of JAK enzymes to therapeutic effectiveness is not currently known.

12.2 Pharmacodynamics

Deuruxolitinib Inhibition of IL-6 Induced STAT3 Phosphorylation

Deuruxolitinib inhibited whole blood IL-6 stimulated pSTAT3 in healthy subjects 2 hours post-dose. The relevance of this finding in patients is unknown.

Cardiac Electrophysiology

At concentrations approximately 4-fold higher than the Cmax associated with the highest dose evaluated clinically, 12 mg twice-daily, deuruxolitinib does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Following oral administration of deuruxolitinib, Cmax and AUCs increased dose proportionally over a dose range from 8 mg to 48 mg (6 times the approved recommended dosage) in healthy subjects. Steady-state plasma concentrations were achieved within 1 to 2 days, with minimal accumulation, after twice daily administration.

Absorption

Deuruxolitinib bioavailability is 90%, with peak plasma concentrations reached within 1.5 hrs.

Effect of Food

No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed following administration of a high fat, high calorie meal (approximately 50% fat and 800-1000 calories).

Distribution

The deuruxolitinib steady state volume of distribution is approximately 50L. Deuruxolitinib plasma protein binding is 91.5% and blood to plasma concentration ratio is approximately 1.3.

Elimination

The deuruxolitinib mean elimination half-life is approximately 4 hrs.

Metabolism

Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%) and to a lesser extent by CYP1A2 (3%). The two most abundant human metabolites C-21714 and C-21717, each of which accounted for approximately 5% of total drug-related AUC and both are approximately 10-fold less pharmacologically active than deuruxolitinib.

Excretion

After a single dose of radiolabeled deuruxolitinib, there was no unchanged dose recovered in either urine or feces.

Specific Populations

No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed based on race [White (75%), African American (17%) and Asian (6%)], ethnicity [Hispanic or Latino (12%)], age (18-65 years), body weight (40.4-173 kg), mild to moderate renal impairment (eGFR 30-89 mL/min, MDRD), or mild to moderate hepatic impairment (Child Pugh A or B). The effect of severe renal impairment (eGFR < 30 mL/min, MDRD) or severe hepatic impairment (Child Pugh C) on deuruxolitinib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Other Drugs on LEQSELVI

Strong CYP3A4 and Moderate or strong CYP2C9 Inducers: Deuruxolitinib AUC decreased by 78% and Cmax by 41% following concomitant use of multiple doses of 600 mg rifampin (strong CYP3A4 and moderate CYP2C9 inducer) with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Strong CYP2C9 Inhibitors: Based on modeling, deuruxolitinib AUC is predicted to be increased by 200% and Cmax by 25% following concomitant use of multiple dosages of a strong CYP2C9 inhibitor with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Moderate CYP2C9 Inhibitors: Deuruxolitinib AUC increased by 140% and Cmax by 21% following concomitant use of multiple dosages of 200 mg fluconazole (dual moderate CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Other Drugs: No clinically significant differences in deuruxolitinib pharmacokinetics were observed when used concomitantly with itraconazole (strong CYP3A4 inhibitor) or are expected with efavirenz (moderate CYP3A4 inducer).

Effect of LEQSELVI on Other Drugs:

No clinically significant differences in the pharmacokinetics of the following drugs were observed when co-administered with deuruxolitinib: midazolam (a sensitive CYP3A4 substrate), oral contraceptives (ethinyl estradiol and levonorgestrel).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Deuruxolitinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4. Deuruxolitinib is not an inducer of CYP1A2 or CYP2B6, CYP2C8 or CYP2C19.

Transporter Systems: Deuruxolitinib is a substrate of BCRP and MDR1 but not a substrate of the uptake transporters OATP1B1 and OATP1B3. Deuruxolitinib is not an inhibitor of OATP1B1, OATP1B3 and OCT1 but is an inhibitor of BCRP, BSEP, OAT3 and MATE2-K.

12.5 Pharmacogenomics

Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%). CYP2C9 activity is reduced in patients with genetic variants in CYP2C9, such as the CYP2C9∗2 and CYP2C9∗3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of deuruxolitinib has not been directly evaluated. Based on drug-drug interaction modeling data, CYP2C9 poor metabolizers (e.g., ∗2/∗3, ∗3/∗3) may have up to 2-fold higher concentrations of deuruxolitinib, when compared to normal metabolizers [see Warnings and Precautions (5.6)].

The pharmacokinetics of deuruxolitinib were not evaluated in individuals who are intermediate metabolizers (e.g., individuals with ∗1/∗3 genotype).

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in Black or African American populations. Other decreased or nonfunctional CYP2C9 alleles (e.g., ∗5, ∗6, ∗8, ∗11) are more prevalent in Black or African American populations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Deuruxolitinib was not carcinogenic when administered orally in a 6-month transgenic rasH2 mouse study at doses up to 100 mg/kg/day. In a 2-year rat carcinogenicity study, no drug-related tumors were observed at oral doses of deuruxolitinib up to 30 mg/kg/day (0.6 times the MRHD based on AUC comparison).

Deuruxolitinib was positive in an in vitro micronucleus assay, but negative in a bacterial mutation assay (the Ames test), an in vitro chromosome aberration assay and an in vivo rat micronucleus assay.

In fertility and early embryonic development studies in rats, deuruxolitinib was administered to male rats prior to mating to conception, or to female rats prior to mating, through conception, to gestation day 7. Deuruxolitinib had no adverse effects on male or female fertility at oral doses up to 100 mg/kg/day (2.2 times MRHD in males and 14 times MRHD in females based on AUC comparison). However, adverse effects on early embryonic development were noted, including decreased viable embryos and increased pre-implantation loss observed at doses ≥ 30 mg/kg/day (0.9 times MRHD based on AUC comparison), and increased post-implantation loss and resorption at 100 mg/kg/day (14 times MRHD based on AUC comparison). No adverse effects on early embryonic development were observed at 10 mg/kg/day (0.2 times MRHD based on AUC comparison).